way employment is.  It is an “inducement,” hopefully not unduly
large, that encourages participation.  The word “remuneration”
should be changed to “inducement” throughout the section and the
document (search and replace) so that the ethical issue regarding
payments is not lost.

  Page 57, line 5 is the first use of the word “compensation” in
this section.  This term is a “regulatory word” and is therefore
associated with “compensation for injury.” It would be clearer and
more accurate to use the term “payment” throughout the section and
the document – for example in the Executive Summary on page 5 -
(search and replace) so that the ethical issue regarding payments is not
clouded.

Page 61, lines 4-5 indicates that community input can be obtained from
research team members.  While true, to be truly representative of
community attitudes, non-research team members should be sought out as
they should be free from any potential scientific biases.

	HSRB Consensus and Rationale

Section 5 identifies most of the major areas and issues where ethical
considerations should be addressed, with the exception of
communication/language issues.  However, in many cases the section takes
the tone of reporting what others have said, with and without comment;
and sometimes (and more appropriately) stating “it is recommended.”
A document with clear recommendations will be more useful by researchers
than one raising issues without giving direction. The Board raised three
overall questions in reviewing this section of the document.   The
questions were as follows:

1. Can the authors define “a strong relationship”, and what is a
strong scientific relationship?

2. Are there specific OMB guidelines on remuneration that could be
included?

3. Should the participant grievance procedures include also any
component of EPA or the IRB(s) who approved the study?

Section 6:  Building and Maintaining Appropriate Community and
Stakeholder Relationships

Strengths

Section 6 identifies many important areas and issues that need to be
considered in addressing ethical aspects of observational exposure
studies.  This section addresses the rationale for and the complexity of
building and maintaining trustworthy and effective relationships with
communities and stakeholders who are either directly or indirectly
affected by observational exposure studies.  The authors are to be
commended for identifying the key components of this complex and
multi-faceted process.

This section identifies options for researchers with regard to community
involvement including CABs, which have been shown to be quite successful
in several observational epidemiologic studies in which exposures are
quantified in relation to human health effects.   The composition of
CABs is not well defined.  Such boards should be representative of the
community.  This section also does not clearly articulate the advantages
and disadvantages of engaging a community of research, nor does it
clearly describe best practices.  For example, investigators should be
advocates for the data, not for the community and a CAB is not a
substitute for ethical decisions.

Section 6 carefully defines important concepts and operationalizes them
for researchers.   Definitions, by design, are relatively broad offering
flexibility to meet specific study objectives tailored for particular
communities.

Document Enhancements

This section identifies and provides some of the supporting
documentation for key components required for building relationships;
e.g., within an overall conceptual framework that builds largely upon
the diffusions of innovations literature (Rogers, 1995a, 1995b).
However, much of the presentation is in the form of assertions rather
than supported by sound science.  While many of the assertions are
quoted from references, there may be no hard data in the references to
back up the statements.  The Board recommended that the final report
include evidence-based discussions and/or tables that show better
compliance, retention, and data quality when community involvement is
obtained compared to when it was not.  Scientific rigor is essential in
the exposure science field and therefore should be attended to carefully
in this document.

Both moral and “best practice” considerations are included as
ethical aspects of these studies.  (For example, moral principles with
aspirational results are listed on p. 67, lines 12-15, while Text Box
6-1 lists “best practice” considerations.)  Clearer distinction of
the types of ethical issues and the better use of text box listings to
highlight the differences would strengthen this section [and document].
Further, clarification would make it easier for the reader to understand
whether “ethical issues” in this section refers to moral principles,
“best practices,” or both.

Examination of the many ethical issues raised in Section 6 suggests that
the section [and document] may benefit from a text box or table (i.e., a
box that would be parallel to Table 1-3) summarizing the ethical
principles, which are essential for observational exposure studies.  The
advantage of such a summary would be to pull out the principles that
resonate throughout the document; i.e., the ones that are more than
single mentions.  [This summarization may be more effective on a
section-by-section basis, rather than across the entire document.]

Specific Suggestions to the Document

Important points that may merit emphasis in text boxes or other
mechanisms in Section 6 include the underlying principles essential for
effective relationships (now spread throughout Section 6):

Respect, fairness, beneficence, honesty, openness, trust, commitment,
confidentiality, and responsiveness [Note that justice and other
principles are listed on pages 2 and 5 (etc.).  Perhaps a
cross-reference to earlier, more complete text or supporting materials
is needed in Section 6.]

As appropriate for the contexts, early and active community involvement,
meaningful community roles and responsibilities, and two-way
communications

Effective representation of the community’s diverse views

Dignity, veracity, sustainability, justice and community (p. 69)

Establishing a relationship with the community before a study (p. 71)

Build community capacity (p. 73)

Researchers need to be forthright with communities (e.g., p. 73)

Research relevant to communities (p. 74)

Introductory paragraphs

Community-based studies involve numerous ethical issues that are
fundamentally different in important ways from clinical studies (p. 67,
lines 19-21).  Some of these issues are addressed in the earlier
sections of the document, but not discussed in Section 6.  The one issue
highlighted here is two-way communications (p. 67, line 30), but this
emphasis is not consistently presented throughout Sections 6 and 7.

Section 6.1

This section is quite good and includes a compendium of ways to approach
the community and get the community involved with a study.  Such
information is invaluable to the neophyte researcher attempting to
gather data in a new community.

However, some of the reasoning presented in Section 6.1.1 and
sub-sections borders on philosophical, is convoluted and occasionally
circular: ethical action requires trust and trust is essential in
ethical action.  Still, the points are of interest and should be
developed.  Exposure researchers typically have “hard science”
backgrounds, and therefore need both guidance in this area and
substantial evidence supporting the points (e.g., those cited from the
EPA November 2007 workshop on observational exposure studies).  Perhaps
the use of examples would be a better teaching tool and would serve
EPA’s needs better.

Sections <IP_ADDRESS> and <IP_ADDRESS>

	The sections are not balanced in their discussions of community and
stakeholders, giving less attention to the latter.  The reason for this
imbalance is not apparent and may confuse researchers about who
stakeholders are and what their roles are.

Who is to be involved in community-based studies and how involves a
variety of ethical concerns.  The distinction between “community”
and “stakeholder” should be made clearer (see pp. 69-70).  The
“stakeholder” descriptions on p. 70 (lines14-17) and p. 74 (lines
19-20) could be improved; e.g., stakeholders can physically speak for
communities but may not be seen as legitimate spokespersons for
community interests.  The key issue is whether the community has
actually or officially delegated any of its representation or speaking
rights to stakeholders (whether stakeholders are also members of the
community or not); this seems to be the intent of p. 70, lines 21-23,
27-29, and 38-39.  Perhaps minor editing of this page will clarify and
strengthen the Agency’s guidance, or – more likely – a major
reconsideration of the definitions and differences between
“community” and “stakeholder” may be needed for use throughout
the document.

Section <IP_ADDRESS>

Reading comprehension needs to be stressed more and, possibly,
operationalized further.  While there is at least one comment to strive
for an 8th grade reading level, many IRBs require materials prepared for
a 5th grade level.  Also, if translation is required, many IRBs require
a certified translating service and increasingly are requiring back
translation when certificated services are not available.  In the
advisory spirit, some reference may be needed with regard to
translation.

Additionally, data collection instruments can be designed so that
reading comprehension is objectively measured.  To this end, researchers
could be advised to formally evaluate grade level reading and
comprehension while capturing data relevant for exposures.

Sections <IP_ADDRESS> and <IP_ADDRESS>

A new section should be included since means of communication (sometimes
referred to as channels of communication) are not discussed here.  Just
as the level and type of language used is important, means of
communication should align with communities’ preferences.
Understanding and using the ways in which communities want to receive
and share information are essential ways of demonstrating respect for
communities’ interests and showing that their input makes a
difference.  The Board suggests that a brief section about this issue be
added between Sections <IP_ADDRESS> and <IP_ADDRESS>.

Section <IP_ADDRESS>

Cultural differences should include race/ethnicity but, minimally, also
religious beliefs or other unique lifestyles.  Currently, the text only
pertains to the former and thus is unbalanced and potentially
misleading.  The Board recommended that the authors consider adding
language about providing study results to the communities (and
stakeholders) before publication.

Section <IP_ADDRESS>

The role of the researcher as an advocate (in addition to capacity
building) for the community is alluded to in the document (e.g., p. 73,
lines 73-75), but is noticeably absent here.   This is an important
aspect for this section but one that is strongly resisted by many
researchers.  The Agency needs to consider this section very carefully
as it will embark on a new expected path for many EPA researchers -
advocacy – in addition to researcher.

Section 6.2

This section could also provide advice about a reasonable length of time
for communicating study values (including personal exposure results) to
participants.  Ideally, such times should be determined upfront with
community input.  For example, a reasonable time might be within 6-12
months upon quantification of biospecimens.

Perhaps, attention should be given to the planned inclusion for health
alerts in real time.  Some observational epidemiologic studies have
health alerts built into web-based data management structures so that
researchers and participants can be alerted to any value requiring
further attention.  This approach needs formalization and guidelines for
implementation in the overall study protocol.

This section also should address the lessons learned from various
observational epidemiologic studies that have utilized CABs or other
forms of participatory research.  For example, a wealth of information
has been learned from the environmentally oriented studies involving
adults and children or from the Long Island Breast Cancer research
(Gammon et al., 2002).

Section 6.3

The use of “other stakeholders” (p. 74) is confusing to the reader;
what types of stakeholders are “other?”  If the definition of
“stakeholder” is broad, then the concept of “other” becomes
moot.  The text of this section is not fully aligned with the
stakeholder concepts in Section <IP_ADDRESS> (p. 70, lines 13-14) or the
Glossary (p. 107) and therefore needs to be reconsidered.

Further, the stakeholder discussion in Section 6.3 is given short shrift
when compared with the Community Involvement discussion (Sections 6.1
and 6.2).  Buy-in from stakeholders is often as important as buy-in from
the community even if for the reason that stakeholders often have more
fiscal resources to draw upon.  Without their buy-in, this would limit
financial resources, potentially hampering the ability for the study to
be conducted.  Stakeholders may offer alternative points of view
involving jobs for the community versus the views of some groups in the
community that may want “no pollution and no risk” without regard to
fiscal and social costs.  More comprehensive information about
stakeholders, particularly the needs of local government and business
stakeholders, should be included.

The importance of continually attending to the dynamics of relationships
is not recognized in this section.  Beyond identifying stakeholders (p.
74, lines 25-29), an additional benefit of Mitchell et al’s (Mitchell
et al, 1997) framework is that it offers a means for ongoing assessment
of the shifts in power, legitimacy and urgency that occur during studies
and that affect views of who is which type of “stakeholder” (as
defined in their article) and how they should be involved.  Further,
Michell et al (1997)  describe different ways in which organizations may
interact with different types of stakeholders throughout a dynamic
process (such as occurs in observational studies).  Recognition and
guidance about anticipating and strategically managing relationships
throughout observational studies would strengthen this section.

It is important to be sure the text boxes (not just in this section) are
fully documented in the text in order to avoid careless use of the
points without regard to the broader issue of community and/or
stakeholder involvement.  Ordering of bulleted items should reflect
logical steps in the process or importance; nonetheless, the rationale
for ordering should be stated.

Editorial Suggestions

Page	Line/s	Section	Comment

67	5	intro	The word exposure is missing   “…observational exposure
research…”

67	36	intro	Add c after 2003. [See reference on page 76.]

68	5	6.1	Consider revising this sentence to read “…nature of the
research itself and affected (or targeted) community…”

68	12	6.1	Do you really mean all qualified members?  Possibly add text
to say how to select among qualified members if the number is high
(e.g., randomly select, established rotations, etc…)

68

to

69	47

to

30	6.1	The section gets a bit far a field in its discussion of new forms
for Institutional Review Boards.  Perhaps a new section or sub-section
is warranted at this point.

69	7-8	6.1	Ensure that these lines reflect the author’s intent.  As
now written they could be misinterpreted.  “CAB members

…have to be educated” sounds directive and could be read as
condescending; is that what the author said?  [The point made on p. 69,
lines 24-26 is related.]

…should represent their communities honestly…” sounds judgmental,
as if the presumption is that CABs will not do so.  Is that what the
author said?

…need to be willing to interact…” involves the same issues as the
bullet immediately preceding this one.

69	28-30	6.1	What is the evidence base for the conclusion made here?  If
none, consider rephrasing this point.

70	13-14	<IP_ADDRESS>	This definition of stakeholder could overlap with the
definition of community found on p. 69, lines 39-41.  Inserting a
well-accepted definition for “stakeholder” here and in the Glossary
is recommended.

70	29-32	<IP_ADDRESS>	Delete this sentence.  It doesn’t add to the
document.

70	46-47	<IP_ADDRESS>	Is this a “should” or “must” issue?  The latter
implies that it is a critical issue, while the former does not.  If the
agency believes that reaching out to multiple organizations is
essential, this sentence would benefit from rephrasing.  There are other
should/must issues in the document; these also may benefit from similar
reconsideration by Agency authors.

71	4-6	<IP_ADDRESS>	Delete this sentence.  It doesn’t add to the document.

71	20-21	<IP_ADDRESS>	This sentence could be misinterpreted as being
directive to communities, rather than advisory to researchers.
Rephrasing is recommended.

72	10	<IP_ADDRESS>	“Materials distributed” implies written and/or visual
tools only.  This suggests that oral/aural and interactive forms of
communication are excluded; the Board doubts that the authors intended
to exclude such forms of communication here and suggest rephrasing.

72	19	<IP_ADDRESS>	“Explanation” is a limited concept in light of the
document’s earlier discussion of the importance of two-way
communications.  Listening to communities’ feedback about the research
should be coupled here to complement the explanation function noted.

72	30-32	<IP_ADDRESS>	The key points from this reference should be included
here.  Without them, this sentence is of little use to the reader and
does not provide a level of information about ethical issues comparable
to the rest of the paragraph.

72	35-39	<IP_ADDRESS>	This sentence uses the terms “relational paradigm”
and “societal context.”  These terms stand in sharp contrast to the
urgings earlier to present information in a manner understandable to
subjects in a study. These words are jargon and are not clear; this
sentence should be re-worked.

73	6-7	<IP_ADDRESS>	An important ethical issue not mentioned here is the need
to attend to the dynamics of relationships; these may change whether one
or more parties judge pre-established roles and responsibilities as
acceptable.  An ongoing process of assuring mutual understanding and
acceptability is often needed because community research environments
are inherently complex and dynamic.

73	17-19	<IP_ADDRESS>	Same issue as on p. 71, lines 20-21.

HSRB Consensus and Rationale

In large part, the information is presented accurately and clearly in
each section; however, suggestions for improvements are noted.  Section
6 addresses many of the major issues requiring ethical considerations
but lacks the level of scientific rigor needed by exposure scientists.
Major suggestions by the Board included:

More data to support points made and less assertion or “theory”
would strengthen this section.

It is important to differentiate the terms stakeholder and community as
well as their interrelationships and discussing the value of community
advisory boards and community sensitive piloting of procedures.

Successful community advisory board procedures, how the
scientist-community relationship will evolve and be monitored over time,
how the results of research are disseminated and the informational
benefits to the community should be discussed.

The Board cautioned about editing the section so that readers would not
erroneously conclude that the EPA is advocating that scientists become
community advocates.

Section 7:  Designing and Implementing Strategies for Effective
Communication

Strength

Section 7 discusses principles for designing and implementing effective
communication strategies between all affected stakeholders in an
observational exposure study.  One of the important messages coming from
this section is that an effective communication strategy should be a
structured, formal plan and should be given extensive forethought prior
to beginning the study.  Additionally the communication strategy plan
should be a living document that is constantly reexamined and updated as
the study progresses.  It should be stressed that this involves a
two-way communication strategy and an intentional process.  It is as (or
more) important for the researchers to listen to the stakeholders as it
is for them to give information to the stakeholders.

Document Enhancements

However, Section 7 emphasizes one-way, media-directed, and crisis
communications, which conflicts with the rest of the document.  These
aspects of communications may be part of a comprehensive, strategic
communication program but often are not appropriate as the major
emphasis for community-based, observational exposure studies.  Instead,
community concerns about potentially being stigmatized by research
participation and/or results are often important issues.

In Section 7.1, the importance of formative evaluation should be noted.
Ongoing evaluation is a means to identify community needs and issues,
thereby permitting researchers the opportunity not only to improve
conduct of the study but also to actively demonstrate respect to
participants, showing that their input makes a difference.

Section 7.2 states it is essential to engage all stakeholders early and
often in the process.  One area that has been commented on for previous
sections is the definition of “stakeholder”.   On page 74 of the
document (Section 6.3) it states “stakeholders may include business,
industry, and local or state governments or agencies with jurisdiction
over the community.”  In contrast, Section 7 includes the community as
one of the stakeholders.  It is important upfront to define the term
“stakeholder” and what groups it encompasses and to use that
definition consistently throughout the document.  The community from
which  the subjects are to be drawn has traditionally been considered as
one of the stakeholders.

While it is critical to identify all pertinent stakeholders, there is a
danger that the group would become so large that it becomes
unmanageable.  In a group such as this there is the potential for having
strong divergent interests.  This could generate enough conflict that it
could impede the research from moving forward in a timely manner.  It is
therefore advisable to add as references some articles on managing
conflict with a diverse population.  A sidebar with some salient points
on managing conflict might help.

Specific Suggestions to the Document

Section 7.3 discusses communication timetables.  It encourages
researchers to begin the dialogue with the community as soon as
possible, learn from the participants and the community,  and continue
exchanges of data and information through the reporting of the study
results and beyond.  It suggests using press releases as an important
tool to engage the community.  Section 7 states that observational
studies should also be announced to stakeholders and the public via
media, community interactions, or other means well in advance of study
implementation.  It is strongly recommended that there be some
“buy-in” by the community before any public announcement.

Section 7.4 talks about the importance of developing communication
materials at different levels of science literacy.  It stresses that all
materials be written in “plain language.”  However, there are no
follow-up references on available “plain language” strategies and
tools.  Below is the link to the Department of Health and Human Services
Plain Language webpage.  Other empirically-based references could also
be included in the document along with a sidebar on “plain language”
tips.

http://www.health.gov/communication/literacy/plainlanguage/PlainLanguage
.htm

While comprehension is correctly identified as an issue, testing of
tools is under-emphasized here and at the end of Section 7.5.. Empirical
testing of communication methods and content is known to be essential
and demonstrates respect for communities (cf. Health Canada’s
strategic risk communication handbook available at
http://www.hc-sc.gc.ca/ahc-asc/activit/ris-comm/index_e.html).

Section 7.5 discusses the development of communication materials.  An
example of a pediatric assent document is given.  The point that should
be stressed with this example is that it must be written at the level of
understanding of the reader.  The use of generic communication materials
for several different stakeholders would not be appropriate, contrary to
what the document might suggest, because each stakeholder will be unique
in its understanding, level of involvement, and connection to the
research.  Researchers should be strongly encouraged to gather data
about individual stakeholder needs and priorities prior to developing
communication materials geared towards that population.  Again two way
communication is essential because stakeholders can best define their
strengths and limitations in understanding.

Another communication tool emphasized in this section is the use of the
internet to communicate with study subjects and with interested
stakeholders.  One important point that should be stressed here is that
a communication tool is only useful if it is readily available and
readily understood by the target stakeholder population.  For example,
if the researcher chooses to communicate by internet, he/she should be
certain that everyone in the stakeholder population has ready access to
the internet and has the requisite computer skills to navigate the
research site.  Researchers will have to be even more creative in
developing communication strategies with stakeholder groups that include
 populations of illiterate members or those which do not speak English.

The real emphasis should be on listening carefully to and the learning
from the stakeholders and looking carefully at the communication needs
and limitations of all the pertinent stakeholders before beginning the
development of communication materials.

The end of this section brings up the important issue of conflicting
ethical values and study elements.  However, the final lines only
address remuneration and communication materials (see comments above);
two elements of a study that are not tools for addressing conflicting
values and elements.  The text should segue into comments about methods
appropriate for addressing conflicting values and study disputes.

Section 7.6 states that researchers need to make a commitment to
communicating with and educating the study participants and the
community on the purpose of the study.  Some discussion should be
included about the issue of whether behavior will be adversely changed
as a result of educating the participants.  If too much education
results in a behavior change, the goals of the research will be
compromised.

Section 7.7 discusses that approaches for reporting results to the
participants but does not note that these approaches should be developed
with community input.   In communicating the results, it is vital to
make sure the study participants clearly understand the meaning of the
results.  Additionally the study participants and the community should
be directed to sources of additional information, resources, and
counselors where they can turn to for additional information or
follow-up information in case of additional questions or concerns.

Participants should also be given the option of not receiving any
results.  Their options about receiving results should be clearly laid
out and discussed prior to initiation of the study.

The community and stakeholders should be notified prior to the
publication of any study results or any press releases relating to the
publications.  These interested parties have a right to know when data
are going to be made public but do not have the right to change the
science or the researcher’s interpretation of the science in the
publication.  They can, however, dispute the interpretations in public.

It is unclear why part of this Section focuses on crisis communications
and “responding.”  There is no rationale to help researchers
understand why this discussion is included, or how this advice for a
specific type of communication would fit in a comprehensive risk
communication strategy for observational exposure studies. However,
judging people’s perceptions as “accurate” is not appropriate;
perceptions are what they are whether someone else agrees with them or
not.  Perceptions may differ among individuals and groups; perhaps the
intent here is that lay people may have perceptions that differ from
that of experts (see Morgan et al. 2002. Risk communication: a mental
models approach.) .  Section 7.9 deals with communicating with the
interested stakeholders when a dispute in interpretation of data results
occurs.   This is an important area to stress so that researchers
discuss strategies to deal with this as they develop their
implementation plan.  An additional section on how to deal with
litigation, should it occur, might be helpful to researchers should they
find themselves in this situation.

HSRB Consensus and Rationale

Section 7 covered most of the important issues.  This section had a very
comprehensive and informative list of reference and several suggestions
for additional references have been noted.   While this section is very
well-written, it does not clearly focus on the risk communication
methods most suitable for observational exposure studies.  The use of
side bars is a very effective tool to communicate small bits of
information clearly and quickly.  Other areas that need additional
discussion include: (a) the goals of communication; (b) data sharing and
how to address potential scientist community disagreements; (c) the
context in which communication occurs; and (d) the importance of
formative evaluation.

B.  Completed Oral Therapeutic Study with Sodium Azide

Charge to the Board

1.  The Agency has concluded that this study contains information
sufficient for assessing human risk resulting from potential acute and
chronic exposure.  Please comment on whether the study is sufficiently
sound, from a scientific perspective, to be used as the point of
departure to estimate a safe level of acute and chronic exposure to
sodium azide.

Board Response to the Charge

The Black et al. (1954) study was not designed adequately to estimate a
NOAEL rather it focused on evaluating the therapeutic nature of sodium
azide.  Accordingly, the study did not investigate the critical effect
and it also did not report the administered dose precisely.  Further,
the study lacked clarity on baseline data and overlap of subjects in the
various treatment groups. The Board felt that the study did not meet the
prevailing standard in scientific conduct and reporting in clinical
trials.  Sir A. Bradford Hill’s randomized, placebo-controlled trial
of streptomycin for treatment of tuberculosis reported in the British
Medical Journal in 1948 had better experimental design, conduct,
analysis and reporting of results from a clinical trial.  The Black et
al. (1954) study, however, suggested increased sensitivity in several
subjects with chronicity, even though the basis of that sensitivity is
undefined.  Whether that was due to additional blood pressure-lowering
effect or another adverse effect is really not clear. In its
discussions, the Board noted that it may also not be relevant to make
direct comparisons of these human data with animal data, without body
surface correction or appropriateness of the endpoint measured.  The
specific concerns of the Board are summarized below:

Dose: The information provided by Black et al. (1954) suggested that
doses of 0.65 and 1.3 mg were given three to five times to individuals
with no known body weight gender, race, and age.  In the case of chronic
study, the doses were given during 5 days to more than 2 years.  In page
15 of the report, the authors refer to decreasing the dose from 0.5 to
0.25 mg in 20 patients.  However in  Table I which lists 30 out of the
39 patients, only 2 patients received 0.5 mg dose.  This kind of
reporting does not facilitate confident determination of the point of
departure for establishing a safe level of acute and chronic exposure to
sodium azide.

Toxicity: The study looked for some side effects (liver, kidney) and
clinical measures (no description of methodology or control values) at
the therapeutic doses given to people.  There was no focus on the
critical organ or critical toxicological effect.  Further, toxicity was
evaluated only in 3 individuals and it did not involve any time course
analysis.  The rationale regarding why, when and what was evaluated –
is missing.  One out of three subjects reported pounding of the head
after taking sodium azide, and this level of information is not adequate
to determine a scientifically-defensible NOAEL or LOAEL for acute and
chronic exposures to sodium azide.

Subjects: There was no baseline/pre-treatment information about the
patients, other than pre-treatment blood pressure, limiting the value of
the results presented in Black et al. (1954).  It is also unclear
whether there was an overlap of patients for the acute and chronic
effects of sodium azide.

The blood pressure data for the 30 hypertensive patients given in Table
I appeared to be included in the data presented in Figures 2 and 3 for
the acute blood pressure change for 35 patients, but only partially.  In
Table I, there are 19 patients with pre-treatment systolic blood
pressure (SBP) of > 190 mmHg and 11 patients with pre-treatment SBP of
≥ 140 but  ≤ 190 mmHg among 30 hypertensive patients.  However, in
Figure 2, there are only 13 patients with pre-treatment SBP of > 190
mmHg, 13 patients with pre-treatment SBP of  ≥ 140 but  ≤ 190 mmHg,
and 9 normotensive patients with pre-treatment SBP of < 140 mmHg. The
gap in the data cannot be accounted for, and as a result, the veracity
of the data is being called into question.  As shown in the figure
below, the plots of the acute systolic and diastolic blood pressure
changes based on the data presented in Table I for 30 hypertensive
patients in contrast to Figures 2 and 3 from Black et al. (1954).

n=35

n=30

n=35

n=29

HSRB Consensus and Rationale

Based on the inadequacies in the design, methodology and reporting, the
Board concluded that the Black et al study was not sufficiently sound,
from a scientific perspective, to be used as a point of departure to
estimate a safe level of acute and chronic exposure to sodium azide.  In
addition, it was not informative as to whether human responding confirms
estimates based on animal studies.

Charge to the Board

2. Please comment on the following:

Is there clear and convincing evidence that the conduct of the study was
fundamentally unethical?

Is there clear and convincing evidence that the conduct of the study was
significantly deficient relative to the ethical standards prevailing at
the time the research was conducted?

Board Response

The Board noted the lack of documentation pertaining to the ethical
conduct of the research reported by Black and colleagues (Black, et al.,
1954).  It was not unusual for clinical reports of this era to be vague
with respect to matters related to subject recruitment and informed
consent.  The publication by Black and colleagues does not provide many
details with regard to the protection of human volunteers but does hint
at the following: (1) the public-health rationale for the study was
supported by prior research, (2) medical monitoring was in place to
minimize potential risks to research volunteers, and (3) initial dosing
schedules were set at levels believed to be substantially below acutely
toxic levels.  A full assessment of these issues is not possible,
however, due to the limited information available. Even if more
information were available, the Board’s analysis is complicated by the
absence of widely agreed upon standards for the ethical conduct of
research during the time this study was conducted.

The report makes just a single statement that is related directly to the
adequacy of the process used to obtain informed consent from research
volunteers.  That statement is that the study drug “was administered
without informing the patient of either the nature of the drug, or the
change to be expected.”  Contemporary standards of informed consent
would suggest that this was ethically worrisome because key facts
affecting the assessment of the study’s risk-to-benefit ratio were
withheld from volunteers.  Without a more detailed description of the
set of procedures used to present the study, however, it is difficult to
conclude that the researchers deliberately sought to deceive research
subjects about the nature of the research—which might be seen as a
reason for regarding the study as significantly deficient with regard to
the prevailing ethical standards of the mid 1950s.  For example,
subjects might have been informed that, to avoid a possible placebo-like
effect, they would be “blinded” to the nature of the study drug or
the clinical features being studied.  If subjects were informed about
other pertinent aspects of the study, and agreed to participate, then
that might be viewed as consistent with prevailing ethical standards of
the time.  Alternatively, the researchers conducting the study may have
conceptualized this experimental intervention as “innovative care”
and not felt it appropriate to present the intervention as a research
study.

In summary, two factors combine to limit the ability to assert that the
study was “significantly deficient relative to the ethical standards
prevailing at the time the research was conducted”: (1) lack of
additional detail regarding the procedures used to recruit research
subjects and obtain their consent to participate in the Black study, and
(2) lack of unambiguous ethical standards for determining what
information must be disclosed to potential research volunteers.

HSRB Consensus and Rationale

Based on lack of documentation in the Black et al. study, the Board was
unable to conclude that there was clear and convincing evidence that the
conduct of the study was fundamentally unethical.   The Board was also
unable to assert that the study was significantly deficient relative to
the ethical standards prevailing at the time the research was conducted.

C.  Science Issues in Mosquito Repellent Efficacy Field Research

	Appendix A provides background and discussion questions for Board
member and consultant consideration concerning mosquito repellent
studies.  Board responses to the questions are provided below.

Board Response

Issue 1: Factors Affecting Repellent Efficacy

Presentations by EPA and consultants indicated that factors which may
affect the variability of initial and confirmed landings include biotic
factors such as characteristics of the mosquito population (genus and
species distribution, level of ambient mosquito pressure) or abiotic
factors, which are related to characteristics of the test site such as
season, time of day/brightness, or the microclimate (including
temperature, humidity, and wind speed and direction).  Other factors
that may affect landings include characteristics of the test subjects
(such as differences in mosquito attractiveness; use of alcohol,
tobacco, or scented products; or behavior).  Characteristics of the test
methods used that may affect variability include the pattern and
duration of exposure, area of skin treated, method used to determine the
amount of test material applied, and number of concurrent treatments per
subject.

Variable factors that affect first or second landing or bite include
characteristics of the subjects’ skin, temperature, age, hair on the
skin surface, and the density of the mosquito population at the test
site.  Usually, mosquitoes will bite within 5 to 15 minutes after the
subject enters the area; after that, the mosquitoes have acclimated to
the subject’s presence and bite much less frequently.  Temperature
plays a major role in landing or biting activity; an increase in skin
temperature is associated with a decrease in repellency.  Skin color or
type does not have a major effect on landing or biting, and hair on the
skin surface has a small effect.  The density of the insect population
has a major effect on landing or biting activity.

Factors affecting landing or biting activity also include
characteristics of the mosquito population and the test sites.  There is
significant disagreement among researchers concerning the most
appropriate mosquito population to use for testing.  Density of the
population can affect landing or biting activity.  The age of the
mosquito population also plays a role, with mosquitoes between 5 to 15
days of age being the most avid biters.  Susceptibility of the test
subjects to mosquito bites also can affect landing and biting, although
most people are susceptible to bites.  Selection of test sites
critically affects landing and biting.  Weather, particularly
temperature, can significantly affect biting behavior; repellency
decreases by 8 minutes for every 1 degree Celsius (°C) increase in
ambient temperature.  Human skin temperature (30-32°C) is considered to
be constant.  Wind can significantly affect the efficacy of vapor
repellents because the wind will quickly remove the vapors; increased
wind speed is associated with decreased repellency.  Humidity interferes
with evaporation and repellency.  Light does not appear to have a
significant impact because different mosquito populations exist that are
active either during the day or at night.  The local fauna or flora can
impact repellency, especially if the local fauna are the mosquitoes’
preferred hosts.

Test subject attraction for mosquitoes is variable.  Skin chemistry may
have an impact, but the delivery mechanism used to apply the repellent
to the skin has a larger effect.  Skin temperature is constant and thus
has no impact.  Skin permeability affects repellency, but it is
dependent on the formulation of the repellent.

HSRB Consensus and Rationale

Based on the thorough and highly informative presentations by the
consultants the Board concluded that in general a protocol needs to
elucidate environmental, insect, and subject factors that would create
variability and then provide a rational for the design, sampling method,
number of subjects based on those factors.  Efficacy relevant
information that might be included: a description and rationale for the
activity level of the subject population, the proximity of subjects to
one another (or to a partner), the expected density of the insect
population, comparison of insect density and other environmental factors
(e.g. temperature, wind) across sites. The Board also concluded that
while replication is important it is difficult to define across
different studies.

Issue 2:  Designing for length based sampling

The rationales for different designs should be available by reference
and the effects of different designs should be noted.  It is unknown
what, if any temporal protocol for exposure is standard (classical).
That is, how were the designs derived and who accepted them as standard.
Each design has different length based sampling.  One rationale for
using first confirmed intent to bite (LIBe) rather that first confirmed
bite (FCB), as stated by Dr. Carroll, is that using LIBe minimizes the
probability that a subject is actually bitten by a foraging mosquito
[that might contain a pathogen or produce an irritant or allergic
reaction, etc.].

Exposures in one study were during one-minute periods of exposure in
15-minute intervals, and in another study 5 minutes every  30-minutes.
The time between first and second (or subsequent) landings is likely to
be very variable. Thirty minutes is usually suggested as a long enough
interval to allow for any mosquitoes in the area to land.

The Board raised the following general questions.   Were these periods
at the beginning, the middle, or the end of the interval, or were their
timing randomly determined, and what impact did these choices have?
What impact is there of using 1 or 5 minute periods, and/or of 15 or
30-minute intervals, compared to other period intervals?

Investigators have calculated Complete Protection Time (CPT) as the
interval between application and the first confirmed LIBe or first
confirmed bite (FCB).  However, investigators state that the first
confirmed criterion has to be followed by another within a period of
time (e.g., “one-half hour, i.e., in either of the subsequent two
exposure periods” for the LIBe).  Dr. Carroll has indicated but not
confirmed that LIBe is identical to that of ‘First Confirmed Bite’,
which was classically used in measures of repellency to biting insects.

Dr. Carroll has indicated that it is most likely that a second LIBe (or
bite - FCB) would occur within that 30-minute period.   However, from an
analytic perspective, caution is warranted where FCB is calculated on
the basis of non-continuous field exposure because it reduces biting
pressure by a factor equivalent to: 1/(1-proportional decrease in
exposure).  The upshot (where RP < 100%) is a decrease in the
probability of receiving a first and confirmatory bite in any 30 min
period.

Dr. Carroll’s  modeling of continuous versus. two intermittent
exposure scenarios indicates that the intermittent exposures can
substantially reduce the probability of seeing a FCB at a given RP”,
though this has not been validated experimentally.

Intermittent exposure of treated subjects to establish FCB has not been
used widely in field studies.  This implies that continuous exposure
approaches have been used widely in field studies.  To make intermittent
exposure protocols standard should require comparison testing for
experimental validation.  Board consultants acknowledge that a 30-minute
or one-hour design is more common in the literature, but does not state
whether such designs are continuous or intermittent exposure designs but
imply (from other statements) that is continuous exposure.  It is never
really accurate to do a repellent trial continuously for more than about
an hour or two because the avidity of the mosquito population will start
to change significantly. The best designs treat people the appropriate
number of hours before the peak biting time and then expose all subjects
simultaneously.

The military, USDA and ICR do various types of continuous periods of
measurements. The military may do numbers of landings in 20-minute
exposures (challenges) with a criterion of 1 mosquito per minute (and
compare treated versus  untreated leg), with exposures (challenges) at
2, 4, 6, 8, 10 and 12 hours post-application.  Or they can have a
protocol with staggered treatment times during the day (e.g., 800, 1200
or 1600) with specified continuous exposures at two times during the day
(e.g., 1800, 2000).  USDA may do 6-hour duration testing starting at
0730 and 1345.

There are further concerns regarding such protocols and their effects on
CPT.  A set of concerns has to do with situational factors within the
field setting.  What  differential effect is there within such studies
from light intensity, such as obtained during days in which dusk was
included?  Dr. Schofield states there is an [unspecified] effect, as
there are effects due to variations in temperature (partially related to
the mosquito species in that area as well), and the impact of
subject-activity patterns.  One Board member believed that there must be
also effects of field variations in relative humidity, barometric
pressure, wind speed, and smoke pollution, etc., on mosquito behavior.
Such variations probably affect species-specific and general mosquito
behavior and may be relevant to CPT calculations.

The Board consultants added that it might be possible to adjust for wind
and temperature, if the studies have been done for that particular area
and those species of mosquitoes. A much more serious problem is that the
biting activity of mosquitoes varies systematically with time of day.
Variability is due to subjects, location, date and time, and one would
not obtain a normally-distributed (Gaussian) result.  Lab variability
has been related to biotic factors (in subjects and mosquitoes) and
abiotic factors (temperature, relative humidity, light, dose and
exposure time).  These are likely to be variability factors in the
field.

The impact on the factors listed described for Issue 1 on the likelihood
and timing of a first and confirming bite can be predicted and
quantified.  For example, we can reasonably predict that moderate-level
exercise will attenuate product performance thereby resulting in a
(probabilistic) systematic decrease in the time of the first and
subsequent bites.  Similarly, we can design a set of protocols to
evaluate the phenomena and to quantify (a posteriori) the effect for
that specific suite of experimental circumstances. However, given the
lack of standardization between studies, the paucity of research
specifically directed towards evaluation of the above-mentioned factors
and the complexity of the test system, elaboration of anything more than
a very basic general model is not possible.

HSRB Consensus and Rationale

	The Board noted that the choice of intermittent vs. continuous exposure
designs depends upon the goal of the study (e.g. relative or complete
protection) as well as other factors. The Board concluded that more
research is needed to determine the relative benefits of these designs
and concurred with EPA that future guidance on this matter would be
helpful.

Issue 3: Complete Protection Time

	Dr. Matt Kramer, a USDA statistician, has suggested that the precision
of CPT estimates in repellent testing could be significantly increased
by defining failure of efficacy as the mean time from treatment to a
series of several [e.g., five] landings or bites.  The Board consultants
were asked to determine whether this approach would markedly increase
the precision of CPT estimates without requiring additional subjects
and, if so, whether the increased precision would justify
the incremental risk to the subjects resulting from their exposure to
mosquitoes.  The consultants also were asked to consider the
practicalities involved in testing long-lasting repellents to the point
of five landings.

The complete protection time for a subject is clearly defined as the
time of repellent application to the first bites/LIBe’s with or
without the confirmation of a second bites/LIBe’s.  It is unclear what
the mean of the times to the first 5 bites/LIBe’s is measuring.  A
discussion on the precision seems irrelevant when one is not so sure
what is being measured.  Besides, these 5 times are all correlated
within each subject, and so the efficiency gain is not so obvious due to
lack of independence among measurements.  With the censoring of efficacy
failure seen in a number of mosquito repellency studies, it is
unrealistic to be able to observe, say first 5 bites or LIBe’s, and
probably impractical to test to the point of 5 bites/LIBe’s.

Perhaps more critical is the artifact of taking average of times to the
first five bites/LIBe’s, which is to overestimate the time to efficacy
failure.  This seems to make sense if one is interested in understanding
the average mosquito biting/LIBing behavior.  However, it seems
unsuitable if one is interested in characterizing the “efficacy” of
repellent products.

The rationale for this idea of measuring times to five bites/LIBe’s
became very clear during the consultant’s presentation.  If the
population for statistical inference is the population of mosquitoes and
the statistical inference is on the mosquito biting behavior, it makes
sense.  However, that is not the case in these mosquito repellency
efficacy studies.  The population for statistical inference is the
population of repellent users, not mosquitoes, and the statistical
inference is on the time from application of repellent to failure of its
efficacy.

Currently there is no consensus on whether continuous or intermittent
methods are most desirable. Prior to the new regulations, continuous and
intermittent methods were used. A preference for the intermittent method
became dominant after the new regulations were in place because it is
more protective of individual subjects since they are exposed to less
bites. However the use of continuous methods might also call for less
subjects.

HSRB Consensus and Rationale

Based upon information provided by the consultants, the Board remains
unclear of what the mean of the times to the first 5 bites/(landings
with intent to bite) would measure of relevance to EPA determinations of
efficacy.  Therefore The Board concluded that precision of CPT estimates
in repellent testing would not be significantly increased by defining
failure of efficacy as the mean time from treatment to a series of
several [e.g., five] landings or bites.

	The Board concluded it would be helpful to their deliberations if
protocols submitted to the HSRB included rationales for sample size,
outcome measures, number of treatment groups and controls, why a field
study is preferable, why a specific environment was selected, how
different environments differ, and how controls for environmental shifts
in temperature or time of day are determined.

	The Board understands that the need for smaller sample sizes and the
accompanying lack of power must be balanced with subject protection, but
it is also important to understand which variables can be controlled.
The expertise of control and treated subjects with respect to detecting
mosquito landings must be balanced and the activity of subjects also
should be controlled.

D.  Completed Insect Repellent Efficacy Study (SCI-001) of DEET
Formulations

Charge to the Board

Is this study sufficiently sound, from a scientific perspective, to be
used to assess the repellent efficacy of the formulations tested against
mosquitoes?  Please comment specifically on:

Whether participation in field testing by several subjects on the day
after they had been treated with a different test repellent is likely to
have affected the validity of the results for those subjects on those
days.

Board Response

The active ingredient DEET formulated in three forms 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 the HSRB.  The results
were reported in SCI.001.1, LipoDEET 302; SCI.001.2, LipoDEET 3434; and
SCI.001.3 Coulston’s Duranon, all compared to Ultrathon (approved by
the military). All experiments were conducted using Good Laboratory
Practices.

The dosimetry for the three products was done in the laboratory on July
3-5, 2007.  The field tests were conducted at Site 1 in Butte County, a
grassland habitat, on July 7, 8 and 15, and at Site 2 in Glenn County, a
forest habitat, on July 12, 13 and 14.  Different mosquito species
composition occurred at the two sites. Ten subjects were used for the
dosimetry tests.  Ten subjects were used for each of the three products.
Some of the subjects participated for all three of these test articles
as well as for the Ultrathon. The subjects were required to be above 18
years of age and no more than 55 years of age, active in rural outdoor
settings, and having used no repellent on the day before the test. Only
legs were tested in this study because of greater biting pressure on
legs than arms. 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.  No evidence of West
Nile Virus (WNV)  was present in either test site. Mosquitoes landing
were taken to the laboratory for later identification, and for screening
for WNV, Western Equine Encephalitis, and St. Louis Encephalitis Virus,
and all mosquitoes were negative.  All subjects wore Tyvek coverall,
head nets and surgical gloves, and they worked in pairs.  There was a
one minute observation period during each 15 minute interval, starting
150-210 minutes post application.  Toward the end of the day, controls
were reduced from 2 to 1 subject to limit exposure to mosquitoes.
Complete protection time (CPT) was measured, defined as the time to the
First Confirmed Landing with Intent to Bite (FCLIBe). Adequate LIBing
pressure was maintained throughout the test period.

LipoDEET 302 is 30% DEET on lipid spheres designed to improve the
durability and to improve the cosmetic properties. Six females and four
males were tested for dosimetry, 7 females and 3 males at Site 1, 3
females and 7 males at Site 2.  The MOE was 522.  It yielded a CPT of
10.3 ± 1.3 hr in Site 1 and 9.5 ± 1.8 hr in Site 2.

LipoDEET 3434 is DEET at 34.34%; this protocol SCI.001.2 was amended to
test a different test article than the original protocol described  Five
females and five males were tested at Site 1, 4 females and 6 males at
Site 2.  The MOE was 492.  It yielded a CPT of 10.6 ± 1.3 hr in Site 1
and 10.4 ± 1.9 hr in Site 2.

Coulson’s Duranon is 20% DEET in microscopic protein spheres to
reduced skin absorption of DEET, improve cosmetic properties and inhibit
evaporation.  Five females and five males were tested at Site 1, 3
females and 7 males at Site 2.  The MOE was 856.  It yielded a CPT of
8.4 ± 1.9 hr in Site 1 and 9.5 ± 1.3 hr in Site 2.

Data were presented for the comparison article, Ultrathon, CPT of 10.1
± 2.3 hr for Site 1 and 10.0 ± 2.2 hr for Site 2.  While this
comparison may have been of interest to the sponsor, it is unclear why
this information was provided in this report.

The report was clearly written and a greater attention to statistical
analysis was provided than has been provided in the past by Carroll-Loye
Biological Research.  The study was justified in that additional insect
repellents that are more efficacious and/or more acceptable cosmetically
to the public would be an advantage from both the standpoint of health
(to reduce the chances of contracting a mosquito-borne disease) and of
comfort.  The information should be generalizable to the public,
although the exclusions, which were highly appropriate, excluded some
subpopulations that would likely use insect repellents.  The experiment
was necessary to determine the field efficacy of these test
formulations, and the experiments were set up to meet the study
objective.  Measurements taken were appropriate for the objective and
quality assurance considerations were in place.

The experiment was conducted according to the approved protocol with
some deviations. One of the most serious deviations, which was not
acknowledged in the description, was the fact that some of the subjects
were tested on the day following a test with another product, despite
the fact that the protocol stated “Use of insect repellent within one
day of preceding the study” was an exclusion criterion.  Additionally,
the tests on any given repellent (including the repellent used in study
WPC-001) were not conducted on a single day and the statistical
treatment of the data did not account for different days of testing.

The deviation of not allowing a day of non-repellent use before testing
was of concern to the Board because of potential persistence of the
repellent of one day’s test into the test of the following day.
However, information provided by the Carroll-Loye Biological Research
via public comments indicated that the repellent was carefully washed
off at the end of the experiment both with soap and water and with
alcohol.  The public comments also indicated that the reason for the one
day wait in the protocol was not related to concerns about the
persistence of the repellent.  Therefore this deviation did not affect
the validity of the results obtained.  In addition, the public comments
indicated that the reason for the compression of the tests on these
several test materials into a short span of time was because of the
reports that West Nile virus-contaminated mosquitoes were moving close
to the test area and that this test region would have been unsafe in a
matter of just a few more days. This explanation was adequate to explain
why the testing days were set up as they were.  It would have been
advisable to have had this deviation and the rationale for it presented
in the report.

Charge to Board

b.	The effects of changes to the experimental design resulting in
evaluation of repellents using fewer than ten subjects per treatment per
day, followed by pooling of results by site for statistical analysis.

Board Response

Strengths

One of the strengths of the study is the inclusion of the positive
control treatment with 3M’s Ultrathon.

Weaknesses

SCI-001 studies are very troubling from a statistical design point of
view.  There is some indication that there was no desire to compare the
various repellents to one another, and yet each of reports compared a
repellent to a positive control, the Ultrathon repellent.  The
statistical analysis assumes that there are 20 different subjects on
each repellent over two sites, but many of the subjects wore both
repellents and a few subjects were used in both sites.  Subjects that
were used at both sites were subjects:  8, 13, 14, 15, 37, 40, 46, 52,
53, 60, 61, 62, 63, 67, 71, 72, and two control subjects.  Almost all
subjects wore more than one repellent.  This is not an inherent flaw in
the design, although if subjects are going to be used more than once,
there should have been some counterbalancing of the repellents to the
subjects.  The major flaw is in the statistical analysis, particularly
when repellents are being compared to one another as is done in the
reports by comparing each repellent to Ultrathon.  The analysis assumes
that there are 20 different subjects involved in each of the three
write-ups.  That is, the analysis assumes that the experimental design
is a parallel subjects design and it is clearly not.

In the combined  experiments, there were only 33 unique subjects,
representing 80 data points, excluding the negative controls.  Subjects
do not appear to have been randomly allocated to four test materials,
between Sites 1 and 2, and over five days.  This lack of statistical
independence of data between different test materials, Sites 1 and 2,
and different dates of experiment renders the analysis incorrect.  For
example, due to overlap of subjects between Sites 1 and 2, one cannot
pool the results by site for statistical analysis.  Also there is
substantial overlap of subjects among and between test materials, the
comparison among and between test materials cannot be made.  This
renders the analysis scientifically invalid.

In SCI-001, there is 0% censoring.  This differs to previous studies
conducted and reported by Carroll-Loye Biological Research, Inc and
reviewed by the Board.  As an example, there was 40% censoring in
EMD-004.1, 10-30% censoring in EMD-004.2, and 90-100% censoring in
EMD-004.3.  The Board supports the EPA’s evaluation that “Further
clarification is needed to verify the accuracy of the data generated.”

The data analysis (pairwise comparison between three test materials and
the positive control Ultrathon) is inadequate and is inconsistent with
the experimental design and conduct of the study in which subjects were
allocated to four treatment groups.  As was suggested by the HSRB in its
January 2007 meeting, the appropriate analysis would have been an
analysis of variance type.  Wilcoxon rank sum test in the presence of
censored data is known as Gehan’s test, and is known to be inefficient
for comparison of Kaplan-Meier estimates.  A more appropriate test
comparison of censored time to event data is the log rank test or better
yet a regression analysis for censored time to event data based on Cox
proportional hazards regression models.   The analysis of the number of
LIBe’s is inappropriate as it ignores the duration of follow-up during
which LIBe’s are recorded.  An appropriate analysis would have been
Poisson analysis.

Having ten subjects spread over  five days and combining the results
into the current analysis has a potential to confound the effect of
repellent with the different mosquito pressures on different days. This
would have been better if it were planned in advance.  The whole idea is
that the experimenter has  control over the experiment by using random
mechanism for subject selection and for allocation of subjects to
repellents, days and sites. One solution would be to perform the
analysis of variance as was done when the results for two sites were
pooled, i.e., by including the day as the main effect and the two-way
repellent by day interaction (repellent effect modification by day
effect) in the analysis of variance, in Table 5, on page 17 of 217, of
the report for SCI-001.3.  Of course, this requires making the
assumption that the experimenter had adequate control of the experiment
as described above and that observations are statistically independent,
which is not the case.  With the proper experimental design using site
and day of experiment as blocking factors, the analysis of variance
would allow evaluation of the three main effects of repellent, day and
site, along with the two-way and three-way interactions.  There is no
inherent problem with pooling across studies.  Study site can be
considered as a blocking factor, and as such it would generally be
appropriate to pool across the two blocks.  This assumes independence of
data from sites, namely, no overlap in subjects between the sites.  This
was not the case for these experiments, and as a consequence the data
cannot be pooled across the two sites.

Pooling of results by site for statistical analysis is generally
preferable if the other experimental design aspects are the same, which
appears to be the case with the reported studies.  The main advantage of
a  pooled analysis versus   marginal analyses  for each site is
two-fold: 1) by doubling the sample size for the analysis, you increase
the statistical efficiency by a factor of 1.41 in the point estimation
of the CPT exactly or in the analysis of variance approximately (as you
lose one degree of freedom for site effect) and 2) you can assess the
effect of repellent more accurately by accounting for the potential
effect of site difference in mosquito pressure.  However, this assumes
that the data from two sites are independent, which is again obviously
not the case.  There are three subjects (40, 18 and 62) used in both
sites with LipoDEET 302, two subjects (53 and 46) used in both sites
with Ultrathon, and three subjects (40, 8 and 63) used in both sites
with Duranon.

HSRB Consensus and Rationale

While the Board concluded that the participation of several subjects on
the day after they had been treated with a different test repellant was
not ideal and there were errors (i.e. choice of test limb) in the study,
this did not affect the validity of the results.

However with only 33 subjects for 80 data points (excluding the negative
controls), the overlap  of some of the same subjects for different test
materials, for Sites 1 and 2, and for different dates of the experiment
without proper experimental design and control, the Board concluded that
it is impossible to interpret the reported data adequately thus
rendering scientific validity of the results into question.  In
addition, the study may not have been sufficiently sound to estimate
within  population variances.

Thus, the Board concluded that the study was not sufficiently sound,
from a scientific perspective, to be used to assess the repellent
efficacy of the formulations tested against mosquitoes.

Charge to Board

2.  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?  Please comment specifically on:

a.	The decision to use a different test formulation in place of one of
the test materials described in the protocol reviewed by the IRB, EPA
and the HSRB.

b.	How to assess the ethical conduct of an insect repellency study
involving multiple test formulations when there is an ethical deficiency
in the conduct of the study with respect to one of the test
formulations.  If the ethical deficiency warrants not relying on the
results of the testing with regard to one test formulation, under what
circumstances (if any) does the ethical deficiency affect the
acceptability of the results from testing the other formulations?

Board Response

Brief Overview of the Study

The basic protocol for these studies (SCI-001) was initially reviewed at
the January 2007 meeting of the HSRB, at which time the Board concluded
that the study would meet the requirements established in the
Environmental Protection Agency’s final human studies rule (40 CFR
Part 26) pending minor revision.  In particular, the Board was concerned
about several matters relevant to subject recruitment and the overall
conduct of the study.  For example, the protocol did not describe how
untreated controls would be recruited, but instead implied that controls
will be recruited in the same manner as subjects in the “exposure”
arm—via “word-of-mouth” and a Volunteer Data Base maintained by
the Principal Investigator.  The Board recommended that the protocol
clarify how untreated controls will be recruited, and that the IRB of
record (Independent Investigational Review Board [IIRB], Inc. of
Plantation, FL) review any materials used for recruiting purposes,
including any telephone scripts fliers, emails, letters, or local ads.
The Board also felt that the risks associated with DEET exposure during
the course of the study are mischaracterized, and that the
informed-consent document was also structured in a manner that did not
apply to unexposed control subjects.  In light of these deficiencies,
the Board recommended that the informed-consent document be redesigned
and re-reviewed by IIRB (EPA HSRB 2007a).

Subsequent to the aforementioned meeting of the HSRB, the informed
consent documents were revised in accordance with Board and EPA
recommendations, submitted to IIRB for re-review, and approved (Carley,
2007). It is unclear, however, whether the protocol was also revised in
accordance with the Board and EPA recommendations, and submitted to the
IIRB for review.

The documents provided by Carroll-Loye (Carroll, 2007a; Carroll, 2007b;
Carroll, 2007c) specifically state that each 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).  Each study was also
reviewed and approved by a commercial human subjects review committee,
IIRB.  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 Agency, each completed study consists of two
interdependent analyses: 1) a dosimetry study designed to determine the
amount of an insect-repelling compound (30% or 34% DEET in liposomal
capsules, or 20% DEET in protein capsules) that typical users would
typically apply when provided with a lotion formulations; and 2) an
efficacy study designed to measure the effectiveness of each compound as
a mosquito repellent.  For each dosimetry and efficacy studies,
commercially available and obtained 3M Ultrathon (34.34% polymerized
DEET) was used as a comparator.  Ultrathon is the principal insect
repellent used by American military forces and is considered to be one
of the most effective insect repellents available.

Dosimetry and efficacy studies for personal insect repellents containing
LipoDEET 302 and 3434 (30% and 34% DEET in liposomal capsules,
respectively) and Duranon (20% DEET in protein capsules) were conducted
from July 3 through August 2, 2007 (Carroll 2007a; Carroll 2007b;
Carroll 2007c).  All studies (one using each test compound) were
performed simultaneously at a laboratory site in Davis, California, and
at field sites in Butte and Glenn Counties, California, by researchers
at Carroll-Loye Biological Research.  The study sponsor was Scientific
Coordination, Inc., of Rockville, Maryland.  The studies were conducted
using products from two manufacturers:  LipoDEET 302 and 3434 was
manufactured and supplied by DermAegis, Inc. of Rockford, Illinois;
Duranon was manufactured and supplied by Sawyer Products of Safety
Harbor, Florida.  It is important to note, however, that the protocol
originally reviewed and approved at the January 2007 HSRB meeting listed
a different set of test compounds; at the sponsor’s request
Carroll-Loye Biological Research changed one of the test compounds from
Insect Guard II (EPA Reg. No. 54287-8) to LipoDEET 3434 (an unregistered
compound) at the sponsor’s request.

Dosimetry was determined by direct measurement of compound application.
The efficacy of each as a mosquito repellent was determined by measuring
the ability of the formulations to prevent mosquito landings (defined as
“Lite with Intent to Bite”; LIBe) under field conditions.
Mosquitoes were aspirated mechanically prior to biting; prior to
initiation of the efficacy study, all volunteers will be trained both to
recognize a mosquito landing with the intent to bite and to remove such
mosquitoes with an aspirator 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
strengths and weaknesses of each study design are described above.

The dosimetry study enrolled a total of 10 individuals, each of who
tested all four formulations (the three test compounds and the
comparator).  Each efficacy study enrolled 10 subjects for each
formulation at each of the two field sites.  Many volunteers
participated in multiple analytic phases.  For example, six of the 10
participants in the dosimetry study also participated in one or more of
the field tests.  In total, 39 volunteers participated in at least one
analytic phase of SCI-001.1, SCI-001.2 or SCI-001.3.  Fifteen of these
volunteers also participated in the dosimetry and/or efficacy phase of
Carroll-Loye study WPC-001 described below.  In addition to these 41
volunteers, two controls (described as “experienced personnel” and
who were untreated with repellent) also participated to determine
ambient LIBe pressure at field site. On any given day at a field site,
the same pair of participants served as controls for SCI-001.1,
SCI-001.2, SCI-001.3 and the concurrently run WPC-001 study.  Five
individuals served (repeatedly) as controls during each of the six field
tests; two also participated in the repellent efficacy tests, to give a
cumulative total of 45 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

The Board concurred with the factual observations of the ethical
strengths and weaknesses of the study, as detailed in the EPA’s
Science and Ethics Review (Carley, 2007).  The risks to study
participants, in general, were minimal and were justified by the likely
societal benefits, including data on the efficacy of these new
formulations (30% or 34% DEET in liposomal capsules, or 20% DEET in
protein capsules) as personal insect repellents.  Higher concentrations
of DEET are commercially available and have been used as repellents for
years; the subjects enrolled in this study were thus 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 will 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 will be exposed to illnesses
like WNV, the study protocol called for field tests of repellent
efficacy to be conducted only in areas where known vector-borne diseases
have not been detected by county and state health or vector/mosquito
control agencies for at least one month.  Mosquitoes collected during
the field studies also were subjected to serologic or molecular analyses
to confirm that they were free of known pathogens.  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.

Regrettably, several serious protocol deviations occurred during the
conduct of these studies. Most notably, due to the study
investigator’s failure to obtain IRB approval for fundamental changes
to one of the study protocols, the research described in SCI-001.1,
SCI-001.2 and SCI-001.3 does not comport with the applicable
requirements of 40 CFR Part 26, subparts K and L.

First, as mentioned previously, many study volunteers participated in
multiple analytic phases of SCI-001.1, SCI-001.2 and SCI-001.3, testing
the field efficacy of different insect repellents on different days.
Many volunteers participated in field trials conducted on consecutive
days, and were re-randomized to receive the same or a different test
compound each time.  The approved protocol, however, includes clear
criteria excluding any participant who “[used an] insect repellent
within one day preceding the study” (c.f., Carroll, 2007a; Carroll,
2007b; Carroll, 2007c).  This change is unlikely to have increased the
risks to study participants, but several Board members nevertheless
raised the concern that compromising these exclusion criteria may
adversely affect the scientific validity of the study data (as described
above).  The decision to disregard previously established exclusion
criteria was also made without submitting the protocol for approval or
informing study participants of this change, and may represent a
departure from accepted review and approval practices.  There was some
disagreement among Board members, however, as to whether the phrase
“one day preceding the study” specifically excluded participants who
had used or been exposed to an insect repellent on the day preceding a
field trial, or simply prior to consent and enrollment in the study
overall.  Dr. Carroll submitted a response to the EPA that implied the
former (Carroll, 2007d), but the Board nevertheless recognized the
uncertainty surrounding this issue.

Second, to minimize the risk that study participants will be exposed to
arthropod-borne illnesses like WNV, for example, during its review of
another Carroll-Loye protocol at the April 2007 HSRB meeting (EPA HSRB,
2007b) the Board recommended conducting serologic or molecular analyses
to confirm that mosquitoes collected during the field studies were free
of known pathogens.  Study investigators did conduct such analyses in
the context of these studies, but did so without submitting the protocol
for approval or informing study participants of these analyses in the
informed consent document.  Although this change is likely to have
actually reduced the risks faced by study participants, it is
nevertheless a substantial departure from accepted review and approval
practices.

Finally, and most seriously, at the sponsor’s request Carroll-Loye
Biological Research changed one of the test compounds from Insect Guard
II (EPA Reg. No. 54287-8) to LipoDEET 3434 (an unregistered compound)
without IRB or HSRB review or approval.  Dr. Carroll has justified the
decision to substitute a test material by stating that, in conversations
that he has previously had with the IRB and the California EPA, that IRB
review and approval is needed only for “proposed changes … that are
likely to increase risk to participants” (Carroll 2007d, 3).  Because
the substituted material (LipoDEET 3434) was nearly identical to another
compound approved for testing (LipoDEET 302), and contained a
concentration of DEET considerably less than that in already approved
and marketed personal insect repellents, Dr. Carroll felt that the
substitution posed no increase in risk to study participants and fell
within the “latitude” given to study investigators with respect to
minor protocol changes.  The Board disagreed, feeling that a change of
test materials was not simply a minor protocol change; although it is
unlikely that study participants were subjected to greater risk, the
substitution of LipoDEET 3434 for Insect Guard II was a protocol change
of sufficient magnitude to warrant IRB notification and review.  More
importantly, the failure to seek IRB review and approval is a
significant and serious departure from accepted review and approval
practices, as well as a violation of the letter and intent of the
Agency’s Final Human Studies Rule.

Federal guidelines from the Office of Human Research Protections (OHRP)
clearly state that all proposed protocol changes must be reviewed by the
IRB of record at convened meetings, in accordance with HHS regulations
at 45 CFR 46.108(b), although institutions may adopt policies describing
the types of minor changes in previously approved research that can be
approved under an expedited review procedure in accordance with HHS
regulations at 45 CFR 46.110(b)(2).  Except in cases when necessary to
prevent imminent harm to study participants, an investigator should
never institute a protocol change without IRB review.  Federal
regulations regarding review and approval of human subjects research,
for example, explicitly prohibit investigators from implementing any
protocol changes without prior IRB approval unless such changes are
necessary to prevent immediate, serious harm to study participants.  It
is never an investigator’s prerogative to determine which protocol
changes warrant IRB review and which do not; only the IRB (or some
authority other than the investigator) has that authority.

The failure of Carroll-Loye Biological Research to 1) obtain IRB
approval of the revised protocol; and 2) report these protocol
deviations to the Independent Investigational Review Board in a timely
manner are serious regulatory breaches.  The failure of Dr. Carroll to
notify the EPA and the HSRB of protocol deviations such as the
substitution of LipoDEET 3434 for Insect Guard II in submitted study
documents for studies SCI-001.1 and SCI-001.3 is also troubling.  The
Board recommended the 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.

Because of the serious nature of these deviations, the research
described in SCI-001.2 using the unapproved pesticide formulation failed
to comport with the applicable requirements of 40 CFR Part 26, subparts
K and L, and the Board recommended that the Agency not accept for
regulatory decision-making purposes any of the data obtained during the
conduct of that particular study.  Furthermore, this particular ethical
deficiency also affects the acceptability of the results from testing
the other two formulations. SCI-001.1, SCI-001.2 and SCI-001.3 were run
concurrently, and study participants enrolled in all three studies ran
the risk of being randomized to receive treatment with the unapproved
investigational compound, LipoDEET 3434.  It is thus impossible to
separate the data collected in SCI-001.1 and SCI-001.3 from that
collected in SCI-001.2, and the Board recommended that the Agency not
utilize any the data obtained during the conduct of these three studies.

HSRB Consensus and Rationale

Based on a careful review of the study documents provided, the Board
concluded that the research was conducted in a manner that failed to
meet the applicable requirements of §40 CFR 26, subparts K and L.  The
study investigator failed to obtain IRB approval for fundamental changes
to one of the study protocols and, as a result, the data collected from
these three concurrently run studies cannot be used by the Agency for
regulatory decision-making purposes.

E.  Completed Insect Repellent Efficacy Study with Oil of Lemon
Eucalyptus (WPC-001)

Charge to the Board

1.  Is the research conducted under WPC-001 sufficiently sound, from a
scientific perspective, to be used to assess the repellent efficacy of
the formulation tested against mosquitoes?  Please comment specifically
on whether participation in field testing by several subjects on the day
after they had been treated with a different test repellent is likely to
have affected the validity of the results for those subjects on those
days.

Board Response

The active ingredient Oil of Lemon Eucalyptus (OLE) formulated as a pump
spray was tested for its ability to repel mosquitoes from the legs of
volunteers by a study presented by Carroll-Loye.  All experiments were
conducted using GLP. This study was conducted similarly to and in
conjunction with the DEET efficacy studies of SCI-001, and the
descriptions of the experimental conditions and design of SCI-001,
above, are appropriate for this study and will not be repeated here.

The test product had 30% OLE in a pump spray. Seven females and three
males were tested at Site 1, 3 females and 7 males at Site 2.  It
yielded a CPT of 6.1 ± 1.5 hr in Site 1 and 4.2 ± 0.8 hr in Site 2.

As was discussed for the SCI-001 study, the experiment was conducted
according to the approved protocol with some deviations, with the most
serious being the lack of at least a one day wait for some of the
subjects before they were tested with another product.  The Board’s
analysis of this deviation and design of this experiment was discussed
above for SCI-001, and is pertinent to this experiment also and will not
be repeated here.

	The science assessment of WPC-001 was the same as that for SCI-001.
However, unlike SCI-001 the residual effects of successive days of
testing were unlikely to have had an effect (CPTs were shorter) and the
data therefore are useable.  Treatment of subjects on successive days is
not intellectually satisfying, but it was unlikely to have a significant
effect.

HSRB Consensus and Rationale

The Board concluded that despite problems estimating variability and
some of the same design problems found in study SCI-001, the
Carroll-Loye study WPC-001 assessing the repellent efficacy of the
formulation tested was sufficiently sound for the purposes for which it
was intended.

Charge to Board

2.  Does available information support a determination that the research
covered by WPC-001 was conducted in substantial compliance with subparts
K and L of EPA regulations at 40 CFR part 26?  If the conduct of any
part of SCI-001 is deemed not to substantially comply with the
requirements of subparts K and L, please comment specifically on how to
assess the ethical conduct of research conducted under WPC-001 in light
of the fact that it was conducted at the same times and at the same
places as the research covered under protocol SCI-001.

Brief Overview of the Study

The protocol for this study was initially reviewed at the April 2007
meeting of the Human Studies Review Board, at which time the Board
concluded that the study would meet the requirements established in the
Environmental Protection Agency’s final human studies rule (40 CFR
Part 26) pending minor revision.  In particular, the Board was concerned
about several matters relevant to subject recruitment and the overall
conduct of the study.  To minimize the risk that study participants
would be exposed to arthropod-borne illness, for example, the Board
recommended that investigators trap landing mosquitoes or other vectors
for pooled serologic or nucleic acid-based testing and alert research
participants if they had been inadvertently exposed to vector-borne
pathogens.  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.
Finally, the Board raised questions about the informed consent
procedures for control subjects, suggesting that the informed consent
procedures should be modified to more clearly explain the risks to
control (untreated) research subjects.  In light of these deficiencies,
the Board recommended that the protocol and informed-consent document be
revised and submitted to re-review by IIRB (EPA HSRB, 2007b).  The
protocol and informed consent documents subsequently were revised in
accordance with Board and EPA recommendations, submitted to IIRB for
re-review, and approved (Carley, 2007).

The documents provided by Carroll-Loye (Carroll, 2007e) specifically
state that each 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).
 Each study was also reviewed and approved by a commercial human
subjects review committee, IIRB.  Documentation provided to the EPA by
IIRB indicated that it reviewed these studies pursuant to the standards
of the Common Rule (45 CFR Part 46, Subpart A) and determined them to be
in compliance with that Rule.

As submitted to the EPA, the completed study consists of two
interdependent analyses: 1) a dosimetry study designed to determine the
amount of oil of lemon eucalyptus-based personal insect repellent that
typical users would typically apply when provided with a pump spray
formulation; and 2) an efficacy study designed to measure the
effectiveness of the pump spray formulation as a mosquito repellent.
The dosimetry and efficacy studies were conducted from July 10 through
August 1, 2007 (Carroll, 2007e).  The studies were performed
simultaneously at a laboratory site in Davis, California, and at field
sites in Butte and Glenn Counties, California, by researchers at
Carroll-Loye Biological Research.  The study sponsor was WPC Brands,
Inc. of Bridgeton, Missouri.  The studies were conducted using product
manufactured and supplied by ChemRite CoPac, Inc. of Lannon, Wisconsin.

Dosimetry was determined by direct measurement of compound application.
The efficacy of each as a mosquito repellent was determined by measuring
the ability of the formulations to prevent mosquito landings (defined as
“Lite with Intent to Bite”; LIBe) under field conditions.
Mosquitoes were aspirated mechanically prior to biting; prior to
initiation of the efficacy study, all volunteers were  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
strengths and weaknesses of each study design are described above.

The dosimetry study enrolled a total of 10 individuals.  Each efficacy
study enrolled 10 subjects at each of the two field sites.  Many
volunteers participated in multiple analytic phases. For example, six of
the 10 participants in the dosimetry study also participated in one of
the field tests.  In total, 23 volunteers participated in at least one
analytic phase of WPC-001. Fifteen of these volunteers also participated
in the dosimetry and/or efficacy phase of Carroll-Loye studies
SCI-001.1, SCI-001.2 or SCI-001.3 described previously (Carroll, 2007a;
Carroll, 2007b; Carroll, 2007c).  In addition to these 23 volunteers,
four controls (described as “experienced personnel” and who were
untreated with repellent) also participated to determine ambient LIBe
pressure at field sites.  On any given day at a field site, the same
pair of participants served as controls for WPC-001 and the
concurrently-run SCI-001.1, SCI-001.2, and SCI-001.3 studies.  Three
individuals served (repeatedly) as controls during each of the three
field tests; all three also participated in the repellent efficacy
tests, 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

The Board concurred with the factual observations of the ethical
strengths and weaknesses of the study, as detailed in the EPA’s
Science and Ethics Review (Carley, 2007). In general, the research
described in WPC-001 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 this formulation as a personal insect repellent.  Based
on toxicological data currently available, the subjects 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 will be exposed
to illnesses like WNV, the study protocol called for field tests of
repellent efficacy to be conducted only in areas where known
vector-borne diseases have not been detected by county and state health
or vector/mosquito control agencies for at least one month.  Mosquitoes
collected during the field studies also were subjected to serologic or
molecular analyses to confirm that they were free of known pathogens.
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 a majority of the Board concluded that research described in
WCP-001 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.  In particular, as noted in the EPA’s review of
these studies, several significant protocol deviations occurred.

As discussed in greater detail in the Board’s review of Carroll-Loye
studies SCI-001.1, SCI-001.2 and SCI-001.3, for example, some members
were concerned that the study investigator failed to obtain IRB approval
for significant changes to the study protocol.  Many of the study
volunteers participated in multiple analytic phases of WPC-001 (as well
as phases of SCI-001.1, SCI-001.2 and SCI-001.3), participating in field
trials conducted on consecutive days and being re-randomized to receive
the same or a different test compound each time.  The approved protocol,
however, includes clear criteria excluding any participant who “[used
an] insect repellent within one day preceding the study” (c.f.,
Carroll, 2007e).  As mentioned previously, however, there was
substantial disagreement among Board members as to whether this
constitutes a deviation 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; and 2) report these
protocol deviations to IIRB in a timely manner are serious regulatory
breaches.  The Board recommends the 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.

Although the research conducted under WPC-001 was conducted at the same
times and at the same places as the research covered under protocol
SCI-001, there is no evidence that study participants enrolled in this
study ran the same risk of being randomized to receive treatment with an
unapproved investigational compound as participants in SCI-001.1,
SCI-001.2 and SCI-001.3.  A majority of the Board thus concluded that
there was no clear and convincing evidence that the conduct of study
WPC-001 was fundamentally unethical, and concluded that the research
described therein meets the applicable requirements of §40 CFR 26,
subparts K and L.  A significant minority of the Board, however, argued
that the Agency should not utilize any data obtained during the conduct
of this study; these Board members concluded that the study
investigator’s repeated failure in this and other studies to obtain
IRB approval for significant protocol changes or to report study changes
and protocol deviations to the IRB, created an unprecedented pattern of
departure from accepted review and approval practices that could have
study participants at increased risk or significantly impaired the
informed consent process.

HSRB Consensus and Rationale

The Board agreed that the investigator’s failure to report changes to
the IIRB were ethical violations. However while a majority of the Board
agreed that these violations did not rise to the level of substantial
noncompliance, some Board members believed it did meet that level.  Thus
a majority of the Board concurred with the initial assessment of the
Agency that the study submitted for review by the Board meets the
applicable requirements of §40 CFR 26, subparts K and L.

F(1).  Proposed Carroll-Loye Picaridin Insect Repellent Efficacy Studies
(SPC-001)

Charge to the Board

1.  If the proposed research described in Protocol SPC-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

The active ingredient Picaridin in three formulations will be tested in
the field for its ability to repel mosquitoes by the Carroll-Loye
company.  The active ingredient will be formulated into 1) a 7% pump
spray that will also be used for a 10% pump spray, an aerosol and a
5.75% towelette; 2) a 15% pump spray that will also be used for a 15%
aerosol and a 12% towelette; and 3) a 15% lotion that will also contain
a sunscreen.  All experiments will be conducted using GLP.  A dosimetry
experiment with 10 individuals will be performed to determine the amount
of product that would be utilized by people using the product as
directed.  The experiment will be a field study.  Two locations in
California would be used.

Legs and/or arms will be tested.  There will be two experienced persons
serving as negative controls (i.e., without any repellent product) to
confirm mosquito biting/landing pressure. Experimental subjects, in
pairs, will monitor LIBe’s during a one minute interval each 15
minute, until the First Confirmed LIBe (FCLIBe) can be determined.
Stopping rules will be employed. The Complete Protection Time (CPT) will
be determined.

With respect to the pertinent science criteria established earlier by
the HSRB for completed studies:

The scientific question was stated (i.e., to test the efficacy of
Picaridin in several formulations to repel mosquitoes).

Because existing data were not adequate to answer the question of
efficacy, new studies involving human subjects are necessary.

The potential benefits of the study are 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.

The risks are minimal because the active ingredient is of very low
toxicity, the other formulation ingredients are of very low toxicity,
the mosquitoes will be aspirated before they have an opportunity to
bite, and the regions selected will not have evidence of West Nile or
encephalitis viruses.

Deficiencies related to information about the lotion formulation have
been addressed.

Study Design Criteria

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

There are specific objectives (i.e., to determine the CPT that Picaridin
in three formulations displays as a mosquito repellent).

The sample size will be 10 individuals per product along with 2
experienced individuals to confirm mosquito biting pressure.  A
dosimetry experiment prior to the field experiment will quantify the
amount of repellent being used.

The Board had some concern that with respect to data interpretation, a
stronger solution would be used to estimate CPT for the lower
concentration towelettes.  However, it was explained during the meeting
that the concentration quoted for the towelette also included the weight
of the fabric, and the picaridin solution was identical to the spray.

There was also insufficient information regarding relevant
environmental, mosquito and subject factors that might contribute to
variability.

Participation Criteria:

The participants will be representative of a subset  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.

Measurement Criteria

There was concern about using data from the tested products to
extrapolate for other products.  Extrapolating information from the
7-percent pump spray to a 10-percent pump spray formulation is
acceptable, however there are problems with extrapolating from the
7-percent pump spray to the 5.75-percent towelette because the towelette
may not administer the same dose. On the other hand, if the dosimetry
phase demonstrates the towelette administers approximately the same
dose, extrapolation would be acceptable. Quality assurance will be a
part of the experimental plan.  If the products will not be compared,
randomization is less of an issue if the experiments can be performed on
separate days, however randomization and allocation of subjects to
treatments needs to be fully specified.

There were also statistical concerns that data generated would not be
appropriately analyzed, especially as it related to the assignment of
subjects to conditions.

The measurements will be accurate and reliable.

The measurements will be appropriate to the question being asked.

Quality assurance will be a part of the experimental plan.

Laboratory and Field Conditions

Laboratory experiments are not proposed, except for the dosimetry

Field experiments will be appropriate.

The study will include a stop rule plan, medical management plan, and a
safety monitor.

	HSRB Consensus and Rationale

While the Board agreed that the study rationale, formulations to be
tested and data collection procedures were scientifically sound, the
protocol did not adequately explain the relationship between the study
design and analytic plan nor did it include an appropriate statistical
analysis plan (including estimation of variability) that could be
evaluated for its validity or utility.  There was also insufficient
information regarding relevant environmental, mosquito and subject
factors that might contribute to variability. Thus, the Board concluded
that the proposed research does not appear likely to generate
scientifically reliable data, useful for assessing the efficacy of the
test substance for repelling mosquitoes.

Charge to the Board

b. If the proposed research described in Protocol SPC-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

Brief Overview of the Study

The research is to be conducted by Carroll-Loye Biological Research, a
private laboratory in Davis, California by using healthy volunteers and
a controlled environment. The study sponsor is Spectrum Brands, Inc. of
Bridgeton, Missouri, a division of United Industries Corporation.  The
study protocol was reviewed and approved by a commercial human subjects
review committee, IIRB of Plantation, Florida. Minutes of IIRB meetings
were provided to the EPA as a separate document, and documentation
previously provided to the EPA by IIRB indicates that it reviewed this
protocol pursuant to the standards of the Common Rule (45 CFR Part 46,
Subpart A).

The research protocol submitted consisted of two interdependent studies:
1) a dosimetry study designed to determine the amount of an
insect-repelling compound, known as picaridin, that normal subjects
would typically apply when provided with one of three compound
formulations (7% Picardin Pump Spray [data will be bridged to 10% Pump
Spray and Aerosol and 5.75% Towelette],15% Picaridin Pump Spray [data
will be bridged to 15% Aerosol and 12% Towelette], and 15% Picaridin
Lotion formulated with sunscreen); and 2) an efficacy study designed to
measure the effectiveness of picaridin as a mosquito repellent.
Dosimetry will be determined either by passive patch dosimetry (spray
formulations) or by direct measurement of compound application (lotion
formulation).  The efficacy of each formulation as a mosquito repellent
will be determined by measuring the ability of the formulations to
prevent mosquito landings (defined as “Lite with Intent to Bite”;
LIBe) under field conditions. Mosquitoes will be 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 will work in pairs to
facilitate identification and aspiration of LIBing mosquitoes during
brief exposure periods.  The strengths and weaknesses of each study
design are described above.

The dosimetry study will enroll a total of 10 subjects, each of whom
will test all three formulations.  The efficacy study will enroll 10
subjects per test formulation per field site, for a total of 30
subjects. Efficacy will be tested independently at two different sites,
representing two different environments.  Two controls (described as
“experienced personnel” and who were untreated with repellent) also
participated to determine ambient LIBe pressure at each field site,
giving a cumulative total of 28 volunteers.  Subjects may participate in
either or both studies, making the total number of volunteers enrolled
no less than 32 but no greater than 74.  In addition, three alternate
subjects will be enrolled to: 1) replace any subject who withdraws from
participating; and 2) protect the confidentiality of any subject
excluded from the study as a result of pregnancy or other potentially
stigmatizing condition, as described below.

Critique

The Board concurred with the factual observations of the strengths and
weaknesses of the study, as detailed in the EPA’s Science and Ethics
Review (Carley and Sweeney, 2007a). The proposed research described in
Protocol SPC-001 comports with the applicable requirements of 40 CFR
Part 26, subparts K and L.

The risks to study participants are minimal and justified by the likely
societal benefits, including data on the efficacy of picaridin as a
mosquito repellent. The risks to study participants are three-fold: 1)
reaction to test materials themselves; 2) exposure to biting arthropods;
and 3) possible exposure to arthropod-borne diseases.

The active ingredient of these three repellent formulations is
commercially available and is present at similar concentrations in other
EPA-registered products; specifically, picaridin is registered and
marketed as an insect repellent in the United States under the
registered trade name BayrepelTM and the brand name Autan.  As
volunteers with known allergic reactions to insect repellents and common
cosmetics are excluded from participating in this study, enrolled
participants are unlikely to be at increased risk of experiencing
adverse side effects upon exposure.  Clear stopping rules also have been
developed, as have plans for the medical management of any side effects
or adverse events associated with product 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 will bite.  All
volunteers will be trained both to recognize LIBe’s and to remove such
mosquitoes with an aspirator prior to biting. Risk of bites is further
minimized through the use of clear stopping rules, limited exposure
periods, and paired observation.

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

Finally, the study protocol also includes several mechanisms designed to
minimize coercive recruitment and enrollment, compensation does not
appear to be so high as to unduly influence participation, and minors
and pregnant or lactating women are 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).  In reviewing similar protocols submitted
by Carroll-Loye Biological Research at previous HSRB meetings, for
example, the Board has expressed concern about the potentially coercive
nature of study subject recruitment.  Although the study is to be
conducted by Carroll-Loye Biological Research, a private research
laboratory in Davis, California, the Principal Investigator of the study
and Co-Owner of the research laboratory, Dr. Scott P. Carroll, also is
an adjunct faculty member of the Department of Entomology at the
University of California, Davis.  As the majority of research
participants will be recruited from the University’s student
population, including from Dr. Carroll’s own department, the Board
previously recommended that the protocol and consent documents be
altered to define clearly the mechanisms in place to prevent coercion.
The current protocol includes several mechanisms, including the
exclusion of any student or employee the Study Director, a substantial
waiting period between recruitment and study enrollment, and an
interview by Dr. Carroll, designed to minimize coercive subject
recruitment and enrollment.

In accordance with the EPA’s final human studies rule, 40 CFR §§
26.1701-1704,  minors and pregnant women are explicitly excluded from
participation, the latter being confirmed by requiring all female
volunteers to undergo a self-administered over-the-counter pregnancy
test on the day of the study.  In reviewing previous protocols, the
Board has previously raised concerns about the potentially stigmatizing
nature of a positive test, and recommended that investigators develop
additional protections to ensure that the results of over-the-counter
pregnancy tests would be kept private.  The use of so-called
“alternate” subjects is one such safeguard; that study participants
may be designated as alternate subjects and automatically excluded from
participation allows for potentially pregnant volunteers to withdraw
without compromising their confidentiality.

HSRB Consensus and Rationale

The Board concurred with the initial assessment of the Agency that the
revised protocol submitted for review by the Board meets the applicable
requirements of §40 CFR 26, subparts K and L.

F(2).  Proposed Carroll-Loye Picaridin Insect Repellent Efficacy Studies
(SPC-002)

Charge to Board

1.  If the proposed research described in Protocol SPC-002 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 ticks?

Board Response

The active ingredient Picaridin in three formulations will be tested in
the laboratory for its ability to repel ticks by the Carroll-Loye
company. The active ingredient will be formulated into 1) a 7% pump
spray that will also be used for a 10% pump spray, an aerosol and a
5.75% towelette; 2) a 15% pump spray that will also be used for a 15%
aerosol and a 12% towelette; and 3) a 15% lotion that will also contain
a sunscreen. These are the same formulations as would be tested in
protocol SPC-001 (to test repellency against mosquitoes). All
experiments will be conducted using GLP..  A dosimetry experiment with
10 individuals will be performed to determine the amount of product that
would be utilized by people using the product as directed; this amount
will be applied by technicians to the subjects in the experiment.
Subjects will be trained in the procedures.  One of each subject’s
arms will serve as a negative control to validate each experimental tick
for its questing behavior.

Ticks will be laboratory reared American dog ticks (Dermacentor
variabilis) and deer ticks (Ixodes scapularis).  Because these are
laboratory reared, the ticks are anticipated to be disease-free.

This protocol is very similar to protocols on tick repellency submitted
by this investigator in the past, using the metric of repellency from
the treated area on the arms of the subjects during a 3 minute
observation period during each 15 minutes of the test.  The Complete
Protection Time from the First Confirmed Crossing will be calculated.

With respect to the pertinent science criteria established earlier by
the HSRB for completed studies:

The scientific question was stated (i.e., to test the efficacy of
Picaridin in several formulations to repel ticks).

Because existing data were not adequate to answer the question of
efficacy, new studies involving human subjects are necessary.

The potential benefits of the study are 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 will be determined in carefully designed laboratory
experiments.

The risks are minimal because the active ingredient is of very low
toxicity, the other formulation ingredients are of very low toxicity,
the ticks should be removed before they have an opportunity to bite, and
the laboratory reared ticks will not possess any diseases.

Study Design Criteria

The purpose of the study is clearly defined (i.e., efficacy testing for
tick repellency).

There are specific objectives (i.e., to determine the Complete
Protection Time that Picaridin in three formulations displays as a tick
repellent).

The sample size will be 10 individuals per product. A dosimetry
experiment prior to the field experiment will quantify the amount of
repellent being used.

It is anticipated that the findings from this study can be generalized
beyond the study sample.

Participation Criteria

The participants will be representative of some of the population of
concern, but are not representative of the entire population, as
acknowledged by the Investigator; however, since it would either be
unethical to test them or would be less appropriate to test them, the
participating population is considered appropriate and reasonable.

Measurement Criteria

The measurements of tick crossing will be accurate and reliable.

The measurements will be appropriate to the question being asked.

Quality assurance will be a part of the experimental plan.

Laboratory and Field Conditions

Laboratory experiments are proposed.

Field experiments are not proposed.

The EPA science review did not identify any questions or concerns that
needed to be addressed by the HSRB. As was true for protocol SPC-001,
the Board had some concern that, with respect to data interpretation, a
more concentrated product appeared to be proposed to estimate CPT for
the lower concentration towelettes.  However, it was explained during
the meeting that the concentration quoted for the towelette also
included the weight of the fabric, and the Picaridin solution was
identical to the spray.

There were a number of concerns from a statistical perspective. The
protocol states in section 8.3.1 that “[s]ubjects will be assigned to
the treatment groups on the basis of a randomly assigned subject
number,” 1-10 to Lotion, 11-20 to 7% Pump, and 21-30 15% Pump.
However, it also states in section 8.3.2 that “individual subjects may
test more than one repellent, on separate days.”  These two statements
are inconsistent as the former statement implies 30 distinct and unique
subjects, whereas the latter implies an overlap, which may render the
statistical interpretation of the data very difficult, depending on how
the experiment is carried out.  If there is going to an overlap of
subjects among test groups, an appropriate experimental design needs be
employed to allow proper statistical inference.  It is also unclear what
is meant by the sentence “The experiment will be partially randomized
by subjects” in section 8.2 on experimental design.

As for the method of analysis, the statement that “Kaplan-Meier
analyses provide median estimates with substantially reduced error
estimates” is incorrect as it can go either way.  One cannot make a
direct comparison between the median and its 95% confidence interval
based on the Kaplan-Meier estimate of survival function and the mean and
the 95% confidence interval based on the normal theory.  Also the
statement that the median based on Kaplan-Meier method is “less
sensitive to data censoring” is incorrect.

Complete Protection Time defined as the mean time across all treated
subjects from application of the repellent to the First Confirmed
Crossing cannot be estimated due to censoring; neither can the standard
deviation or the confidence interval be accurately calculated.  The more
appropriate statistic in the presence of censoring is the median and the
confidence interval based on the Kaplan-Meier estimate of the survival
distribution for the time to efficacy failure.

The Board disagreed with the EPA’s assessment on compliance with
applicable scientific standards on the following items:

Quantification of efficacy of the test materials is inappropriate as the
normality assumption is inadequate and due to potential censoring.

Discussion of the statistical power is irrelevant as there is no
statistical test of hypotheses is involved.

Justification of the sample size for the repellency phase is not
scientific and thus inadequate.

The Carroll-Loye Protocol SPC-002 7/10/07 document contained the Site
Questionnaire (pp 63-66 of 70) and the Study Specific Instructions (p 67
of 70) for SPC-001, which must be in error, as they refer to mosquitoes,
instead of ticks. There appears to be discrepancies in the Material
Safety Data Sheets (MSDS) in the above document: On pp 59 and 61 the EPA
Registration Number is identical (121-92), but Product Item Numbers are
different (53667 on p 59 and 53661 on p 61) for the identical
formulation. There did not seem to be a MSDS included for the
formulation with sunscreen.

The IRB is universally understood as an acronym for “Institutional
Review Board.”  Therefore, reference to “Independent Investigational
Review Board” as “Independent IRB” is inappropriate and
misleading.

HSRB Consensus and Rationale

The Board concluded that the research appears likely to generate
scientifically reliable data, useful for assessing the efficacy of the
test substances for repelling ticks, provided that the revisions
suggested by EPA are incorporated and that the experimental design is
made more specific to the allocation of the test substances into three
groups of subjects and that there is no overlap of subjects from one
test group to the other, if the data are intended to be compared among
test substances.

The Board urges EPA to consider the design of newer studies and the
designs already used for existing products to make certain that labels
reflect information of comparative value to consumers.  If there are
currently inconsistencies in the information used to authorize label
information on efficacy, the Board urges EPA to develop new guidelines
or revisions to the current guidelines that will balance accuracy of
data collected, safety to human subjects and consistency in the ultimate
labels produced.

Charge to Board

2.  If the proposed research described in Protocol SPC-002 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

Brief Overview of the Study

The research is to be conducted by Carroll-Loye Biological Research, a
private laboratory in Davis, California by using healthy volunteers and
a controlled environment.  The study sponsor is Spectrum Brands, Inc. of
Bridgeton, Missouri, a division of United Industries Corporation.  The
study protocol was reviewed and approved by a commercial human subjects
review committee, Independent Investigational Review Board, Inc. (IIRB)
of Plantation, Florida. Minutes of IIRB meetings were provided to the
EPA as a separate document, and documentation previously provided to the
EPA by IIRB indicates that it reviewed this protocol pursuant to the
standards of the Common Rule (45 CFR Part 46, Subpart A).

The research protocol submitted consists of two interdependent studies:
1) a dosimetry study designed to determine the amount of an
insect-repelling compound, known as picaridin, that normal subjects
would typically apply when provided with one of three compound
formulations (7% Picardin Pump Spray [data will be bridged to 10% Pump
Spray and Aerosol and 5.75% Towelette],15% Picaridin Pump Spray [data
will be bridged to 15% Aerosol and 12% Towelette], and 15% Picaridin
Lotion formulated with sunscreen); and 2) an efficacy study designed to
measure the effectiveness of IR3535 as a tick repellent.  Dosimetry will
be determined either by passive patch dosimetry (spray formulations) or
by direct measurement of compound application (lotion formulation).  The
efficacy of IR3535 as a tick repellent will be determined by placing
Western black-legged ticks (Ixodes pacificus) on picaridin-treated and
untreated forearms and measuring the speed and distance that moving
insects would migrate  into the treated area.  The strengths and
weaknesses of each study design are described above.

The dosimetry study will enroll a total of 10 subjects, each of whom
will test all three formulations. The efficacy study will enroll 10
subjects per test formulation.  Each subject will serve as his/her own
control.  Participants in the dosimetry study may or may not participate
in the efficacy study, and participants in the efficacy study may also
test different formulations on different days; this makes the total
number of volunteers enrolled in both the dosimetry and efficacy studies
no less than 10 but no greater than 40. In addition, three alternate
subjects will be enrolled to: 1) replace any subject who withdraws from
participating; and 2) protect the confidentiality of any subject
excluded from the study as a result of pregnancy or other potentially
stigmatizing condition, as described below.

Critique

The Board concurred with the factual observations of the strengths and
weaknesses of the study, as detailed in the EPA’s Science and Ethics
Review (Carley and Sweeney, 2007b). Once the recommended changes
outlined therein are incorporated into the protocol, the proposed
research described in Protocol SPC-002 should comport with the
applicable requirements of 40 CFR Part 26, subparts K and L.

The risks to study participants are minimal and justified by the likely
societal benefits, including data on the efficacy of these
picaridin-based formulations as a tick repellent. The risks to study
participants are three-fold: 1) reaction to test materials themselves;
2) exposure to biting arthropods; and 3) possible exposure to
arthropod-borne diseases.

The active ingredient of these three repellent formulations is
commercially available and is present at similar concentrations in other
EPA-registered products; specifically, picaridin is registered and
marketed as an insect repellent in the United States under the
registered trade name BayrepelTM and the brand name Autan.  As
volunteers with known allergic reactions to insect repellents and common
cosmetics are excluded from participating in this study, enrolled
participants are unlikely to be at increased risk of experiencing
adverse side effects upon exposure.  Clear stopping rules also have been
developed, as have plans for the medical management of any side effects