March 4, 2008

Minutes of the

United States Environmental Protection Agency (EPA)

Human Studies Review Board (HSRB)

February 11, 2008 Public Teleconference Meeting

Docket Number: EPA-HQ-ORD-2007-0942

Committee Members:	(See EPA HSRB Members list – Attachment A)

Dates and Times:  	Monday, February 11, 2008, 2:00 PM – 5:00 PM
(Eastern Time)

(See Federal Register Notice – Attachment B)

Location: 		via teleconference

Purpose: 	The EPA HSRB provides advice, information, and recommendations
on issues related to the scientific and ethical aspects of human
subjects research.

Attendees: 	Chair: 			Celia B. Fisher, Ph.D.

Vice Chair:		William S. Brimijoin, Ph.D.

Board Members: 	Gary L. Chadwick, PharmD, MPH, CIP

			Janice Chambers, Ph.D., D.A.B.T.

Richard Fenske, Ph.D., MPH

Susan S. Fish, PharmD, MPH

Suzanne C. Fitzpatrick, Ph.D., D.A.B.T.

Dallas E. Johnson, Ph.D.

KyungMann Kim, Ph.D., CCRP

Kannan Krishnan, Ph.D.

Michael D. Lebowitz, Ph.D., FCCP

Lois D. Lehman-Mckeeman, Ph.D.

Jerry A. Menikoff, M.D.

Rebecca Parkin, Ph.D., MPH

Sean Philpott, Ph.D., M.Bioethics

Ernest D. Prentice, Ph.D.

Meeting Summary:	Meeting discussions generally followed the issues and
general timing as presented in the meeting Agenda (Attachment C), unless
noted otherwise in these minutes.

Introductory Remarks, Meeting Administrative Procedures, and Meeting
Process

Dr. Celia Fisher (HSRB Chair) opened the teleconference meeting with an
introduction and identification of the HSRB, or Board, members
participating in the call.  Dr. Fisher explained that the purpose of the
meeting was to review and approve the October 24-26, 2007 draft HSRB
meeting report (Attachment D) and respond to questions raised by EPA’s
Office of Pesticide Programs (OPP).

Dr. Paul Lewis (Designated Federal Officer [DFO], HSRB, Office of the
Science Advisor [OSA], EPA) thanked Dr. Fisher and the Board for their
participation in the teleconference and for their review of the draft
October 24-26, 2007 HSRB meeting report.  Dr. Lewis explained that the
HSRB is subject to Federal Advisory Committee Act (FACA) requirements.
As the DFO, Dr. Lewis serves as a liaison between the HSRB and EPA, or
the Agency.  He works with the appropriate officials to ensure
compliance with all appropriate ethics regulations.  Each member of the
Board has filed a standard government financial disclosure form that has
been reviewed by EPA to ensure that all ethics disclosures have been
met.

Dr. Lewis stated that the documents discussed by the HSRB, including the
draft October 24-26, 2007 HSRB meeting report, are available at the
public docket; the address for the docket was included in the Federal
Register notice announcing this teleconference meeting.  As per FACA
requirements, the meeting minutes will include descriptions of matters
discussed and the conclusions reached by the Board.  As the DFO,
Dr. Lewis will prepare the minutes and have them certified by the HSRB
Chair within 90 calendar days of the meeting.  In addition, the minutes
will be available at the public docket and posted on the HSRB Web site.

Public Comments

Dr. Fisher invited oral public comment on the draft October 24-26, 2007
HSRB meeting report.  No oral public comments were presented.

Board Discussion and Decision on Report

Dr. Fisher introduced the written comments submitted by OPP and stated
that the Board discussion during the teleconference would focus on
questions and points of clarification raised by OPP.  Dr. Fisher
suggested that the Board adopt all OPP recommendations that pertained to
factual, grammatical, or editorial corrections.

Scientific and Ethical Approaches for Observational Exposure Studies

Dr. Fisher asked if Board members had any suggested changes to the
discussion points or HSRB Consensus and Rationale for each section of
the Scientific and Ethical Approaches for Observational Exposure Studies
document.  There were no comments for Section 1:  Introduction, Purpose,
and Scope (p. 24, lines 25-37), Section 2:  Elements to be Considered in
Study Conceptualization and Planning (p. 27, lines 34-46), Section 3:
Ensuring Protection of Vulnerable Groups (p. 29, lines 8-21), or Section
4:  Privacy, Confidentiality, and Other Concerns Related to
Observational Exposure Measurement Studies (p. 30, lines 28-38).  For
Section 5:  Creating an Appropriate Relationship Between the Participant
and Researcher, Dr. Gary Chadwick suggested that the language on page
31, line 31, be modified to indicate that the Board does not require
back-translation of documents.  Dr. Fisher suggested that the sentence
be changed to the following:  “Review bodies should obtain
documentation to ensure that the communication accurately conveys the
information in the English version(s).”  The Board agreed with this
change.  Dr. Rebecca Parkin stated that she had minor editorial
corrections regarding Section 6:  Building and Maintaining Appropriate
Community and Stakeholder Relationships (p. 34-40); she will submit the
corrections to Drs. Fisher and Lewis.  No changes were suggested for
Section 7:  Designing and Implementing Strategies for Effective
Communication (p. 43, lines 33-42).

Completed Oral Therapeutic Study with Sodium Azide

OPP’s written comments requested clarification on a sentence
describing “Sir A. Bradford Hill’s randomized, placebo-controlled
trial of streptomycin for treatment of tuberculosis reported in the
British Medical Journal in 1948” (p. 44, line 16-18) as the prevailing
standard for experimental design, conduct, analysis, and reporting of
results from a clinical trial.  Dr. KyungMann Kim explained that this
statement was included in response to OPP’s conclusion that the
scientific conduct and reporting of the sodium azide study met
prevailing standards; Dr. Kim found deficiencies in this study and
included the Hill reference to demonstrate that stronger standards
existed at the time the sodium azide study was performed.  The Board
agreed to add “For example,” to the beginning of the sentence” (p.
44, line 16).

Dr. Fisher inquired if Board members had comments on the HSRB Consensus
and Rationale related to scientific considerations (p. 46, lines 4-10).
Dr. Kannan Krishnan suggested that the consensus be clarified because
the study did not confirm that humans were more sensitive to sodium
azide than animals.  Dr. Michael Lebowitz stated that the study was
informative because it yielded the same risk assessment or
point-of-departure (POD) information that EPA had obtained from animal
studies.  Dr. Fisher asked if the statement should be changed to
indicate the study was not informative concerning whether humans are
more responsive or more sensitive to sodium azide than animals.  Dr.
Stephen Brimijoin noted that EPA assumes that humans are more sensitive
than animals unless proven otherwise, so that the question is whether
the study was sufficiently strong to prove humans are more sensitive is
irrelevant.  The Board agreed to eliminate the following sentence
because the Board concluded that the study could not be used to estimate
a POD and thus the sentence is unnecessary:  “In addition, it was not
informative as to whether human responding confirms estimates based on
animal studies” (p. 46, lines 9-10).  This change will also be
reflected in the meeting report summary (p. 4, line 24).

Dr. Fisher inquired if Board members had comments on the HSRB Consensus
and Rationale related to ethical considerations (p. 47, lines 26-31).
No changes were suggested.

Science Issues in Mosquito Repellent Efficacy Field Research

Dr. Fisher inquired if Board members had comments on the HSRB Consensus
and Rationale related to Issue 1:  Factors Affecting Repellent Efficacy
(p. 48, lines 39-46 and p. 49, lines 1-3).  No changes were suggested.

For Issue 2:  Designing for Length Based Sampling, OPP’s written
comments requested clarification of the Board’s use of the phrase
“first confirmed criterion” (p. 49, line 27).  The Board agreed to
change this sentence to:  “However, investigators state that the first
event must be confirmed by a subsequent event within a period of time
(e.g., ‘one-half hour, i.e., in either of the subsequent two exposure
periods’ for the LIBe [landing with intent to bite]).”

	In response to OPP’s written comment on page 49, lines 44-45, the
Board agreed to delete the following sentences:  “Intermittent
exposure of treated subjects to establish FCB [first confirmed bite] has
not been used widely in field studies.  This implies that continuous
exposure approaches have been used widely in field studies.”

	Mr. John Carley (OPP, EPA) stated that there was a typographical error
within OPP’s written comments on page 50, line 8.  OPP meant to state
that ICR Inc.’s recently submitted proposed protocols did not involve
continuous exposures.  In response to OPP’s comment, the Board agreed
to delete the reference to ICR (p. 50, line 8) because it was unclear
whether discussion of ICR methods occurred during the October 2007 HSRB
meeting.  The Board also agreed to change the word “measurements” to
“exposure.”  The sentence will be revised to read:  “The military
and USDA do various types of continuous periods of exposure.”  OPP’s
written comments questioned the Board’s conclusion that factors
affecting the likelihood and timing of a first and confirming bite could
be predicted and quantified (p. 50, line 34-35).  Dr. Fisher remarked
that this statement was consistent with the Board’s comment regarding
Institutional Review Board (IRB) issues.  Dr. Janice Chambers inquired
whether these factors were truly predictable or quantifiable and
suggested revising the paragraph.  Other Board members agreed that there
were limits to what could be predicted and that the paragraph was
ambiguous.  Dr. Lebowitz suggested deleting the first three sentences of
the paragraph (p. 50, lines 33-39) and the word “However” in the
fourth sentence.  The paragraph would read as follows:  “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.”  The Board agreed with
this revision.  There were no comments on the HSRB Consensus and
Rationale for Issue 2:  Designing for Length Based Sampling (p. 51,
lines 1-4).

	For Issue 3:  Complete Protection Time, OPP’s written comments
suggested that the definition of complete protection time (CPT) be
clarified (p. 51, lines 17-18).  Mr. Carley clarified that EPA defines
CPT as the time from repellent application to first confirmed event.
OPP’s written comments requested explanation of the relationship
between sample size and the number of bites per subject (p. 51, line
42).  Dr. Lebowitz remarked that, given the Board’s concerns regarding
sample size for these experiments, a statement noting that continuous
monitoring may call for fewer subjects is appropriate.  The Board agreed
to retain the sentence, but change the word “call” to “allow.”

	In the HSRB Consensus and Rationale for Issue 3:  Complete Protection
Time, Dr. Dallas Johnson suggested slight changes to the wording of
the first sentence (p. 52, lines 1-3):  “Based upon information
provided by the consultants, the Board remains unclear on what the mean
of the times to the first 5 bites/(landings with intent to bite) would
measure that would be relevant to EPA determinations of efficacy.”
OPP’s written comments requested clarification of the statement
regarding the balance between sample size and subject protection (p. 52,
lines 13-17).  Dr. Johnson suggested revising the sentence as follows:
“The Board understands that the need for larger sample sizes and the
accompanying increase in power must be balanced with subject protection,
but it is also important to understand which variables can be
controlled.”

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

	In response to OPP’s written comments, Dr. Johnson suggested a
revision to the text on page 54, lines 18-19, from “Therefore this
deviation did not affect the validity of the results obtained” to
“Therefore, this deviation may not have affected the validity of the
results obtained.”  The Board agreed with this revision.  The Board
also agreed to change “One of the strengths of the study…” to “A
strength of the study…” (p. 54, line 36).

For the HSRB Consensus and Rationale related to scientific
considerations (p. 56, lines 21-36), OPP’s written comments requested
clarification of the statement regarding errors made in choice of test
limb.  Dr. Chambers indicated that she was unclear why this was stated
and the Board agreed to delete the phrase, “and there were errors
(i.e. choice of test limb) in the study” (p. 56, lines 24-25).  In the
same sentence, the Board agreed to change “this did not affect the
validity of the results” to “this may not have affected the validity
of the results.”

	OPP’s written comments questioned the Board’s conclusion that it
was impossible to adequately interpret the reported data from this study
(p. 56, lines 29-31).  Dr. Kim explained that after the Board reviewed
this protocol, concerns were raised about how the subjects would be
randomized and treated.  At the October 2007 HSRB meeting, Dr. Alicia
Carriquiry specifically described how it would be possible to treat the
same subject with different test materials on different days, but
execution of the protocol did not follow this plan and instead was
haphazard.  Standard error estimates could not be made because of the
way in which the protocol was performed.  The investigator deviated from
what the Board indicated would be acceptable practice and instead
combined two studies; therefore, the data could not be interpreted.  The
Board agreed to add the following sentence to the beginning of the
paragraph:  “The Board reviewed this protocol, generally favorably, in
January 2007 but because it was combined with a second protocol, the
conduct and analysis deviated from expectation.”  “However” will
be replaced with “For example” in the following sentence (p. 56,
line 27).  In the same sentence (p. 56, line 30), the Board agreed to
change the word “rendering” to “bringing the.”  In the last
paragraph of this section, the Board agreed to change “…the study
was not sufficiently sound…” to “…the study was not sufficiently
sound enough…” (p. 56, line 34).

	The Board discussed the Ethics Review of this study.  In response to
OPP’s written comments, Dr. Sean Philpott agreed to delete the
following sentence:  “It is unclear, however, whether the protocol was
also revised in accordance with the Board and EPA recommendations, and
submitted to the IIRB [Independent Investigational Review Board, Inc.]
for review” (p. 57, lines 32-34).  Dr. Philpott replaced the sentence
with:  “The protocol, revised just prior to study execution to meet
Agency and HSRB recommendations, was not submitted to the IIRB for
review or approval as required by Federal regulations.”  In response
to OPP’s written comment on page 58, lines 34-35, Dr. Philpott
recommended deleting the following sentence:  “The strengths and
weaknesses of each study design are described above.”  He also agreed
to delete the word “clear” from “clear criteria” (p. 60, line
1).  OPP’s written comments noted that the scientific reviewers
concluded that changes to the exclusion criteria did not affect the
scientific validity of the study (p. 60, lines 5-7).  Dr. Philpott
stated that he wished to keep the statement explaining that,
“…several Board members nevertheless raised the concern that
compromising these exclusion criteria may adversely affect the
scientific validity of the study data…”  Because the science
reviewers were not concerned that the scientific validity of the study
was affected by the change in exclusion criteria, it was agreed that the
phrase “prospective benefit” would be added in place of
“scientific validity.”  Additionally, the parenthetical statement,
“as described above,” would be removed.

	OPP’s written comments argued that the statement, “…decision to
disregard previously established exclusion criteria…” (p. 60, line
6) was too strong because “disregard” implies a motive for not
following the established criteria.  Dr. Fisher suggested adding the
phrase, “not to follow,” in place of “disregard.”  She also
suggested adding verbiage to indicate that not all Board members agreed
that the exclusion criteria had been violated.  Dr. Jerry Menikoff
stated that the report should indicate that there was disagreement
concerning the definition of the exclusion criteria; Dr. Scott Carroll
(Carroll-Loye Biological Research, Inc.) may not have violated the
exclusion criteria, depending on interpretation of the criteria.  The
Board agreed to change the sentence as follows:  “Several Board
members felt that if the exclusion criteria had been violated without
submitting the protocol for approval, this would represent a departure
from accepted review and approval practices.”  Dr. Philpott suggested
rearranging the paragraph to make the explanation of Board’s
disagreement over this issue more clear.  He suggested moving “There
was some disagreement…” (p. 60, lines 8-12) and the following
sentence (p. 60, lines 12-13) prior to “This change is unlikely
to…”  The word “however” should be removed from page 60, line 9.
 The Board agreed with these revisions.

Dr. Krishnan expressed concern about the measures used to avoid exposure
to West Nile Virus (WNV) (p. 60, lines 15-23) and asked if there was
some way to build flexibility for choosing a test site into the
protocols.  Dr. Philpott stated that mosquitoes collected at the test
site had been analyzed for WNV.  Dr. Chambers noted that it is not
possible to predict when these diseases may be found in an area, and the
time of year during which repellency protocols can be performed is
limited.  Dr. Fisher commented that, from a scientific and ethics
perspective, the primary issue was Dr. Carroll’s failure to inform the
IRB of deviations to the protocol; the deviations themselves may be
secondary.  Dr. Chambers raised concerns that by deciding that EPA
should not use the data from this protocol, it will likely have to be
repeated, thus exposing volunteers to WNV a second time, which may have
ethical implications.  Dr. Fisher inquired whether EPA could use the
data from this protocol even if the Board found violations.  Mr. Carley
explained that 40 CFR §26.1706 states that EPA can use data if it would
result in a more restrictive regulatory judgment; this is not the case
for this study.  Dr. Krishnan agreed that the failure to report
deviations to the IRB was valid, but his concern was that the deviations
occurred in part to reduce risk of exposure to WNV.  Dr. Philpott
commented that the more serious deviation was the substitution of an
unregistered compound in the protocol and the failure of the
investigator to obtain IRB approval for this substitution.  In the HSRB
Consensus and Rationale related to ethical considerations (p. 61, lines
32-39), Dr. Fisher suggested that the Board change the last two
sentences of the paragraph as follows:  “The study investigator failed
to obtain IRB approval for fundamental protocol changes, namely
substitution of an unregistered compound.  As a result, the Board
recommended that the data should not be used because the changes placed
volunteers at risk of being randomized to receive treatment with an
unregistered compound.”  The Board agreed with this revision.

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

In response to OPP’s written comments, the Board agreed to delete the
phrase, “…with the most serious being…” and replace it with,
“including” (p. 62, line 21).  The Board agreed to delete the
following sentences:  “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” (p. 62, lines
26-28).  The last sentence, “Treatment of subjects on successive days
was unlikely to have a significant effect” (p. 62, lines 28-29), will
be moved to become the last sentence of the preceding paragraph.

	For the HSRB Consensus and Rationale related to scientific
considerations (p. 62, lines 33-36), the Board agreed to delete the
phrase “…and some of the same design problems found in study
SCI-001…”

	In the Ethics Review of this study, the Board agreed to delete the
following sentence on page 64, lines 7-8:  “The strengths and
weaknesses of each study design are described above.”  On page 65,
lines 9-21, the Board agreed to incorporate OPP’s suggested changes to
the language in these paragraphs.

The Board discussed the paragraph beginning on page 65, line 16.  This
paragraph raised the issue of disagreement among Board members with
regard to the definition and possible violation of exclusion criteria by
the investigator.  The Board agreed to replace the last sentence, which
begins with “As mentioned previously…” with a sentence indicating
that if exclusion criteria were not followed appropriately, this would
constitute a violation.  OPP’s written comments requested
clarification on the Board’s position concerning deviation from the
exclusion criterion regarding uncontrolled repellent exposures before
the first day of the test because the Board’s science reviews
indicated that the deviation did not affect the results.  OPP disagreed
that this change constituted a “significant change to the study
protocol” (p. 65, line 18).  Also, the Board had indicated that there
were no serious failures for the similar and overlapping WPC-001
protocol.  Dr. Carroll did not believe that this was a protocol
deviation.  Dr. Fisher noted that the Board had described two concerns
(p. 65, lines 27-29), first that Carroll-Loye Biological Research had
failed to obtain IRB approval of the revised protocol and consent forms,
and secondly that the protocol deviations had not been reported to IIRB
in a timely manner.  She agreed to delete the first concern, but also
asked if the paragraph should be revised to reiterate that there was
disagreement among Board members concerning whether deviations occurred,
and, if so, whether the deviations were or were not reported to IIRB.
She added that the phrase “serious regulatory breaches” (p. 65, line
29) may be too strong because the Board was not rejecting the protocol
and had not concluded whether a serious problem existed.  The Board
concluded that the phrase, “resulting in potential deviations from
exclusion criteria” would be added to the end of the sentence
beginning on page 65, line 16, “As discussed in greater detail…”
The word “significant” also would be deleted from this sentence.
Lines 19-29 would be deleted, and the sentence beginning on line 16
would be followed by the sentence beginning on line 29, “The Board
recommended that Carroll-Loye Biological Research report these
deviations…”

	OPP’s written comments argued that the Board’s conclusion that the
investigator repeatedly failed to obtain IRB approval is inappropriately
severe and should be deleted (p. 65, lines 42-44).  Dr. Chambers agreed
that the phrase “repeated failure” sounded punitive.  Dr. Fisher
commented that because the paragraph indicated that a minority of Board
members held this view, the paragraph was not unduly harsh.  Dr.
Philpott noted that the goal of this paragraph was to express that the
Board had previously cautioned the investigator against changing
documents or protocols without submitting these changes to the IRB.  Dr.
Philpott suggested splitting this discussion into two paragraphs.  One
paragraph would describe the view of the minority of the Board
concerning the significance of these deviations and concerns that a
pattern of departure from an approved protocol was becoming evident, and
continued departures could result in increased risk to participants.  A
second paragraph would indicate that most Board members were not
strongly concerned about these deviations.  The text regarding the
investigator’s protocol changes (p. 65, lines 41-46) was revised as
follows:  “Some Board members concluded that the study investigator
repeatedly failed in this and other studies to obtain IRB approval for
protocol changes or to report study changes and protocol deviations to
the IRB.  These members felt on this basis, this created a pattern of
departure from accepted review and approval practices that could put
study participants at increased risk or impaired the informed consent
process.”

	The Board discussed the HSRB Consensus and Rationale related to ethical
considerations (p. 66, lines 2-9).  Suggestions were made to include
language indicating that several Board members questioned whether
failure to adhere to exclusion criteria constituted a violation.  It was
also suggested that the Consensus and Rationale be modified to present
the minority view in a separate paragraph which would describe concerns
that repeated departures from the protocol could result in increased
risk to participants.  Within the HSRB Consensus and Rationale, the
first two sentences and “Thus” of final sentence will be deleted.

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

	The Board agreed to delete the phrase, “i.e., to test the efficacy of
picaridin in several formulations to repel mosquitoes…” (p. 66,
lines 41-42).  The Board agreed with OPP’s written comment that the
results of studies of registered products permit current products to
remain on the market (p. 67, lines 1-3).

	OPP’s written comments questioned the Board’s conclusion that there
was insufficient information regarding relevant environmental, mosquito,
and subject factors that might contribute to variability (p. 67, lines
21-22).  Dr. Chambers stated that because it may be impossible to obtain
this information, it is unfair to conclude that the protocol should
include it; however, it was noted that this comment arose in a
discussion of scientific criteria and was not a Board decision that the
investigator must include the information.  Dr. Chambers argued that the
description of information to include was too broad and vague to be
useful.  The Board agreed to delete this sentence.

	Regarding OPP’s written comments concerning problems with
extrapolation (p. 67, lines 34-37), Dr. Chambers explained that the
dosimetry phase is necessary to determine whether sprays and towelettes
apply the same dose of repellent and thus requested that the Board’s
comment regarding this not be changed.

	OPP’s written comments requested clarification of the sentence
beginning on page 67, line 43, referring to concerns related to
statistics and data analysis.  Dr. Kim explained that this statement was
made in response to the deviations observed for the SCI-001 protocol, in
which overlap among randomization of subjects to the three treatment
arms interfered with data analysis.  He suggested adding the following
language:  “Lack of sufficient information about assignment of
subjects to conditions raised statistical concerns that the data
generated could not be appropriately analyzed.”  This change was
accepted by the Board.

	The Board discussed the HSRB Consensus and Rationale related to
scientific considerations (p. 68, lines 11-20).  The Board agreed to
delete the sentence beginning on line 17, “There was also insufficient
information regarding relevant environmental, mosquito, and subject
factors that might contribute to variability.”  The Board agreed to
change the next sentence to read, “Thus the Board was concerned that
proposed research may not generate…”

On page 70, beginning on line 25, OPP’s written comments suggested
deletion and wording changes to statements concerning recruitment of
subjects from the student population and concerns about privacy issues
related to the use of over-the-counter pregnancy tests.  Dr. Philpott
was concerned that deleting these statements would result in a failure
to accurately reflect the evolution of the protocol and the Board
discussion that contributed to the decision-making process.  Concerning
the sentence on lines 27-29 in which the Board mentions recommendations
to alter consent documents, Mr. Carley stated that if the Board wanted
to recommend the consent documents be altered, they must describe how.
He also noted that the consent documents discussed here were used for
previous protocols.  Dr. Brimijoin agreed that the language in the
Board’s report suggests that the protocol was deficient.  Dr. Philpott
suggested the following revisions of lines 26-32:  “The majority of
research participants will be recruited from the University’s student
population, including Dr. Carroll’s own department, but the current
protocol includes several mechanisms, including the exclusion of current
students or employees of 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.”  The Board agreed with this revision.

	Dr. Philpott disagreed with OPP’s suggested changes for the paragraph
beginning on page 70, line 34 and requested that the Board’s language
for this section remain unchanged to emphasize the Board’s concerns
for subject protection.  The Board agreed.

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

	On page 71, line 19, the Board agreed to change “…results
bridged…” to “results extrapolated.”  This change will also be
made on page 66, line 25.

OPP’s written comments requested clarification of the Board’s
concerns regarding use of appropriate statistics to analyze censored
data (p. 73, lines 12-17).  Dr. Kim explained that although the Board
recognizes EPA standards for such analyses, the Board believed that use
of the median and Kaplan-Meier estimate would be more appropriate.  The
Board agreed to add the following language to the beginning of this
paragraph:  “While the current EPA guidelines define CPT as the mean
time across all treated subjects…”

	To clarify the HSRB Consensus and Rationale related to scientific
considerations (p. 73, lines 40-45 and p. 74, lines 1-9), the Board
agreed to delete the phrase, “if the data are intended to be compared
among test subjects” (p. 74, line 1).

Proposed ICR Picaridin Insect Repellent Efficacy Study (A 117)

Dr. Fisher inquired if Board members had changes or comments for the
HSRB Consensus and Rationale related to scientific (p. 77, lines 29-35)
and ethical considerations (p. 81, lines 9-12).  No changes were
suggested.

Summary and Next Steps

Prior to the teleconference, Dr. Johnson submitted grammatical changes,
which Dr. Lewis will include in the final meeting report as
appropriate.  Dr. Fisher asked each Board member for their approval of
the revised October 24-26, 2007 draft meeting report, including
acceptance of the points of factual clarification and grammatical
changes raised by OPP which were not discussed during the
teleconference.  All Board members in attendance at the conclusion of
the teleconference meeting approved the report.

Dr. Lewis thanked Board members for their preparation for and
participation in the teleconference and for their work on the report.
Dr. Lewis stated that he and Dr. Fisher will revise the report based on
comments made during the teleconference.  The revised report will be
released at regulations.gov and posted on the HSRB Web site.  The next
face-to-face HSRB meeting is scheduled for April 9-10, 2008.  A notice
announcing the meeting will be placed in the Federal Register.

The meeting was adjourned by the Chair.

Respectfully submitted:

Paul I. Lewis, Ph.D.

Designated Federal Officer

Human Studies Review Board

United States Environmental Protection Agency

Certified to be true by:

Celia B. Fisher, Ph.D.

Chair

Human Studies Review Board

United States Environmental Protection Agency

NOTE AND DISCLAIMER:  The minutes of this public meeting reflect diverse
ideas and suggestions offered by Board members during the course of
deliberations within the meeting.  Such ideas, suggestions, and
deliberations do not necessarily reflect definitive consensus advice
from the Board members.  The reader is cautioned to not rely on the
minutes to represent final, approved, consensus advice and
recommendations offered to the Agency.  Such advice and recommendations
may be found in the final report prepared and transmitted to the EPA
Science Advisor following the public meeting.

Attachments

Attachment A 		HSRB Members

Attachment B 		Federal Register Notice Announcing Meeting

Attachment C 		Meeting Agenda

Attachment D 		October 24-26, 2007 EPA Human Studies Review Board
Meeting

Proposed Final Draft Report

Attachment A

EPA HUMAN STUDIES REVIEW BOARD MEMBERS

Chair

Celia B. Fisher, Ph.D.

Marie Ward Doty Professor of Psychology

Director, Center for Ethics Education

Fordham University

Bronx, NY

Vice Chair

William S. Brimijoin, Ph.D.

Chair and Professor

Molecular Pharmacology and Experimental Therapeutics

Mayo Foundation

Rochester, MN

Members

Alicia Carriquiry, Ph.D.*

Professor

Department of Statistics

Iowa State University

Ames, IA

Gary L. Chadwick, PharmD, MPH, CIP

Associate Provost

Director, Office for Human Subjects Protection

University of Rochester

Rochester, NY

Janice Chambers, Ph.D., D.A.B.T.

William L. Giles Distinguished Professor

Director, Center for Environmental Health Sciences

College of Veterinary Medicine

Mississippi State University

Mississippi State, MS

Richard Fenske, Ph.D., MPH

Professor

Department of Environmental and Occupational Health Sciences

University of Washington

Seattle, WA

Susan S. Fish, PharmD, MPH

Professor, Biostatistics & Epidemiology

Boston University School of Public Health

Co-Director, MA in Clinical Investigation

Boston University School of Medicine

Boston, MA

Suzanne C. Fitzpatrick, Ph.D., DABT

Senior Science Policy Analyst

Office of the Commissioner

Office of Science and Health Coordination

U.S. Food and Drug Administration

Rockville, MD

Dallas E. Johnson, Ph.D.

Professor Emeritus

Department of Statistics

Kansas State University

Manhattan, KS

KyungMann Kim, Ph.D., CCRP

Professor and Associate Chair

Department of Biostatistics & Medical Informatics

School of Medicine and Public Health

University of Wisconsin-Madison

Madison, WI

Kannan Krishnan, Ph.D.

Professor

Département de santé environnementale et santé au travail

Faculté de médicine

Université de Montréal

Montréal, QC  Canada

Michael D. Lebowitz, Ph.D., FCCP

Professor Emeritus of Medicine

University of Arizona

Tucson, AZ

Lois D. Lehman-Mckeeman, Ph.D.

Distinguished Research Fellow, Discovery Toxicology

Bristol-Myers Squibb Company

Princeton, NJ

Jerry A. Menikoff, M.D.

National Institute of Health

Office of Human Subjects Research

Bethesda, MD

Rebecca Parkin, Ph.D., MPH

Associate Dean for Research and Public Health Practice

School of Public Health and Health Services

The George Washington University

Washington, DC

Sean Philpott, Ph.D., M.Bioethics

Policy and Ethics Director

Global Campaign for Microbicides

Program for Appropriate Technology in Health

Washington, DC

Ernest D. Prentice, Ph.D.

Associate Vice Chancellor for Academic Affairs

Professor of Genetics, Cell Biology and Anatomy

Professor of Preventive and Societal Medicine

Omaha, NE

Richard R. Sharp, Ph.D.*

Director of Bioethics Research

Department of Bioethics

Cleveland Clinic

Cleveland, OH

* Not in attendance at teleconference

Attachment B

Federal Register Notice Announcing Meeting

Human Studies Review Board (HSRB); Notification of Public Teleconference

[Federal Register: January 25, 2008 (Volume 73, Number 17)]

[Notices]

[Page 4561-4563]

------------------------------------------------------------------------
-------------------------------------------------------

ENVIRONMENTAL PROTECTION AGENCY

[EPA–HQ–ORD–2007–0942; FRL–8521–9]

Human Studies Review Board (HSRB); Notification of a Public
Teleconference To Review Its Draft Report from the October 24–26, 2007
HSRB Meeting

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

------------------------------------------------------------------------
-------------------------------------------------------

SUMMARY: The EPA Human Studies Review Board (HSRB) announces a public
teleconference meeting to discuss its draft HSRB report from the October
24–26, 2007 HSRB meeting.

DATES: The teleconference will be held on February 11, 2008, from 2 to
approximately 5 p.m. (Eastern Time).

Location: The meeting will take place via telephone only.

Meeting Access: For information on access or services for individuals
with disabilities, please contact the person listed under FOR FURTHER
INFORMATION CONTACT, so that appropriate arrangements can be made.

Procedures for Providing Public Input: Interested members of the public
may submit relevant written or oral comments for the HSRB to consider
during the advisory process. Additional information concerning
submission of relevant written or oral comments is provided in Unit I.D.
of this notice.

ADDRESSES: Submit your written comments, identified by Docket ID No.
EPA–HQ–ORD–2007–0942, by any of the following methods:

Internet: http://www.regulations.gov: Follow the on-line instructions
for submitting comments.

E-mail<EMAIL_ADDRESS>

USPS Mail: ORD Docket, Environmental Protection Agency, Mailcode:
28221T, 1200 Pennsylvania Ave., NW., Washington, DC 20460.

Hand or Courier Delivery: EPA Docket Center (EPA/DC), Public Reading
Room, Infoterra Room (Room Number 3334), EPA West Building, 1301
Constitution Avenue, NW., Washington, DC 20460, Attention Docket ID No.
EPA–ORD– 2007–0942. Deliveries are only accepted from 8:30 a.m. to
4:30 p.m., Monday through Friday, excluding legal holidays. Special
arrangements should be made for deliveries of boxed information.

Instructions: Direct your comments to Docket ID No.
EPA–HQ–ORD–2007– 0942. EPA’s policy is that all comments
received will be included in the public docket without change and may be
made available online at http://www.regulations.gov, including any
personal information provided, unless the comment includes information
claimed to be Confidential Business Information (CBI) or other
information whose disclosure is restricted by statute. Do not submit
information through http://www.regulations.gov or e-mail that you
consider to be CBI or otherwise protected. The http://
www.regulations.gov Web site is an “anonymous access” system, which
means EPA will not know your identity or contact information unless you
provide it in the body of your comment. By contrast, if you send an
e-mail comment directly to EPA, without going through
http://www.regulations.gov, your e-mail address will be automatically
captured and included as part of the comment that is placed in the
public docket and made available on the Internet. If you submit an
electronic comment, EPA recommends that you include your name and other
contact information in the body of your comment and with any disk or
CD–ROM you submit. If EPA cannot read your comment due to technical
difficulties and cannot contact you for clarification, EPA may not be
able to consider your comment. Electronic files should avoid the use of
special characters, any form of encryption, and be free of any defects
or viruses.

FOR FURTHER INFORMATION CONTACT:

Members of the public who wish to obtain the call-in number and access
code to participate in the telephone conference, request a current draft
copy of the Board’s report or who wish further information may contact
Lu-Ann Kleibacker, EPA, Office of the Science Advisor, (8105R),
Environmental Protection Agency, 1200 Pennsylvania Avenue, NW.,
Washington, DC 20460; telephone (202) 564–7189 or via e-mail at
<EMAIL_ADDRESS>General information concerning the EPA HSRB
can be found on the EPA Web site at http://www.epa.gov/osa/hsrb/.

I. General Information

A. Does This Action Apply to Me?

This action is directed to the public in general. This action may,
however, be of particular interest to persons who conduct or assess
human studies, especially studies on substances regulated by EPA and to
persons who may sponsor or conduct research with human subjects with the
intention to submit it to EPA for consideration under the Federal Food,
Drug, and Cosmetic Act (FFDCA) or the Federal Insecticide, Fungicide,
and Rodenticide Act (FIFRA) or section 408 of the Federal Food, Drug and
Cosmetic Act (FFDCA). Since other entities may also be interested, the
Agency has not attempted to describe all the specific entities that may
be affected by this action. If you have any questions regarding the
applicability of this action to a particular entity, consult the person
listed under FOR FURTHER INFORMATION CONTACT.

B. How Can I Access Electronic Copies of This Document and Other Related
Information?

You may access this Federal Register document electronically through
http:// www.regulations.gov or through the EPA Web site under the
“Federal Register” listings at http://www.epa.gov/fedrgstr/

Docket: All documents in the docket are listed in the index under the
docket number. Even though it will be listed by title in the index, some
information is not publicly available, e.g., CBI or other information
whose disclosure is restricted by statute. Copyright material, will be
publicly available only in hard copy. Publicly available docket
materials are available either through electronically in http://
www.regulations.gov or in hard copy at the ORD Docket, EPA/DC, Public
Reading Room, Infoterra Room (Room Number 3334), EPA West Building, 1301
Constitution Ave., NW., Washington, DC. The Public Reading Room is open
from 8:30 a.m. to 4:30 p.m., Monday through Friday, excluding legal
holidays. The telephone number for the Public Reading Room is (202)
566–1744, and the telephone number for the ORD Docket is (202)
566–1752.

C. What Should I Consider as I Prepare My Comments for EPA?

You may find the following suggestions helpful for preparing your
comments:

Explain your views as clearly as possible.

Describe any assumptions that you used.

Provide copies of any technical information and/or data you used that
support your views.

Provide specific examples to illustrate your concerns and suggest
alternatives.

To ensure proper receipt by EPA, be sure to identify the docket ID
number assigned to this action in the subject line on the first page of
your response. You may also provide the name, date, and Federal Register
citation.

D. How May I Participate in This Meeting?

You may participate in this meeting by following the instructions in
this section. To ensure proper receipt by EPA, it is imperative that you
identify docket ID number EPA–HQ–ORD–2007– 0942 in the subject
line on the first page of your request.

1. Oral comments. Requests to present oral comments will be accepted up
to February 4, 2008. To the extent that time permits, interested persons
who have not pre-registered may be permitted by the Chair of the HSRB to
present oral comments at the meeting. Each individual or group wishing
to make brief oral comments to the HSRB is strongly advised to submit
their request (preferably via email) to the person listed under FOR
FURTHER INFORMATION CONTACT no later than noon, eastern time, February
4, 2008, in order to be included on the meeting agenda and to provide
sufficient time for the HSRB Chair and HSRB DFO to review the meeting
agenda to provide an appropriate public comment period. The request
should identify the name of the individual making the presentation and
the organization (if any) the individual will represent. Oral comments
before the HSRB are limited to 5 minutes per individual or includes all
individuals appearing either as part of, or on behalf of an
organization. While it is our intent to hear a full range of oral
comments on the science and ethics issues under discussion, it is not
our intent to permit organizations to expand these time limitations by
having numerous individuals sign up separately to speak on their behalf.
If additional time is available, there may be flexibility in time for
public comments.

2. Written comments. Although you may submit written comments at any
time, for the HSRB to have the best opportunity to review and consider
your comments as it deliberates on its report, you should submit your
comments at least 5 business days prior to the beginning of this
teleconference. If you submit comments after this date, those comments
will be provided to the Board members, but you should recognize that the
Board members may not have adequate time to consider those comments
prior to making a decision. Thus, if you plan to submit written
comments, the Agency strongly encourages you to submit such comments no
later than noon, Eastern Time, February 4, 2008. You should submit your
comments using the instructions described earlier in this notice. In
addition, the Agency also requests that person(s) submitting comments
directly to the docket also provide a copy of their comments to the
person listed under FOR FURTHER INFORMATION CONTACT. There is no limit
on the length of written comments for consideration by the HSRB.

E. Background

The EPA Human Studies Review Board will be reviewing its draft report
from the October 24–26, 2007 HSRB meeting. The Board may also discuss
planning for future HSRB meetings. Background on the October 24–26,
2007 HSRB meeting can be found at Federal Register 72 17, 54908
(September 27, 2007) and at the HSRB Web site
http://www.epa.gov/osa/hsrb/. The October 24–26, 2007 HSRB meeting
draft report is now available. You may obtain electronic copies of this
document, and certain other related documents that might be available
electronically, from the regulations.gov Web site and the HSRB Internet
Home Page at http://www.epa.gov/osa/hsrb/. For questions on document
availability or if you do not have access to the Internet, consult the
person listed under FOR FURTHER INFORMATION CONTACT.

Dated: January 17, 2008.

George Gray,

EPA Science Advisor.

[FR Doc. E8–1327 Filed 1–24–08; 8:45 am]

BILLING CODE 6560–50–P

Attachment C

2/5/08

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

HUMAN STUDIES REVIEW BOARD (HSRB)

PUBLIC TELECONFERENCE MEETING

FEBRUARY 11, 2008

2:00 pm -5:00 pm (Eastern Time)

HSRB MEETING FOR REVIEW AND APPROVAL OF

DRAFT OCTOBER 24-26, 2008 HSRB MEETING REPORT *

HSRB WEB SITE http://www.epa.gov/osa/hsrb/

Docket Telephone:<PHONE_NUMBER>

Docket Number: EPA–HQ–ORD–2007–0942

Meeting location via telephone only

Members of the public may obtain the call in number at<PHONE_NUMBER>

• 2:00 PM 	Convene Meeting and Identification of Board Members –
Celia Fisher, Ph.D. (HSRB Chair)

• 2:10 PM 	Meeting Administrative Procedures - Paul Lewis, Ph.D.
(Designated Federal Officer, HSRB, OSA, EPA)

• 2:15 PM 	Meeting Process – Celia Fisher, Ph.D. (HSRB Chair)

• 2:20 PM 	Public Comments

• 2:30 PM 	Board Discussion and Decision on Report - Celia Fisher,
Ph.D. (HSRB Chair)

Scientific and Ethical Approaches for Observational Exposure Studies

Section 1: Introduction, Purpose and Scope

Section 2: Elements to be Considered in Study Conceptualization and
Planning

Section 3: Ensuring Protection of Vulnerable Groups

Section 4: Privacy, Confidentiality, and Other Concerns Related to
Observational 	Exposure Measurement Studies

Section 5: Creating an Appropriate Relationship Between the Participant
and Researcher

Section 6: Building and Maintaining Appropriate Community and
Stakeholder 	Relationships

Section 7: Designing and Implementing Strategies for Effective
Communication

Sodium Azide

Science

Ethics

Science Issues in Mosquito Repellent Efficacy Field Research

Completed Field Efficacy Studies by Carroll-Loye Biological Research:
SCI-001 and WPC-001

SCI-001

Science

Ethics

WPC-001

Science

Ethics

Carroll-Loye Biological Research Insect Repellent Efficacy Protocols

SPC-001

Science

Ethics

SPC-002

Science

Ethics

ICR Repellency Efficacy Protocol A117

Science

Ethics

• 4:45 PM 	Summary and Next Steps - Celia Fisher, Ph.D. (HSRB Chair)
and Paul Lewis, Ph.D. (Designated Federal Officer, HSRB, EPA)

• 5:00 PM 	Adjournment

* Please be advised that agenda times are approximate. For further
information, please contact the Designated Federal Officer for this
meeting, Paul Lewis via telephone:<PHONE_NUMBER> or email:
<EMAIL_ADDRESS>
Appendix D

January 10, 2008

EPA-HSRB-07-04

George Gray, Ph.D.

Science Advisor

Office of the Science Advisor

1200 Pennsylvania Avenue, NW

Washington, DC 20460

Subject:  October 24-26, 2007 EPA Human Studies Review Board Meeting
Report

Dear Dr. Gray:

	The United States Environmental Protection Agency (EPA or Agency)
requested the Human Studies Review Board (HSRB) to review scientific and
ethical issues addressing: (1) the EPA Office of Research and
Development’s document, Scientific and Ethical Approaches for
Observational Exposure Studies; (2) a sodium azide study; (3)
Carroll-Loye Biological Research Completed Field Efficacy Studies
(SCI-001 and WPC-001); (4) Carroll-Loye Biological Research Proposed
Insect Repellent Efficacy Protocols (SPC-001 and SPC-002); and (5) ICR
Proposed Repellent Efficacy Protocol (A 117).  The enclosed HSRB report
provides the Board’s response to EPA charge questions presented at the
October 24-26, 2007 meeting.

At previous HSRB meetings, the Board raised a number of science
questions related to mosquito repellent efficacy field research.  At the
Board’s request, three consultants in the field of entomology were
invited to the October 2007 HSRB meeting to discuss the frequency and
duration of exposure of subjects to potential mosquito landings.  Board
discussion of the consultants comments are briefly provided.  This HSRB
report includes Board discussions on the consultants opinions presented
in the consultants’ responses and supplemental information shared at
the meeting.   Finally, the Board also appreciated the Agency
highlighting progress on issues relating to the design of sampling
strategies for handler research programs proposed by the Agricultural
Handlers Exposure Task Force and the Antimicrobials Exposure Assessment
Task Force II.

On a general note, future protocols should include a statistical
analysis plan for subsequent Board review.  In addition, the Board
requests that revised protocols or subsequent studies submitted to the
Agency should include a response to changes as specified by the Agency.
Such a written response would assist the Board in its review process.
Finally, the HSRB requests expert consultants at a future meeting to
educate the Board and Agency on acceptable statistical approaches to
insect repellent studies.

A summary of the Board’s conclusions is provided below.

Scientific and Ethical Approaches for Observational Exposure Studies

Introduction, Purpose and Scope

The Board concurred that the document is extremely well-written,
presents information accurately and clearly, and will be extremely
useful; however, the Board provided suggestions for improvements.

Expand the discussion on how observational research is distinguished
from intentional exposure research with specific illustrations,
including discussion of the need for ethical review and evaluation of
observational research.

The document presents more ethical than science approaches for
observational exposure studies.  The Board recommends that the document
be revised to present a more balanced presentation and highlight the
interplay between good science and ethics.

The Board also recommended providing examples of study questions, citing
other documents to guide researchers in alternative research designs,
and providing bulleted summary highlights at the end of each chapter.

The abstract states that the document will address chemicals and other
stressors, but focuses on chemicals, which gives the impression that
attention is not needed except for research involving chemicals.  The
language and examples used in the document should reflect the importance
of the document for both chemicals and other stressors.

Elements to Be Considered in Study Conceptualization and Planning

The Board concurred that Section 2 adequately identified the major areas
and issues where ethical considerations should be addressed in the study
conceptualization.  The Board suggested that rather than having distinct
sections and even documents on ethics and science there be just one
document, with the study design elements being a portion of the human
subjects protocol. This would more closely parallel the information
submitted to an IRB.

Bulleted items should also include justification for sample selection
and size and sampling method, discussion of alternative designs that
were rejected to help justify the use of human subjects in the
particular way being proposed, expanded examples of conflicts of
interest, and the importance of using validated measures. Expansion of
text regarding adverse events vs. unanticipated problems, scientific
misconduct, subject attrition, reporting biases etc. were recommended.

Ensuring Protections of Vulnerable Populations

The Board recommended additional discussion on justifications for
including vulnerable populations in research as well as expansion on
discussion of who is vulnerable outside of the federal regulations (e.g.
pregnant women, prisoners, children) such as economic, educational or
social vulnerabilities; noting however that in federal regulations
vulnerability is defined in terms of susceptibility to coercion and
undue influence.

Expand examples of studies that might involve these populations.

Discuss the tension between over and under sampling these populations
including the importance of including vulnerable populations in research
to ensure that there is safety data on compounds to which they are more
likely than other populations to be exposed.

Discuss the weighing of risks and benefits in these types of studies.

Privacy, Confidentiality, and other Concerns Related to Observational
Exposure Studies

This section of the document is sensitive to many key ethical and legal
considerations relating to the safeguarding of research-subject privacy,
including the need to (1) disclose the possibility of incidental
reporting requirements to potential volunteers as part of the
informed-consent process, (2) provide advance notification of research
visits to third parties who may be residing in private environments, and
(3) consider potential harms to research volunteers who display personal
monitoring equipment in public settings.  It would be strengthened by
including specific advice on reporting and disclosure procedures when
confidential information indicates a participant or another person is in
jeopardy, the uses of the Certificate of Confidentiality and additional
references.

Creating an Appropriate Relationship Between Participant and Researcher

Most of the major areas and issues where ethical considerations should
be addressed were included in this section, 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 that raises issues without giving direction.

OMB and other guidelines for payment/remuneration could be included.

Provide more examples of appropriate participant-researcher
relationships to observational studies.

The role of informed consent and the IRB or other institutional
representative who protects subjects’ rights.

Building and Maintaining Appropriate Community and Stakeholder
Relationships

Many of the major issues requiring ethical considerations were included.
However, more data to support points made and less assertion or
“theory” would strengthen this section.  It is also 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 also be discussed.

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

Designing and Implementing Strategies for Effective Communication

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 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.

The goals of the communication should also be included. In this regard,
sections on data sharing and how to address potential
scientist-community disagreements (e.g., interpretation of data) would
be helpful.

The context in which communication occurs (e.g. a participant’s home)
should also be discussed.

The importance of formative (process) evaluation and the importance of
considering in advance how the data might be used should be included.

Science and Ethics of Sodium Azide Study

The HSRB concluded that the Black study does not contain sufficient
information to be used as a point of departure to estimate a safe level
of acute and chronic exposure and is not informative as to whether human
responding confirms estimates based on animal studies.

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.

Science Issues in Mosquito Repellent Efficacy Field Research

The Board concluded that more research is needed to determine biases and
adjustments in mosquito repellent efficacy research..

The Board remains unclear of what the mean of the times to the first 5
bites/(landings with intent to bite is measuring.

The Board concluded that that it would be helpful for HSRB deliberations
if protocols contained 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.

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

While the Board concluded that the participation of several subjects on
the day after they had been treated with a different test repellent 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, some of same subjects for different
test materials, for Sites 1 and 2, and for different dates of 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
variance within the 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.

The Board also concluded that the research was conducted in a manner
that failed to meet the applicable requirements of §40 CFR 26, subparts
K and L.

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

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.

The 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.

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

The Board concluded that the protocol to study the efficacy of three
formulations of picaridin for repelling mosquitoes did not provide
sufficient design or a statistical analysis plan that could be evaluated
for its validity or utility.

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.

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

The Board concluded that the protocol assessing the efficacy of the test
substances for repelling ticks (SPC-002) appears likely to generate
scientifically reliable data, provided that the revisions suggested by
EPA are incorporated.

The Board underscored that the statistical analysis plan was not
well-laid out and urged EPA to ensure there was a sufficient analytic
plan before the study be conducted

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.

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.

Proposed ICR Picaridin Insect Repellent Efficacy Study (A 117)

The Board concluded that proposed research is generally clear and
appropriately designed, with the exception of the appropriate
statistics.

The Board concurred that if the proposed research is revised consistent
with EPA’s recommendations and the Board’s suggestions, the study
should yield valid data regarding the efficacy of these products in
repelling Culex.

The Board concurred with the assessment of the Agency that the protocol
ICR A117 submitted for review by the Board, if revised as suggested in
both EPA’s review and by the Board, would meet the applicable
requirements of §40 CFR 26, subparts K and L.

In conclusion, the EPA HSRB appreciated the opportunity to advise the
Agency on the scientific and ethical aspects of human studies research
and looks forward to future opportunities to continue advising the
Agency in this endeavor.

Sincerely,

Celia Fisher, Ph.D., Chair

		EPA Human Studies Review BoardNOTICE

This report has been written as part of the activities of the EPA Human
Studies Review Board, a Federal advisory committee providing advice,
information and recommendations on issues related to scientific and
ethical aspects of human subjects research.  This report has not been
reviewed for approval by the Agency and, hence, the contents of this
report do not necessarily represent the view and policies of the
Environmental Protection Agency, nor of other agencies in the Executive
Branch of the Federal government, nor does the mention of trade names or
commercial products constitute a recommendation for use.  Further
information about the EPA Human Studies Review Board can be obtained
from its website at http://www.epa.gov/osa/hsrb/.  Interested persons
are invited to contact Paul Lewis, Designated Federal Officer, via
e-mail at<EMAIL_ADDRESS>
	In preparing this document, the Board carefully considered all
information provided and presented by the Agency presenters, as well as
information presented by public commenters.  This document addresses the
information provided and presented within the structure of the charge by
the Agency.

U. S. ENVIRONMENTAL PROTECTION AGENCY HUMAN STUDIES REVIEW BOARD
MEMBERS

Chair

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

Vice Chair

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

Members

Alicia Carriquiry, Ph.D., Professor, Department of Statistics, Iowa
State University

Snedecor Hall, Ames, IA *

Gary L. Chadwick, PharmD, MPH, CIP, Associate Provost, Director, Office
for Human Subjects Protection, University of Rochester, Rochester, NY

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

Richard Fenske, Ph.D., MPH, Professor, Department of Environmental and
Occupational Health Sciences, University of Washington, Seattle, WA*

Susan S. Fish, PharmD, MPH, Professor, Biostatistics & Epidemiology,
Boston University School of Public Health, Co-Director, MA in Clinical
Investigation, Boston University School of Medicine, Boston, MA

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

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

KyungMann Kim, Ph.D., CCRP, Professor & Associate Chair, Department of
Biostatistics & Medical Informatics, School of Medicine and Public
Health, University of Wisconsin-Madison, Madison, WI

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

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

Lois D. Lehman-Mckeeman, Ph.D., Distinguished Research Fellow, Discovery
Toxicology, Bristol-Myers Squibb Company, Princeton, NJ

Jerry A. Menikoff, M.D., Director, Office of Human Subjects Research,
Office of the Director, National Institutes of Health, Bethesda, MD

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

Sean Philpott, Ph.D., MS Bioethics, Policy and Ethics Director, Global
Campaign for

Microbicides, Program for Appropriate Technology in Health, Washington,
DC

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

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

Consultants to the Board

Scientific and Ethical Approaches for Observational Exposure Studies
Session

Germaine Buck-Louis, Ph.D.

Division of Epidemiology, Statistics & Prevention Research

National Institute of Children & Human Development

Rockville, MD

Barry Ryan, Ph.D.

Department of Environmental and Occupational Health

Rollins School of Public Health

Emory University

Atlanta, GA

Frequency, Duration and Timing of Exposure of Subjects to Potential
Mosquito Landings Session

Col. Raj. Gupta, Ph.D.

Director, Research Plans and Programs

Walter Reed Army Medical Center

Medical Research and Material Command

Fort Detrick, MD

Steve Schofield, Ph.D.

Department of National Defence

Canadian Forces Health Services Group – HQ Ottawa

Force Health Protection

Communicable Disease Control Program

Ottawa, Ontario, Canada

Daniel Strickman, Ph.D.

USDA, ARS

National Program Leader

Program 104: Veterinary, Medical, and Urban Entomology

National Program Staff - APP

Beltsville, MD

Human Studies Review Board Staff

Paul I. Lewis, Ph.D., Designated Federal Officer, United States
Environmental Protection Agency, Washington, DC

* Not in attendance at October 24-26, 2007 Public Meeting

TABLE OF CONTENTS

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc182819601"  U. S.
ENVIRONMENTAL PROTECTION AGENCY HUMAN STUDIES REVIEW BOARD MEMBERS
PAGEREF _Toc182819601 \h  30

  HYPERLINK \l "_Toc182819602"  INTRODUCTION	  PAGEREF _Toc182819602 \h
34

  HYPERLINK \l "_Toc182819604"  REVIEW PROCESS	  PAGEREF _Toc182819604
\h  42

  HYPERLINK \l "_Toc182819605"  CHARGE TO THE BOARD AND BOARD RESPONSE
PAGEREF _Toc182819605 \h  44

  HYPERLINK \l "_Toc182819606"  A.  Scientific and Ethical Approaches
for Observational Exposure Studies	  PAGEREF _Toc182819606 \h  44

  HYPERLINK \l "_Toc182819609"  B.  Completed Oral Therapeutic Study
with Sodium Azide	  PAGEREF _Toc182819609 \h  64

  HYPERLINK \l "_Toc182819610"  C.  Science Issues in Mosquito Repellent
Efficacy Field Research	  PAGEREF _Toc182819610 \h  68

  HYPERLINK \l "_Toc182819611"  D.  Completed Insect Repellent Efficacy
Study (SCI-001) of DEET Formulations	  PAGEREF _Toc182819611 \h  73

  HYPERLINK \l "_Toc182819612"  E.  Completed Insect Repellent Efficacy
Study with Oil of Lemon Eucalyptus (WPC-001)	  PAGEREF _Toc182819612 \h
82

  HYPERLINK \l "_Toc182819613"  F(1).  Proposed Carroll-Loye Picaridin
Insect Repellent Efficacy Studies (SPC-001)	  PAGEREF _Toc182819613 \h
86

  HYPERLINK \l "_Toc182819614"  F(2).  Proposed Carroll-Loye Picaridin
Insect Repellent Efficacy Studies (SPC-002)	  PAGEREF _Toc182819614 \h
91

  HYPERLINK \l "_Toc182819615"  G.  Proposed ICR Picaridin Insect
Repellent Efficacy Study (A 117)	  PAGEREF _Toc182819615 \h  96

  HYPERLINK \l "_Toc182819616"  REFERENCES	  PAGEREF _Toc182819616 \h
102

  HYPERLINK \l "_Toc182819617"  APPENDIX A:  DISCUSSION QUESTIONS FOR
MOSQUITO REPELLENT STUDIES	  PAGEREF _Toc182819617 \h  104

INTRODUCTION

From October 24-26, 2007, the United States Environmental Protection
Agency’s (EPA or Agency) Human Studies Review Board (HSRB) met to
address scientific and ethical issues concerning:

A.  Scientific and Ethical Approaches for Observational Exposure Studies

Scientists at the U.S. Environmental Protection Agency’s (EPA’s),
Office of Research and Development’s National Exposure Research
Laboratory (NERL) have conducted observational exposure measurement
research for several decades to understand how and why people come into
contact with chemicals and other stressors in their everyday lives.
These studies are performed to determine what chemicals people are
exposed to, the concentrations of the chemicals, the most important
sources contributing to people’s exposures, the routes and pathways of
exposure, and the factors that have the biggest impact on exposure.

EPA strives to follow the most up-to-date approaches in designing and
performing observational exposure studies to ensure that these studies
are based on sound science and meet the highest ethical standards. To
meet that goal, researchers in NERL have prepared a draft document that
identifies key scientific and ethical issues and provides information
and resources to assist researchers as they plan and implement
observational exposure studies. The document is not meant to represent
an official Agency “guidance document.” Moreover, it recognizes that
researchers will work with others – EPA’s Human Subjects Research
Review Official, Institutional Review Board (IRB) members, the
participants and their community, and other stakeholders – to identify
and address all of the relevant issues for any specific study to ensure
that all participants are respected and protected.

Review material:  EPA provided the following materials to the HSRB
relevant to this topic:

1. External review draft document titled Scientific and Ethical
Approaches for Observational Exposure Studies

2. Charge Questions

3. Report on the Workshop to Discuss State-of-the-Science Approaches for
Observational Exposure Measurement Studies, dated January 25, 2007. The
report provides background on the framework for the document and topic
areas recommended by an expert panel.

B.  Completed Oral Therapeutic Study with Sodium Azide

In its registration program EPA reexamines the safety of pesticides
being proposed for new or amended registration.  The Agency is currently
reviewing an application for registration of the active ingredient,
sodium azide (NaN3), as a limited replacement for the fumigant, methyl
bromide.  The application seeks to register sodium azide for commercial
production of ornamental cut flowers and pre-plant application via drip
tape irrigation on beds under plastic mulch; for sod farms with
pre-plant application to soil with tarping after application; and for
golf course turf area renovation with pre-plant application and
immediate tarping.

Sodium azide also has been used for many years as a laboratory reagent
and as a raw material for production of azide-containing compounds.  It
has been used as a pharmaceutical intermediate and as a preservative of
blood, laboratory reagents, and biological fluids.  It has been used as
a gas generant in automotive airbags, and was commonly used in early
inflator designs.  During the 1990s, however, airbag propellants
containing NaN3 were phased out in favor of more efficient, less
expensive and less toxic alternatives.  In the past, NaN3 was also used
as a pharmaceutical to treat high blood pressure and as an
anti-neoplastic agent.

EPA has identified a study published in 1954 in which human subjects
received oral doses of sodium azide to assess its potential for lowering
blood pressure.  The Agency intends to use this study in its hazard
assessment to derive a “point of departure” (POD) for assessing
acute and chronic toxicity resulting from both acute and chronic
exposures to this chemical.

The Agency’s regulation, 40 CFR §26.1602, requires EPA to seek HSRB
review of an EPA decision to rely on the results of any study if the
research was “initiated before April 7, 2006, and the research was
conducted for the purpose of identifying or measuring a toxic effect.”
 EPA has reviewed the study, applying the standards in 40 CFR
§§26.1703 and 26.1704.  Those provisions state:

§26.1703 Prohibition of reliance on research involving intentional
exposure of human subjects who are pregnant women (and therefore their
fetuses), nursing women, or children.

Except as provided in §26.1706, in actions within the scope of
§26.1701 EPA shall not rely on data from any research involving
intentional exposure of any human subject who is a pregnant woman (and
therefore her fetus), a nursing woman, or a child.

§26.1704 Prohibition on reliance on unethical research with
non-pregnant, non-nursing adults conducted before April 7, 2006

Except as provided in §26.1706, in actions within the scope of
§26.1701, EPA shall not rely on data from any research initiated before
April 7, 2006, if there is clear and convincing evidence that the
conduct of the research was fundamentally unethical (e.g., the research
was intended to seriously harm participants or failed to obtain informed
consent), or was significantly deficient relative to the ethical
standards prevailing at the time the research was conducted.  This
prohibition is in addition to the prohibition in §26.1703.

The Agency’s reviews concluded that the data were scientifically sound
and that there was no clear and convincing evidence that the conduct of
the research was fundamentally unethical or significantly deficient
relative to the ethical standards prevailing at the time the research
was conducted.   Nor was there evidence to show that the subjects
included nursing or pregnant women or children.

Review materials. EPA provided the following materials to the HSRB
relevant to the

completed oral therapeutic study with sodium azide:

MRID 47221401 Black et al 1954

Black, M.; Zweifach, B.; Speer, F. (1954) “Comparison of Hypotensive
Action of Sodium Azide in Normotensive and Hypertensive Patients.”  In
Proceedings of the Society for Experimental Biology and Medicine, Jan
1954, pp. 11-16.  MRID 47221401.

MRID 47221401 Data Evaluation Record

EPA WOE Sodium Azide 9-18-07

Memorandum from Nancy McCarroll to Jack Housenger, Associate Director
Health Effects Division, “Human Studies Review Board: Weight of
Evidence Discussion for Sodium azide (NaN3).” September 18, 2007.

EPA Ethics Review MRID 47221401 9-27-07

C.  Science Issues in Mosquito Repellent Efficacy Field Research

Currently, EPA requires all pesticide products that claim to repel
mosquitoes to provide data on the duration of efficacy under field
conditions at two biologically distinct sites. These data are derived
from human research with subjects who have been treated with the
repellent formulations in the field. The Agency evaluates the duration
of repellent efficacy for a subject by calculating the time from
application of the repellent to the occurrence of an event indicating an
efficacy failure. Historically, for field studies of mosquito
repellency, EPA has used the “first confirmed bite” as an indication
of efficacy failure on a test subject. Several recent studies have
shifted to the “first confirmed landing with intent to bite;” EPA
has accepted this alternative endpoint. A “confirmed landing” on a
test subject is a mosquito landing followed by a second landing on the
same subject within a specified period of time (usually 30 minutes)
after the initial landing.

Field studies typically involve 6 – 10 subjects who have been treated
with a defined amount of the test material. Each subject is then
regularly and repeatedly exposed to ambient mosquito populations for a
fixed interval of time until the subject experiences an efficacy failure
followed by a confirmation with the specified period of time. Mosquito
landing pressure (representing intent to bite) at a site is monitored by
concurrently exposing untreated subjects to mosquito landings. A study
is considered valid only if there are at least a specified minimum
number of mosquito landings on untreated subjects during each exposure
interval.

On October 25, 2007, the HSRB discussed scientific aspects of the design
of field studies to assess the efficacy of mosquito repellents. Prior to
the meeting, the Board requested consultants to provide specialized
information or assistance to the Board.  The Board was particularly
interested in the frequency, duration and timing of exposure of subjects
to potential mosquito landings. The Board requested each consultant to
respond briefly to the series of questions below.

• What do data show about the variability of the time intervals
between first and subsequent landings in mosquito repellent field
trials?

• What is the current scientific understanding of how factors other
than repellent efficacy could affect the likelihood that an initial
event—a mosquito landing or mosquito bite—would be “confirmed”
by another similar event within 30 minutes? Please address at least
these factors:

o Characteristics of mosquito populations

o Characteristics of test sites

o Characteristics of test subjects

o Characteristics of test methods

• Can the impact of such factors on the likelihood or timing of an
initial and confirming event be predicted? Can it be quantified?

Review materials. EPA provided the following materials to the HSRB
relevant to the science issues in mosquito repellent efficacy field
research:

Consultant Responses to Discussion Questions

1.  Col. Raj Gupta’s Responses to Discussion Questions

2.  Dr. Steve Schofield's Responses to Discussion Questions

3.  Dr. Daniel Strickman’s Responses to Discussion Questions

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

In its January 2007 meeting, the HSRB reviewed and commented on
materials related to a comparative insect repellent efficacy protocol
from Carroll-Loye Biological Research, submitted by Dr. Scott Carroll.
The proposal, identified as SCI-001, described a study to evaluate the
efficacy of four repellent formulations containing the active ingredient
DEET.  (Note:  One formulation included two other active ingredients as
well.)  The study was designed to measure the efficacy against
mosquitoes under field conditions of three test formulations as compared
to one “comparison article”—the US military standard repellent.
The HSRB offered comments on the protocol at its January 2007 meeting.
Following that meeting, Dr. Carroll revised the protocol to address
comments from the HSRB.  Dr. Carroll conducted the research in July
2007, and has submitted the results to EPA for review.  EPA presented
the results of this testing at the October 2007 HSRB meeting.

Although the protocol SCI-001 was executed only once, the results are
presented in three separate volumes, each one addressing a single test
formulation as compared to the military standard repellent.  Most of the
material presented in each report is duplicated in the other two
reports, but there are unique elements in each volume.

The Agency’s regulation, 40 CFR §26.1602, requires EPA to seek HSRB
review of an EPA decision to rely on the results of these studies.  The
sponsor has submitted applications for amendment of two of the test
materials citing these data, but the third test material (LipoDEET 3434)
is not registered, nor is it the subject of any application.  EPA has
reviewed the research, applying the standard in 40 CFR §26.1705.  That
provision states:

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

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

	Dr. Carroll conducted the research covered by SCI-001 at the same times
and at the same locations as the research covered by protocol WPC-001,
described below.  Because these two protocols were executed
concurrently, in the same field locations, with the same untreated
controls, and with overlapping sets of treated subjects, EPA believed
that the conduct of WPC-001 study may affect the results of SCI-001, and
vice versa.   Thus EPA conducted a single ethics review addressing both
studies.

The Agency’s science review raised questions about whether the data
are scientifically sound.  In addition, EPA’s ethics review raised
questions about whether the research under SCI-001 was conducted in
substantial compliance with the requirements of subparts K and L of
EPA’s final rule establishing Protections for Subjects in Human
Research—the only subparts of the rule which apply to third-party
research.  EPA requested the Board’s advice on whether the research
data are scientifically sound and whether the available information
supports a determination of “substantial compliance” with the
applicable rules.  If the Board concluded that the data are
scientifically sound and the research substantially complied with the
applicable requirements, EPA would rely on these data in support of
applications for new or amended registration of the test materials.

Review materials. EPA provided the following materials to the HSRB
relevant to the completed repellent efficacy study with four DEET
formulations (SCI-001):

a. 	EPA Ethics Rvw SCI-001 & WPC-001 9-26-07

This review addresses both this study and the concurrently conducted
WPC-001.

b. 	MRID 47211901 SCI-001.1 LipoDEET 302

Carroll, S. (2007) Test of Dermaegis LipoDEET 302 Personal Insect
Repellent: EPA Reg. #82810-1.  Unpublished study prepared by
Carroll-Loye Biological Research under Project No. SCI-001.1.  219 p.

c.	MRID 47208401 SCI-001.2 LipoDEET 3434

Carroll, S. (2007) Test of Dermaegis LipoDEET 3434 Personal Insect
Repellent.  Unpublished study prepared by Carroll-Loye Biological
Research under Project No. SCI-001.2.  222 p.

d. 	MRID 47211801 SCI-001.3 Coulston’s Duranon

Carroll, S. (2007) Test of Coulston’s Duranon Personal Insect
Repellent (EPA Reg. #50404-8).  Unpublished study prepared by
Carroll-Loye Biological Research under Project No. SCI-001.3.  217 p.

e. 	CLBR Supplement Re LipoDEET 3434

Carroll-Loye Biological Research’s September 24, 2007 response to
EPA’s request for additional information about LipoDEET-3434 and the
rationale for the amendment by which it became one of the test
repellents

f. 	EPA Protocol Review SCI-001 12-20-06

g. 	4-16-07 HSRB Report of Jan 07 discussion of SCI-001

h. 	SCI-001 Science Review 9-27-07

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

In the June 2007 HSRB meeting, the Board reviewed and commented on
materials relating to an insect repellent efficacy protocol from
Carroll-Loye Biological Research, submitted by Dr. Scott Carroll.  The
protocol described proposed research to evaluate the efficacy of a
conditionally registered repellent product containing the active
ingredient Oil of Lemon Eucalyptus (OLE).  The protocol, identified as
WPC-001, described a field study of efficacy of the test formulation
against mosquitoes.

Following the June meeting, Dr. Carroll revised the protocols to address
comments from the HSRB, conducted the study, and submitted the results.

The Agency’s regulation, 40 CFR §26.1602, requires EPA to seek HSRB
review of an EPA decision to rely on the results of these studies.  EPA
has reviewed the study, applying the standard in 40 CFR §26.1705.  That
provision states:

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

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

	As noted above, the principal investigator conducted the research
covered by WPC-001 at the same times and at the same locations as the
research covered by protocol SCI-001.  Because these two protocols were
executed together, EPA questioned whether and how this fact affects the
review of the separate reports.

The Agency’s science review raised questions about whether the data
were scientifically sound.  In addition, depending on whether the study
covered by WPC-001 was considered separate from the study covered by
SCI-001, EPA’s ethics review (discussed above under the heading of
SCI-001) raised a question about whether the research under WPC-001 was
conducted in a manner that substantially complies the requirements of
subparts K and L of EPA’s final rule establishing Protections for
Subjects in Human Research—the only subparts of the rule which apply
to third-party research.  The Agency requested the Board’s advice on
whether the research was scientifically sound and whether the available
information supports a determination of “substantial compliance”
with the applicable rules.  If the Board concluded that the data are
scientifically sound and the research substantially complied with the
applicable requirements, EPA would rely on these data to satisfy the
data requirement imposed as part of the conditional registration of this
product.

Review materials. EPA provided the following materials to the HSRB
relevant to the

completed repellent efficacy studies of  oil of eucalyptus:

MRID 47217601 WPC-001 OLE

Carroll, S. (2007) Test of an Oil of Lemon Eucalyptus-Based Personal
Insect Repellent: EPA Reg. #305-62.  Unpublished study prepared by
Carroll-Loye Biological Research under Project No. WPC-001.  225 p.

b. 	CLBR Supplement Re: Consent Documentation

Carroll-Loye Biological Research’s September 20, 2007 response to
EPA’s request for additional information concerning which subjects
signed which version(s) of the consent document on what date(s)

c.	EPA Protocol Review WPC-001 3-13-07

d.	6-13-07 HSRB Report of Apr 07 discussion of WPC-001

e.	WPC-001 Science Review 9-27-07

F.  Proposed Carroll-Loye Picaridin Insect Repellent Efficacy Studies
(SPC-001 & SPC-002)

EPA requires data from efficacy studies using appropriate insect species
to support claims of greater efficacy than have previously been
approved.

EPA’s regulation, 40 CFR §26.1125, requires the sponsor or
investigator to submit to EPA, before conducting a study involving
intentional exposure of human subjects, materials describing the
proposed human research in order to allow EPA to conduct scientific and
ethics reviews.  In addition, EPA’s regulation, 40 CFR §26.1601,
requires EPA to seek HSRB review of the research proposal.

In previous meetings the HSRB has reviewed and commented favorably on
several proposed insect repellent efficacy protocols to be conducted by
Carroll-Loye Biological Research, submitted by Dr. Scott Carroll.  Dr.
Carroll has submitted proposals for new research to evaluate the
efficacy of two registered repellent sprays containing the active
ingredient picaridin, as well as one lotion formulation including both
picaridin and a sunscreen, for which an application for registration is
pending.  The first research protocol, identified as SPC-001, describes
a field study of the efficacy of the test formulations against
mosquitoes.  The second research protocol, identified as SPC-002,
describes a laboratory study of the efficacy of the test formulations
against ticks.  Both proposals bear many similarities to protocols that
the HSRB had previously reviewed favorably.

EPA has concluded that, with some refinements, these protocols appear
likely to generate scientifically sound, useful information and to meet
the applicable provisions of the EPA regulations in 40 CFR part 26,
subparts K and L.

Review materials. EPA provided the following materials to the HSRB
relevant to the

proposed Carroll-Loye picaridin insect repellent efficacy studies
(SPC-001 and SPC-002):

IIRB Minutes 7-17-2007

This single document addresses IIRB review of both protocols.

SPC-001: Field test of mosquito repellency

Carroll-Loye Protocol SPC-001 7-13-07

EPA Science & Ethics Review SPC-001 9-24-07

SPC-002: Laboratory test of tick repellency

Carroll-Loye Protocol SPC-002 7-10-07

EPA Science & Ethics Review SPC-002 9-24-07

G.  Proposed ICR Picaridin Insect Repellent Efficacy Study (A 117)

EPA requires data from efficacy studies with human subjects to support
claims of efficacy of a new pesticide product intended to repel insects
that transmit human diseases.

EPA’s regulation, 40 CFR §26.1125, requires the sponsor or
investigator to submit to EPA, before conducting a study involving
intentional exposure of human subjects, materials describing the
proposed human research in order to allow EPA to conduct scientific and
ethics reviews.  In addition, EPA’s regulation, 40 CFR §26.1601,
requires EPA to seek HSRB review of the research proposal.

Dr. Niketas Spero has submitted a proposal for new research to evaluate
the efficacy of two registered products containing picaridin, to be
conducted by Insect Control & Research, Inc. (ICR).  The research
protocol, identified by Protocol ID G0590607001A117 describes a
laboratory study of the efficacy of the test formulations against
mosquitoes of the genus Culex.

EPA has reviewed ICR’s protocol and has concluded that, with a number
of required revisions, it appears likely to generate scientifically
sound, useful information and to meet the applicable provisions of the
EPA regulations in 40 CFR part 26, subparts K and L.  The sponsor wishes
to submit the data to EPA later this year in support of an application
to amend the registration of these picaridin products in order to claim
specifically that the products are effective at repelling the mosquito
species that transmit West Nile Virus.  In the interest of providing a
thorough and timely decision on such applications, and since EPA found
the protocol can meet applicable scientific and ethical standards, EPA
presented this protocol for review at the October 2007 HSRB meeting.

Review materials. EPA provided the following materials to the HSRB
relevant to the

Insect Control & Research Inc. Repellent Efficacy Protocol A117:

a.	ICR Protocol A117 Transmittal 8-8-07

b.	ICR Protocol A117 8-8-07

This protocol proposes a laboratory test of repellency of Culex spp.
mosquitoes by two formulations containing picaridin

c.	EPA Science & Ethics Review  ICR A117 9-24-07

  This report transmits the HSRB’s comments and recommendations from
its October 24-26, 2007 meeting.

REVIEW PROCESS

From October 24-26, 2007, the Board had a public face-to-face meeting in
Arlington, Virginia.  Advance notice of the meeting was published in the
Federal Register “Human Studies Review Board: Notice of Public Meeting
(72 Federal Register 187, 54908).  At the public meeting, following
welcoming remarks from Agency officials the Board then heard
presentations from the Agency on the following topics:

EPA’s draft document Scientific and Ethical Approaches for
Observational Exposure Studies.  The document, prepared by researchers
in EPA’s National Exposure Research Laboratory, identifies the types
of issues that should be considered in planning and implementing
observational human exposure studies and provides information and
resources to assist EPA researchers in these studies.

A published report of a completed clinical trial measuring the effects
of single and repeated treatments with sodium azide on blood pressure in
human subjects.  Sodium azide is a pesticidally active ingredient being
proposed as a replacement for the fumigant methyl bromide.

An overview of the discussion questions related to the Science Issues in
Mosquito Repellent Efficacy Field Research.

A research proposal from Carroll-Loye Biological Research to evaluate
the field efficacy in repelling mosquitoes of three registered products
containing picaridin.

A research proposal from Carroll-Loye Biological Research to evaluate
the laboratory efficacy in repelling ticks of three registered products
containing picaridin.

A research proposal from Insect Control & Research, Inc. to evaluate the
laboratory efficacy in repelling mosquitoes of the genus Culex of two
registered products containing picaridin.

A report of a completed field study by Carroll-Loye Biological Research
of the mosquito repellent efficacy of a registered product containing
Oil of Lemon Eucalyptus.

Three closely related product-specific reports from a single completed
field study by Carroll-Loye Biological Research of the mosquito
repellent efficacy of four pesticides, all containing DEET.

Design of sampling strategies for handler research programs proposed by
the Agricultural Handlers Exposure Task Force and the Antimicrobials
Exposure Assessment Task Force II.

 The following oral comments were presented at the meeting:

Judith Hauswirth, Ph.D., and Mr. Douglas Richards  - representing
American Pacific Corporation and addressing the Completed Oral
Therapeutic Study with Sodium Azide.

Thomas Osimitz, Ph.D., and M. Keith Kennedy, Ph.D., - representing
Science Strategies and addressing the Science Issues in Mosquito
Repellent Efficacy Field Research.

Scott Carroll, Ph.D. - representing Carroll-Loye Biological Research and
addressing: (1)  Science Issues in Mosquito Repellent Efficacy Field
Research; (2) Completed Field Efficacy Studies by Carroll-Loye
Biological Research: SCI-001 and WPC-001; and (3) Proposed Insect
Repellent Efficacy Studies SPC-001 and SPC 002.

Mr. Niketas Spero and Robin Todd, Ph.D. - representing ICR, Inc. and
addressing the ICR Repellency Efficacy Protocol A117.

	For their deliberations, the Board considered the materials presented
at the meeting, written public comments and Agency background documents
(e.g., the published literature, Agency data evaluation record, weight
of evidence review, ethics review, pesticide human study protocols and
Agency evaluation of the protocol).   For a comprehensive list of
background documents visit the www.regulations.gov, Docket ID No.
EPA-HQ-ORD-2007-0942, or EPA’s HSRB website at   HYPERLINK
"http://www.epa.gov/osa/hsrb/oct-24-26-2007-public-meeting.htm"
http://www.epa.gov/osa/hsrb/oct-24-26-2007-public-meeting.htm .

CHARGE TO THE BOARD AND BOARD RESPONSE

A.  Scientific and Ethical Approaches for Observational Exposure Studies

Charge to the Board

1.   One of the goals of the document is identify the major scientific
and ethical areas and issues that researchers should address in the
design and implementation of observational human exposure measurement
studies, with the emphasis on the areas requiring ethical
considerations.  Does each section identify the major areas and issues
where ethical considerations should be addressed?

2.   The document is intended to serve as a reference and resource of
information that researchers can use in the design and implementation of
observational exposure studies. For each section, are there additional
sources of information that should be considered for inclusion?

3.   Is the information presented accurately and clearly in each
section?

Board Response

Board discussion focused on responding to the three charge questions
together by section (Section 1 to 7) of the EPA draft document.

Section 1:  Introduction, Purpose and Scope

Strengths

The document received nearly universal praise from the Board for the
clarity of its writing and its thoughtful consideration of the many
issues involved in observational studies of toxicant exposure in human
subjects.  The introduction set the tone for this excellent document.
In particular, the Board found that it did a superb job of explaining
the purpose of the document and defining its scope. It gave attention to
the proper goals of such studies and the nature of the data to be
collected. Most importantly, it outlined the range of ethical issues in
the conduct of such studies.  And finally, it accomplished exactly what
an introduction must do by clearly indicating the organization and
general contents of the several sections to follow in the main body of
the document.

Document Enhancement

	The document can be enhanced by:

Expanding the discussion on how observational research is distinguished
from intentional exposure research with specific illustrations,
including discussion of the need for ethical review and evaluation of
observational research.

Revising the document to present a more balanced presentation and
highlight the interplay between good science and ethics.

Providing examples of study questions, citing other documents to guide
researchers in alternative research designs, and providing bulleted
summary highlights at the end of each chapter.

HSRB Consensus and Rationale

	Section 1 is well written and sets the tone for ethical consideration
of observational exposure studies. The document could be enhanced by
examples distinguishing observational from intentional exposure studies,
introducing the appropriate balance between scientific and ethical
concerns, and providing study questions and bullets.

The abstract states that the document will address chemicals and other
stressors, but focuses on chemicals, which gives the impression that
attention is not needed except for research involving chemicals.  The
language and examples used in the document should reflect the importance
of the document for both chemicals and other stressors.  Finally, while
the Agency does define and differentiate observational versus
intentional exposure, such a definition should be more prominently
displayed in the body of the report versus as a footnote.

Section 2:  Elements to be Considered in Study Conceptualization and
Planning

Strengths

Section 2 is very strong in its consideration of the overall
conceptualization of study planning, especially the ethical component
often insufficiently conceptualized by the scientists in their initial
approach to the study.  The planning and scoping of the study
conceptualization includes both the science and the ethics, as does the
review process (in which each component reviews the other component as
well).  The strong emphasis on the ethical issues is beneficial.
Recognizing some of the needs and scope of exposure sciences is
noteworthy, as well. The text boxes are particularly helpful, as they
summarize many of the important points from the text quite succinctly.

Document enhancements

	The Board made many constructive comments with the intent of making a
good document better.  As with other chapters, Section 2 has a strong
emphasis on ethics, to the apparent lack of emphasis on scientific
aspects.  In addition, a primary concern is that separating the study
design document from the human subjects protocol will potentially lead
to inconsistencies between the documents (Figure 2-1).  The Board
suggests that there be just one document, with the study design elements
being a portion of the human subjects protocol.  Science cannot easily
be separated from ethics, so any single document should contain elements
of both study design and implementation, as well as other elements that
may be required for an IRB to assess whether all regulatory requirements
have been met.

The major area of deficiency, given the purpose of the document, is in
the paucity of information, materials, and references regarding the
purpose, design and conduct of exposure studies.  Even the initial
paragraphs place more emphasis on the ethical issues (covered
extensively elsewhere) than on the scientific ones; there should be more
of a balance. In addition there are contradictions starting in Section
1.1 as to whether epidemiologic studies are included or not.

Specific Suggestions to the Document

There is little explanation or coverage of exposure study designs and
methods, and their different attributes.  Well-recognized study designs
such as cross-sectional, case-control, and cohort (both prospective and
retrospective) designs should be fully described.  Sufficient examples
are not provided and references to such discussions, as well as to such
studies, are inadequate.  There are excellent sources for such material
to guide researchers, starting with EPA documents (e.g., actual examples
and references for TEAM, PTEAM, NHEXAS, the pesticide studies, etc.).
There are also excellent NRC/NAS & WHO documents that could be utilized.
 There are many lessons learned from such that could be culled to
provide research guidance.  Some of these sources include the NRC/NAS
1991 report on Human Exposure Assessment for Airborne Pollutants, the
WHO EHC 27 (1983) report on Guidelines on Studies in Environmental
Epidemiology, and the WHO/EURO & EC/EU documents on Exposure Assessment
from the ECEHs & EU Lab.  Additional suggestions are provided below.

1.  Section 2.1.1 does not define the types of study problems and
questions scientifically (or specific EPA & other references where such
can be found).

2.  Section 2.1.2 does not provide any basis or criteria for
justification of the science component (or specific EPA & other
references where such can be found), only the ethical component.

3.  In Text Box 2-1 Elements to be Considered in Justifying a Study,
there should be a bullet added “A discussion of alternative designs,
alternative models, or alternative populations”

4.  Page 21, line 4: “considers” should be changed to
“considered”

5.  Section 2.2 does not outline the steps in planning the study
scientifically (or specific EPA & other references where such can be
found).  Section 2.2.1 has only one sentence about the scientific
aspects, and does not really discuss “innovative” scientific
aspects.  Text Box 2-2, Study Elements that Could Affect People’s
Behavior, is the closest the section comes to delineating the components
of the study that are relevant also to its planning.

6.  Section 2.2 Planning and Scoping:  The latter term is jargon and can
be eliminated, or if not, it should at least be defined.

7.  Section 2.2.1 is entitled Innovative Study Designs, but is actually
about adding direct benefit (such as educational materials) for research
subjects in studies for which there is not direct benefit. Innovative
designs might instead include computer modeling or Bayesian designs.
Either the section title or the content needs to be changed.  In
addition, the section’s current content could be said more directly
and succinctly.

8.  Page 23, line 42 “…community’s perspective” . Sentence
should read, “…community’s perspective better, the
researcher…”

9.  Section 2.2.4 states that conflicts due to project funding are
“the most likely to occur.” Please verify that this is the case in
EPA related to observational exposure studies, or change the sentence.
Unless this type of research is unique, it is likely that financial
conflicts are not necessarily the most common, but rather they are the
easiest to identify and manage.

10.  Text Box 2-3 (Elements That May Be Included in a Study Design) and
its corresponding section list elements to be included in a study
design. One bullet lists items to describe technical approach and
conceptual model. The Board recommended adding to the list that endpoint
or outcome measures should include a description of their accuracy and
precision. Survey instruments and questionnaires should include a
description of whether they have been previously validated and, if not,
how they will be validated prior to use within a study. A source for
additional elements that might be included in a study description can be
found at PLoS Medicine, http://medicine.plosjournals.org, volume 4,
number 10, October 2007 in two articles concerning STROBE:   HYPERLINK
"http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.
1371%2Fjournal.pmed.0040296" \o "Read Open Access Article"  The
Strengthening the Reporting of Observational Studies in Epidemiology
(STROBE) Statement: Guidelines for Reporting Observational Studies  (von
Elm E et al., 2007) and   HYPERLINK
"http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.
1371%2Fjournal.pmed.0040297" \o "Read Open Access Article"
Strengthening the Reporting of Observational Studies in Epidemiology
(STROBE): Explanation and Elaboration  (Vandenbroucke et al., 2007)

11.  Section 2.3 did not provide some of the more important specifics of
the scope and technical approaches (or specific EPA and other examples
and references where such can be found). Sec. 2.3.1 does not include all
the important  appropriate questions regarding scientific feasibility
– its one “bullet” does not even include questions about the
feasibility of measurement methods.   The sub-sections also did not
include monitoring of observer errors and biases, participant reporting
biases and reliability, inappropriate (as well as inadequate) selection
criteria, representativeness (refusals and withdrawals), etc. (or
specific EPA and other examples and references where such can be found).
 Enrollment criteria (inclusion and exclusion) need to be included, and
a discussion of the ethical issues of subject selection should be added.

12.  Section <IP_ADDRESS> Sample Size Determination:  The authors are to be
commended for including this section.  However, the section should be
written in consultation with a biostatistician. There are, in fact, many
references on this topic, and to state that there is “surprisingly
small amount of literature” is inaccurate.  In addition, the
methodology cited may not be optimal. One needs to quote and reference
statistical specifics as provided in the documents previously mentioned,
specific survey statistical textbook questions approaches, and also more
from other statistics books), and the issue of design factors (e.g.
Clickner book and other books) as well as expected refusals and expected
losses that need to be taken into account.  Issues of intra- and
inter-participant and observer variability are not discussed.

13.  A section on obtaining an appropriate sample or a representative
sample in order to derive generalizable data should be written.
Descriptions of sampling methods with their relevant strengths and
weaknesses are critical, and would help investigators enormously.

14.  Text Box 2-5, Potential Topics in a Human Subjects Research
Protocol, lists potential topics for a submission to an IRB.

Item #6 should be changed to “Affirmation of Belmont Principles…”
rather than Belmont Report.

Item #13 should be changed to “Sample size/power and statistical
analysis plan.”

Item #22 should either be changed to include “unanticipated
problems” or a separate item should be added.

Item #32 should also include a comment concerning unforeseen uses, if
appropriate.

Item #42 should be changed to state “Procedures for preventing
falsification of data” with the emphasis on prevention rather than on
what to do if falsification occurs.

HSRB Consensus and Rationale

The Board concurred that Section 2 adequately identified the major areas
and issues where ethical considerations should be addressed in the study
conceptualization.  The Board suggested that rather than having distinct
sections and even documents on ethics and science there be just one
document, with the study design elements being a portion of the human
subjects protocol. This would more closely parallel the information
submitted to an IRB.  Bulleted items should also include justification
for sample selection and size and sampling method, discussion of
alternative designs that were rejected to help justify the use of human
subjects in the particular way being proposed, expanded examples of
conflicts of interest, and the importance of using validated measures.
Expansion of text regarding adverse events vs. unanticipated problems,
scientific misconduct, subject attrition, reporting biases etc were
recommended.

Section 3:  Ensuring Protection of Vulnerable Groups

Strengths

Section 3 is of high quality and does a very good job in addressing the
major areas and issues related to vulnerable subjects. The section
presently devotes the bulk of the discussion to issues relating to
children and women.  It might be helpful to present a somewhat more
balanced discussion, with added material devoted to discussing issues
relating to other vulnerable groups.

Specific Suggestions to the Document

1.  Section 3.1, Identification of Vulnerable Groups, it might be
helpful to more specifically point out the differences between the rules
under which the EPA is operating with regard to identification of
vulnerable groups (primarily, the Common Rule), as compared to the
concepts of vulnerability that the lay public might have.  In addition,
a discussion of how vulnerability can be context-dependent could be
helpful.

2.  In Section 3.2, the current discussion puts an emphasis on the
“special justification” needed for inviting vulnerable subjects to
participate in research, without expanding on how that concept plays out
in observational studies.  In fact, many of the observational studies
with regard to which this document will apply are studies that are
intended to collect important health information regarding the
well-being of various vulnerable groups (such as children and pregnant
women).  Moreover, unlike many other studies (such as interventional
studies), observational studies generally do not impose more than
minimal risks on subjects.  Those circumstances—the possible large
benefits to the vulnerable populations from gaining the information to
be learned, and the minimal risk regarding including them in the studies
–combine to often make a strong ethical case for including such groups
in these studies.  Thus, it would be appropriate for this section to
also discuss the harms from inappropriately excluding various groups of
vulnerable subjects from this category of studies, and how those harms
would often be to those very groups.  This point is already made in
Section 3 in some of the discussions of specific subject groups (e.g.,
in the discussion in Section 3.4 with regard to children), but it would
be helpful to highlight it as a general proposition in the analysis of
the general issue of the justification for including vulnerable
subjects.

3.  It might be helpful to have a more expanded discussion of how to
mitigate risks to vulnerable subjects in these studies.  This point is
particularly important given the substantial reasons (as noted in item 2
above, and already discussed in portions of Section 3) for including
such vulnerable subjects in these studies.  This discussion could go
beyond the risks created or imposed by the inclusion of the subjects in
the study (which are often minimal), and also address the extent to
which it is appropriate for researchers to be standing by and observing
while vulnerable groups are exposed to risks not created by the study.

4.  It could be helpful to add a subsection dealing specifically with
workplace-based studies. The types of vulnerabilities of workers who
participate in those studies are somewhat unique, and can vary depending
on the specific type of study.

5.  Given the very substantial literature on the topic of vulnerable
subjects, the list of references in Section 3.7 might be expanded.

HSRB Consensus and Rationale

The Board determined that Section 3 is of high quality, accurate and
written clearly.

The Board recommended additional discussion on justifications for
including vulnerable populations in research as well as expansion on
discussion of who is vulnerable outside of the federal regulations (e.g.
pregnant women, prisoners, children) such as economic, educational or
social vulnerabilities; noting however that in federal regulations
vulnerability is defined in terms of susceptibility to coercion and
undue influence.

The Board also recommended the document: (a) expand examples of studies
that might involve these populations; (b) discuss the tension between
over and under sampling these populations including the importance of
including vulnerable populations in research to ensure that there is
safety data on compounds in which they are more likely than other
populations to be exposed; and (c) discuss the weighing of risks and
benefits in these types of studies

Section 4:  Privacy, Confidentiality, and Other Concerns Related to
Observational Exposure Measurement Studies

Strengths

Section 4 provides a good discussion of several privacy concerns
associated with observational studies, particularly those conducted in
private or semi-private places such as homes and schools.  Although
research volunteers allow study staff to access these environments,
others who may be residing in these environments may object or feel that
their privacy is not being appropriately respected.  Additionally,
during the course of collecting research data, study staff may observe
illegal or immoral activities that may challenge their ability to
maintain the confidentiality of research volunteers or others who may be
living in these environments.

	Document Enhancement

 Considerations relating to the protection of the vulnerable groups,
where more active intervention by study staff may be appropriate should
be strengthen.  For example, Section 4 suggests that researchers develop
a plan for responding to the incidental observation of illegal behaviors
such as child or elder abuse.  It does not recommend that research staff
be trained with regard to the recognition of such behaviors, which is
essential for avoiding both missed opportunities for intervention and
inappropriate accusations of abuse.  Similarly, this section provides
little guidance with respect to the observation of environmental
situations associated with imminent harm, such as observations of
combustible materials near an open flame, a child playing unattended by
a pool, a firearm placed near young children, etc.  Section 4 could be
strengthened by including advice for addressing such situations or
offering general guidance for determining when members of the research
team should act in circumstances involving imminent harm.  It would also
be helpful to reinforce the point that local and state reporting
requirements may vary considerably.

Section 4 does not consider the potential risks to members of the
research staff who may find themselves in situations involving illegal
activities such as drug use or sales, nor does it consider the potential
burdens that research staff members may feel when presented with
behaviors that they find morally objectionable.  In contrast to several
of the other sections in the document, the citations to relevant
literature provided in this section are lacking (e.g., no recent review
articles are cited, nor are there any references to important privacy
documents such as HIPAA).

Specific Suggestions

Section 4 could be strengthened by including advice for addressing
environmental situations associated with imminent harm and offering
guidance for determining when members of the research team should act in
circumstances involving imminent harm.

Purpose and use of the Certificate of Confidentiality should be
included.  Such certificates do not diminish the need to protect
personally identifiable information and does not relieve the
requirements for reporting illegal behaviors.  While the Agency’s
document states that certificates should be used for “sensitive
matters,” it does not define sensitive matters.  Finally, Federal
regulations exist that clearly define populations needing certificates
of confidentiality.  Such regulations should be noted in the document.

HSRB Consensus and Recommendations

This section of the document is sensitive to many key ethical and legal
considerations relating to the safeguarding of research-subject privacy,
including the need to (1) disclose the possibility of incidental
reporting requirements to potential volunteers as part of the
informed-consent process, (2) provide advance notification of research
visits to third parties who may be residing in private environments, and
(3) consider potential harms to research volunteers who display personal
monitoring equipment in public settings.  It would be strengthened by
including specific advice on reporting and disclosure procedures when
confidential information indicates  a participant or another person is
in jeopardy, the uses of the Certificate of Confidentiality and
additional references.

Section 5:  Creating an Appropriate Relationship Between the Participant
and Researcher

Strengths

The Board also commented that this section, like other sections of the
document is excellent; it is readable and useful. In general, Section 5
accurately and clearly discusses the ethical considerations in the
relationship between investigator and participant.  A major strength of
this work is its focus on researcher responsibilities and guidance for
researchers.  A strength is that it includes consideration of the
context of the participant’s community, etc. (One assumes that
“community” includes all the socio-cultural aspects in which the
investigators are competent and respectful.)  In relation to these
strengths, it would help if the document stressed the importance on
researcher training in human subject protection, with emphasis on
observational techniques and community-based research,

The sub-section relating to remuneration (payment) is highly appropriate
and well written. Likewise, Section 5.3 on rights is well done.  Section
5.4, Creating a Supportive Environment for Research and Interaction , as
defined, is very useful and well stated also.

Section 5.5 provides good discussion of equitable selection and of IRB
guidelines (Text Box 5-3) for selecting sub-populations for study from
the ethical standpoint (see below re: scientific standpoints). Section
5.6 on retention issues and ideas, especially in longitudinal studies,
is useful and generally well done.

Document Enhancements

One of the areas that is important not only to recruitment, but to the
successful conduct of studies is language.  The regulations require
information be presented in a language that is “understandable” to
the subjects/potential subjects.  That has always been interpreted to
mean two things; at a literacy level (oral and reading) that is
appropriate for the target population and, in a language that the
listener/reader speaks/reads.  Because various populations to be studied
in the U.S. tend to include persons who speak/read little, if any,
English, it is very important that researchers address how
communications will be handled.  At a minimum, written documents, such
as consent forms, advertising flyers, instruction sheets, etc must be
developed in more than just English.  Such written materials must be
reviewed and approved by an IRB prior to use.  Those review bodies
should obtain independent back-translations to ensure that the
communication accurately conveys the information in the English
version(s).  That is only part of the issue, however, because during the
conduct of the research, investigators and the research team must be
able to communicate orally with subjects, including those who may not
speak English.  Thus researchers must address in protocols how planned
and ad hoc translations will be accomplished.  It should be stressed in
this document that untrained persons (e.g., co-workers etc.) generally
do not meet the ethical requirement for facilitating full understanding
and protecting subject welfare.

Too many discussions/descriptions/examples are correct, but the examples
given are for/applicable to research in general.  Section 5 would be
more useful to researchers conducting observational studies if the
discussion were more focused on the special needs/considerations in that
type of research.  In a related vein, Section 5 makes some global
statements, such as “additional considerations arise …” or “a
number of issues have been identified …,” but there is no
expansion/explanation; so there is no “teaching point.”  These
generalities should be removed or used to start a description of the
concern or issue; Text Boxes 5-2, 5-3 and Appendix C are good examples
of getting the key points into this section without repeating the source
verbatim.

There are additional sources of information that should be considered
for inclusion in the section, specifically the NRC/NAS 1991 report on
Human Exposure Assessment for Airborne Pollutants and the WHO EHC 27
(1983) report on Guidelines on Studies in Environmental Epidemiology,
statistical survey sampling textbooks, the Board’s discussions of
“purposive” sampling, EPA and NIEHS documents on environmental
equity/justice, and other references contained in this document on
community and Community Advisory Boards (CAB) involvement.  Also, the
literature on observational studies, such as the developing community
based participatory research literature may be informative.  With a
caution about keeping the focus on observational research, there is also
a wealth of “good clinical practice” (GCP) references which could be
used to expand some issues (such as payment and other incentives in
section 5.2.1).

Specific Suggestions to the Document

Section 5.1.1 seems to include descriptions of consent elements that are
of general application, but this section would be more useful to
researchers conducting observational studies if the discussion was
focused on the special needs/considerations in that type of research.

Section 5.5, Recruiting Strategies, does not address the scientific
necessities of sometimes including over-sampling (via stratified/cluster
methods) of sub-populations, including the underrepresented and the
overexposed.  Thus, there should be a similar delineation of when such
sampling and recruitment are necessary, similar to Text Box 5-3, which
discusses those needs from an exposure science standpoint. For instance,
it is not  inappropriate to study minority/poor children when evaluating
exposures to lead, pesticides, etc., under existing laws/rules/statutes.
 Some of the “environmental equity/justice” issues need to be
discussed.  CABs need to be involved in approving recruitment materials.

Section 5.5 should discuss consideration of the limitations, especially
statistical issues (representativeness & generalizability) and
non-random sampling (i.e., the scientific problems inherent in
“convenience,” “purposive,” etc. sampling).

There should be a parallel section to Section 5.7 that discusses the
benefits of longitudinal follow-up for the participants, communities,
and responsible agencies and the decrease of risks that may be so
obtained.

The way some references are used (e.g., Grady (page 58, lines 13-21)
seems more suited to a journal article than a review document; that is,
“what does this mean for the researcher” and “what is the
application to observational research” is lost.

Additional Specific Suggestions

The Board had a few suggestions for possible additional information that
might be included in the chapter:

  Page 51, lines 37-39 makes the comment that the consent process must
explain risks, but in order for subjects to make decisions about
participation that reflect their individual concerns, it would be well
to state that an accurate and realistic description of possible benefits
must be included as well.  See lines 41-44.

  Page 52, lines 2-3 refers the reader to three sources for additional
information.  It would be more useful for readers if key points made in
these publications were listed or summarized.  That allows the point to
be made or the issue to be raised.

  Page 52, lines 36-39 discusses one interpretation of “language
understandable to subjects” (native tongue), but it also should be
pointed out that this has a readability requirement too.  Page 53, lines
1-4 and Page 55 lines 1-2 seem to relate this requirement just to a
description of purpose.  This should be fixed.

  Page 53, line 16 makes a reference to a court case; its relevance
needs to be explained.

  Page, line 24 uses the term “informed consent” incorrectly to
imply the form, not the process of information exchange needs to be
presented to parents. (Note the rest of that bullet is fairly dense and
could be revised to make it more readable.)

  Page 55, line 9 uses the term “administration procedure” when
“consent procedure” would be more appropriate.

  Page 55, line 28 uses the term “study elements” when “study
characteristics” would be better.

  Page 55, line 29 is the first use of the word “remuneration” in
this section.  This term clouds the reason subjects are offered payment
for participation in research.  It is not payment for services in the