I w
% UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
^ PRO"V^
WASHINGTON, D.C. 20460
OFFICE OF
PREVENTION, PESTICIDES AND
TOXIC SUBSTANCES
September 26, 2007
MEMORANDUM
SUBJECT: Ethics Review of Reports of Completed Carroll-Loye Field Efficacy Studies SCI-
001 andWPC-001 for Mosquito Repellents
FROM: John M. Carley
Human Research Ethics Review Officer
Office of Pesticide Programs
TO: Marion Johnson, Chief
Insecticides Branch
Registration Division
Linda Hollis, Chief
Biochemical Pesticides Branch
Biopesticides & Pollution Prevention Division
REF: 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 Unpublished study prepared by Carroll-Loye Biological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. 219p. (MRID 47211901)
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Unpublished study prepared by Carroll-Loye Biological Research under Project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. (MRID 47208401)
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 Unpublished study prepared by Carroll-Loye Biological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. 217p. (MRID 47211801)
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 Unpublished study prepared by Carroll-Loye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. (MRID 47217601)
I have reviewed all available information concerning the ethical conduct of the research
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reported in the referenced documents, which describe the concurrently executed Carroll-Loye
protocols SCI-001 and WPC-001. Both are field tests of the efficacy of mosquito repellents.
Background
I have reviewed the reports of SCI-001 and WPC-001 together because the protocols are
very similar, and because they were executed concurrently in the field. Many of the treated
subjects participated in both studies; both studies relied on the same untreated controls at each
site on each day of field testing. Although there are some important distinctions to be made
between the two studies, their conduct cannot be adequately understood if they are treated
separately.
It is even more important to review the three separately submitted reports of SCI-001 as a
single study. This protocol called for comparing the performance of each of three test repellents
to the U.S. military standard repellent. It was executed only once, but the results were reported
separately for each of the three test repellents. Most of the 200+ pages in each of the three
reports duplicate pages in the other two reports. I have highlighted in this memorandum where
the information unique to each sub-study can be found.
The principal differences between the protocols are (1) whereas the same consent
document served for both treated and untreated subjects in SCI-001, separate consent documents
for treated and untreated subjects were used in WPC-001; (2) whereas SCI-001 tested four
repellents, WPC-001 tested only one; and (3) whereas SCI-001 was not amended to better
explain recruitment of "experienced subjects" to serve as untreated control, WPC-001 was.
Scope of Review:
SCI-001
This review reflects consideration of the three separate sub-study reports cited above, and
the following additional documents:
EPA's protocol review of December 20, 2006
The HSRB's April 16 report of its January 2007 discussion of SCI-001
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
WPC-001
This review reflects consideration of the study report cited above, and the following
additional documents:
EPA's protocol review of March 13, 2007
The HSRB's June 13 report of its April 2007 discussion of WPC-001
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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)
Completeness of Submission: SCI-001
As noted above, much of the content of the three submitted sub-study reports is
duplicative. The submitter has highlighted the passages in the body of the reports of sub-studies
SCI-001.2 and SCI-001.3 which differ from SCI-001.1. Table 1 below shows how the content of
the appendices of the three reports differ.
Table 1
Content of Appendices to Study Reports SCI-001.1, -001.2, and -001.3
Material unique to a single report is highlighted in color
Page Range in Each Volume
of Report
App
No.
Content of Appendix
MRID 47211901
SCI-001.1
MRID 47208401
SCI-001.2
MRID 47211801
SCI-001.3
LipoDEET 302
LipoDEET 3434
Duranon
1
Efficacy Data Spreadsheets
19-22
20-23
20-23
2
Efficacy Data Capture Forms
23-35
24-36
24-36
3
Subject Treatment and Dosing
36-37
37-38
37-38
4
Environmental Conditions
38-44
39-45
39-45
5
Dosimetry Data Spreadsheet
45-46
46-47
46-47
6
Subject Limb Measurements1
47-77
48-80
48-76
7
Dosimetry Data Capture Forms
78-98
81-101
77-97
8
Approved protocol and consent forms
12/29/06 protocol
99-134
103-137
99-133
Data recording forms
135-138
138-141
134-137
Subject training documents
1/2/07 IRB Approval Letter
139-143
144-145
142-146
147-148
138-142
143-144
1/2/07 Approved CD & CDPR Bill of Rights
146-155
149-158
145-154
1/22/07 IRB Correction Letter
156
159
155
1/22/07 Corrected CD & CDPR Bill of Rights2
157-174
160-177
156-173
Label & MSDS for Insect-Guard II3
175-179
178-182
174-178
Label & MSDS for Coulston's Duranon
180-187
183-190
179-186
Label & MSDS for LipoDEET 302
188-196
191-199
187-195
Label & MSDS for 3M Ultrathon
197-208
200-211
196-207
Amendment to change test material
n/a
212
n/a
Amendment to add virus assay
209
213
208
Deviations from protocol
210-211
214-215
209-210
9
Mosquito ID and Viral Assay
212-215
216-219
211-214
10
Physical plan of Carroll-Loye Laboratory
216-217
220
215
11
Additional Correspondence C-L:IIRB 1/22/07
218-219
221-222
216-217
1 Although there are slight differences, this material is largely the same across the three study reports.
Measurements for subjects 22, 25, and 62 are reported only in SCI-001.1; for subjects 28, 32, 43, and 70 only in
SCI-001.2, and for subjects 10 and 69 only in SCI-001.3
2 The cited page range in each report includes two duplicate copies of the 1/22/07 corrected consent document
3 This material describes the test repellent deleted from testing by amendment of 2 July 07
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All three submitted sub-study reports contain an apparently complete record of
correspondence between the investigators and the IIRB after the January HSRB meeting. In
response to a request from EPA on September 18, Carroll-Loye Biological Research submitted a
completed EPA "Confidential Statement of Formula" form and an MSDS describing LipoDEET
3434. Both documents were dated September 24, 2007. The checklist used by EPA to verify
satisfaction of the requirements of §26.1303 as they apply to the reports of SCI-001 appears as
Attachment 1 to this memorandum.
Completeness of Submission: WPC-001
The study report as submitted contains an apparently complete record of correspondence
between the investigators and the IIRB after the April HSRB meeting. In response to a request
from EPA on September 13, Carroll-Loye Biological Research submitted to EPA on September
20 a clarification of which subjects had signed which versions of the consent document on what
date(s). The checklist used by EPA to verify satisfaction of the requirements of §26.1303 as they
apply to the report of WPC-001 appears as Attachment 2 to this memorandum.
Table 2
Content of Appendices: WPC-001
App
No.
Content of Appendix
Page
range
1
Efficacy data spreadsheet
20-21
2
Efficacy data capture worksheets
22-25
3
Calculation of individual subject doses
26-29
4
Environmental measures
30-33
5
Deviations from protocol
34-35
6
Plan of Carroll-Loye laboratory
36
7
Protocol, amendments, and approved revisions to consent documents
37-167
16 Jan 07 Protocol
38-112
14 Jun 07 Amendments
113-119
19 Jun 07 IIRB approval of amendments and revised CDs
120
19 Jun 07 Approved CD - treated subjects
19 Jun 07 Approved CD - untreated subjects
10 Jul 07 IIRB Approval of further revised CDs
121-129
130-138
139
10 Jul 07 Approved CD - treated subjects
10 Jul 07 Approved CD - untreated subjects
13 Jul 07 IIRB approval of further revised CD for untreated subjects
13 Jul 07 Approved CD - untreated subjects (pp. 159-167)
140-148
149-157
158
159-167
8
Subject limb dimension forms
168-193
9
Dosimetry data spreadsheet and data capture forms
194-216
10
Certificate of analysis
217
11
Additional IIRB correspondence, including "sponsor letters" cited in IIRB
approvals of 10 Jul and 13 Jul
218-222
12
Mosquito ID and virus assay
223-225
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Protocol Deviations
The same six deviations from the protocols are reported for both studies, as well as one
additional deviation specific to WPC-001. None were considered by the investigator to have
affected the integrity of the research or the safety of the subjects. Two, however, may have
important implications.
In both studies "experienced subjects"presumably those who also served as untreated
controls, although this is not made explicitassisted the investigators to treat the other
subjects. It is unclear whether participation in treatment of other subjects was
appropriate for these subjects, whatever their level of experience; it certainly wasn't
described to them in the consent documents they signed.
In both studies it is reported that on July 12 subjects failed to maintain the distance
between themselves and other subjects specified in the protocol. This is explained with
the assertion that "Because all subjects were wearing the same repellent, any
interactions among them with regard to repellent performance that might have been
augmented by excessive proximity are unlikely to complicate the interpretation of the
results. " Without disputing the likelihood that interactions between subjects might have
complicated the interpretation of results, it is beyond dispute that on July 12 all subjects
were in fact not wearing the same repellent, due to the concurrent execution of the two
protocols.
Although it was not reported as a deviation from the protocol, subject limb measurement
was initiated for WPC-001 before the reported date of "study initiation" or the date on which the
subjects were reported to have signed consent documents. Since the same measurements applied
when the same subject participated in SCI-001 and WPC-001, and since the initiation of SCI-001
preceded that of WPC-001 by a week, this is only of concern in the case of subject 29, who did
not participate in SCI-001, whose limbs were measured on July 7, and who did not sign a
consent form until July 11. In his response to EPA of September 24, reporting which subjects
signed which versions of the consent documents on which dates, the investigator acknowledges
that available records show that subject 60 signed the consent document for WPC-001 on July
12, two days after participating in dosimetry testing for WPC-001.
Also not reported as a deviation from the protocols, because field trials were conducted
on consecutive days (July 7-8 and July 12-13-14-15) using many of the same subjects, in many
instances a subject's participation on July 8, 13, 14, or 15 violated the exclusion criterion
common to both protocols disallowing participation by anyone who had used a repellent "within
one day preceding the study." This affected 35 of the 81 efficacy values reported for SCI-001,
and 11 of the 20 efficacy values reported for WPC-001.
Calendar of Activities: SCI-001 and WPC-001
Table 3 below arrays key events in the development, review, execution, and reporting of
both studies, demonstrating the many interconnections between them.
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Table 3
Integrated Timeline of Key Events: SCI-001 and WPC-001 Repellent Studies
SCI-001
Date
WPC-001
EPA Science & Ethics Review of SCI-001
12/20
Carroll-Loye revises SCI-001 protocol and CD
12/29
IIRB approves revised protocol and CD
1/2
1/16
Carroll-Loye submits protocol and CD for IIRB review
IIRB approves corrected version of 1/2/07 CD
1/22
1/23
IIRB approves 16 Jan protocol and (single) CD
HSRB discussion of SCI-001
1/24
3/13
EPA Science & Ethics Review of WPC-001
HSRB report of Jan 24 meeting released
4/16
4/18
HSRB discussion of WPC-001
6/13
HSRB report of April 18-20 meeting released
6/14
C-LBR submits amendments to protocol and revised
separate CDs for treated and untreated subjects for IIRB
review
6/19
IIRB approves amendments and revised CDs
Amendments to add viral assay of collected
mosquitoes and to change test repellent to
LipoDEET-3434
7/2
"Study Initiation Date"
7/3
7/4
C-LBR submits further revised CDs for treated and
untreated subjects for IIRB review
Subject limb measurement
7/3-11
Dosimetry testing
7/3-5
7/4-11
Subject limb measurement (Subject 29, measured 7/7, and
subjects 17, 36, and 38, measured 7/11, participated only
in WPC-001. Other subjects also participated in SCI-001.
Only subject 29 was measured before signing CD.)
Field testing in Butte County
7/7
Field testing in Butte County
7/8
7/9
C-LBR explains revisions to CDs in e-mail to IIRB
7/10
IIRB approves revised CDs for treated and untreated
subjects
7/10
"Study Initiation Date"
7/10-15
Treated subjects sign CD approved 7/10
7/10-11
Dosimetry testing (Only subject 60 may have participated
on 7/10 before signing CD on 7/12)
7/11
Untreated subjects sign CD approved 7/10
7/12
C-LBR submits further revised CD for untreated subjects
for IIRB review
Field testing in Glenn County
7/12
Field testing in Glenn County
Field testing in Glenn County
7/13
Field testing in Glenn County
7/13
IIRB approves further revised CD for untreated subjects
Field testing in Glenn County
7/14
Field testing in Butte County
7/15
Field testing in Butte County
7/16
Untreated subjects sign CD approved 7/13
8/1
"Study completion date"
"Study completion date"
8/2
9/13
EPA requests clarification of which subjects signed which
CDs, and when
EPA requests additional information about
LipoDEET 3434
9/18
9/20
C-LBR provides requested clarification
C-LBR provides requested information
9/24
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Analysis by Subject Number
It is not possible to adequately understand the degree to which execution of these two
studies was interconnected except by tracking the participation of each subject. Attachment 3 to
this memorandum arrays information garnered from all four study reports by subject number,
with associated explanatory notes.
Applicable Ethical Standards
Both studies were initiated after April 7, 2006, so prior submission of the protocol and
supporting materials to EPA was required by 40 CFR §26.1125. 40 CFR §26.1601(c) required
EPA to provide the protocol to the HSRB for review. Suggestions made in EPA and HSRB
reviews, and the investigator's response to them, are noted for each protocol below.
EPA and HSRB Comments in Prior Reviews of SCI-001
EPA noted the following ethical deficiencies in its December 20, 2006 review of SCI-001:
The protocol does not describe how the "experienced" subjects who will serve as
untreated controls will be recruited, or how the process of informing them and obtaining
their consent to this special role in the research will differ from the process used for the
treated subjects.
No changes were made in the SCI-001 protocol or consent document in response to
this comment.
Risks from exposure to the test materials themselves are mischaracterized in the
Informed Consent Form, which refers to test materials intended for spray application and
containing alcohol. This passage must be replaced by a description of the risks
associated with exposure to the test materialsall of which are lotions not containing
alcohol.
This was corrected in the consent document approved by IIRB on January 2, 2007.
Either a revised Informed Consent Form covering both the untreated and treated subjects,
or a separate form for the untreated controls, must be provided and approved by the IRB.
Satisfactorily addressed in consent document revised subsequent to EPA review,
approved by IIRB January 2, 2007 and corrected by IIRB January 22, 2007.
In its April 16, 2007, final report of the January 24, 2007 meeting, the HSRB stated its
concurrence with EPA's finding that if protocol SCI-001 were revised as suggested by EPA and
the HSRB it would meet the applicable ethical requirements of 40 CFR 26 subparts K and L.
The HSRB report also included the following specific suggestions:
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The investigator should collect mosquitoes during the field studies and subject them to
serologic or molecular analysis to confirm absence of known pathogens.
The protocol was amended on July 2, 2007 to incorporate viral assay of field-
collected mosquitoes.
The protocol should clarify how untreated controls will be recruited.
Not addressed.
The informed-consent document (1) mischaracterizes the test materials as containing
alcohol; (2) is structured so it doesn't apply to untreated control subjects; and (3) should
say "up to 48 (10 exposed and 2 controls per arm of the study)" subjects will participate.
Point (1) was corrected in the January 2 2007 consent document. Point (2) was
addressed by the January 2, 2007 consent document, which applied to both treated
and untreated subjects. The consent document has not been changedfurther since
the HSRB's January meeting. The consent document was not changed to address
point (3); the actual number of participants was 37-41 subjects. 37 were uniquely
identified by number; up to 4 more served as untreated controls on July 8 and 14, but
were identified only by function.
It is difficult to assess qualifications of IIRB; the Board would like to see some evidence
of member training, IIRB accreditation, etc.
No additional information about IIRB member qualifications or IIRB accreditation
has been provided.
EPA and HSRB Comments in Prior Reviews ofWPC-001
EPA noted the following ethical deficiencies in its March 13, 2007 review ofWPC-001:
Methods proposed for managing information about prospective and enrolled subjects will
generally protect their privacy from compromise. Greater assurance could be provided,
however, if data collection forms referred to subjects only by coded number rather than
by name.
Forms were changed as requested by amendment #7 of June 14, 2007
Although additional inclusion factors are defined for the "experienced" subjects who will
serve as untreated controls, the protocol does not describe how they will be recruited, or
how the process of informing them and obtaining their consent to this special role in the
research will differ from the process used for the treated subjects.
Satisfactorily addressed in §9.1.6.2 as amended June 14, 200 7.
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The process for recruiting, screening, informing, and consenting subjects in Florida
should be described in detail comparable to that of the description of the same process in
California, with particular attention to the role played in the process by the mosquito
control district administration.
Amendment #4 of June 14, 2007 deleted references to testing in Florida.
In its June 13, 2007, draft final report of the April, 2007 meeting, the HSRB stated its
concurrence with EPA's finding that with minor revisions protocol WPC-001 would meet the
applicable requirements of 40 CFR 26 subparts K and L. The HSRB report also made the
following specific suggestions:
First, the Board recommended that investigators trap landing mosquitoes or other vectors
for pooled serologic or nucleic acid-based testing. Such testing would allow research
participants to be warned of their potential exposure to vector-borne pathogens, and
allow them to seek appropriate testing and treatment if necessary.
Amendment #5 of June 14, 2007 added viral analysis of collected mosquitoes.
Secondly, the Board expressed concerns about plans to recruit research subjects in
Florida, as these recruitment procedures were not described adequately in the protocol
and supporting materials. If the investigators do not plan to recruit research subjects in
Florida, this change should be made in the protocol and consent materials.
Amendment #4 of June 14, 2007 deleted references to testing in Florida.
Finally, the Board raised questions about the informed consent procedures for control
subjects. Since control subjects would be presented with higher risks than treated
subjects, the informed consent procedures should modified to more clearly explain the
risks to control (untreated) research subjects.
Separate consent documents are providedfor untreated subjects in amendments of 14
June, approved by IIRB 6/19/07 andfurther revised (approved on 10 July and 13
July) to resolve language concerning pregnancy risks to untreated subjects.
Resulatory and Statutory Standards
Because this research was initiated after April 7, 2006, the following provisions of 40
CFR 26 Subpart Q, as amended effective August 22, 2006, define the applicable ethical
standards, which read in pertinent part:
§26.1703: Except as provided in §26.1706, . . . 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.
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§26.1705: Except as provided in §26.1706, . . . 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. . . .
In addition, §12(a)(2)(P) of the Federal Insecticide, Fungicide and Rodenticide Act
(FIFRA) applies. This passage reads:
In general, [i]t shall be unlawful for any person ... to use any pesticide in tests on human
beings unless such human beings (i) are fully informed of the nature and purposes of the
test and of any physical and mental health consequences which are reasonably
foreseeable therefrom, and (ii) freely volunteer to participate in the test.
Findings
Protocol Review by EPA and HSRB
The requirements of 40 CFR §26.1125 for prior submission of the protocols to EPA and
of §26.1601 for HSRB review of the protocols were satisfied.
Responsiveness to EPA and HSRB suggestions
Suggestions by both EPA and HSRB calling for clarification in the SCI-001 protocol of
how "experienced subjects" would be recruited to serve as untreated controls were not
implemented by changes to the protocol or consent documents after the January HSRB
discussion. Given the concurrent execution of the two protocols, it is likely that the
actual practice of recruiting untreated subjects in SCI-001 tracked closely to that
described in the WPC-001 protocol.
The suggestion by the HSRB that the consent document for SCI-001 be changed to
project up to 48 subjects was not implemented. The actual number of subjects was 37-
41, depending on the actual number of untreated control subjects, some of whom were
not identified uniquely, but only by function.
Most other suggestions by EPA and HSRB were implemented responsively.
Prohibition of research involving pregnant or nursing women or children
The requirement of 40 CFR §26.1703 prohibiting research involving intentional exposure
of pregnant or nursing women or of children under 18 was met by both studies.
Substantial compliance with 40 CFR 26 subparts A through L
40 CFR §26.1705 requires that EPA have "adequate information to determine that the
research was conducted in substantial compliance with subparts A through L of this
part." Within this range, only subparts K and L are applicable to third-party research.
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Subpart K, §26.1108(a)(4), reads in pertinent part:
In order to fulfill the requirements of this subpart each IRB shall:
(a) Follow written procedures:
(4) For ensuring that changes in approved research, during the period for
which IRB approval has already been given, may not be initiated without
IRB review and approval except where necessary to eliminate apparent
immediate hazards to the human subjects.
The procedures of the IIRB were not effective in ensuring that the amendments to the
SCI-001 protocol changing one of the test repellents from Insect-Guard II to LipoDEET
3434 and adding a viral analysis of collected mosquitoes were not initiated without IRB
review and approval. In this case the changes were not necessary to eliminate apparent
immediate hazards to subjects. The investigator has explained his understanding that
"the PI takes considerable responsibility, and has considerable authority, in determining
whether an amendment represents a sufficiently great change to the risk-benefit profile of
a study to require additional ethical review." (Communication of September 24, 2007).
This understanding appears to be discrepant with the plain language of the rule quoted
above.
Subpart K, §26.1116, reads in pertinent part:
No investigator may involve a human being as a subject in research covered by this
subpart unless the investigator has obtained the legally effective informed consent of
the subject.
In executing WPC-001, Subject 29 is reported to have undergone limb measurement on
July 7, but to have signed a consent document on July 11. No explanation is provided of
this apparent violation of the rule. In the same study, Subject 60 is reported to have
participated in dosimetry testing on July 10, but to have signed a consent document on
July 12. The investigator says of the latter case "We do not believe that that subject was
consented late, but rather that she inadvertently consented anew during a visit to the lab
on the 12th, and that that form was then retained rather than her signed form from the
10th."
Compliance with 40 CFR $26 subpart M
As is documented in Attachments 1 and 2 to this memorandum, the requirement of 40
CFR §26 subpart M to document the ethical conduct of research involving human
subjects has been met for both SCI-001 and WPC-001.
Compliance with FIFRA ^ 12(a)(2)(F)
The requirement of FIFRA §12(a)(2)(P) that human subjects of research be "fully
informed of the nature and purposes of the test and of any physical and mental health
consequences reasonably foreseeable therefrom," and "freely volunteer to participate in
the test," was met for both studies.
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Conclusions
These studies meet most applicable ethical standards for the protection of human subjects
of research, but I am concerned by several aspects of the conduct of each of them:
SCI-001
The amendment changing the test material, implemented without IRB review or
approval, and the explanation of the investigator's understanding that it is within his
discretion to determine which amendments to an approved protocol require the IRB's
attention;
The failure to acknowledge the change of test material in the sub-study reports
addressing the unchanged test materials;
The amendment to add viral analysis of collected mosquitoes, also without IRB review or
approval;
The failure to acknowledge concurrent execution with WPC-001, and the misstatement
that "all subjects were wearing the same repellent" on July 12;
The change in role of the "experienced subjects" to include service as assistants to the
investigators, without amendment to the protocol of consent documents, and without IRB
review or approval; and
The compromise of the exclusion factor prohibiting participation in field testing by
subjects who had used repellents on the previous day.
WPC-001
Reporting of a "study initiation date" six days later than the date on which limb
measurement of participating subjects is reported to have begun;
Limb measurement of subject 29 on July 7 before he signed a consent document on July
ii;
Inclusion of subject 60 in the dosimetry phase of testing on July 10 before she is reported
to have signed a consent document on July 12;
Reported signature by untreated controls of the July 13 revised consent document on July
16, the day after the final day of field testing;
The failure to acknowledge concurrent execution with SCI-001, and the misstatement
that "all subjects were wearing the same repellent" on July 12;
The change in role of the "experienced subjects" to include service as assistants to the
investigators, without amendment to the protocol of consent documents, and without IRB
review or approval; and
The compromise of the exclusion factor prohibiting participation in field testing by
subjects who had used repellents on the previous day.
The multiple failures to fully report deviations from the protocols, to ensure documented
consent is obtained before a subject begins service as a research subjects, and to report all
amendments to the IRB represent at least "technical noncompliance" with the cited passages of
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subpart K. In my judgment, these shortcomings did not put the subjects at greater risk than they
would have faced had the protocols been executed without exceptions, but, taken together with
the other deficiencies noted, they may have compromised the studies to the point that even the
low risks to the subjects were no longer justified by the information obtained.
I defer to the Human Studies Review Board for guidance concerning whether the
instances of noncompliance I have noted in this review rise to the level of "substantial"
noncompliance with the requirements of 40 CFR §26 subparts K and L.
Attachments:
1. §26.1303 completeness check for SCI-001
2. §26.1303 completeness check for WPC-001
3. Analysis of Activities by Subject: Carroll-Loye Studies SCI-001 and WPC-001
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Attachment 1
§26.1303 Submission of Completed Human Research for EPA Review
SCI-001.1 (MRID 47211901), SCI-001.2 (MRID 47208401), SCI-001.3 (MRID 47211801)
Any person who submits to EPA data derived from human research covered by this subpart shall provide at the time of submission
information concerning the ethical conduct of such research. To the extent available to the submitter and not previously provided to
EPA, such information should include:
Requirement
Y/N
Comments/Page References
(a) Copies of all of the records relevant to the research specified by
§26.1115(a) to be prepared and maintained by an IRB
§1115(a)(1): Copies of
all research proposals reviewed,
scientific evaluations, if any, that accompany the proposals,
approved sample consent documents,
progress reports submitted by investigators, and reports of injuries to
subjects.
Y
Satisfied with protocol submission;
Amendments 001.2 pp. 212-213
not reviewed by IRB
§1115(a)(2): Minutes of IRB meetings which shall be in sufficient detail to show
attendance at the meetings;
actions taken by the IRB;
the vote on these actions including the number of
members voting for, against, and abstaining;
the basis for requiring changes in or disapproving research;
a written summary of the discussion of controverted issues and their
resolution.
Y
Satisfied with protocol submission
§1115(a)(3): Records of continuing review activities.
n/a
§1115(a)(4): Copies of all correspondence between the IRB and the investigators.
Y
001.1 pp. 218-219
§1115(a)(5):
A list of IRB members identified by name; earned degrees; representative
capacity; indications of experience such as board certifications, licenses,
etc., sufficient to describe each member's chief anticipated contributions to
IRB deliberations;
any employment or other relationship between each member and the
institution, for example, full-time employee, a member of governing panel
or board, stockholder, paid or unpaid consultant.
Y
Satisfied with protocol submission
§1115(a)(6): Written procedures for the IRB in the same detail as described in §
26.1108(a) and § 26.1108(b).
Y
Satisfied by prior submission to
EPA and assurance of no change
§1115(a)(7): Statements of significant new findings provided to subjects, as
required by § 26.1116(b)(5).
n/a
(b) Copies of all of the records relevant to the
information identified in §26.1125(a)-(f)
§1125(a)
A discussion of:
(1) The potential risks to human subjects;
Y
Satisfied with protocol submission
(2) The measures proposed to minimize risks to the human subjects;
Y
Satisfied with protocol submission
(3): The nature and magnitude of all expected benefits of such research,
and to whom they would accrue;
Y
Satisfied with protocol submission
(4) Alternative means of obtaining information comparable to what would
be collected through the proposed research; and
Y
Satisfied with protocol submission
(5) The balance of risks and benefits of the proposed research.
Y
Satisfied with protocol submission
§1125(b): All information for subjects and written informed consent agreements as
originally provided to the IRB, and as approved by the IRB.
Y
Satisfied with protocol submission
§1125(c): Information about how subjects will be recruited, including any
advertisements proposed to be used.
Y
Satisfied with protocol submission
§1125(d): A description of the circumstances and methods proposed for presenting
information to potential human subjects for the purpose of obtaining their informed
consent.
Y
Satisfied with protocol submission
§1125(e): All correspondence between the IRB and the investigators or sponsors.
Y
See §1115(a)(4) above
§1125(f): Official notification to the sponsor or investigator, in accordance with the
requirements of this subpart, that research involving human subjects has been
reviewed and approved by an IRB.
Y
Final approval 001.1 pp. 144-145;
156
(c) Copies of sample records used to document informed consent as specified by §26.1117,
but not identifying any subjects of the research
Y
001.1 pp. 157-174
(d) If any of the information listed in paragraphs (a) through (c) of this section is not
provided, the person shall describe the efforts made to obtain the information.
n/a
Page 14 of 18
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Attachment 2
§26.1303 Submission of Completed Human Research for EPA Review
WPC-001 (MRID 47217601)
Any person who submits to EPA data derived from human research covered by this subpart shall provide at the time of submission
information concerning the ethical conduct of such research. To the extent available to the submitter and not previously provided to
EPA, such information should include:
Requirement
Y/N
Comments/Page References
(a) Copies of all of the records relevant to the research specified by
§26.1115(a) to be prepared and maintained by an IRB
§1115(a)(1): Copies of
all research proposals reviewed,
scientific evaluations, if any, that accompany the proposals,
approved sample consent documents,
progress reports submitted by investigators, and reports of injuries to
subjects.
Y
Satisfied in protocol submission;
Amendments pp. 113-119
Approved revised consent docs
pp. 121-138; 140-157; 159-167
§1115(a)(2): Minutes of IRB meetings which shall be in sufficient detail to show
attendance at the meetings;
actions taken by the IRB;
the vote on these actions including the number of
members voting for, against, and abstaining;
the basis for requiring changes in or disapproving research;
a written summary of the discussion of controverted issues and their
resolution.
Y
Satisfied with protocol submission
§1115(a)(3): Records of continuing review activities.
n/a
§1115(a)(4): Copies of all correspondence between the IRB and the investigators.
Y
pp. 219-222
§1115(a)(5):
A list of IRB members identified by name; earned degrees; representative
capacity; indications of experience such as board certifications, licenses,
etc., sufficient to describe each member's chief anticipated contributions to
IRB deliberations;
any employment or other relationship between each member and the
institution, for example, full-time employee, a member of governing panel
or board, stockholder, paid or unpaid consultant.
Y
Satisfied with protocol submission
§1115(a)(6): Written procedures for the IRB in the same detail as described in §
26.1108(a) and § 26.1108(b).
Y
Satisfied by prior submission to
EPA and assurance of no change
§1115(a)(7): Statements of significant new findings provided to subjects, as
required by § 26.1116(b)(5).
n/a
(b) Copies of all of the records relevant to the
information identified in §26.1125(a)-(f)
§1125(a)
A discussion of:
(1) The potential risks to human subjects;
Y
Satisfied with protocol submission
(2) The measures proposed to minimize risks to the human subjects;
Y
Satisfied with protocol submission
(3): The nature and magnitude of all expected benefits of such research,
and to whom they would accrue;
Y
Satisfied with protocol submission
(4) Alternative means of obtaining information comparable to what would
be collected through the proposed research; and
Y
Satisfied with protocol submission
(5) The balance of risks and benefits of the proposed research.
Y
Satisfied with protocol submission
§1125(b): All information for subjects and written informed consent agreements as
originally provided to the IRB, and as approved by the IRB.
Y
Satisfied with protocol submission
§1125(c): Information about how subjects will be recruited, including any
advertisements proposed to be used.
Y
Satisfied with protocol submission
§1125(d): A description of the circumstances and methods proposed for presenting
information to potential human subjects for the purpose of obtaining their informed
consent.
Y
Satisfied with protocol submission
§1125(e): All correspondence between the IRB and the investigators or sponsors.
Y
See §1115(a)(4) above
§1125(f): Official notification to the sponsor or investigator, in accordance with the
requirements of this subpart, that research involving human subjects has been
reviewed and approved by an IRB.
Y
Approvals pp. 120, 139, 158
(c) Copies of sample records used to document informed consent as specified by §26.1117,
but not identifying any subjects of the research
Y
pp. 140-157; 159-167
(d) If any of the information listed in paragraphs (a) through (c) of this section is not
provided, the person shall describe the efforts made to obtain the information.
n/a
Page 15 of 18
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Attachment 3
Analysis of Activities by Subject:
Carroll-Loye Studies SCI-001 and WPC-001
Subj/Sex
Limb
Measure
-ment
Dosimetry
Efficacy Trials
Butte County
Glenn County
Butte County
SCI-
001
WTC
-001
7 Jul
8 Jul
12 Jul
13 Jul
14 Jul
15 Jul
1 F
11 Jul
Lipo302 R
Duranon R
Lipo3434 R
3 ?
NR
Control
5 M
11 Jul
Ultrathon L
6 M
5 Jul
10 Jul
Control
7 F
5 Jul
5 Jul
8 M
6 Jul
10 Jul
Duranon ?
Lipo3434 ?
Lipo302 ?
Ultrathon ?
Duranon ?
OLER
10 M
5 Jul
Duranon L
13 M
3 Jul
3 Jul
Duranon ?
Ultrathon ?
Control
Control
Control
14 M
5 Jul
5 Jul
10 Jul
Control
Control
Control
Lipo3434 ?
15 M
5 Jul
5 Jul
Ultrathon L
OLEL
Lipo3434 L
OLEL
17 F
11 Jul
11 Jul
OLEL
18 M
11 Jul
Duranon L
Lipo3434 L
Lipo302 L
Lipo302 L
20 F
11 Jul
Lipo302 R
Ultrathon R
OLER
21 M
11 Jul
Lipo302 L
Ultrathon L
OLEL
22 M
11 Jul
Lipo302 R
24 M
5 Jul
10 Jul
Ultrathon L
Lipo3434 L
25 F
11 Jul
Lipo302 R
27 F
5 Jul
5 Jul
28 F
7 Jul
Lipo3434 ?
29 M
7 Jul
OLEL
32 M
5 Jul
Lipo3434 R
36 F
11 Jul
OLER
37 F
4 Jul
4 Jul
10 Jul
Ultrathon L
Lipo3434 L
OLEL
38 F
11 Jul
OLEL
39 F
7 Jul
Lipo302 R
Ultrathon R
Lipo3434 R
40 F
6 Jul
Lipo302 ?
Lipo3434 ?
Duranon ?
OLE?
Lipo302 ?
Duranon ?
43 M
10 Jul
Lipo3434 L
OLEL
46 M
10 Jul
Duranon R
Lipo3434 R
Ultrathon R
Ultrathon R
52 M
5 Jul
Lipo302 L
Duranon L
OLEL
Lipo3434 L
Ultrathon L
53 F
5 Jul
Lipo302 L
Duranon L
OLEL
Ultrathon L
Lipo3434 L
Ultrathon L
56 F
4 Jul
4 Jul
57 M
5 Jul
5 Jul
60 F
5 Jul
5 Jul
10 Jul
Lipo3434 L
Lipo 302 L
Duranon L
OLEL
61 F
5 Jul
5 Jul
10 Jul
Lipo3434 L
Duranon L
Ultrathon L
62 F
6 Jul
10 Jul
Lipo302 L
Lipo302 L
Lipo3434 L
63 M
6 Jul
Lipo3434 L
Duranon L
Lipo302 L
OLEL
Duranon L
Ultrathon L
64 M
6 Jul
Lipo3434 ?
67 M
7 Jul
10 Jul
Lipo302 R
Ultrathon R
Duranon R
OLER
68 F
8 Jul
Ultrathon L
Duranon L
69 F
8 Jul
Duranon R
OLER
70 F
13 Jul
Lipo3434 L
71 M
10 Jul
Ultrathon ?
Duranon ?
Lipo302 ?
OLEL
72 M
10 Jul
Ultrathon R
Duranon R
Lipo302 R
OLER
CI ?
NR
Control
Control
C2 ?
NR
Control
Control
Page 16 of 18
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Notes to Attachment 3:
1. Each treatment is identified in the table by a color code. Colored entries in the "Limb Measurement"
column indicate that the limb measurements for that subject were only reported in the study report
associated with the color. In the cells indicating participation in the field efficacy trials, the color indicates
the treatment by that subject on that day.
2. The entry ("R", "L", or "?") to the right of the treatment name indicates which leg was treated. This was
reported directly for WPC-001 (pp. 26-29). The treated leg was not reported in any of the three reports for
SCI-001, but could be inferred inmost cases by comparing the treated area (SCI-001.1 p. 37, SCI-001.2 p.
38, and SCI-001.3 p. 38) with the reports of measurements for each subject contained in Appendix 6 of
each volume. When the measured area of a subject's left and right legs was the same, the identity of the
treated leg could not be inferred. In all cases where the identity of the treated leg was reported or could be
inferred, treatment of each subject was invariably to the same leg every time that subject participated in
field testing.
3. Forty-three subjects (20 . 22 plus subject #3, whose sex was not reported) are identified by subject
number in one or more of the four study reports. The subjects who served as untreated controls on 8 July
and 14 July were not identified by number; they could bring the total number of subjects involved up as
high as 47, but it seems likely that the control subjects on those two days were selected from the same small
group that served in that capacity on the other four test dayssubjects 3,6, 13, and 14.
4. Subject 62 is reported to have been treated with both LipoDEET 302 and LipoDEET 3434 on the same leg
on 15 July. See SCI-001.1 p. 37 and SCI-001.2 p. 38.
5. Two subjects (3, 6) served only as untreated controls in the efficacy phase, although subject 6 also
participated in the dosimetry phase of WPC-001. Two subjects (13, 14) served both as untreated controls,
as treated subjects in SCI-001, and participated in dosimetry testing for all four materials in SCI-001.
Subject 14 also participated in dosimetry testing for WPC-001. Four more subjects (7, 27, 56, and 57)
participated only in the dosimetry phase of SCI-001.
6. Sixteen subjects (1, 5, 10, 18, 22, 24, 25, 28, 32, 39, 46, 61, 62, 64, 68, and 70) served as treated subjects
only for SCI-001, although three of them (24, 61, and 62) also participated in dosimetry testing for WPC-
001, and one (61) in dosimetry testing for all four materials in SCI-001.
7. Four subjects (17, 29, 36, and 38) served as treated subjects only for WPC-001. One of them (17) also
participated in dosimetry testing for WPC-001.
8. Fifteen subjects (8, 15, 20, 21, 37, 40, 43, 52, 53, 60, 63, 67, 69, 71, and 72) served as treated subjects in
both WPC-001 and SCI-001. Five of these also participated in dosimetry testing: three (15, 37, and 60) for
SCI-001 and four (8, 37, 60, and 67) for WPC-001.
9. On 7 July 16 subjects participated in field testing at the site in Butte County. Subjects 13 and 14 served as
untreated controls. Three subjects were treated with Duranon (8, 10, and 13); three with Ultrathon (15, 24,
and 37); four with LipoDEET 302 (39, 40, 52, and 53) and four with LipoDEET 3434 (60, 61, 63, and 64).
No field testing of OLE occurred on this date.
10. On 8 July 15 subjects participated in field testing at the site in Butte County. Two unidentified subjects
served as untreated controls. Five subjects were treated with Duranon (52, 53, 61, 63, and 69); three with
Ultrathon (13,39, and 68); two with LipoDEET 302 (60, 67); and three with LipoDeet 3434 (8, 32, and 40).
No field testing of OLE occurred on this date.
Page 17 of 18
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11. On 12 July 21 subjects participated in field testing at the Glenn County site. Subjects 13 and 14 served as
untreated controls. Four subjects were treated with Duranon (18, 40, 46, and 60); four with Ultrathon (61,
67, 71, and 72); three with LipoDEET 302 ( 8, 62, and 63); four with LipoDEET 3434 (24, 28, 37, and 43);
and four with OLE (36, 38, 52, and 53).
12. On 13 July 20 subjects participated in field testing at the Glenn County Site. Subjects 13 and 14 again
served as untreated controls. Three subjects were treated with Duranon (67, 71, and 72); three with
Ultrathon (5, 8, and 53); three with LipoDEET 302 (1, 20, and 21); three with LipoDEET 3434 (18, 46, and
70); and six with OLE (15, 37, 40, 43, 60, and 63).
13. On 14 July 15 subjects participated in field testing at the Glenn County Site. Two unidentified subjects
served as untreated controls. Three subjects were treated with Duranon (1,8, and 63); three with Ultrathon
(20, 21, and 46); four with LipoDEET 302 (18, 40, 71, and 72); and three with LipoDEET 3434 (15, 52,
and 53). No field testing of OLE occurred on this date.
14. On 15 July 25 subjects participated in field testing at the Butte County Site. Subjects 6 and 13 served as
untreated controls. Two subjects were treated with Duranon (40, 68); four with Ultrathon (46, 52, 53, and
63); four with LipoDEET 302 (18, 22, 25, 62); four with LipoDEET 3434 (1, 14, 39, and 62); and ten with
OLE (8, 15, 17, 20, 21, 29, 67, 69, 71, and 72).
15. Field testing took place on six different days. Four subjects (7, 27, 56, and 57) did not participate at all in
field testing. Fourteen subjects (3, 5, 6, 10, 17, 22, 25, 28, 29, 32, 36, 38, 64, and 70) participated in only
one day of field testing. Five subjects (24, 43, 62, 68, and 69) participated in two days of field testing; six
subjects (1, 20, 21, 37, 39, and 61) participated on three days; eight subjects (14, 15, 18, 46, 60, 67, 71, and
72) participated on four days; two subjects (13, 52) participated on five days; four subjects (8, 40, 53, 63)
participated on all six days. On average, each of the 39 subjects who participated in at least one day of field
testing participated in 2.8 days of testing.
Page 18 of 18
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