Science and Ethics Review of Protocol for Human Study of Mosquito Repellent Performance May 24, 2007 Efficacy Test of KBR 2023

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

MEMORANDUM: OFFICE OF

PREVENTION, PESTICIDES AND
TOXIC SUBSTANCES

May 24, 2007

SUBJECT: Science and Ethics Review of Protocol for Human Study of Mosquito Repellent
Performance

John M. Carley

Human Research Ethics Review Officer

Kevin Sweeney,

Science Reviewer

Marion Johnson, Chief
Insecticide Branch, RD

Carroll, S. (2007) Efficacy Test of KBR 2023 (Picaridin; Icaridin)-Based Personal
Insect Repellents (20% Cream and 20% Spray) with Mosquitoes Under Field
Conditions: Efficacy Test Protocol LNX-001, dated April 10, 2007. Unpublished
document prepared by Carroll-Loye Biological Research. 82 p.

We have reviewed the referenced protocol for a field test of mosquito repellency from
both scientific and ethics perspectives. This review assesses the scientific aspects of the
proposed research in terms of the recommendations of the draft EPA Guidelines 810.3700 and of
the EPA Human Studies Review Board, and the ethical aspects of the proposed research in terms
of the standards defined by 40 CFR 26 subparts K and L and the recommendations of the EPA
Human Studies Review Board.

A. Completeness of Protocol Submission

The submitted protocol was reviewed for completeness against the required elements
listed in 40 CFR §26.1125. EPA's checklist is appended to this review as Attachment 5. IRB
procedures are on file at EPA, and need not be resubmitted. The only missing required element

FROM:

TO:
REF:

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was the Informed Consent document as submitted to the IRB. The approval letter from the IRB
reports that some unidentified changes were made to the IC. This deficiency does not
compromise a review of the protocol.

In addition to the protocol itself and the associated informed consent document, the
following supporting documents were considered in this review:

• IIRB Approval letter of 4/5/07 (pp. 42-43)

• Subject training materials for aspiration and dosimetry (pp. 59-67)

• Labels for test products (pp. 68-69)

• Toxicology Profile of KBR 3023 (pp. 70-71)

• Site Questionnaire: LNX-001 (pp. 72-75)

• Study Specific Instructions: LNX-001 (p. 76)

• IIRB Membership roster dated 1/2/07 (pp. 77-78)

• CITI Course Completion Record for Scott Carroll (p. 79)

• Email transmittal of protocol from Carroll-Loye Biological Research to
Independent Investigational Review Board (p. 80)

• Email from R Roogow of IIRB to John M. Carley of EPA transmitting IIRB
minutes and asserting that IIRB procedures were unchanged from previous report
(p. 81)

• Minutes of IIRB consideration of LNX-001 at their meeting on 4/5/07 (p. 82)

B. Summary Assessment of Ethical Aspects of the Proposed Research

Here is a summary of our observations about the ethical aspects of the proposed protocol.
Supporting details are in the attachment.

1. Societal Value of Proposed Research: This study will test the field efficacy
against mosquitoes of two conditionally registered formulations of the active
ingredient Picaridin (KBR 3023). EPA requires efficacy testing of these specific
formulations to support continued registration of the products. Direct testing of
the duration of efficacy is important because consumers, who rely on repellents to
avoid insect bites, cannot readily assess the efficacy of a product independent of
EPA's approval. There is potential benefit to society in demonstrating field
effectiveness of picaridin repellents at this concentration, which users may prefer
to other repellent products because of their cosmetic or other qualities.

2. Subject Selection: Subjects will be recruited from a "Volunteer Database" of
previous subjects and others who asked to be added to the database. The database
is racially diverse, 75% in the age range from 20-40 and 25% in the range 40-55.
The youth and high education levels of candidates in the database reflect the
university community where the laboratory is located. Explicit factors exclude as
subjects children, pregnant or lactating women, those in poor health or physical
condition, or those unable to speak and read English. The sample will thus not be

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fully representative of the population of potential repellent users. There is no
indication that any subjects will be from vulnerable populations.

Two "experienced" subjects will serve as untreated controls to verify ambient
biting pressure from mosquitoes in the field. Although it includes additional
inclusion criteria for these experienced subjects, 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.

3.	Risks to Subjects: Risks of three kinds are identified: risks from exposure to the
test material, risks of exposure to biting arthropods, and risks of exposure to
arthropod-borne disease. The test material is accurately characterized in the
Informed Consent Form as an eye irritant, harmful if swallowed—consistent with
the required hazard statements on the registered product label.

All practical steps to minimize subject risks have been taken:

•	Risks from exposure to the test materials are minimized by excluding
candidates with known sensitivity to product ingredients, by monitoring
subjects closely during the dosimetry phase of the research, and by
applying materials in the repellency phase by technicians.

•	Risks from arthropod bites are minimized by excluding candidates with
known sensitivity, by training candidates to remove landing mosquitoes
before they have time to bite, and by minimizing exposure of skin.

•	Risks of contracting disease are minimized by conducting the research in
areas where mosquito-borne viruses have not been detected for at least a
month, and by the same steps that minimize mosquito bites.

Because of the generally low acute and chronic hazard profile of the material, the
design of the research to minimize exposure, and the training of subjects to
aspirate landing mosquitoes before they have time to probe or bite, the probability
of the identified risks is accurately characterized as "extremely small".

4.	Benefits: There are no direct benefits to subjects. This is made clear in the
protocol and Informed Consent, but discussion of benefits is otherwise weak. If
the testing shows good field efficacy the direct beneficiary of the research is
likely to be the sponsor. Assuming eventual regulatory approval, indirect
beneficiaries may also include repellent users who prefer these products to other
repellents.

5.	Risk/Benefit Balance: No practical opportunities to further reduce risk to
subjects while maintaining the robustness of the scientific design have been

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overlooked. The residual risk to subjects is very low, and reasonable in light of
the potential benefits to repellent users, which are likely to be realized.

6. Independent Ethics Review: The Independent Investigational Review Board,
Inc., of Plantation FL has reviewed and approved the protocol and informed
consent materials. The IIRB is independent of the investigators and sponsors.
Documentation of IIRB procedures was not provided, but a statement was made
by the IIRB that this information had not changed since it was previously
submitted to EPA.

7. Informed Consent: The protocol contains a complete and satisfactory
description of the process by which potential treated subjects will be recruited and
informed and for seeking their written consent to participate. A copy of the
Informed Consent Form showing approval by the IIRB is included in the protocol.
The same Informed Consent materials are intended to be used for and are
appropriate for both the untreated control subjects and repellent-treated subjects.

8. Respect for Subjects: 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. Subjects
will be free to withdraw at any time, and will be reminded of this at several
points. Subjects who withdraw will be compensated for time spent up to the point
of withdrawal. Medical care for research-related injuries will be provided at no
cost to the subjects.

C. Compliance with Applicable Ethical Standards

This is a protocol for third-party research involving intentional exposure of human
subjects to a pesticide, with the intention of submitting the resulting data to EPA under the
pesticide laws. Thus the primary ethical standards applicable to this proposal are 40 CFR 26,
Subparts K and L. In addition, the requirements of FIFRA §12(a)(2)(P) for fully informed, fully
voluntary consent of subjects apply. Because the test will be conducted in California, the
provisions of the California Code of Regulations, Title 3, §6710 apply as well. A point-by-point
evaluation of how the requirements of 40 CFR 26 Subparts K and L and the criteria
recommended by the HSRB are addressed is appended as Attachment 1.

These specific deficiencies should be corrected before the research is initiated:

• 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.

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• It is stated erroneously on p. 7 that the concentrations of the active ingredient are
lower than in other picaridin products previously registered by EPA. In fact, the
concentrations of the active ingredient in the test materials are higher than in
other registered picaridin products.

• The data collection forms should be modified to delete the subject's name, and
refer to subjects only by their coded ID to protect their privacy.

When these deficiencies have been corrected, the entire proposal must be re-reviewed and
approved by the IRB before research can proceed or subjects can be enrolled.

40 CFR 26 Subpart L, at §26.1703, as amended effective August 22, 2006, provides in
pertinent part:

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.

The protocol requires that subjects be at least 18 years old and excludes female subjects who are
pregnant or lactating. Thus §26.1703 would not forbid EPA to rely on a study executed
according to this protocol.

D. Summary Assessment of Scientific Aspects of the Proposed Research

The study will test the field efficacy as a mosquito repellent of two conditionally
registered repellent products containing picaridin (KBR 3023). The main objective of the study
is to quantify the efficacy of the formulations to prevent mosquito landings in the field. A
secondary objective of the study is to characterize through dosimetry testing the amount of each
formulation typically self-applied by consumers.

Biting pressure will be monitored for one minute every 15 minutes during the test by two
untreated subjects, each attended by two technicians. Mosquitoes landing on untreated subjects
will be aspirated by the attending technicians to prevent biting and for later identification.

Treated subjects will work in pairs to facilitate observations, and will expose treated skin for 1
minute at 15 minute intervals until they experience a confirmed landing with intent to bite (LIBe)
or until the end of the test period—whichever comes first.

1. Study design: The protocol has two objectives: to test the field repellent efficacy
of the conditionally registered KBR 3023 formulations, and to establish a typical
consumer dose for each product, to be used as the standard dose in the efficacy
phase. These objectives can be met by the study as proposed.

2. Statistical design: The sample size of 10 treated subjects per test material per
field trial is larger than is required by EPA guidelines —large enough to ensure
robust averages across subjects, but small enough to be economical. Two

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untreated subjects per field trial are proposed to establish and confirm ambient
biting pressure; no statistical comparisons to the untreated controls are proposed.
No positive control or negative vehicle control is proposed. Because each test
material is obviously different, efficacy testing will not be blinded. Repellency
will be reported as "Complete Protection Time", calculated as the mean time
across all treated subjects from application of the repellent to the first confirmed
landing with intent to bite (LIBe). Time of LIBes will be reported with a
precision of 15-minute intervals, with standard deviation and 95% confidence
interval.

3. How and to what will human subjects be exposed? In the initial dosimetry
phase, subjects' lower arms and legs will be exposed for a few minutes to test
materials to estimate a "typical consumer dose." In the repellency phase the
standardized typical dose, expressed as volume per unit area, is scaled to the
measured surface area of each subject's limb and applied by a technician to the
subject's forearm or lower leg. The repellent will remain in place for 8 to 14
hours during the field test. In addition, subjects in the field efficacy phase will be
exposed to potential bites by wild mosquitoes, and (with very low probability) to
arthropod-borne diseases.

4. Endpoints and Measures: In the dosimetry phase the applied dose will be
expressed as mass per unit area; a "typical consumer dose" will be calculated for
each formulation as the grand mean of individual mean doses applied. This
standard unit dose will be used for each subject in the repellency phase. In the
field repellency phase, complete protection time (CPT) will be measured as the
mean time from initial application of a typical consumer dose to the first
confirmed LIBe, and will be presented with standard deviation and 95%
confidence interval. Subjects will be trained in the laboratory to recognize a
"LIBe", and to aspirate landing mosquitoes before they have time to bite. In the
field subjects will work in pairs, checking each other as well as themselves. All
reported LIBes will be verified by a research technician.

E. Compliance with applicable Scientific standards

This protocol adequately addresses the following elements according to applicable
scientific standards:

• Scientific objectives

• Experimental design for achieving objectives

• Methods for estimating dose of test material

• Quantification of efficacy of the test materials

• Data collection, compilation and summary of test results

• Discussion of the statistical power of the study.

• Justification for sample size in dosimetry and repellency phases

• Rationale for use of two untreated negative control subjects to monitor biting pressure.

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This protocol does not adequately address the following elements:

•	No explicit hypothesis is stated.

•	No explanation is given for employing a negative control in the dosimetry assay as stated
in §6.2.1 on p. 11.

•	Information on diagnostic statistical tests for normality, or information on how to analyze
non-normally distributed data is lacking.

•	Justification is needed for selection of the Kaplan-Meier statistical analysis

•	The procedure by which limb surface area will be measured is not described in detail.
The exact location of the 4 dosimeters should be recorded for later placement at the same
limb location, and their length before and after application of the test material should
coincide.

Attachments:

1.	Summary Review of Carroll-Loye Protocol WPC-001 dated 1/16/2007

2.	§26.1111 Criteria for IRB approval of research

3.	§26.1116 General requirements for informed consent

4.	§26.1117 Documentation of informed consent

5.	§26.1125 Criteria for Completeness of Proposals for Human Research

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Attachment 1

EPA Protocol Review: WPC-001

Title:	Efficacy Test Protocol #LNX-001: Efficacy Test of KBR 3023 (Picaridin;

Icaridin)-Based Personal Insect Repellents (20% Cream and 20% Spray) with
Mosquitoes under Field Conditions

Date:	10 April 2007

Principal Investigator and any sub-investigators:

Scott P. Carroll, Ph.D.

Participating Laboratories:

Carroll-Loye Biological Research, Inc.

711 Oak Avenue
Davis CA 95616

Sponsor:	Lanxess Corporation

111 RIDC Park West Drive
Pittsburgh PA 15275-1112

IRB:	Independent Investigational Review Board

6738 West Sunrise Blvd. Suite 102
Plantation FL 33313

1. Societal Value of Proposed Research

(a)	What is the stated purpose of the proposed research?

"The objective of this study is to test the repellent efficacy characteristics of the test
materials to mosquitoes. . . . [EJfficacy will be measured as Complete Protection Time, . .
. defined herein as the time between application of test material and the First Confirmed
'Lite with Intent to Bite.'" (p. 5)

(b)	What research question does it address? Why is this question important?

Would the research fill an important gap in understanding?

"This study will test the efficacy of two newly registered formulations of KBR 3023 that
are intended ... to provide information on Complete Protection Time achieved by a
single application of the product. ... As part of the registration review of the 20%
forumulations, US EPA has requested new, US-based efficacy data as a condition of
registration." (p. 5)

(c)	How would the study be used by EPA?

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EPA will consider the study in defining acceptable label claims for repellent efficacy for
the test materials.

(d) Could the research question be answered with existing data? If so, how? If not,
why not?

The concentration of KBR 3023 in this product is higher than that in other registered
repellents containing it, so EPA requires product-specific efficacy data to support its
registration.

(e) Could the question be answered without newly exposing human subjects? If so,
how? If not, why not?

"Human subjects are . . . the target system for the test material, and sufficiently reliable
models for repellency testing have not been developed. In addition, subjects will self-
administer the test articles during dose determination." (p. 6)

2. Study Design

(a) What is the scientific objective of the study? If there is an explicit hypothesis, what
is it?

"The objective of this study is to test the repellent efficacy characteristics of the test
materials to mosquitoes. . . . [EJfficacy will be measured as Complete Protection Time, . .
. defined herein as the time between application of test material and the First Confirmed
'Lite with Intent to Bite.'" (p. 5)

"Determining dosage is part of the main objective of this study. Dosage for repellency
testing will be the mean of the subject means determined ... in the dosimetry portion of
this study." (p. 9)

No explicit hypothesis is stated.

(b) Can the study as proposed achieve that objective or test this hypothesis?

The two objectives cited above can be achieved by the study as proposed.

2.1 Statistical Design

(a) What is the rationale for the choice of sample size?

"In efficacy testing, we will use 10 subjects per treatment and 2 untreated control
subjects per field trial. In the dosimetry potion of the study, 10 subjects will be
engaged to apply each repellent." (p. 18) The rationale for this sample size appears

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on pp. 18-20. A sample size of 10 reflects a compromise between cost and precision;
it is larger than the minimum of 6 required by EPA, and promises to provide an
acceptably robust measure of average complete protection time at reasonable cost.

(b) What negative and positive controls are proposed? Are proposed controls
appropriate for the study design and statistical analysis plan?

"In efficacy testing, we will use ... 2 untreated control subjects per field trial." (p.
18) "There are no controls by which the formulation matrices without the repellent
active ingredient are tested." (p. 12) There are no positive controls. Use of two
untreated controls to confirm continued pest pressure throughout the field testing is
appropriate for the study design. Omission of matrix and positive controls is
appropriate for the study design. No direct comparisons of treated and untreated
subjects are contemplated in the statistical analysis plan.

(d) How is the study blinded?

"Because the treated condition will be evident to experimenters and subjects, and the
test materials are readily distinguishable (opaque lotion versus clear, low viscosity
liquid), neither group will be effectively blinded." (p. 14)

(d) What is the plan for allocating individuals to treatment or control groups?

"All subjects that are not untreated controls will be assigned to the treatment group. . .
. Negative control subjects will be selected exclusively from among experienced
personnel. To be regarded as experienced personnel, a candidate subject must have
an undergraduate (or higher) degree in life sciences, or be a vector control
professional, or have participated in at least five Carroll-Loye repellent efficacy
studies." (pp. 14-15)

(e) Can the data be statistically analyzed?

Yes. The dosimetry phase provides for three applications of each test material per
limb per subject. The three values per limb will be averaged for each subject, and
those individual means will be used to estimate the grand mean across all 10 subjects
for each test material.

The efficacy phase provides for testing in two distinct locations. At each location ten
individual values for CPT will be obtained for each test material and averaged. At
least some of the subjects are likely to be different in the two field tests.

(f) What is the plan for statistical analysis of the data?

Statistics will be computed with the software 'SAS JMP' Version 5.0.1.2 (SAS
Institute, Cary, NC). (p. 34)

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For the spray formulation, the typical consumer dose will be calculated in the
dosimetry phase from the average amount of product (in grams) delivered by subjects
and captured by 4 evenly-spaced gauze 'bracelets' on the subject's forearm or lower
leg. The surface area of subject's limbs is calculated as the product of the length of
the limb by the average of 4 evenly-spaced circumferences. The dosimeter
'bracelets' are 2.5 cm wide, and centered on the points at which the circumferences of
the limb were measured. The surface area of the dosimeters is 4 times the average
limb circumference times 2.5 cm. The unit dose in g/cm2 applied to the dosimeters is
calculated as the weight difference in the dosimeters before and after application
divided by the area of the dosimeters. (Calculation of overall unit dosage in the
dosimetry phase is unnecessarily complicated by scaling up from the area of the
dosimeters to the full skin area of the treated limb; this does not add any precision to
the calculation of the applied dose.) Once calculated, the grand mean unit dose in
g/cm2 is divided by the specific gravity of the formulation to obtain a standard
volumetric unit dose in ml/cm2. This is scaled up to the volumetric dose for the
treated limb of each subject in the efficacy phase, based on the surface area of the
limb to be treated, (pp. 29-30, 34-35)

For the lotion formulation, the typical consumer dose will be calculated in the
dosimetry phase "in a series of three applications analogous to the Spray Sampling. . .
. However, dosimeters are not required, nor are the extensive practice sessions. The
amount applied is the weight difference in the dispensing tube before and after
application." (p. 30)

"Subject effects on dosing behavior will be examined with non-parametric tests for n-
sample independent cases (Kruskal-Wallis tests). In multiple regression analysis, the
average amount of test material intercepted by each subject's dosimeters, as well as
dosing per unit skin surface area, will be examined in relation to the distance from
nozzle to skin, the number of times the pump was actuated, and limb size. The
relationship between dosing behavior and dosage will also be examined with
Spearman-rank correlation tests." (p. 35)

In the efficacy phase "Complete protection time is measured as the length of time
from initial application to the first confirmed LIBe. . . . CPT measured in this way
will yield a single time value for each subject. Mean CPT will be calculated across
all 10 subjects, and will be presented with standard deviation and 95% confidence
interval." (p. 36)

"Mean LIBing pressure will be calculated as the number of LIBes received per
untreated control subject and per period and span of exposure." (p. 36)

"To examine the temporal pattern of failure further, we will employ Kaplan Meier
survival analyses by subject. Kaplan-Meier survival analysis permits us to account
for censoring in the event that any subjects withdraw before failure. In addition, we
will estimate the Kaplan-Meier median, and the time until 25% failure, for each test
product." ((p. 36)

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(g)	Are proposed statistical methods appropriate to answer the research question?

The proposed statistical measures for dose determination and duration of repellency
are appropriate in the case that the data are normally distributed. The protocol does
not address how to analyze non-normally distributed data. Based on efficacy data for
other repellents, a distribution effectively close to a normal fit would be expected, but
the protocol should incorporate a diagnostic test for normality, and discuss data
transformation procedures or alternate non-parametric tests for statistical analyses of
data which may not fit a normal distribution.

The protocol should explain the rationale for choosing the Kruskal-Wallis and the
Kaplan-Meier tests and what information they will provide to answer the research
question.

(h)	Does the proposed design have adequate statistical power to definitively answer
the research question?

Yes. It will produce a data set more robust than most on which past decisions by EPA
concerning acceptable claims of repellency have been based.

2.2 How and to what will human subjects be exposed?

(a)	What is the rationale for the choice of test material and formulation?

The test materials are conditionally registered by EPA as Reg No. 39967-50 (Lotion)
and 39967-53 (Spray). Product specific efficacy testing of this material was required
by EPA as a condition of the product's registration.

(b)	What is the rationale for the choice of dose/exposure levels and the staging of
dose administration?

A "typical consumer dose" will be estimated in the dosimetry phase for each test
material as the average quantity of product applied per unit area of treated skin by ten
subjects. This standard unit dose will be used for all subjects in the efficacy phase.
One limb (forearm or lower leg) of each subject will be treated; exposure to the
repellent will be continuous throughout the period of the efficacy test.

Subjects will also be exposed for one of every 15 minutes during the efficacy phase to
"all or some of wild Aedes vexans, Aedes melanimon, Aedes taeniorhynchus, Culex
tarsalis and Culexpipiens mosquitoes, and possibly other mosquito species that occur
in the same habitats." (pp. 12-13)

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(c) What duration of exposure is proposed?

The dosimetry phase will involve 16 brief exposures to one test material over a period
of about two hours. The repellency phase will last for 8-14 hours, including travel
time; the period of exposure is unclear, but the data collection form (p. 56) can
accommodate reports over a period of 7.5 hours. A second form could be used to
record efficacy over a longer test period.

2.3 Endpoints and Measures

(a)	What endpoints will be measured? Are they appropriate to the question(s) being
asked?

"Variables to be measured" are listed in §10.1. They include "Subject forearm and
lower leg surface area, subject self-dosing behaviors, weight of test materials
delivered to the surrogate skin (gauze dosimeters), and number of mosquito lites with
intent to bite (LIBes) on the treated surface." (p. 28)

These are appropriate endpoints to measure, but the list should include weight of
lotion delivered to the skin in the dosimetry phase. Clarity would be improved if the
language were made consistent between this listing and the discussion of each
measure in sections 10.4.1, 10.4.2, 10.4.3, and 10.4.5. In addition:

•	§10.4.1 defines the formula by which subject limb surface area will be
calculated, but does not describe the procedure by which it will be measured,
or how the location of the centers of the four circumferences will be recorded
to enable later placement of the dosimeters at the same location.

•	§10.4.3 refers incorrectly to "dosimeters of known surface area." The surface
area of the dosimeters is a calculated value, known only as the product of limb
circumference and 2.5 cm, the width of the gauze. To ensure complete
coverage of the full circumference, the gauze material will have to be cut long
and overlapped; thus the area of the dosimeter gauze before application will
be greater than the surface area of the dosimeter once it is in place.

(b)	What steps are proposed to ensure measurements are accurate and reliable?

•	Alternate subjects will be enrolled to ensure adequate sample size

•	Subjects will be trained to recognize a "LIBe"

•	Subjects will work in pairs, checking each other as well as themselves

•	LIBes will be verified by a research technician

(c)	What QA methods are proposed?

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"Protocol Review and Comments must take place before data collection commences.
In-Life Inspection must include observing the measurement and recording of key
variables by subjects and researchers. In addition, the final report will be audited for
completeness and accuracy. A QAU Statement will address compliance and
noncompliance or any omissions in auditing. Findings from the In-Life Inspection
and the Final Report, as well as the QAU Statement will be transmitted to both the
Study Director and to the Sponsor Monitor." (p. 37)

Reports of QAU findings should be incorporated into the final report.

(d) How will uncertainty be addressed? Will point estimates be accompanied by
measures of uncertainty?

"Mean CPT will be calculated across all 10 subjects, and will be presented with
standard deviation and 95% confidence interval." (p. 36)

3. Subject Selection

3.1 Representativeness of Sample

(a) What is the population of concern? How was it identified?

The population of ultimate concern consists of people who would purchase and use
insect repellents. Little information is available to characterize this population, but it
is presumed that users of insect repellents are highly diverse in age, gender, physical
size, general health, attractiveness to biting insects, and other characteristics. The
population from which subjects are recruited appears to be chosen largely on the basis
of convenience, and is not screened for past or likely future use of repellents.

(b) From what populations will subjects be recruited?

"For reasons of practicality and control, we work with people from the community in
which our business is located (Davis, CA). Davis is a university-dominated
community, and so the population demography differs somewhat from nonuniversity
communities. Based on census data, the four major race/ethnicity grouping in the
local population is approximately 70% White, 15% Asian, 8% Hispanic, and 2%
African-American.

"Initial contact is through word-of-mouth and telephone contact with subjects who
have participated in similar previous Carroll-Loye repellent efficacy tests and have
agreed or requested to be in our Volunteer Database. At present that database consists
of 30 males and 28 females. Of the 58 total subjects, 44 (76%) identify themselves as
Caucasian, 8 (14%) as Asian, 3.5 (6%) as Hispanic (white), and 2.5 (4%) as African
American. These proportions match the city's racial distribution quite closely.

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"Three-quarters of the subjects are age 20-40; the remainder is between 40 and 55.
Educational levels are as follows: 7 PhD, 8 MS, 18 in graduate programs, 14 others
with BS/BA, and 10 undergraduate students. Among those who are not students, there
is one professor, 15 professional researchers, 5 professional artists, 3 teachers, 3
office workers, 2 business owners, 2 sales people, 1 massage therapist, and a few
unspecified. The youth of the age distribution reflects the collegiate community.
Education levels are very high for the same reason. Profession is heavily slanted
toward life science researchers and students, reflecting the community as well as
perhaps the nature of the studies and the people who are interested in participating in
them. While many of the subjects with whom we have worked show a keen and
enduring interest in participating, such interest is not likely predictive of anything
atypical about the results stemming from their presence in a study.

"Compared to the US population (all potential repellent users), our sampling frame
tends to under-represent blacks and over-represent Asians. It is also young, and well
educated. Based on review of the scientific literature regarding individual differences
in repellent performance and attractiveness to mosquitoes, we conclude that those
deviations from the ideal frame will not influence the representativeness of the
results, or their generalizability to the greater population. Lastly, because our
Volunteer Database cohort is comprised by individuals who regularly spend time in
outdoor setting (and thereby may have relatively frequent encounters with biting
arthropods), this group is probably appropriate for insect repellent users in general."
(pp. 22-23)

(c)	Are expected participants representative of the population of concern? If not,
why not?

By excluding children, pregnant or lactating women, non-English speakers, and those
in poor physical condition, among others, the exclusion criteria will mean that
participants will not be representative of at least some segments of the population of
concern.

(d)	Can the findings from the proposed study be generalized beyond the study
sample?

Yes.

3.2 Equitable Selection of Subjects

(a) What are the inclusion/exclusion criteria? Are they complete and appropriate?

Inclusion: age 18-55, written consent, speak and read English, (p. 16)

Additional inclusion criteria specific to the two untreated subjects: "To qualify for
candidacy as a subject who exposes untreated skin, an individual must be regarded as

Page 15 of 28

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competent to do so by the Principal Investigator, must have participated in at least
five prior Carroll-Loye repellent efficacy trials, or have participated in at least three
such trials and have a least two years of experience as a college life sciences major, or
be professionally employed in vector control services." (pp. 16-17)

This statement of criteria for untreated controls paraphrases and differs in
insignificant detail from other statements of the same criteria for untreated controls in
sections 8.2 and 8.3.1, on pp. 14-15. The criteria should be stated only once,
preferably in §9.1.2.

Exclusion: hypersensitivity to mosquito bites; sensitivity to any product ingredients;
poor physical condition; unwillingness to submit to brief query about personal
condition; use of insect repellent within one day before study; unwillingness to
abstain from alcohol, smoking, and perfumed products; pregnant or lactating; unable
to apply test materials; unable to see mosquitoes on skin or to remove landing
mosquitoes; student or employee of Study Director; unaccustomed to outdoor
activity, (pp. 15-16)

In general, these criteria for inclusion and exclusion appear appropriate. More
discussion of how they affect the representativeness of the sample is desirable.

(b)	What, if any, is the relationship between the investigator and the subjects?

Subjects are recruited from "the community in which [the Investigator's] business is
located .... Initial contact is through word-of-mouth and telephone contact with
subjects who have participated in previous Carroll-Loye repellent efficacy tests and
have agreed or requested to be in our Volunteer Database." (p. 22)

"Our Volunteer Database has grown through people who . . . learn of our work from
persons who have worked with us; we do not direct or actively encourage that
process. In those initial contacts, the prospective subjects typically have prior
knowledge of our work and its general purpose, and what their fellows have
experienced in prior studies. . . . About half of our subjects are present or past
University of California—Davis . . . students ... in life science programs. Students
in the laboratory of the Principal Investigator who depend on him directly for
employment or scholastically are not eligible to participate." (p. 23)

(c)	If any potential subjects are from a vulnerable population, what is the
justification for including them?

No subjects from a vulnerable population are proposed.

(d)	What process is proposed for recruiting and informing potential subjects?

The recruiting/informing process to be used is extensively described in the protocol
on pp. 24-25 and in the informed consent document.

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(e) If any subjects are potentially subject to coercion or undue influence, what
specific safeguards are proposed to protect their rights and welfare?

"Students in the laboratory of the Principal Investigator who depend on him directly
for employment or scholastically are not eligible to participate." (p. 23)

3.3 Remuneration of Subjects

(a)	What remuneration, if any, is proposed for the subjects?

"[E]ach research study participant will receive a cash payment of $20 per hour. ... If
you are designated as an 'alternate subject' you will be paid for the hours you spent
being trained, plus you will receive a payment of $50 to compensate for being
inconvenienced." (p. 51)

(b)	Is proposed remuneration so high as to be an undue inducement?

No.

(c)	Is proposed remuneration so low that it will only be attractive to economically
disadvantaged subjects?

No.

(d)	How and when would subjects be paid?

"Payment will be made at the end of each visit or whenever you withdraw from the
study." (p. 51)

4. Risks to Subjects

4.1 Risk characterization

(a) Have all appropriate prerequisite studies been performed? What do they show
about the hazards of the test materials?

"A complete toxicology package required for the registration of an insecticide
including acute and subchronic neurotoxicity and metabolism studies was conducted.
. . . KBR 3023 and its formulated products have low acute toxicity by oral, dermal, or
inhalation routes of exposure. They were not irritating to the skin nor sensitizers in
the animal studies. A slight to moderate ocular irritation was observed in the animal
studies." (p. 70)

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The lotion formulation bears the signal word "Warning" because the product causes
"substantial but temporary eye injury." (p. 68)

(b) What is the nature of the risks to subjects of the proposed research?

Risks are of three kinds: the risk of reaction to the repellents tested, the risk of
reaction to arthropod bites, and the risk of contraction of an arthropod-borne disease.

"The repellent active ingredient has a low acute and chronic risk profile. . . . The
concentration of the active ingredient in the product being tested is lower than that of
other products currently EPA-registered and marketed in the US." (p. 7) This passage
in the protocol asserts inaccurately that the concentration of AI in the products being
tested is lower that other currently registered picaridin repellents, and fails to mention
the potential for eye irritation. Product risks are better characterized in the informed
consent document: the repellent "will irritate the eyes on contact, and it is harmful if
swallowed." (p. 49).

"[E]ven if you have not had a serious skin reaction to a mosquito bite previously, it is
possible that such a reaction could occur if you receive any bites during this study.
Swelling, redness and itching near the site of the bite are all symptoms of an allergic
reaction to a mosquito bite." (p. 49)

"[TJhere is a slight possibility that you will contract a disease carried by mosquitoes if
you are bitten, such as West Nile virus or equine encephalitis." (p. 49)

No numerical probability is estimated. Potential subjects are told (with respect to the
risks of mosquito bites and of contracting an arthropod-borne disease) "since you are
wearing repellent and/or other protective measures, and are carefully watching for
mosquitoes that land and try to bit, you are probably at no more risk than you would
experience when engaged in normal outdoor activities in a similar rural area at the
same time of year. . . . Since you will work to quickly remove mosquitoes before they
have an opportunity to bite, and few of the mosquitoes present are likely to carry the
virus, your chances of getting West Nile fever or another disease from a mosquito
bite are probably extremely small." (p. 49)

4.2 Risk minimization

(a) What specific steps are proposed to minimize risks to subjects?

• The risk of a skin reaction to a mosquito bite is reduced by excluding
candidate subjects who are aware of having a history of such reaction.

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•	Candidates with known allergic reactions to insect repellents and common
cosmetics are excluded.

•	Subjects will be trained to quickly remove any mosquitoes that attempt to bite
them, before penetration or injection of saliva if possible.

•	Mosquitoes used for aspirator training will be lab-reared and disease-free.

•	Subjects will be instructed to cover any exposed skin immediately if more
than one mosquito attempts to bite during any exposure period.

•	Subjects will expose small areas of treated skin for only 4 minutes per hour.
Other parts of the body will be protected with provided gloves, headnets and
full body suits made of Tyvek, through which mosquitoes to not bite.

•	At the end of each one-minute exposure period subjects will move away from
the area with mosquito activity. Partners will assist each other to cover the
treated area.

•	Subjects will be teamed with a partner for joint observation; experienced
technical personnel will be present at all times to assist.

•	Field tests are conducted in an area where West Nile virus has not been
detected by county or state agencies for at least a month.

•	Only 2 untreated controls to confirm biting pressure.

•	Exposure of untreated controls for no more than 4 min/hour; exposed skin
may be covered immediately following the first LIBe.

•	Untreated controls will be attended by two assistants with aspirators to
remove any mosquitoes that land with intent to bite.

•	First Aid materials will be available on-site

•	Epi-Pens will be on-site to treat anaphylactic allergic reactions.

•	No control with formulation matrix exclusive of active repellent ingredients.

•	A physician who has read the protocol and discussed the research with the
Study Director will be on call on the day of field testing.

(b) How do proposed dose/exposure levels compare to established NOELs/NOAELs
for the test materials?

Actual dose levels will only be established by the results of the first, dosimetry phase
of the proposed study. The dosimetry phase is intended to establish a "typical
consumer dose".

At an estimated dose rate of about 1 g/600 cm2, each treated subject will receive a
dose of about 1000 mg of repellent. Since the concentration of the products is 20%,
this is the equivalent of 200 mg picaridin. Because of the ethanol in the formulation
this figure is adjusted by an "ethanol enhancement" factor of 2.26, yielding an
adjusted dose of 452 mg, or 6.5 mg/kg for a 70 kg adult. The NOAEL for acute
dermal toxicity in the rat for picaridin is 5000 mg/kg bodyweight, picaridin is less
readily absorbed by human skin than by rat skin, and we do not expect the inert
ingredients other than ethanol to affect the systemic dermal toxicity. Thus the
estimated margin of exposure for picaridin acute dermal toxicity is not less than and
may be substantially greater than 5000/6.5 or 769.

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(c)	What stopping rules are proposed in the protocol?

"Any subject showing adverse skin reactions will immediately stop further
participation." (p. 26)

"Subjects are instructed to immediately cover exposed skin with the protective mesh
provided if more than one LIBe occurs in a one-minute exposure period. Similarly, if
subjects receive a LIBe and recall receiving another in either of the two previous
exposure periods, they are to ask their data recording technician to verify the
recollection from the data record. If verified, the subject is instructed to immediately
cover the limb as above." (p. 33)

"If more than one mosquito attempts to bite you on your treated skin in one of the
one-minute periods, or if one mosquito attempts to bite in two of three consecutive
exposure periods (that is, 15 or 30 minutes apart), you should cover the skin and not
expose it again." (p. 48)

(d)	How does the protocol provide for medical management of potential illness or
injury to subjects?

"If you are injured as a result of being in this study, a consulting physician who is
aware of the study will be contacted immediately by telephone. Medical treatment
will be available from a health care facility." (p. 50)

(e)	How does the protocol provide for safety monitoring?

"[TJechnical personnel will monitor, and subjects will self-monitor, for allergic and
irritant skin reactions, particularly redness, edema, itching or pain, and report any
such reactions to the Study Director. Any subject showing adverse skin reactions will
immediately stop further participation. The treated skin will be gently washed with
clean water and mild soap to remove the test product, and the area will be gently
dried with a clean towel. The subject will be removed from further exposure to
mosquitoes.

"On the day of testing, a physician who has read the protocol and discussed the
research with the Study Director will be on call. In unlikely event of a Type 1
allergic reaction (anaphylaxis), we will contact 9-1-1 by cellular or satellite telephone
and cooperate as instructed with emergency personnel. . . .

"[T] Study Director will assess skin condition of affected subjects should any bites
inadvertently occur during efficacy testing."

"As part of Medical Management, the Study Director will record all benign and
adverse health observations." (pp. 26-27)

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(f) How does the protocol provide for post-exposure monitoring or follow-up? Is it
of long enough duration to discover adverse events which might occur?

"All subjects are asked to contact the Study Director and a physician of their own
choice at any time should they develop a rash . . . within 48 hours of the conclusion of
the test day." (p. 27) While subjects may indeed be asked to do this, the Informed
Consent Document is silent on this point.

"If you experience any of the symptoms described above [flu-like symptoms (unusual
tiredness or unusually severe headaches, body aches, fever), swollen glands or a rash
on the trunk] in the month following the field test you should contact a medical
practitioner and inform the Principal Investigator." (p. 49)

(g) How and by whom will medical care for research-related injuries to subjects be
paid for?

"Carroll-Loye Biological Research will cover the costs of such medical treatment that
are not covered by your own insurance or by a third party. If necessary, Carroll-Loye
Biological Research will transport you to receive medical attention and pay costs
associated with the reasonable and appropriate treatment for any injuries incurred as a
result of participation in the study." (p. 50)

5. Benefits

(a) What benefits of the proposed research, if any, would accrue to individual subjects?

"There are no immediate benefits to you from your participation." (p. 50)

(b) What benefits to society are anticipated from the information likely to be gained
through the research?

"Against the slight risks are balanced substantial and reasonably likely benefits. Insect-
borne disease is of growing significance in the United States and around the world where
U.S. citizens are active. Moreover, discomfort associated with nuisance biting restricts
many work and pleasure activities. Because EPA registration requires efficacy data, a
test such as that proposed here is the only path toward further product development and
greater availability of new KBR 3023 mosquito repellents to consumers in the United
States." (pp. 8-9)

"[B]y serving as a participant you may assist in making new insect repellent products
available to consumers." (p. 50)

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The direct beneficiary of the research is likely to be the sponsor. Assuming eventual
regulatory approval, indirect beneficiaries would include those repellent users who prefer
the new formulations to previously available repellents.

(d) What is the likelihood that each identified societal benefits would be realized?

The testing is likely to demonstrate that the new formulations are effective, and thus the
sponsor is likely to realize a direct benefit from the research. Realization of other societal
benefits will depend on consumer acceptance of the new formulations.

6. Risk/Benefit Balance

(a) How do the risks to subjects weigh against the anticipated benefits of the research,
to subjects or to society?

The protocol systematically reduces risks to subjects without reducing the robustness of
the scientific design. No reasonable opportunities to further reduce subject risk have
been overlooked. The resulting residual risk to subjects is very low—as low as or lower
than the risk to anyone engaged in outdoor activity where mosquitoes are active. The
potential benefits to repellent users from a wider variety of effective repellents with
different cosmetic characteristics are likely to be realized, and make the residual risks to
subjects in this proposed research reasonable.

7. Independent Ethics Review

(a) What IRB reviewed the proposed research?

Independent Investigational Review Board, Plantation FL

(b) Is this IRB independent of the investigators and sponsors of the research? Yes

(d) Is this IRB accredited? If so, by whom?

Not reported. IIRB is not listed as accredited on the AAHRPP website.

(e) Does this IRB hold a Federal-Wide Assurance from OHRP?

Not reported. IIRB is not listed as holding an FWA on the OHRP website.

(d) Are complete records of the IRB review as required by 40 CFR 26.1125 provided?

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The transmittal of the protocol and related materials to the IIRB, the IIRB's approval
letter, and minutes of the IIRB discussion are provided. The Informed Consent document
as submitted to the IIRB is not provided. No other correspondence is provided by the
Investigator.

Documentation of IRB procedures was not provided, but a statement is included from the
IIRB (p. 81) that there had been no changes since this information had previously been
submitted to EPA.

(e) What standard(s) of ethical conduct would govern the work?

"U.S. EPA Good Laboratory Practice Regulations (40 CFR 160); 40 CFR 26 subparts K
and L; FIFRA §12(a)(2)(P); California State EPA Department of Pesticide Regulation
study monitoring (California Code of Regulations Title 3, Section 6710)." (p. 8)

8. Informed Consent

(a)	Will informed consent be obtained from each prospective subject? Yes.

(b)	Will informed consent be appropriately documented, consistent with the
requirements of 40 CFR 26.1117? Yes.

(c)	Do the informed consent materials meet the requirements of 40 CFR 26.1116,
including adequate characterization of the risks and discomforts to subjects from
participation in the research, the potential benefits to the subject or others, and the
right to withdraw from the research? Yes.

(d)	What is the literacy rate in English or other languages among the intended research
subjects?

100%. English literacy is a requirement for participation.

(e)	What measures are proposed to overcome language differences, if any, between
investigators and subjects? n/a

(f)	What measures are proposed to ensure subject comprehension of risks and
discomforts?

Frequent opportunities to ask questions.

(g)	What specific procedure will be followed to inform prospective subjects and to seek
and obtain their consent?

See pp. 22-25 and Informed Consent Form.

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(h) What measures are proposed to ensure fully voluntary participation and to avoid
coercion or undue influence?

Candidates are offered repeated opportunities to decide not to participate; participants are
offered repeated opportunities to withdraw. Exclusion factors rule out participation by
employees or students of the Study Director. Recruitment of alternate subjects ensures
that subjects will not be reluctant to withdraw lest the validity of the investigation be
compromised.

9. Respect for Subjects

(a) How will information about prospective and enrolled subjects be managed to
ensure their privacy?

Subjects are identified by name and by number. Only the number is used on data
collection forms for the repellency phase, but the full name as well as the subject number
appears unnecessarily on all other sample forms provided (pp. 54-58.) It would be better
to use only the subject number on all but one master directory that linked names to
numbers. Recruitment of alternate subjects provides an opportunity for discrete
withdrawal without explanation. Subjects are told they "may access [their] own records
by contacting the Study Director," and that they will not be identified in any published
reports of the study, (p. 51)

(b) How will subjects be informed of their freedom to withdraw from the research at
any time without penalty?

Subjects are so informed in the recruitment process (pp. 22-25) and in the Informed
Consent Form.

Subjects who decide not to participate will simply go their way. Subjects identified as
alternates, and any who withdraw from the research, will be paid for their time (p. 51).
How soon after they withdrew subjects in the efficacy phase would be able to leave the
field study site would depend on how they got there; this is not explained.

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Attachment 2

§ 26.1111 Criteria for IRB approval of research
Protocol LNX-001

Criterion

Y/N

Comment/Page Reference

(a)(1 )(i) Risks to subjects are minimized by using procedures which are consistent with
sound research design and which do not unnecessarily expose subjects to risk.

Y



(a)(1)(H) Risks to subjects are minimized, whenever appropriate, by using procedures
already being performed on the subjects for diagnostic or treatment purposes.

N/A



(a)(2) Risks to subjects are reasonable in relation to anticipated benefits, if any, to
subjects, and the importance of the knowledge that may reasonably be expected to
result. In evaluating risks and benefits, the IRB should consider only those risks and
benefits that may result from the research (as distinguished from risks and benefits
subjects would receive even if not participating in the research). The IRB should not
consider possible long-range effects of applying knowledge gained in the research (for
example, the possible effects of the research on public policy) as among those
research risks that fall within the purview of its responsibility.

Y



(a)(3) Selection of subjects is equitable, taking into account the purposes of the
research and the setting in which it will be conducted, and being particularly cognizant
of the special problems of research involving vulnerable populations, such as
prisoners, mentally disabled persons, or economically or educationally disadvantaged
persons.

Y



(a)(4) Informed consent will be sought from each prospective subject or the subject's
legally authorized representative, in accordance with, and to the extent required by
§26.1116.

Y



(a)(5) Informed consent will be appropriately documented, in accordance with, and to
the extent required by §26.1117.

Y



(a)(6) When appropriate, the research plan makes adequate provision for monitoring
the data collected to ensure the safety of subjects.

Y



(a)(7) When appropriate, there are adequate provisions to protect the privacy of
subjects and to maintain the confidentiality of data.

Y



(b) When some or all of the subjects are likely to be vulnerable to coercion or undue
influence, additional safeguards have been included in the study to protect the rights
and welfare of these subjects.

N/A



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Attachment 3

§26.1116 General requirements for informed consent
Protocol LNX-001

Criterion

Y/N

Comment/Page Reference

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 or the subject's legally authorized representative

OK

All subjects will provide legally effective
informed consent.

An investigator shall seek such consent only under circumstances that provide the
prospective subject or the representative sufficient opportunity to consider whether or
not to participate and that minimize the possibility of coercion or undue influence

OK

The procedure described in §9.1.6.3
provides sufficient opportunity to
consider. . . and minimizes the
possibility of coercion or undue
influence.

The information that is given to the subject or the representative shall be in language
understandable to the subject or the representative

OK

Information is clearly presented in plain
English

No informed consent, whether oral or written, may include any exculpatory language
through which the subject or the representative is made to waive or appear to waive
any of the subject's legal rights, or releases or appears to release the investigator, the
sponsor, the institution or its agents from liability for negligence

OK

The IC contains no exculpatory
language

(a) In seeking informed consent the following information
shall be provided to each subject

(1) A statement that the study involves research, an explanation of the
purposes of the research and the expected duration of the subject's
participation, a description of the procedures to be followed, and identification
of any procedures which are experimental

OK

p. 44

(2) A description of any reasonably foreseeable risks or discomforts to the
subject

OK

pp. 48-50

(3) A description of any benefits to the subject or to others which may
reasonably be expected from the research

OK

p. 50

(4) A disclosure of appropriate alternative procedures or courses of
treatment, if any, that might be advantageous to the subject

OK

p. 50

(5) A statement describing the extent, if any, to which confidentiality of
records identifying the subject will be maintained

OK

p. 51

(6) For research involving more than minimal risk, an explanation as to
whether any compensation and an explanation as to whether any medical
treatments are available if injury occurs and, if so, what they consist of, or
where further information may be obtained

OK

Compensation p. 51
Treatment p. 50

(7) An explanation of whom to contact for answers to pertinent questions
about the research and research subjects' rights, and whom to contact in the
event of a research-related injury to the subject

OK

p. 51

(8) A statement that participation is voluntary, refusal to participate will
involve no penalty or loss of benefits to which the subject is otherwise
entitled, and the subject may discontinue participation at any time without
penalty or loss of benefits to which the subject is otherwise entitled

OK

p. 51

(b) When appropriate, one or
more of the following elements
of information shall also be

(1) A statement that the particular treatment or procedure may involve risks to
the subject (or to the embryo or fetus, if the subject may become pregnant)
which are currently unforeseeable

OK

p. 50

(2) Anticipated circumstances under which the subject's participation may be
terminated by the investigator without regard to the subject's consent

OK

p. 52

(3) Any additional costs to the subject that may result from participation in the
research

OK

p. 51

(4) The consequences of a subject's decision to withdraw from the research
and procedures for orderly termination of participation by the subject

N/A



(5) A statement that significant new findings developed during the course of
the research which may relate to the subject's willingness to continue
participation will be provided to the subject

OK

p. 50

(6) The approximate number of subjects involved in the study

OK

p. 45

(e) If the research involves intentional exposure of subjects to a pesticide, the subjects
of the research must be informed of the identity of the pesticide and the nature of its
pesticidal function.

OK

p. 44

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Attachment 4

§26.1117 Documentation of informed consent
Protocol LNX-001

Criterion Y/N Comment/Page Reference

(a) Informed consent shall be documented by the use of a written consent form
approved by the IRB and signed by the subject or the subject's legally authorized
representative. A copy shall be given to the person signing the form.

OK

Form pp. 44-53
Procedures pp. 24-25

(b)(1) The consent form may be a written consent document that embodies the
elements of informed consent required by §26.1116. This form may be read to the
subject or the subject's legally authorized representative, but in any event, the
investigator shall give either the subject or the representative adequate opportunity to
read it before it is signed; or

OK
N/A

Proposed IC form meets requirements
of §26.1116; procedure described in
protocol §9.1.6.3 provides adequate
opportunity to read it before it is
signed.

(b)(2) The consent form may be a short form written consent document stating that the
elements of informed consent required by §26.1116 have been presented orally to the
subject or the subject's legally authorized representative. When this method is used,
there shall be a witness to the oral presentation. Also, the IRB shall approve a written
summary of what is to be said to the subject or the representative. Only the short form
itself is to be signed by the subject or the representative. However, the witness shall
sign both the short form and a copy of the summary, and the person actually obtaining
consent shall sign a copy of the summary. A copy of the summary shall be given to the
subject or the representative, in addition to a copy of the short form.



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Attachment 5

40 CFR 26.1125 Submission of proposed human research for EPA review
Carroll-Loye LNX-001 (Version of 4/10/2007)

Any person or institution who intends to conduct or sponsor human research covered by §26.1101 (a) shall, after receiving
approval from all appropriate IRBs, submit to EPA prior to initiating such research all information relevant to the proposed
research specified by §26.1115(a), and the following additional information, to the extent not already included:

Requirement

Y/N

Comments/Page Refs

The following Information, to the
Extent not already included:

§1125(a)
a discussion of:

(1) The potential risks to human subjects

Y

pp. 6-9, 48-50

(2) The measures proposed to minimize risks to the human subjects;

Y

pp. 6, 7, 11, 13, 15, 22-24, 27-29

(3) The nature and magnitude of all expected benefits of such
research, and to whom they would accrue

Y

pp. 8-9, 50

(4) Alternative means of obtaining information comparable to what
would be collected through the proposed research; and

Y

p. 6

(5) The balance of risks and benefits of the proposed research.

Y

00

CL
Q_

§1125(b): All information for subjects and written informed consent
agreements as originally provided to the IRB, and as approved by the IRB.

Y

pp. 44-53 (only approved version)

§1125(c): Information about how subjects will be recruited, including any
advertisements proposed to be used.

Y

pp. 22-25. No advertisements used

§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

pp. 24-25

§1125(e): All correspondence between the IRB and the investigators or
sponsors.

Y

pp. 72-82

§1125(f): Official notification to the sponsor or investigator. . . that research
involving human subjects has been reviewed and approved by an IRB.

Y

p. 42-43

all information relevant to the proposed research
specified by § 26.1115(a)

(1) Copies of

•	all research proposals reviewed by the IRB,

•	scientific evaluations, if any, that accompanied the proposals
reviewed by the IRB,

•	approved sample consent documents,

•	progress reports submitted by investigators, and reports of injuries to
subjects.

Y
n/a

Y
n/a

pp. 1-41; 44-71

None accompanied the proposal
p. 44-53

Initial review of new proposal

(2) Minutes of IRB meetings ... 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

Y

Y

n/a
n/a

IRB minutes p. 82

Unidentified changes required in IC
No controverted issues

(3) Records of continuing review activities.

n/a

n/a for protocols

(4) Copies of all correspondence between the IRB and the investigators.

Y

Provided by investigator; pp. 42-43;
72-82

(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

Y

pp. 77-78

(6) Written procedures for the IRB in the same detail as described in
§26.1108(a) and §26.1108(b).

N

On file with EPA (Claimed CBI)

(7) Statements of significant new findings provided to subjects, as required by
§26.1116(b)(5).

n/a

n/a for protocols

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