Page 1 of 36 UNITED STATES ENVIRONMEN TAL PROTECTION AGENCY WASHINGTON D.C., 20460

OFFICE OF CHEMICAL SAFETY AND

POLLUTION PREVENTION

March 20, 2014

MEMORANDUM

SUBJECT: Science and Ethics Review of USDA Pr otocol for Laboratory Evaluation of Bite Protection from Repellent-t reated Clothing for the United States Military

FROM: Kevin J. Sweeney, Senior Entomologist Registration Division Office of Pesticide Programs

Kelly Sherman, Human Research Ethics Review Officer

Office of the Director Office of Pesticide Programs

TO: Deborah McCall, Chief, Insecticides Branch Registration Division Office of Pesticide Programs

REF: Bernier, U. (2014) Laboratory Evaluati on of Bite Protec tion from RepellentImpregnated Clothing for the United St ates Military. Unpublished document prepared by United States Department of Agriculture – Agricultural Research Service, Center for Medical, Agricultur al and Veterinary Entomology. March 7, 2014. 210 p.

We have reviewed the referenced protocol for a laboratory test ofmosquito repellentimpregnated clothing for the United States Military from both scientific and ethics perspectives.

This review assesses the scientific aspects of th e proposed research for a special efficacy study to assess etofenprox-treated U.S. Military uniforms in terms of the recommendations of the EPA

and of the EPA Human Studies Review Board. Et hical aspects of the pr oposed research are

assessed in terms of the standards defi ned by 40 CFR 26 subparts K and L and the

recommendations of the EPA Hu man Studies Review Board.Page 2 of 36 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 appe nded to this review as Attachment 5. All elements of required documentation are provid ed in the submitted protocol package.

Volume 1 of USDA’s submitted package includes the following documents—all

considered in this review:

 WIRB-approved protocol da ted 2/28/14 (pp. 5-192)

 WIRB-approved informed consent fo rm (approved 3/04/14) (pp. 193-203)

 WIRB-approved recruiting advertisement (p. 204)

 WIRB-approved telephone script for re ceiving phone calls in response to advertisement (p. 205)

Volume 2 of USDA’s submitted package includes documentation of communications with WIRB, as well as copies of CVs and ethi cs training certifications for the principal investigator and staff.

Volume 3 of USDA’s submitted package provi des statistics analysis for the proposed study.

B. Summary Assessment of Ethical Asp ects of the Proposed Research

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

1. Societal Value of Proposed Research: This study is designed to determine the bite protection level of etofenprox-treated U.S. Military Fire Resistant Army Combat Uniforms (FRACUs) treated initially at an app lication rate of 1% wt/wt, and to assess the bite protection performance after 0x, 20x, and 50x washes. The results of this research will allow for determination of whether etofenprox-treated FRACUs meet the Department of Defense’s specifications for mi nimum bite protection level. The research has societal value because U.S. military personn el serving domestically and abroad are at risk of contracting insect-transmitted diseases . Currently, permethrin is the only pesticide that is EPA registered for treatment of military uniforms. Due to global issues regarding

disease vector resistance to pyrethroids such as permethri n, other insecticide candidates must be considered. This protocol provides a method for evaluating the bite protection of

fabrics that are treated or impregnated with substances that repel or reduce arthropod

bites.

2. Subject Selection: Ten adult subjects will be recruited from the general population in Gainesville, Florida (8 initia lly assigned for participat ion, plus two alternates). Participants will self-identify in response to a printed advertisement in a local newspaper (the Gainesville Sun) or pos ted on bulletin boards in University of Florida buildings. Callers responding to the advertisement will be screened, scheduled for informed consentPage 3 of 36 meetings, and enrolled. While it is possible that people who respond to the advertisement are different in some unknowable ways from those who do not respond, there is no reason to think that respondents in the Gainesville, Florida area are not typical of people who would respond to these types of advertisements in other ar eas of the United States.

3. Risks to Subjects: Risks to subjects include the risk of exposure to biting mosquitoes; the risk of exposure to disease vectors; the risk of exposure to the test material; risks related to receiving an unexp ected result on a pregnancy tes t; and the risk of a loss of confidentiality related to the pregnancy test and subjects’ pa rticipation in the study. Risks are minimized in the protocol by excluding can didates known to be hype rsensitive to or phobic of mosquito bites; using disease- free colony-raised mosquitoes; excluding

candidates known to be sensitive to the test material; applying clea r stopping rules; and by incorporating procedures to keep the subj ects’ identities and results of pregnancy testing private, and to permit discrete withdrawal. All practi cal steps to minimize subject risks have been taken, and the remaining ri sks have a low probab ility of occurrence.

4. Benefits: This research offers no direct benefi ts to subjects, but may provide indirect benefits to subjects and societ y by providing data that could be used by EPA to register a novel repellent treatment for military clothi ng, thereby allowing for better protection of American military forces from nuisance bite s and bites that lead to arthropod-borne diseases. The results may also lead to better protection of U.S. civilians both domestically and while they travel abroad because novel repellents may be incorporated into civilian clothing as a potentially better alternative to the repellent-trea ted clothing already

available on the market.

5. Risk/Benefit Balance: No practical opportunities to furthe r reduce risk to subjects while maintaining the robustness of the scientific design have been overlooked. The residual risk to subjects is very low, and reasonable in light of the potential benefits of the data to society.

6. Independent Ethics Review: The Western Institutional Review Board (WIRB) has reviewed and approved the protocol, informed consent form, and recruitment materials. WIRB is independent of the investigators a nd sponsors. Satisfactory documentation of WIRB procedures and membership is on file with the Agency and has been provided to the HSRB members with the backgro und materials for this protocol.

7. Informed Consent: The protocol contains a complete and satisfactory description of the process by which potential subjects will be r ecruited and informed, and the process for seeking their consent to participate. A copy of the WIRB-approved consent documents meeting all requirements of 40 CFR §§26.1116 a nd 26.1117 is included in the proposal.

8. Respect for Subjects : Subject-identifying information will be recorded only once; all subsequent data records and reports will refe r to individual subjects only by an arbitrary code. Provision is made for discrete handling of the pregnancy testing that is required of female subjects on the day of testing. Candidate s and subjects will be informed that they are free to decline to participate or to wit hdraw at any time for any reason. Subjects whoPage 4 of 36 withdraw will be compensated for time spent up to the point of w ithdrawal. Medical care for research-related injuries will be provi ded by the sponsor Landis International at no cost to the subjects.

C. Compliance with Applicable Ethical Standards

This is a protocol for third-party resear ch involving intentio nal 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 standa rds 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 appl y. A point-by-point evaluation of how this protocol addresses the requirements of 40 CFR 26 Subparts K and L and the criteria recommended by the HSRB is appended as Attachment 1.

EPA Ethics Comments

Before the research is conducted, the documents should be revised as follows and resubmitted for review by the approving IRB:

 In section 8.6 of the protocol (V1:33), titled “Deta iled Stepwise Test Procedure,” insert an explanation of how, when, and by whom subjects’ hands and arms will be inspected for cuts or other skin conditions. Language similar to wh at appears on page 4 of the informed consent (V1:196) form would suffice.

 In section 8.6 of the protocol (V1:33), titled “Deta iled Stepwise Test Procedure,” insert an explanation of how the pregnancy testing for female subjects will be handled, clarifying where in the sequence of stepwise procedures the pregnancy testing will occur. Language similar to what appears on page 3 of the info rmed consent form (V1:195) or in section 8.1.4 of the protocol (V1:24) would suffice.

 Please clarify which member of the research team will verify pregnancy test results of female subjects who desire to remain in the study af ter taking the pregnancy test. The protocol and consent form are inconsistent on this point. Sect ion 8.1.3 of the protocol says that the result must be presented “to a staff member” (V1:24), and section 8.1.4 of the protocol states that the result must be shown to “the study director or an appropriate desi gnee for verification of negative results” (V1:24). The cons ent form states that if, after taking the test, a subject still wishes to participate, she must show the result to a female laboratory technician. (V1:195) A

female member of the research team would be the best person to verify negative pregnancy

test results.

 Please revise the first sentence in section 11.0 of the protocol, titled “B enefits and to Whom Benefits Accrue,” as follows: “While there are no direct bene fits to the subjects participating in this research study beyond a small compensation for their time , there are...” The proposed payment to subjects is considered compensation for lost time and inconvenience,Page 5 of 36 not a benefit of participating in the resear ch. This study provides no direct benefits to subjects. (V1:45)

 In section 8.1.2 of the protocol, titled “Inclu sion/Exclusion Criteria,” consider expanding

exclusion #6 as follows: “Exclusion of people known to be sensitive to the test material, pesticides, or other chemical products ” (V1:23)

 In section 8.1.2 of the protocol, titled “Inc lusion/Exclusion Criteria” (V1:23), add an exclusion for people with open cuts or scrapes or skin conditions such as psoriasis or eczema on their hands or forearms. Cut, scrapes or othe r skin conditions might increase the risk of skin reactions or sensitivity during the testing. Also, add this exclusi on to the “Restrictions” section of the consent form (V1:195).

 In the “Study Procedures” section of the consen t form (V1:196), insert text similar to what appears below as #2, and adjust the numbering of the subsequent procedures accordingly: “2. It is important that you NOT be in this study if you are pregnant. So, before the testing begins, each female volunteer will be asked to go to a private area and will be given a home pregnancy test kit. A female re searcher will be able to explain how to use it and answer questions. If you are a female , you will be asked to take the test in a private restroom. If, after taki ng the test, you still wish to participate in the study, you will be asked to show the result of the test to a female laboratory technician so that she can verify that you are not pregnant. If you withdraw from the study after taking the pregnancy test, you will not be asked to share the result of the test with anyone.”

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

EPA shall not rely on data from any rese arch involving intent ional exposure of any human subject who is a pregnant wo man (and therefore her fetus), a nursing woman, or a child.

This protocol requires that s ubjects be at least 18 years old an d 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 objective of this proposed study is to dete rmine the bite protection level of etofenprox treated U.S. Military Fire Resi stant Army Combat Un iforms (FRACUs) treated initially at an application rate of 1% etofenprox (weight/weigh t), and to assess the bite protection performance after 0x, 20x, and 50x washes. This is a non-guideline study; therefore, it is not designed to fulfill the requirements of a specific OC SPP (formerly OPPTS) Guideline. This is considered a special study. This study will be conducted in acco rdance with EPA, FIFRA (Federal Insecticide,Page 6 of 36 Fungicide and Rodenticide Act), Good Laboratory Practice Standards (GLP ); 40 CFR, Part 160 (October 1989) .” (V1:16).

The basic experimental unit in this study is a sleeve test. Each test involves a subject exposing a (unwashed treated, untreated, washed tr eated) fabric-sleeved arm into a cage of one species of mosquito for 15 minutes per hour fo r up to eight hours (See Figure 8.2.1, V1:26). The

data obtained from each 15 minutes test with each experimental unit will be counts of the number of bloodfed female mosquitoes and the to tal number of female mosquitoes in each test cage. The observed bite-through proportion (or ‘rate’) is the proportion of bloodfed female mosquitoes to the total number of mosquitoes in each test cage, which will be expressed as percent bite protection. Etofenpr ox treatment bite through rates wi ll be corrected using Abbott’s formula for ‘background’ bite throug h rates in the control (untreated fabric sl eeve). To increase testing precision, each subject wi ll serve as their own treatment and control. Therefore, the experimental design consists of 4 groups tested in the following order per mosquito species. The
test groups are:

 1 test with an untreated FRACU fabric-sleeve, which serves as the control.

 1 test with treated unwas hed (0x) FRACU fabric.

 1 test with treated washed (20x) FRACU fabric.

 1 test with treated washed (50x) FRACU fabric.

FRACU fabric from coats (shirts/blouses) and trous ers will be tested as described in the tables below (3.5.3, and 3.5.4). Each subject (8 subjec ts) will test each group once per species for a total 8 replicates per group per species, resulti ng in 16 replicates per fabric group for this experiment as shown in Table 3.5.2.

The widely accepted method of evaluating the effi cacy of insecticide treated clothing includes laboratory aging of this treated clothing by launder ing through standardized wash cycles per the

American Association of Textile Chemists and Colorists (AATC) laundering protocol (See Appendix E on V1:171). Testing will be conducted w ith treated and untreat ed clothing prior to laundering (0x wash cycle) and at the 20x and 50x wash cycles. This protocol is similar to the protocol accepted as Standard Operating Proced ure by the U.S. Military to evaluate their repellent treated combat uniforms.

The unit of measure for determin ation of the repellent effects in this proposed experiment (% bite protection based on the propor tion of bloodfed to total mosquitoes in a cage) differs from skin applied repellent evaluations where the “La nding with Intent to Bite” measure is used and efficacy is measured as Complete Protection Time. A detailed justification for the proposed test system is presented in the protocol (V1:16). In brief, the repellent effect created by skin applied repellents is instantaneous and non-toxic, wherea s mosquitoes exposed to the treated clothing

must remain in contact with the treated cloth for a longer time period to illicit a repellent effect. The resulting repellent effect is usually a toxic effect that re sults in ‘excito-repellency’ or incapacitation due to exposure to the fast acting insecticide. The proposed specifications for testing success are shown in the table below, which is take n from the table on p.12 of 210 in Volume 1 and page 3 of 21 in Volume 3. Thes e specifications are in-line with current U.S. Military specifications for treated uniforms.Page 7 of 36 Bite Protection Specifications (%)

Uniform 0x wash cycle 20x wash cycle 50x wash cycle Army FRACUs (test material in the proposed protocol) 85% 80% 70%

This protocol also proposes to ev aluate the repellent effect (% bite protection) of treated clothing using only two mosquito species - unlike skin applied repellent studies conducted under field conditions where three species ar e evaluated. In the proposed st udy representative species from the genus Anopheles (malaria vector) and genus Aedes (vector of dengue and yellow fever) will be evaluated. A mosquito species from the genus Culex (vector of West Nile virus or St. Louis encephalitis) will not be tested. Justification fo r exclusion of the third species is not mentioned with referral to current military test specifications instead.

The study director included a ju stification for sample size in Table 3.5.1 (V1:19). These tables show that the overall bite protection value for a treated fabric is dependent on control bite through rates and the percentile of bite protection. Precisi on improves with the number of subjects based on the width of the 95% confidence interval for the 80 th and 95 th percentiles with control bite through of 50% and 20%. However, this precision does not improve very much beyond 8 test subjects. Precision can decline if pe rcent control bite through rates decline or are low, therefore, as proposed by the study dire ctor, mosquitoes will be screened for their ‘aggressiveness’ to ensure that c ontrol bite through rate s are substantial. The testing paradigm including replication is described in Tables 3.5.2, 3.5.3, and 3.5.4 (V1:20).

The objective of the data analysis is to estimate the mean level of bite protection and associated

95% confidence intervals for different ‘treatments’ [i.e. different combinations of fabric types (coats and trousers), number of washes, and mo squito species]. The numbers of bloodfed and total female mosquitoes found with treated and control fabric (clothing) for each subject will be analyzed as binomial distribute d data in a generalized linear model (GLiM) using a log link, generalized estimating equations or a mixed effect GLiM. This is largely dependent on the ‘subject term’, which may be treated as a fixed or random effect to adjust for within-subject differences (V1:22). Volume 3 includes a very detailed explanation of the analysis and justification for the study design. Alternate subject data appear to be treated together with existing subject data in the event of a dropout but the protocol is silent on this aspect of data analysis. The analysis does not take into account what happens if less than 8 subjects complete the study.

1. Study design:

Replicate subjects will be used in this study to evaluate bite protection for a U.S. military clothing fabric (FRACU) treated with insectic ide/repellent (etofenprox). A fabric’s “bite protection” is a measure of th e relative level to which a treated fabric prevents bites compared to the untreated control. As de scribed in §8.5 (V1:30) of the protocol the observed bite protection for a subject is calc ulated using the subject’s bite-through rates for the treated fabric and for a correspondi ng untreated/unwashed control fabric. (Each subject serves as their own control.) The pur pose of the control is to compensate for influences related to the subject’s individua l attraction level, the general host-seekingPage 8 of 36 response of the test mosquito population, a nd to correct for bite-through rate of the

untreated fabric. The treatment and control va lues for a subject are then used in Abbott’s formula to calculate the observed bite protectio n level of the sleeve for that subject.

Treated clothing sets will be evaluated at the specific st andardized wash intervals: unwashed (0x), 20x washes, and 50x washes. Separate fabric specimens for each wash interval are tested, similar to that desc ribed in U.S. military GL/PD specifications (Appendix C, pg. 34 and Appendix D, pg. 36). Two species of mosquitoes, Aedes aegypti and Anopheles albimanus

, will be tested separately. Eight subjects (preferably the same eight subjects) will be used to test each fabric and mosquito species combination. Two alternate subjects will al so be recruited. The exposure time to mosquitoes at each test interval (once per hour) for control and treated replicates is 15 minutes per arm. A summary of the experime ntal design and testi ng paradigm for each mosquito species are shown below (Vol 1:18-20):

Table 3.5.2 Experi mental Design

Fabric and Treatment Condition 1 Number of

Fabric Specimens Number of Subjects Number of Species 2 Total Replicates per Fabric Type

Coat Untreated Unwashed Control 3 1 8 2 16

Coat Treated Washed 50x 1 8 2 16

Coat Treated Washed 20x 1 8 2 16
Coat Treated Unwashed (0x) 1 8 2 16

Trouser Untreated Unwashed

Control 3 1 8 2 16

Trouser Treated Washed 50x 1 8 2 16

Trouser Treated Washed 20x 1 8 2 16

Trouser Treated Unwashed (0x) 1 8 2 16

1 Fabric treatment conditions are eith er untreated and unwashed (Contro l) or treated and unwashed (0x), treated and washed 20 times (20x) or treated and washed 50 times (50x).

2 The test species are Aedes aegypti or Anopheles albimanus.

3 Each subject serves as their own contro l for the bite protection calculation.

Table 3.5.3 Test ing Paradigm using Aedes aegypti

Subject Right Arm Subject Left Arm

Test
Set 1 Treatment Condition Specimen Designation Treatment Condition Specimen Designation

1 Coat Untreated Unwashed

Control 2 Sleeve 1 Trouser Untreated Unwashed

Control 2 Sleeve 2

2 Coat Treated Washed 50x Sleeve 3 Trouser Treated Washed 50x Sleeve 4

3 Coat Treated Washed 20x Sleeve 5 Trouser Treated Washed 20x Sleeve 6

4 Coat Treated Unwashed (0x) Sleeve 7 Trouser Treated Unwashed (0x) Sleeve 8

* Each subject will have both their right arm and left arm tested simultaneously and complete Test

Set 1-4 for Aedes aegypti . Each subject will have a break between test sets when new cages are being filled with mosquitoes. All cages will be washed after all test sets for each participant are completed.

1 Each test set runs for 15 minutes.

2 Each subject serves as th eir own control for the bite protection calculation.Page 9 of 36 Table 3.5.4 Test ing Paradigm using Anopheles albimanus

Subject Right Arm Subject Left Arm

Test

Set 1 Treatment Condition Specimen Designation Treatment Condition Specimen Designation

5 Coat Untreated Unwashed

Control 2 Sleeve 9 Trouser Untreated Unwashed

Control 2 Sleeve 10

6 Coat Treated Washed 50x Sleeve 11 Trouser Treated Washed 50x Sleeve 12

7 Coat Treated Washed 20x Sleeve 13 Trouser Treated Washed 20x Sleeve 14 8 Coat Treated Unwashed (0x) Sleeve 15 Trouser Treated Unwashed (0x) Sleeve 16

* Each subject will have both their right arm and left arm tested simultaneously and complete Test

Set 5-8 for Anopheles albimanus. Each subject will have a break between test sets when new cages are being filled with mosquitoes. All cages will be washed af ter all test sets for each participant are completed.

1 Each test set runs for 15 minutes.

2 Each subject serves as their own cont rol for the bite protection calculation.

Laboratory-reared 6-11 day old adult mosquitoes will be used for the bite protection assay. Mosquito species have differing behavior and levels of ‘aggressiveness’, therefore, adult female mosquitoes of two of the more aggressive and anthro pophilic species will be tested.

One of these select ed species will be Aedes aegypti , a vector of yellow fever and dengue fever that is found heavily in Asia and South America. The second species will be Anopheles albimanus , a tropical mosquito that is a highly aggressive biter, one of the most tolerant species when tested with topical sk in repellents, and is a competent vector for

malaria transmission. The mos quito colonies are reared at the Center for Medical, Agricultural, and Veterinary Entomology in a USDA facility in Gainesville, Florida. The

colonies used have been maintained since be ing established in 1952 while in Orlando for Ae. aegypti , and in El Salvador in 1974 for An. albimanus . There have been period introductions of wild type sp ecies. Mosquitoes from a co lony will respond on the whole more aggressively to attractant stimuli than strains reared from freshly collected wild-types (V1:27).

“The test cages are approximately 59,000 cm 3 in volume and each w ill contain 175 to 225 female mosquitoes (dens ity of ~1 mosquito/300 cm 3 ). Female mosquitoes will be preselected from stock cages by using a speci ally designed draw box that uses odors from the hand of a laboratory staff person to attrac t mosquitoes upwind in to a trap (Fig. 8.3.1). The trap containing the mosquito es will then be transferred to the test cage for subsequent testing by subjects (Fig 8.3.2, V1:28).”

2

. Statistical design:

The proposed research will include eight human subjects and two alternates. As described, the subjects will serve as their own treatments and controls. Each fabric type will be replicated 16 times, 8x fo r each species. An analysis of the impact of the number of replications on the number of subjects was conducted as described below in Table 3.5.1 (V1:19) from the protocol. The effects of control bite thr ough rates (20% and 50%) as well as bite protection (80 th and 95 th percentile) were evaluated in this analysis using 1000 simulated datasets for each number of subjects. (Volume 3 includes the complete explanation of this approach, the simulati ons, and related justifications on pp. 5-12)Page 10 of 36 These simulated data show that reliable data sets can be coll ected with 8 subjects and that increasing the number of subjects slightly increases precision, but this increase in precision does not provide enough information to justify a larger experiment.

Table 3.5.1 Impact of the Number of Replications on the Number of Subjects

True bite-through rate for control fabric ( θ C

) 50% 20%

True bite protection for treated fabric ( β T

) 1 80% 95% 80% 95%

Number of Subjects Expected half-width of a 95% confidence interval for % bite protection 2

3 5.2% 2.7% 8.8% 4.5%

4 4.5% 2.3% 7.5% 3.8%

5 4.0% 2.0% 6.7% 3.4%

6 3.7% 1.9% 6.0% 3.0%

7 3.4% 1.7% 5.6% 2.8%

8 3.2% 1.6% 5.2% 2.6%

9 3.0% 1.5% 4.9% 2.4%

10 2.8% 1.4% 4.7% 2.3%

15 2.3% 1.2% 3.8% 1.9%

20 2.0% 1.0% 3.3% 1.3%

1 Bite incidence for treated fabric is calculated from bite protection as θ T = θ C (1 - β T /100)

2 Average half-width from 1,000 simulated datasets. E ach dataset consisted of S subjects testing a pair of fabrics (control and treated). For each pair th e total number of mosquitoes (M) was a Poisson (200) random variable, and the number of bloodfed mosquitoes was simulated as a binomial ( θ ,M) random variable. Subject-subject di fferences were simulated by a dding a subject-specific normal (0,0.3) random variable to the logit of the true incidence for both control and treatment fabrics. For each simulated dataset a binomial generalized linea r model was fit to the data using the GENMOD procedure in SAS. The model specified fixed effects for both subject and test material and used a log link. Bite protection confidence intervals were then obtained by back-transforming the confidence intervals for the contrast log( θ T )-log( θ C ).

The primary objective of the data analysis is to estimate the ove rall (or ‘mean’) level of bite protection and associated 95% confidence interval for different ‘treatments’ (i.e., different combinations of fabric type, number of wash es, and mosquito species). Subject-specific bite protection values will be calculated fo r each treatment using Abbott’s formula as described in §8.5. These values will be averag ed over all subjects to obtain mean observed bite protection values that can be used as a check on any model-based bite protection

estimates.

The numbers of bloodfed and total female mosq uitoes found with trea ted and control fabric for each subject will be analyzed as binomial distributed data in a generalized linear model (GLiM) using a log link. A subj ect term will be added as a fi xed effect in the model to adjust for subject-subject differ ences. (Alternatively, subjects could be treated as a random effect and the within-subject correlation accomm odated using either generalized estimating equations or a mixed effect GLiM. The decision on how to analyze the collected data needs to be finalized.) Use of the log link makes it possible to obtain an estimate and confidencePage 11 of 36 interval for the ratio of the treatment and control bite-through rates. The estimates and confidence intervals for percent bite prot ection are obtained from the relationship:

Percent Bite Protection = [1 – (treat ment rate) / (control rate)] × 100%

The GLiM model-based bite protection estimate s could be obtained by analyzing multiple models each with just a single treatment gro up and the matched contro l group. However, it may also be of interest to compare the bite pr otections of different types of treated fabric, number of washes, or mosquito species. In this case, it would be necessary to include all of the treatments (and species) of interest in the same model. Because the GLiM uses a log link, hypothesis tests concerning ratios of bite protection can be formulated as linear contrasts in the GLiM (V1:21-22) (V3:3-5).

3. How and to what will human subjects be exposed?

Subjects will be exposed to test material and two species of cage d mosquitoes in the laboratory. Each subject will have etofenprox treated sleeves placed on both forearms and both arms will be exposed to caged mosquito es for 15 minutes per hour [The step-wise procedure is described in detail in §8.4 (V 1:28-30) and §8.6 (V1:33-42)]. This period of time allows mosquitoes to land, probe, and bloodfeed. The greates t number of bites is expected to be received duri ng the first set of tests with the untreated, unwashed control sleeves. Subsequent tests will involve treate d sleeves and it is expected that far fewer bites will be received by the test subjects.

4. Endpoints and Measures:

Efficacy will be measured as pe rcent bite protection. The prop osed study will estimate the overall (or ‘mean’) level of bite protection an d associated 95% confidence interval for different ‘treatments’ (i.e., different combina tions of fabric type, number of washes, and mosquito species). Subject-specific bite pr otection values will be calculated for each treatment using Abbott’s formula as described in §8.5 based on expo sure to mosquitoes during a 15 minutes bioassay ever y hour for up to 8 h ours. These values will be averaged over all subjects to obtain mean observed bite pr otection values that can be used as a check on any model-based bite pr otection estimates.

E. Compliance with Applicable Scientific Standards

This protocol adequately addresses the following elements according to applicable

scientific standards:

 Prerequisite acute toxicity research to characterize t oxicological profile of the

formulation and calculate ma rgin of exposure (MOE).

 Experimental design

 Pre-training of subjectsPage 12 of 36 EPA Science Comments

The following elements in the protocol requir e revision before the research goes forward:

 Provide justification for testi ng two vector mosquito specie s instead of three (V1: 27).

 The statistical analysis must be finalized. Two approaches to GLiM use are discussed in the present version (V1: 21-22). “Recommendati ons for Data Analysis” expands on this discussion in V3: 13. The protocol should be amended to include the selected analysis before the study is executed.

 The protocol proposes only two alternate su bjects. Consider recruiting more than two alternates in case more than two subj ects withdraw midway through the study

.

 Describe how the data will be analyzed if the number of test subjects at the end of the test is less than eight.

 Please add more details to the protocol about what will ha ppen if a subject withdraws midway through the study and an alternate is brought into the study as a replacement. Will data from the subject who withdraws be discar ded, or used alone, or used in combination with data from the alternate subject? Will an alternate who replaces an original subject complete all eight pairs of sleeves, or only the pairs of sleeves that were not completed by the original subject? If the latter, that person must also be tested with an untreated sleeve against each mosquito species to establish their baseline . The statistical plan for analyzing the data

will need to take into account how alternate subjects will be handled. There may be statistical implications of combining partial da ta sets from different subjects.

 The subjects and alternates need to be random ly selected from a larger pool of qualified potential subjects. The protocol states that th e first 20 respondents to the advertisement will undergo a preliminary telephone screening. Plea se continue screening respondents to the advertisement until you have at least 20 qualifie d potential subjects. Then, randomly select the 8 subjects and 2 or more alternates from the pool of qualified potential subjects. The random selection may be accomplished by drawing names from a hat or through the use of a randomizer program such as http://randomizer.org.

 Section 8.1.5 of the protocol states that “it is desired that random sel ection will yield a nearly equal distribution of male and female candida tes...” (V1:24) However, it is possible that random selection will yield an unequal distribu tion of males and females. Please revise the protocol to specify exactly what will happen if there is unequa l distribution or if only one sex is represented. Will you continue to randomly sel ect from the pool of eligible subjects until you have an equal number of males and females? Or until you have at least one subject of

each sex?

 Due to dermal observations resembling skin ir ritation in a 28-day de rmal toxicity study conducted with technical etofenprox on rabbits, th e etofenprox registrant , Mitsui Chemicals, will soon be conducting a product-specific 28-day dermal toxicity study in rabbits withPage 13 of 36 etofenprox-treated fabric. The new study will te st the same fabric that subjects will be exposed to in the proposed efficacy study under review here. Do not initiate this research until the results of the product specific fa bric study have been submitted to and reviewed by EPA.

 Present values for 70% true bite protection for treated fabric in the protocol in Table 3.5.1 to illustrate the change in the 95% confidence interv al with the number of subjects as this value was selected as the performance standard for FRACU fabric washed 50x (V1: 12). The change in the width of the 95% confidence interval is addressed in Volume 3 for the 70% level of bite protection performan ce in Tables 4, 5 and 6 on pp. 10-12.

 Data compilation and processing. The protocol pr ovides a sample data sheet that is to be used for every 15 minute sleeve test (V1:190 and 192) . However, little de tail is provided in the protocol on how the data from these sheets will be compiled and processed before entry into Excel, JMP, or SAS and how the resulti ng records will be handl ed and archived (§9.0, V1:43).

 Amend the protocol to identify the Quality Assurance Unit (V1:15).

Attachments:

1. Summary Review of Pr otocol (dated 2/28/14) 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 ResearchAttachment 1

Page 14 of 36 EPA Protocol Review

Title: Laboratory Evaluation of Bite Protection from Repe llent-Impregnated Clothing for the United States Military

Date: February 28, 2014

Principal Investigator a nd any sub-investigators: Ulrich R. Bernier, Ph.D.

Participating Laboratory: United States Department of Agricu lture-Agricultural Research Service Center for Medical, Agricultural, and Veterinary Entomology

1600 SW 23rd Drive Gainesville, FL 32608

Sponsor: United States Department of Agricu lture-Agricultural Research Service Center for Medical, Agricultural, and Veterinary Entomology

1600 SW 23rd Drive Gainesville, FL 32608

IRB:

Western Institutional Review Boards

1019 39 th Avenue, SE Suite 120 Puyallup, WA 98374-2115

1. Societal Value of Proposed Research

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

In this study, military uniform fabric will be treated with a pesticide calle d etofenprox. Treated fabric will be compared to untreated fabric to determine if the treatment can decrease mosquito bites to human skin that is covered by the sleeve. Specifically, this study will determine the bite protection level of etofenprox treated U.S. Military Fire Resistant Army Combat Unifor ms (FRACUs) treated initially at an application rate of 1% wt/wt, and to assess the bite protec tion performance after 0x, 20x, and 50x washes against two species mosquitoes ( Aedes aegypti and Anopheles albimanus ). (V1:16 1 )

1 This pagination convention is used throughout this review . “V1” refers USDA Volume 1, “V2” refers to USDA Volume 2, etc. Entries after the colon are page references ; many page images bear more than one page number. In Volume 1, the cited page number is from the expression “Page n of 210” found at the bottom right-hand corner. Volume 2 page references are from the expression “Page n of 580” found at the bottom right-hand corner. Volume 3 page references are from the expression “Page n of 25” found at the bottom center of the page.Attachment 1

Page 15 of 36 (b) What research question does it addre ss? Why is this question important?

Would the research fill an im portant gap in understanding?

The purpose of this study is to develop a standardized protocol that can be used to evaluate the bite protection of fabrics that are treated or impregnated with substances that repel or reduce arthropod bites to determine if they provide sufficient protection against mosquitoes. Due to global issues regarding mo squito resistance to ester-pyrethroids, other

insecticide candidates must be considered. Th us, comparisons of new insecticide/repellent candidates should be evaluated in produc ts where performance has already been determined with a known standard, i.e. permethrin.

A standardized protocol will enable the EPA to receive cons istent and scientifically reliable data for new repellent clothing treatments. The bite protection data will provide information about: 1) the relativ e level to which bites are rece ived through the fabric with the repellent treatment compared to bites recei ved through the untreated control fabric; 2) whether the fabric is in the “plateau” region of bite protection for the repellent-treated surface, such that application of additiona l chemical does not improve bite protection performance; 3) the relative bite protection capability of one fabric construction and composition vs . another fabric construction and com position; and 4) the bite protection efficacy of a new product fo r EPA registration. Because these data are acquired in a laboratory setting, there are fewer associated risks than determining where the optima lie than using wild-type mosquitoes in a field setting. Bites are measured in these studies by the presence of a blood meal in the ab domen of the female mosquito (V1:9).

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

EPA will consider the study to satisfy product specific efficacy data requirements and acceptable label claims for repellent efficacy for the test material.

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

EPA requires product-specific efficacy data to support its registration. No previous testing of this product against mosquitoes under the proposed use pattern has been

conducted.

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

Human subjects are required because they re present the target system for the test material, and sufficiently reliable non-human models for repellency te sting have not been developed.Attachment 1

Page 16 of 36 2. Study Design

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

is it? “The objective of this study is to determine th e bite protection level of etofenprox treated U.S. military Fire Resistant Army Combat Uniform s (FRACUs) treated initially at an application rate of 1% wt/wt, and to assess the bite protection performance after 0x, 20x,

and 50x washes.” (V1:16)

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

The objective cited may be achieved by the study as proposed if the protocol is revised and amended to explain, in more detail, th e following items noted on pages 12-13 of this

review.

2.1 Statistical Design

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

The rationale for the sample size app ears on pp. 18-19 of 210 (§ 3.5) in Volume 1. The researcher’s justification for sample size is based on the argument that the precision of the overall (mean) bite protecti on value for a treated fabric will depend on the true bite through rate for the control fa bric and the true leve l of bite protection. This justification is illu strated in Table 3.5.1 on p. 19 of 210 in Volume 1. Based on

the width of the 95% confidence intervals in th is table: 1) the experimental variability

decreases as control treatment bite through rates increases; 2) as true bi te protection increase, the width of the 95% interval decr eases; and 3) the precision of overall bite protection value does not appear to increas e very much once the number of subjects in the experiment exceeds 8.

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

Each subject will serve as their own treatment and negative control for each test set as described on p. 20 of 210 in Volume 1 in Tables 3.5.2, 3.5.3, and 3.5.4. The controls are appropriate to calculate the overall bite protection because pe rcent bite protection will be calculated by counting bloodfed fe male mosquitoes in the treatments and comparing them to the untreated control. Bo th arms will serve as a control treatment replicate, one for coat fabric a nd the other for trouser fabric.

(c) How is the study blinded?

The study is not blinded. Untreated sleeves will be tested first followed by 50x, 20x

and 0x fabrics.Attachment 1

Page 17 of 36 (d) What is the plan for allocating individuals to t reatment or control groups?

All subjects will be assigned to control and treatment groups as described on p. 20 of

210 in Volume 1.

The subjects and alternates need to be randomly selected from a larger pool of qualified potential subjects. The protocol st ates that the first 20 respondents to the advertisement will undergo a preliminary telephone screening. Please continue screening respondents to the advertisem ent until you have at least 16 qualified potential subjects. Then, randomly select the 8 subjects and 2 or more alternates from the list of 16+ qualified poten tial subjects. The random selection can be accomplished by drawing names from a hat or through th e use of a randomizer program such as http://randomizer.org.

(e) Can the data be statistically analyzed?

Yes. “Treated clothing sets will be evaluat ed at the specific standardized wash intervals: unwashed (0x), 20x washes, and 50x washes. Separate fabric specimens for each wash interval are tested, similar to that described in U.S. military GL/PD specifications (Appendix C, pg. 34 and A ppendix D, pg. 36). Two species of mosquitoes, Aedes aegyp ti and Anopheles albimanus

, will be tested separately. Eight subjects will be tested using each fa bric and mosquito species combination” (V1:19). Each subject will serve as their own treatment and control. The experimental design together with the testing paradigms for Ae. aegypti and An. albimanus , respectively

, are illustrated in tables 3.4.2, 3.5.3, and 3.5.4 on p. 20 of 210 in Volume 1.

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

“ The primary objective of the data analysis is to estimate the overall (or ‘mean’) level of bite protection and associ ated 95% confidence interval for different ‘treatments’ (i.e., different combinations of fabric type , number of washes, a nd mosquito species). Subject-specific bite protection values will be calculated for each treatment using Abbott’s formula as described in Section 8 .5. These values will be averaged over all subjects to obtain mean observed bite protec tion values that can be used as a check on any model-based bite protection estimates.

“The numbers of bloodfed and total female mosquitoes found with treated and control fabric for each subject will be analyzed as binomial distributed data in a generalized linear model (GLiM) using a log link. A subj ect term will be added as a fixed effect in the model to adjust for subject-subject diffe rences. (Alternatively, subjects could be treated as a random effect and the wi thin-subject correlation accommodated using either generalized estimating equations or a mixed effect GLiM.) Use of the log link makes it possible to obtain an estimate and confidence interval for the ratio of the treatment and control bite-through rates. The estimates and con fidence intervals for percent bite protection are obtained from the relationship:Attachment 1

Page 18 of 36 “Percent Bite Protection = [1 – (treat ment rate) / (control rate)] × 100%

“The GLiM model-based bite protection es timates could be obtained by analyzing multiple models each with just a single treatment group and the matched control group. However, it may also be of inte rest to compare the bite prot ections of different types of treated fabric, number of washes, or mos quito species. In this case, it would be necessary to include all of the treatments (and spec ies) of interest in the same model. Since the GLiM uses a log link, hypothesis te sts concerning ratios of bite protection can be formulated as linear contrasts in the GLiM” (V1:21-22). A complete explanation and related justifications can be found in Volume 3.

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

The analysis will provide the overall bite protection values for each treatment group and the controls. As proposed, the analys is addresses mean values and associated

uncertainties.

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

Statistical power is adequately described in §3.5 of Volume 1 a nd is illustrated in Table 3.5.1. An in-depth analysis is presen ted in Volume 3. As expected the width

of the 95% confidence interval decreases as the number of subjects increases but the relative improvement or ‘gain’ from increas ing the number of subjects decreases as the number of subjects increase. The proposed sample size of 8 subjects represents a reasonable compromise between decreasi ng confidence interval width and limiting unnecessary human experimentation.

2.2 How and to what will human subjects be exposed?

Subjects will be exposed to test material and mosquitoes in the laboratory. The test material will be cut out of treated military trou sers or coats and sewn into “sleeves” at the USDA-ARS testing facility. Th e test material’s active ingr edient, etofenprox, has a low acute and chronic risk prof ile (§3.3 and §3.4, V1:17-18), and the inert ingredients are classified by the Agency as safe for this use. The test material has been tested in animals for acute toxicity. Subjects with known a llergic reactions (§8.1.2) are excluded from participation in the test.

Subjects will be exposed to laboratory r eared populations of mosquitoes free of mosquito-borne pathogens in the laboratory (V1:27, 44). Subjects w ith known allergic reactions to mosquito bites will be exclude d from research participation (V1:23).

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

Efficacy data to satisfy product performan ce requirements and to support label claims for this product are required by EPA fo r registration. EPA requires submission ofAttachment 1

Page 19 of 36 product performance data for all products claiming efficacy against public health
pests.

(b) What is the rationale fo r the choice of dose/exposure levels and the staging of

dose administration?

There is no dosimetry phase in this expe riment. Test sample sleeves contain 1% etofenprox (wt/wt). As explained in Volu me 1 on page 11 of 210 in the ‘Background’ section of this protocol, th e registrant performs the dosimetry experiments before efficacy testing is conducted to determin e: 1) the ‘plateau region’ at which no additional bite protection is gained from additional compound and 2) the point at which the bite protection begins to decr ease substantially, typi cally this done by treating fabric with a range of concentrati ons to determine the dose-response curves. The range of concentrations for these prelim inary tests is selected to be within an acceptable range based on the toxicity profile of the insecticide/repellent compound to

minimize risk to the indi vidual wearing the fabric.

(c) What duration of exposure is proposed?

The exposure period is eight 15-minute periods (2 hours total) for both arms of each subject.

2.3 Endpoints and Measures

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

asked?

Endpoints/Measures for efficacy evaluation:

 Number of bloodfed and total number of females mosquitoes in each test. The proportion of bloodfed/total will be calcula ted and expressed as a percentage value. This calculation will be perfor med for untreated control sleeves and treated sleeves (0x, 20x, and 50x washes).

 For each test set, the treatment % bite values will be corrected to account for the bite through values in the untreated control us ing Abbott’s Formula.

 The overall % bite protection will be calculated and expressed as a mean value for each treatment: 0x, 20x, 50x washes for coats and trousers.

The endpoints are appropriat e to the questions being as ked and address uncertainty associated with the samples size, between subject variation, % bite values, and the overall bite protection value.

The data form for each 15 minutes sleeve test is presented in Appendix I on page 190 of 210. A completed sample data sh eet is shown in Appendix J on page 192

of 210.Attachment 1

Page 20 of 36 (b) What steps are proposed to ensure measurements are accurate and reliable?

 Standard Operating Procedures (SOPs) will be in place that must meet Good Laboratory Practices requirements.

 Laboratory technicians will assist subj ects with placing the test sleeves on their arms and excluding all expose d skin from mosquito exposure.

 Laboratory technicians will assist subject s with insertion and removal of their arms in/from the cages.

 Laboratory technicians and the study dire ctor will track test sleeve samples and closely monitor the testing.

 Alternate subjects will be enrolled to ensure adequate sample size.

 Counts of bloodfed mosquitoes and the to tal number of mosquitoes in the cage will be determined by a research technician.

 The test sleeve samples will be assayed by the Anal ytical Unit (p. 15 of 210) and the amount of etofenprox reporte d (pp. 31-32 of 210) as a surface

concentration of etofe nprox in units of mg/cm 2 , which is commonly done for

treated fabrics.

(c) What QA methods are proposed?

As explained in Volume 1, §7.0 on p. 22 of 210 a separate, professional Quality Assurance Unit (QAU) will insp ect the study: “Qua lity assurance of this study will be

carried out in accordance with Good Labor atory Practice (GLP) Standards 40 CFR 160. Written reports of all findings from the Quality Assurance Officer will be provided to the study director and mana gement. Any part of the study found by the Quality Assurance Officer to be likely to affect th e integrity of the study will be brought the attention of the study director. A statemen t signed by the Qua lity Assurance Officer listing the phases inspected, inspection dates, and dates reported to the study director and management will be included in the fina l report. All deviations and amendments will be recorded and report ed as per GLP guidelines.

Additionally, fabric samples will be retained indefinitely for further analysis and verification as requested by NSRDEC for quality control.

The quality assurance unit of the analytical laboratory will provide the study director and the study director’s management with re levant data, process, and report audits to meet Environmental Protection Agency GLP requirements.”

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

Uncertainty is addressed in the experiment al design and selection of the number of subjects as described in §3.5. The statisti cal analysis also discusses uncertainty in §6.0. Volume 3 provides any in-depth discus sion of uncertainty a ssociated with the experimental design and data to be genera ted and analyzed. The objective of the data analysis is to estimate the mean level of bite protection and associated 95%Attachment 1

Page 21 of 36 confidence intervals for different ‘treatments’ [i.e. different comb inations of fabric types (coats and trousers), number of washes , and mosquito species]. The numbers of bloodfed and total female mosquitoes found w ith treated and contro l fabric (clothing) for each subject will be analyzed as binomial distributed data in a generalized linear model (GLiM) using a log link, generalized estimating equations or a mixed effect GLiM. This is largely dependent on the ‘subject term’, which may be treated as a fixed or random effect to adjust for w ithin-subject differences (V1:22). Volume 3 includes a detailed explanation of the statistical analysis.

3. Subject Selection

3.1 Representativeness of Sample

(a) What is the population of concern?

The population of concern is U.S. military personnel who would wear FRACUs treated with etofenprox.

(b) From what populations will subjects be recruited?

Subjects will be recruited from the general population in Gain esville, Florida through the use of an advertisement placed in a local ne wspaper and on bulletin boards in University of Florida campus buildings.

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

Since Gainesville, Florida is a university community and given that the advertisements will be placed within campus buildings, the population from which subjects will be recruited is likely younger than the ge neral U.S. population, but may mirror the population of concern – U.S. military personne l – in terms of over-representation of younger individuals.

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

Yes.

3.2 Equitable Selection of Subjects

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

The inclusion/exclusion criteria are complete and appropriate except that “sensitivities to pestic ides or other chemical products” and “people with cuts, scrapes or skin conditions such as psoriasis or eczema on their arms or hands” should be

added as additional exclusions.Attachment 1

Page 22 of 36 “Inclusion/Exclusion Criteria

1. Must be between the ages of 18-62 years old.

2. Must be able to speak and read English.

3. Children (under the age of 18), and pregna nt or lactating women will be excluded.

4. Exclusion of people in poor health or physical condition.

5. People who are hypersensitive to or phobi c of mosquito bites will be excluded.

6. Exclusion of people known to be sensitive to the test material.

7. Exclusion of people with a relationship to the study director or sponsor (students or employees of the study di rector or sponsor).” (V1:23)

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

None. People with a relationship to the study director or sponsor (students or employees of the study director or spons or) are excluded from becoming subjects.

(c) Are any potential subject s from a vulnerable population?

No.

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

“Subjects will be recruited from the gene ral population in Gainesville, Florida through a printed advertisement placed in the Gainesville Sun (local newspaper) and on bulletin boards in University of Flor ida buildings. The advertisement (Appendix F) will contain a brief description of th e testing and financial compensation for participation. Subjects will be compensate d $20 for participating in the initial research consent meeting and $25 for each se t of sleeves in the testing paradigm. Subjects that are pregnant (see below) will not be allowed to participate but will be paid $25 for screening process. Subjects will receive $200 for comple tion of testing with the full set of 8 pairs of sleeves. Th e advertisement will provide a phone number where interested respondents can leave a message. The messages will be reviewed by the study director. Respondents will be called by the study director and undergo preliminary screening via te lephone interview to determin e if they meet the inclusion

and exclusion criteria. Individuals will be recruited from the community and are not from any particular employer or agency, and will have no relationship to the study director.” (V1:23)

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

Subjects will be recruited th rough advertisements in local newspapers. There will be

no connection or communication between the researchers and the potential subjects’ employers, which minimizes the potential for coercion or undue influence. InAttachment 1

Page 23 of 36 addition, students or employees of the st udy director or sponsor are excluded from participation.

3.3 Remuneration of Subjects

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

“Subjects will be compensated $20 for participating in the initial research consent meeting and $25 for each set of sleeves in the testing paradigm. Subjects that are pregnant (see below) will not be allowed to participate but will be paid $25 for completing the screening process. Subjects will receive $200 for completion of testing with the full set of 8 pairs of sleeves.” (V1:23) Subjects that begin the study but do not complete it will be paid for each pair of sleeves at a rate of $25 per pair. (V1:201)

(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 in cash before subjects leave the test facility.

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 material?

Etofenprox is an EPA-registered pesticid e with an essentially complete supporting toxicity database. It has been tested extens ively in animals and is of low toxicity by all routes of exposure. The acute dermal LD 50 of etofenprox is greater than 2,100 mg/kg body weight. Etofenprox is not a skin sensitizer.

The treated fabric that will be placed on th e forearm of subjects will contain at most 105.9 mg of etofenprox (for 0x washes), which results in a maximum dose of 211.8 mg/subject. Assuming an adult weighs 70 kg, the maximum etofenprox dose from exposure to the treated fabric equals 3.02mg/kg per subjec t, assuming that there is 100% absorption through the skin, resulti ng in an estimated MOE = 695. This MOE

does not exceed EPA’s level of concern (MOE= 100) (V1:18).Attachment 1

Page 24 of 36 Results from toxicity testing :

 A primary eye irritation study on rabbits showed that etofenprox is a minimal irritant to the eyes.

 A dermal sensitization study in Guinea pigs (Buehler method) showed that etofenprox is not a contact sensitizer.

 A primary skin irritation study in ra bbits study showed that etofenprox is minimally irritating to the skin.

 The single dose acute dermal LD 50 of the etofenprox is >2,100 mg/kg in rabbits.

 The acute oral LD 50 of etofenprox is >5,000 mg/kg in dogs.

Due to dermal observations resembling skin irritation in a 28-da y dermal toxicity study with rabbits, the etofenprox regist rant, Mitsui Chemicals, will soon be conducting a 28-day dermal toxi city study in rabbits with etofenprox-treated fabric.

Do not initiate this research until the results of that study have been submitted to and reviewed by EPA.

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

Risks to subjects include the risk of e xposure to biting mosquitoes; the risk of exposure to disease vectors; th e risk of exposure to the test material; risks related to receiving an unexpected result on a pre gnancy test; and the risk of a loss of confidentiality.

(c) How do proposed dose/exposure levels compare to the established NOAELs for

the test material?

A dose/endpoint was not chosen for a dermal risk assessment since no systemic toxicity was observed at the limit dose (1000 mg/kg/day) following repeated dermal exposure to rabbits for 28 days to etofenpr ox technical. However, in the same study a dermal LOAEL was identified that equa led 400mg/kg/day based on an increased incidence of dermal observations (scabbi ng, crusting, desquamation, and exfoliation) together with histopathological changes th at included diffuse epidermal hyperplasia

in both sexes of rabbits. Based on a dermal absorption study in rats with etofenprox technical, very little etofenpr ox is absorbed through skin (7% of the applied dose) and metabolism is rapid with nearly all etofe nprox excreted in feces and urine within 24 hours after application to the skin of test animals. Taken together, subjects in this study will be exposed to very little etofe nprox when the treated fabric is placed on the skin during testing with the maximum dos e of 3.02 mg/kg per subject being much lower than the systemic NOAEL >1000 mg/kg/ day for the dermal route of exposure

and more than 100x less than the dermal LOAEL observed in rabbits.

Due to dermal observations resembling skin irritation in a 28-da y dermal toxicity study conducted with techni cal etofenprox on rabbits, th e etofenprox registrant, Mitsui Chemicals, will soon be conducting a product-specific 28-day dermal toxicity study in rabbits with etofenprox-treated fa bric. The new study will test the same fabric that subjects will be exposed to in the proposed efficacy study under reviewAttachment 1

Page 25 of 36 here. Do not initiate this research until th e results of the product specific fabric study have been submitted to and reviewed by EPA.

(d) What is the probability of each risk associated with the research? How was this probability estimated?

No numerical probability is estimated, but risks have a low probability of occurrence. Risks are minimized in the protocol by excluding candidates known to be hypersensitive to or phobic of mosquito bites; using disease-free colony-raised mosquitoes; excluding candidates known to be sensitive to the test material; applying clear stopping rules; and by in corporating procedures to k eep the results of pregnancy testing private and permit discrete withdrawal.

4.2 Risk minimization

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

Risks from exposure to biting mosquitoes.

 Candidates who are hypersensitive to or phobic of mosquito bites are excluded (V1:23, 195)

 Subjects are alerted in the consent form to the possibility of experiencing a skin reaction to mosquito bites, and are advised to inform the study director, laboratory technician, or on-call nurse if they believe they are having a reaction (V1:199)

 Over-the-counter topical steroid cream to relieve itching w ill be available for use by subjects (V1:199)

 A nurse familiar with the protocol will be on-call to provide advice or assistance in the event that a subj ect experiences a reaction (V1:199)

Risks of exposure to disease vectors

. “Since these mosquitoes are colony reared and not exposed to disease agents, the risk of contracting an infectious disease fr om bites is negligible. Mosquitoes from colony have been reared through immature stages and delivered to the laboratory testing room just prior to pupal eclos ion. Mosquito pupae are received from colony and allowed to eclose into cages in the laboratory. Fo r those mosquitoes to transmit pathogens such as dengue fever or malaria, they would need to escape, bite an infected human and then retu rn back to the cage for selection in tests. Even if a mosquito escapes, the pr obability that it could return into a cage and be used in testing is negligible. There is also an incubation period during which the disease must be in the mosquito in order to transmit to another organism. Additionally, all mosquitoes that are contained in the cages are not allowed to feed on any organisms and t hus do not have the opportunity to be infected with pathogens prior to testing. The mosquito colonies are reared at the Center for Medical, Agricultural, and Ve terinary Entomology in a USDA facility in Gainesville, Florida using a membr ane feeding system and bovine blood. The citrated bovine blood is pathogen free ( certified sterile by the supplier). TheAttachment 1

Page 26 of 36 mosquitoes will not have been fed on any humans prior to the study. The colonies

used have been maintained in this manne r since being estab lished in 1952 while in Orlando for Ae. aegypti, and in El Salvador in 1974 for An. albimanus. ” (V1:27)

Risks from exposure to the test material.

 Candidates who are known to be sensitive to the test material are excluded. (V1:23) It is also recommended that the protocol exclude subjects who are sensitive to pesticides or other chemical products.

 It is recommended that the protocol exclude subjects with cuts, scrapes, or skin conditions such as psoriasis or eczema on their arms or hands. These conditions could increase the possibility of a reaction to test material.

Risks of stress and loss of confiden tiality related to pregnancy testing

 The protocol provides for discrete hand ling of the pregnanc y testing that is required of female subject s on the day of the study.

 Female subjects self-administer the pr egnancy test in a private restroom. (V1:34, 195)

 After completing the test, each female s ubject is asked if she would like to continue in the study. If her answer is no, then no further questions are asked;

she will not be asked to share the result w ith anyone. If her answer is yes, the result of pregnancy test will be verifi ed by only one member of the research (EPA has recommended that the protocol specify that it be a female member of the research team). (V1:34, 195)

 For females who proceed with the testi ng, the result of the pregnancy test is recorded in the raw data and kept confidential. (V1:34)

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

“The study will be stopped if the test s ite becomes unsafe for any reason, biting pressure falls below threshold needed, b iting pressure rises too high for subject comfort or safety, subject asks to withdraw , subject is unattractive to target species, subject exhibits hypersensitivity to insect b ites during test, subject exhibits sensitivity to the test materials during the test.” (V1:46)

(c) How does the protocol provide for me dical management of potential illness or injury to subjects?

“On the day of the testing, there will be a nurse on call who has read the protocol and discussed the research with the study di rector to assist if needed. UF Health Shands Hospital is located 0.5 miles from th e testing facility. Medical care for research-related injuries will be provided at no cost to the subjects.” (V1:43)

“If you are injured or become ill during the study, tell the study director, laboratory technician, or on call nurse immediately. The study director will obtain emergency medical treatment for you, if necessary. If your illness or injury is a direct result of being in this study, the sponsor of this re search will cover the costs of any necessaryAttachment 1

Page 27 of 36 medical treatment that is not covered by y our insurance or the insurance of a third party under which you are covered.

“If, after participating in the study, you believe you have become ill as a direct result of your participation in the study, please call the study director, Ulrich Bernier Ph.D., at (352) 871-8469 (24 hours) or 352-374-5917 or Wendy L. Morrison, RN, BSN at 352-339-2179 (24 hours).” (V1:202)

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

Subjects are clearly and repeatedly informed that they may remove themselves for any reason from the study at any time. All s ubjects are asked to immediately tell the study director, laboratory technician, or on-call nurse if they believe they are experiencing a reaction or feel ill during the study. The cons ent form also states that if, after participating in the study, a subject believes he or she has become ill as a result of their participation in the study, they should contact the Study Director or the on-call nurse anytime, 24-hours a day. Th eir telephone numbers are provided.

On the day of testing, a nurse who has read the protocol and di scussed the research with the study director will be on call. (V1:43)

(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?

The consent form states: “If, after partic ipating in the study, you believe you have become ill as a direct result of your partici pation in the study, please call the study director, Ulrich Bernier Ph.D., at (352) 871-8469 (24 hours) or 352-374-5917 or Wendy L. Morrison, RN, BSN at 352-339-2179 (24 hours).” There is no time limit given. (V1:202)

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

“If your illness or injury is a direct result of being in th is study, the sponsor of this research will cover the costs of any necessa ry medical treatment that is not covered by your insurance or the insurance of a third party under which you are covered.” (V1:202)

5. Benefits

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

There are no direct benefits to subjects.Attachment 1

Page 28 of 36 (b) What benefits to society are anticipate d from the information likely to be gained through the research?

“While there are no direct bene fits to the subjects participa ting in this research study beyond a small compensation for their time, there are indirect benefits to both the subjects and society. First, the data collected in this study will be used establish the level at which insecticide/repellent treated unifo rms prevent mosquito bites. Data generated from this study may be used for U.S. EPA re gistration of a novel insecticide/repellent treatment for military clothing.

“It is expected that this l aboratory data can be translated to bite protection of covered areas of the body for individuals in the field. Because not al l individual biting arthropods carry disease agents, a reduction (not nece ssarily complete elimination) of biting pressure is expected to also minimize the risk of diseas e transmission and subsequently reduce overall arthropod-borne disease rates. Reduction of disease rates is dependent upon the infectivity rates of the insects in a given area, the overall biting pressure, and use compliance. Through factory treatment, we can ensure a high level of compliance for use of treated military clothing which s hould significantly reduce overall arthropodborne disease among military populations, partic ularly when used in conjunction with other prevention methods, such as topical repellents and mosquito netting.

“These studies are conducted to better prot ect American military forces from nuisance bites and from bites that lead to arthropod-bor ne diseases. The resu lts of these studies may also lead to better protection of U .S. civilians both domestically and while they travel abroad because novel repellents can be incorporated into civilian clothing as a potentially better alternative to the permethr in-treated clothing already available on the market.” (V1:45)

(c) How would societal benefi ts be distributed? Who woul d benefit from the proposed

research?

One beneficiary will likely be the spon sor who is seeking EPA-registration for etofenprox-treated clothing. Indi rect beneficiaries would include the U.S. military and civilians who may benefit from w earing etofenprox-treated clothing.

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

The testing is likely to demonstrate that the formulation is effective at providing the level of bite protection sought by the U.S. military, which could result in better protection of the U.S. military from mosquito bites and perhaps better protection of U.S. civilians through the use of a new type of repellent-treated clothing.Attachment 1

Page 29 of 36 6. Risk/Benefit Balance

(a) How do the risks to subjects weigh agains t the anticipated bene fits of the research, to subjects or to society?

“Risks have been minimized in terms of dise ase (through use of colony mosquitoes in a laboratory setting only) and with respect to num bers of replicates that a subject will be testing (one control and 3 treated specimens). In this study, the biting of subjects will be incurred voluntarily to help develop a new product that will provide optimized protection against mosquito bites in a field setting where the risk of disease is a bona fide threat.” (V1:45)

The protocol systematically reduces risks to subjects without reduc ing the robustness of the scientific design. No reasonable opportuni ties to further reduce subject risk have been overlooked. The resulting residual risk to subjects is very low. The potential benefits from availability of a wider variet y of effective repellent-treated clothing are likely to be realized, and make the residual ri sks to subjects in th is proposed research

reasonable.

7. Independent Ethics Review

(a) What IRB reviewed the proposed research?

Western Institutional Review Board

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

(c) Is this IRB registered with OHRP? Yes

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

WIRB has full AAHRPP accredditation.

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

Yes.

(f) Are complete records of the IRB rev iew as required by 40 CFR 26.1125 provided?

Yes.

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

This is a protocol for third-party research involving what EPA has interpreted to be intentional exposure of human s ubjects to a pesticide. The study is being conducted with the intention of submitting the resulting da ta to EPA under the Federal InsecticideAttachment 1

Page 30 of 36 Fungicide and Rodenticide Act (FIFRA). Thus , the primary ethical standards applicable to this proposal are 40 CFR 26, Subparts K a nd L. In addition, the requirements of FIFRA §12(a)(2)(P) for fully informed, fully voluntary consent of subjects apply.

8. Informed Consent

(a) Will informed consent be obtain ed from each prospective subject?

Yes.

(b) Will informed consent be appropri ately documented, consistent with the requirements of 40 CFR 26.1117?

Yes.

(c) Do the informed consent material s meet the requirements of 40 CFR 26.1116, including adequate characterization of th e risks and discomforts to subjects from participation in the research, the potential be nefits 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?

Ability to speak and read English is a requirement for participation.

(e) What measures are proposed to overco me language differences, if any, between investigators and subjects?

N/A

(f) What measures are proposed to en sure subject comprehension of risks and

discomforts?

Frequent opportunities to ask ques tions during the consent process.

(g) What specific procedure will be followed to inform prospective subjects and to seek

and obtain their consent?

“The consent meeting will be held priv ately between the respondent and the study director....During the consent meeting, respondents will be given a detailed explanation of the procedures of the study and be asked to watch a movie of the testing process. They will be allowed sufficient opportunity to consider whether or not to participate before signing the consent form. The participants will be informed of how many bites they are likely to obtain and what symptoms of arthr opod-borne reactions they should be alert forAttachment 1

Page 31 of 36 after participation in the study. Participants will be provided a detailed consent form (Appendix H) outlining the risks of participating in the study.” (V1:25)

(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 factor s rule out participation by employees or students of the Study Director. Recruitment of alternate subjects reduces the likelihood that subjects might be reluctant to withdraw.

9. Respect for Subjects

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

Subject-identifying information will be record ed only once; all subsequent data records and reports will refer to individual subjects only by an arbitrary code. “To protect your privacy, we will give you an identification num ber for this study and we will record and report all data under that number. We will keep only one record linking your name to this number, and we will store it away from other data. We will not identify you by name or in any other way in the study report.” (V1:201)

Provision is made for discrete handling of the pregnancy testi ng that is required of female subjects on the day of testing. “You will be asked to take the te st in a private restroom. If, after taking the test, you still wish to partici pate in the study, you will be asked to show the result of the test to a female laboratory technician so that she can verify that you are not pregnant. If you withdraw from the study after taking the pregnancy test, you will not

be asked to share the result of the test with anyone.” (V1:195)

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

The informed consent form states: “Your participation in this study is voluntary. You may decide not to be in the study or you may le ave the study at any tim e. Your decision will not result in any penalty or loss of benefits to which you are entitled.” (V1:202)

“If you cannot keep your arms in the cage for the entire 15 minutes, you may remove them at any time.” (V1:199)

(c) How will subjects who decline to participate or who withdraw from the research be

dealt with?

Subjects who decide not to pa rticipate after completing th e informed consent meeting will be paid $20. Subjects who decide not to pa rticipate after taking a pregnancy test willAttachment 1

Page 32 of 36 be paid $25. Subjects who withdraw from the research will be paid for the number of pairs of sleeves that they completed at the rate of $25 per pair. (V1:201)Attachment 2

Page 33 of 36 § 26.1111 Criteria for IRB approval of research USDA Protocol for Bite Protection of Etofenprox-treated Fabric

Criterion Y/N Comment/Page Reference (a)(1)(i) Risks to subjects are minimized by us ing procedures which are consistent with sound research design and which do not unnecessarily expose subjects to risk. Y

(a)(1)(ii) 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 re asonable in relation to antici pated benefits, if any, to subjects, and the importance of the knowle dge 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 resear ch (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 appl ying knowledge gained in the research (for example, the possible effects of the re search 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 in volving 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 prot ect the privacy of subjects and to maintain t he 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/AAttachment 3

Page 34 of 36 §26.1116 General requirements for informed consent USDA Protocol for Bite Protection of Etofenprox-treated Fabric

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 le gally authorized representative Y

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

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

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 a gents from liability for negligence Y(a) In seeking informed consent the following informationshall 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 t he procedures to be followed, and identification of any procedures which are experimental Y

(2) A description of any reasonably fo reseeable risks or discomforts to the subject Y

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

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

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

(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 Y

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

(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 Y(b) When appropriate, one ormore of the following elements ofinformation shall also be providedto each subject (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 Y

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

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

the research Y

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

(5) A statement that significant ne w 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 N/A

(6) The approximate number of subjects involved in the study Y (e) If the research involves intentional exposur e of subjects to a pesticide, the subjects
of the research must be informed of the iden tity of the pesticide and the nature of its pesticidal function. YAttachment 4

Page 35 of 36 §26.1117 Documentation of informed consent USDA Protocol for Bite Protection of Etofenprox-treated Fabric

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 gi ven to the person signing the form. Y Consent form pp. 193-203

(b)(1) The consent form may be a writt en 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 authoriz ed 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 Y Consent form meets requirements of §26.1116; procedure described in protocol §8.1.6 pr ovides 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 r epresentative. 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 subjec t or the representative. Only the short form itself is to be signed by the subject or t he 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 co py of the summary shall be given to the subject or the representative, in add ition to a copy of the short form. N/AAttachment 5

Page 36 of 36 40 CFR 26.1125 Submission of proposed human research for EPA review USDA Protocol for Bite Protection of Etofenprox-treated Fabric

Any person or institution who intends to conduct or sponsor hu man 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 addition al information, to the extent not already included:

Requirement Y/N Comments/Page RefsThe following Information, to theExtent not already included:§1125(a)a discussion of: (1) The potential risks to human subjects Y V1:43-44

(2) The measures proposed to minimize risks to the human subjects; Y V1:43-44 (3) The nature and magnitude of all expected benefits of such research, and to whom they would accrue Y V1:45

(4) Alternative means of obtaining information comparable to what would be collected through the proposed research; and Y none

(5) The balance of risks and benefits of the proposed research. Y V1:45 §1125(b): All information for subjects and written informed consent agreements as originally provided to the IRB, and as approved by the IRB. Y V1:25

§1125(c): Information about how subjects will be recruited, including any advertisements proposed to be used. Y V1:23, 204

§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 V1:25

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

sponsors. Y Volume 2

§1125(f): Official notific ation to the sponsor or inve stigator. . . that research involving human subjects has been reviewed and approved by an IRB. Y V1:208-210all information relevant to the proposed researchspecified 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 investi gators, and reports of injuries to subjects. Y
n/a

Y
n/a Volume 2

V1:193-203

(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 Separately provided to HSRB

members

(3) Records of continuing review activities. n/a (4) Copies of all correspondence between the IRB and the investigators. Y Volume 2 (5)

 A list of IRB members identified by name; earned degrees; representative capacity; indications of experience such as board certifications, licenses, etc., suffi cient to describe each member’s chief anticipated contributions to IRB deliberations;

 any employment or other relationship between each member and the institution, for example, fu ll-time employee, a member of governing panel or board, stock holder, paid or unpaid consultant. Y

Y V2:22

(6) Written procedures for the IRB in the same detail as described in §26.1108(a) and §26.1108(b). N Separately provided to HSRB

members (7) Statements of significant new findings provided to subjects, as required by §26.1116(b)(5). n/a n/a for protocols