December 30, 2008

EPA-HSRB-08-04

George Gray, Ph.D.

Science Advisor

Office of the Science Advisor 1200 Pennsylvania Avenue, NW Washington, DC 20460

Subject: October 21-22, 2008 EPA Human St udies Review Board Meeting Report

Dear Dr. Gray:

The United States Environmental Protecti on Agency (EPA or Agency) requested the

Human Studies Review Bo ard (HSRB) to review scientific and ethical issues addressing: (1) Agricultural Handlers Exposure Task Force (AH ETF) pesticide handler protocols: closed-cab airblast scenario, with addition of chlorothalonil, (2) AHETF pesticide handler protocols: opencab airblast scenario and (3) completed Carro ll-Loye Biological Research picaridin-based mosquito repellant efficacy study LNX-001. In addition, the Board provided comments on the Guidelines for Product Performance Testing of Sk in-Applied Insect Repellents. The Board also addressed procedural issues that surfaced as points of concern at the meeting.

Consideration to Add Sulfur and Copper as Surrogate Chemical for AHETF Airblast

Studies

Prior to the Human Studies Re view Board meeting in October, the AHETF submitted to the Agency a request to support th e addition of copper and sulfur as surrogate chemical for the open and closed cab scenario designs. Specifi cally, background information and sample product

risk statements were submitted to the EPA on October 10 th and transmitted to the HSRB on

October 17 th , but a revised and IRB-approved protocol reflecting the addition of these two compounds was not available for Agency or Board review.

The Board recommended that copper and sulf ur not be used as surrogate chemicals for airblast applications based on concerns regard ing exposure measurements and the applicability of data produced by such studies for the generi c database under development. The Board also noted that it was not provided with a specific proposal describing the ra tionale and procedures for using these two chemicals. The Board affirm ed its understanding that regulations governing HSRB review of third-party pesticide intentional exposure studies precludes the Board from reviewing a protocol unless the Agency (a) provides the Board with explicit information regarding scientific design and hum an subject protections and (b) evidence that the protocol has been submitted to an IRB for approval.

Following the Board’s statement to this effect, the EPA stated that copper and sulfur would not be used as surrogates in the protocols under review and the Board proceeded to review the original protocols.

Page 1 of 281. AHETF Pesticide Handler Protocols: Closed-C ab Airblast Scenario, with Addition of

Chlorothalonil

Science

If the proposed closed-cab airblast application field st udy protocols are revised as suggested in the EPA review, a nd data collection and design wea knesses are modified as detailed by the HSRB in this report, then the research is li kely to generate scientifically reliable data, useful for assessing the exposure of handlers who apply liquid pestic ides using airblast equipment drawn by vehicles with closed cabs. However, due to the limitations posed by the use of purposive sampling, small sample size, reduced range of exposures and representativeness of participating growers noted in previous Board repo rts, the data will not meet the assumptions of most statistical analyses that rely on mean scor es or continuous data. Conclusions drawn from these data must recognize these limitations.

Ethics

If revised as suggested by the Board, the re search described in th ese three protocols is likely to meet the applicable requirement s of 40 CFR part 26, subparts K and L.

2. AHETF Pesticide Handler Protocols: Open-Cab Airblast Scenario

Science

For the open-cab airblast protocols the Board reiterated its recommendations already put forward for the closed-cab protocols. In addition, the Board recommended that a careful evaluation be conducted before combining old and new open cab datasets. Finally, the Board concluded that a more even distribution of monitoring units across the five proposed categories of active ingredient handled might strengthen th e design and provide great er insight into the question of proportionality.

Ethics

If revised as suggested by the Board in its review, the research described in these three protocols is likely to meet the applicable requirements of 40 CF R part 26, subparts K and L.

3. Completed Carroll-Loye Biological Resear ch Picaridin-Based Mosquito Repellant Efficacy Study LNX-001

Science

The Carroll-Loye Biological Research st udy LNX-100 is sufficiently sound, from a scientific perspective, to be used to assess the repellent efficacy of the tested formulations against mosquitoes. However, the calculation of Mean “Complete Protection Time” is

Page 2 of 28inappropriate for censored data and the Agency shoul d not rely on this aspect of the data analysis to assess the repellent efficacy of the tested formulations.

Ethics

The Board concurred with the Agency’s a ssessment that the study submitted for review was conducted in substantial compliance with subparts K and L of 40 CFR 26.

Guidelines for Product Performance Test ing of Skin-Applied Insect Repellents

While the Board was not provided a charge for consideration of the guidelines, it did have several comments to enhance the utility of the document. The Board noted that improvements in insect repellent protocols would be derived from portions of the guidelines and

that the document was well written and clear. The Board appreciated the inclusion of landings as well as bites as an endpoint and encouraged the Agency to consider landi ngs as the preferred endpoint.

The Board expressed serious conc erns that if the erroneous assumptions and inconsistent statements regarding the statistical analysis pl an are not corrected prio r to publication of the Guidelines, investigators followi ng the guideline recommendations would develop sc ientifically unreliable protocols. The Board underscored that it would continue to evaluate protocols submitted for review to the HSRB based on appropri ate statistical assumptions and analytic plans and on that basis might recommend rejection of a protocol that followed those elements of the

Guidelines that were incorrect. Based on continue d statistical concerns with the guidelines, the Board strongly recommended that a Board worki ng group provide a review of the statistical portion of the guidelines, for subsequent consider ation by the HSRB at a p ublic meeting, prior to the final guidelines being released by EPA to the public.

Clarification of Board Report Process

Prior to the posting of and public meeting to finalize the June 2008 report, the Agency wrote a memo to the Board stating that the Ag ency had approved the implementation of AHETF studies based in part on their interpretation of Board discussion at the June meeting and the Chair’s minutes. The Board recognized the need for a more rapid turn around of its final report to

avoid future confusion. The Boar d clarified its process for approving final recommendations and adopted a new report schedule and format.

Sincerely,

Celia Fisher, Ph.D., Chair

EPA Human Studies Review Board

Page 3 of 28NOTICE

This report has been written as part of th e activities of the EPA Human Studies Review Board, a Federal advisory committee providing advice, information and recommendations on

issues related to scientific and ethical aspects of human subjects research. This report has not been reviewed for approval by the Agency a nd, hence, the contents of this report do not necessarily represent the view a nd policies of the Environmental Protection Agency, nor of other agencies in the Executive Branch of the Fede ral government, nor does the mention of trade names or commercial products constitute a reco mmendation for use. Further information about

the EPA Human Studies Review Board can be obtained from its website at http://www.epa.gov/osa/hsrb/. Interested persons are invited to contact Paul Lewis, Designated Federal Officer, via e-mail at lewis.paul@epa.gov.

In preparing this document, the Board caref ully considered all information provided and presented by the Agency presenters, as well as information presented by public commenters. This document addresses the information provide d and presented within the structure of the charge by the Agency.

Page 4 of 28U. S. ENVIRONMENTAL PROTECTION AGENCY HUMAN STUDIES REVIEW

BOARD MEMBERS

Chair

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

Vice Chair

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

Members

Alicia Carriquiry, Ph.D., Professor, Departme nt of Statistics, Iowa State University Snedecor Hall, Ames, IA

Gary L. Chadwick, PharmD, MPH, CIP, Associat e Provost, Director, Offi ce for Human Subjects Protection, University of Ro chester, Rochester, NY

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

Richard Fenske, Ph.D., MPH, Professor and Associ ate Chair, Department of Environmental and Occupational Health Sciences, Univer sity of Washington, Seattle, WA

Susan S. Fish, PharmD, MPH, Professor, Bi ostatistics & Epidemiology, Boston University School of Public Health, Co-Director, MA in Clin ical Investigation, Bost on University School of Medicine, Boston, MA

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

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

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

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

Page 5 of 28Lois D. Lehman-Mckeeman, Ph.D., Distinguish ed Research Fellow, Discovery Toxicology, Bristol-Myers Squibb Co mpany, Princeton, NJ

Jerry A. Menikoff, M.D., Direct or, Office of Human Subjects Res earch, Office of the Director, National Institutes of Health, Bethesda, MD

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

Sean Philpott, Ph.D., MS Bioethics, Scie nce and Ethics Officer, Global Campaign for Microbiocides, PATH , Washington, DC

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

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

Linda J. Young, Ph.D., Professor, Department of Statistics, Institute of Food and Agricultural Sciences, University of Fl orida, Gainesville, FL

Human Studies Revi ew Board Staff

Paul I. Lewis, Ph.D., Executive Director, Huma n Studies Review Board Staff, Office of the Science Advisor, United States Environm ental Protection Agency, Washington, DC

* Resigned from the HSRB at the end of October 21-22, 2008 Public Meeting

** Not in attendance at the October 21-22, 2008 Public Meeting

Page 6 of 28INTRODUCTION

On October 21-22, 2008, the United States Envi ronmental Protection Agency’s (EPA or Agency) Human Studies Review Board (HSRB) me t to address scientific and ethical issues concerning: (1) Agricultural Handlers Expos ure Task Force (AHETF ) pesticide handler protocols: closed-cab airblast scenario, with addition of chlo rothalonil, (2) AHETF pesticide handler protocols: open-cab airblast scenar io, and (3) completed Ca rroll-Loye Biological Research picaridin-based mosquito repellan t efficacy study LNX-001. The Board also provided comments on the Agency’s draft guidelines for product performance testing of skin-applied insect repellents. In addition, the Board addressed procedural issues that surfaced as points of concern at the meeting. Each of these topics is discussed more fully below.

Regulations Relevant to Studies Submitted for Review

EPA’s regulation, 40 CFR §26.1125, requires a sponsor or investigator to submit to EPA, before conducting a study involvi ng intentional exposure of human subjects, materials describing the proposed human research in order to allow EP A to conduct scientific and ethics reviews. In addition, EPA’s regulation, 40 CFR §26.1601, require s EPA to seek HSRB review of the proposed research. Because the two AHETF proposed studies i nvolves scripted exposure, it meets the regulatory definition of “research invo lving intentional exposure of a human subject” and thus these cited provisions of regulation apply to it.

The Agency’s regulation, 40 CFR §26.1602, requ ires EPA to seek HSRB review of an EPA decision to rely on the results of these studies. Carroll-Loye Biological Research has submitted data to support continued registration of two test materials. EPA has reviewed the research, applying the standard in 40 CFR §26.1705, which states: “Except as provided in §26.1706, in actions within the scope of §26.1701, EPA shall not rely on data from any research initiated after April 7, 2006, unless EPA has adequate information to determine that the research was conducted in substantial compliance with subparts A through L of this part...This prohibition is in addition to the prohibition in §26.1703. “

REVIEW PROCESS

On October 21-22, 2008, the Board had a publ ic face-to-face meeting in Arlington, Virginia. Advance notice of the meeting was pub lished in the Federal Register “Human Studies Review Board: Notice of Public Meeting” (73 Federal Register 73, 53422). At the public meeting, following welcoming remarks from Agency officials, the Board heard presentations from the Agency on the following topics: (1) Agricultural Handlers Exposure Task Force (AHETF) pesticide handler protocols: closed -cab airblast scenario, with addition of Chlorothalonil, (2) AHETF pesticide handler pr otocols: open-cab ai rblast scenario, (3) completed Carroll-Loye Biological Research pica ridin-based mosquito repellant efficacy study LNX-001, and (4) Agency Guidelines for Product Performance Testing of Skin-Applied Insect Repellents.

Page 7 of 28Oral comments The following oral comments were presented at the meeting:

Agricultural Handlers Exposure Task Force (AH ETF) Pesticide Handler Protocols: Closed-Cab Airblast Scenario, with Addition of Chlorothalonil

Victor Canez, Ph.D. from BASF on behalf of the AHETF

AHETF Pesticide Handler Protocol s: Open-Cab Airblast Scenario

Victor Canez from BASF on behalf of the AHETF

Completed Carroll-Loye Biological Research picar idin-based mosquito repellant efficacy study

LNX-001

Scott Carroll, Ph.D., on behalf of Carroll-Loye Biological Research

Guidelines for Product Performance Tes ting of Skin-Applied Insect Repellents

Tom Osimitz, Ph.D. of Science Strategies LLC on behalf of the DEET Task Force Scott Carroll, Ph.D., on behalf of Carroll-Loye Biological Research Mr. Nick Spero and Robin T odd, Ph.D. on behalf of ICR

Written comments

Written comments were received from: B. Sachau, a public citizen

For their deliberations, the Board considered the materials presented at the meeting, written public comments and Agency background documents (e.g., the published literature, Agency data evaluation record, weight of evidence review, ethi cs review, pesticide human study protocols and Agency evaluation of the protoc ol or study). For a comprehensive list of background documents visit www.regulations.gov

CHARGE TO THE BOARD AND BOARD RESPONSE

Board Response to Request to Add Sulfur a nd Copper as Surrogate Chemicals for Closed and Open Cab Airblast Studies

HSRB Recommendation

The Board decided not to consider the a ddition of copper and sulfur as surrogate chemicals for open and closed cab protocols based on concerns that the lack of a detailed and IRB approved protocol pr evented adequate Board review regarding exposure measurements, the

Page 8 of 28applicability of data pr oduced by such studies for the gene ric database under development and human subjects protections.

HSRB Detailed Recommendations and Rationale

Prior to the Human Studies Review Board meeting in October, the AHETF submitted to the Agency a request to support th e addition of copper and sulfur as surrogate pesticides for the open and closed Cab scenario designs discus sed previously. Speci fically, background information and sample product informati on were submitted to the EPA on October 10 th and

transmitted to the HSRB on October 17 th , but a revised and IRB-appr oved protocol reflecting the addition of these two compounds was not av ailable for Agency or Board review.

The Board recognized the practic al considerations underlying the request, but expressed a

number of scientific concerns. It was not cl ear to the Board that these compounds would be applied in the same manner as the current surrogate pe sticides; e.g., nozzle size, droplet size. It was thought that the replacement of organic, semi- volatile pesticides with inorganic, non-volatile compounds would present significant challenges in regard to air sampling measurements. It was noted that the sampling methods typically used for these two categories of chemicals were substantially different. The Board was not convinced that measurement of c opper or sulfur in air samples would properly represent in halation exposures to the insecticides. It was also not clear to the Board that the current dermal sampling meth ods would be adequate to assess exposures to copper or sulfur. It was noted that copper and sulf ur are present at much higher concentrations in their formulated products than are insecticides, and that they may be applied at much higher

rates. It was not clear if the potential for breakthrough of the de rmal sampling garments or the removal efficiency of hand wash and wi pe procedures would be comparable.

Based on an internal review of the toxi cological profiles of these two compounds, the Agency concluded that copper and sulfur did not pose significant additional safety concerns and thus supported their use as surrogate pestic ides in the protocols AHE57, AHE58, and AHE59 pending protocol amendment and IRB review. Th e Board expressed concern that the lack of revised and IRB-approved protocols and supporting docum entation prevented careful

consideration of the risks that the addition of these two compounds could pose to study participants. In addition the Final Human Studies rule preclud ed the HSRB from reviewing the protocols if the AHETF intended to amend the three submitted protocols to include the two compounds after the October 2008 HSRB meeti ng was over. The Board affirmed its understanding that regulations governing HSRB review of third- party pesticide intentional exposure studies precludes the Board from review ing a protocol unless the Agency (a) provides the Board with explicit information regarding sc ientific design and human subject protections and (b) evidence that the protocol has been subm itted to an IRB for approval. Specifically, 40

CFR 26.1125 states that:

Any person or institution who intends to c onduct or sponsor human research covered by Sec. 26.1101(a) shall, after receiving approva l from all appropriate IRBs, submit to EPA prior to initiating su ch research all information rele vant to the proposed research specified by Sec. 26.1115(a).

Page 9 of 28At the time of the October 2008 HSRB m eeting, the IRB of record, Independent Institutional Review Board, Inc. of Plantati on, FL (IIRB) had not received an application, reviewed or approved the addition of copper and sulfur to these th ree protocols, so the regulatory requirements of 40 CFR 26.1125 were not met.

The Board thus declined to consider the addition of coppe r and sulfur as surrogate pesticides for open and closed cab protocols. Fo llowing the Board’s statement to this effect, the EPA stated that the copper and sulfur would not be used as surrogates in the protocols under review and the Board proceeded to review the original protocols.

1. Assessment of AHETF Pesticide Handler Protoc ols: Closed-Cab Airblast Scenario, with

Addition of Chlorothalonil

Overview

The HSRB has previously considered the desi gn and conduct of research to measure the levels of exposure received by workers when handling (i.e., mixing, lo ading, or applying) pesticides. Two industry Task Forces, the Antimic robials Exposure Assessment Task Force II (AEATF) and the AHETF, have previously submitted materials for HSRB review. The Board

had addressed this kind of research in its mee tings in June 2006, June 2007, April 2008, and June

2008.

At its June 2008 meeting the Board reviewed and provided recommendations for enhancing the scientific validity and usefulness of two AHETF field studies on the exposure of workers applying liquid pesticides using closed-cab airblast equipment. At the October 2008 meeting EPA presented proposals from the AHETF for the th ree additional field studies required to fulfill this scenario design. These protocol s are very similar to those revi ewed by the Board in June, but involve monitoring workers making pesticide applica tions to different crops in different regions. In addition, these protocols in corporated numerous refinements agreed to by EPA and the AHETF shortly after the June HSRB meeting.

The three new protocols involve monitoring applications of surr ogate pesticides to Michigan cherry orchards (AHE57), California vineyard s (AHE 58), and Washington apple orchards (AHE59). Together with the data generated unde r the two field study protocols reviewed by the Board in June 2008, these will fulfill the design of the closed-cab air blast application scenario.

Because of the widespread use of chlorothalon il on Michigan cherries, the Agency requested

that the Board consider a revision to the scenario design to add several form ulations of this active ingredient to the list of perm issible surrogate pesticides.

Page 10 of 28Charge To The Board

Science

If the proposed closed-cab airblast application field study protocols AHE57, AHE58, and AHE59 are revised as suggested in EPA’s reviews and if the research is performed as described: Is the research likely to generate scientifically reliable data, us eful for assessing the exposure of handlers who apply liquid pesticid es using airblast equipment dr awn by vehicles with closed

cabs?

Board Response to the Charge

HSRB Recommendation

If the proposed closed-cab ai rblast application fi eld study is revised as suggested in the

EPA review and data collection and design weaknesses are modified as detailed below, then the research is likely to generate scientifically reliable data, useful for asse ssing the exposure of handlers who apply liquid pesticid es using airblast equipment dr awn by vehicles with closed cabs. However, due to the limitations posed by th e use of purposive sampling, small sample size, reduced range of exposures and representativene ss of participating growers, the data will not meet the assumptions of most statistical analyses that rely on mean scor es or continuous data.

Conclusions drawn from these data must recognize th ese limitations.

HSRB Detailed Recommendations and Rationale

The Board learned at the October meeti ng that, following the June 2008 HSRB meeting, the Agency had instructed the AHETF to move fo rward with airblast application studies. Since the Board’s report for the June meeting was not fi nalized until the October meeting, the protocols

that will be used for airblast studies will not necessarily incorporate some of the Board’s recommendations from the June meeting. Thus, the primary concerns raised by the Board at this meeting were similar to those presented in the HSRB June meeting report. The Board recommended that the Agency consider the con cerns listed below when it provides its final response to AHETF regarding these protocols. In particular, the Board viewed the selection of monitoring units from separate farms to be a m odification needed to ensure that the design and analyses are scientifically sound.

1. The Board again noted that selecting 5 monito ring units in each cluster, each from a different

farm is needed to ensure that the desi gn and analyses are sc ientifically sound.

2. The Board reiterated its observation that many aspects of the proposed studies were likely to reduce the range of exposures that would be measured with applic ators under real-world

conditions. While a reduction in the range of exposures may be unavoidable due to practical considerations, it should be cons idered by the Agency when evaluating the usefulness of the data produced by these studies.

Page 11 of 283. The Board once again advised the Agency to re quire collection of information on growers who do not respond or who decline to participate, such that the repr esentativeness of participating growers can be evaluated. The usefulness of the da ta will be enhanced by statistical comparisons between characteristics of participating grower s and those that declin e. The Board expressed concern regarding the inadequacies of a master list for which 43% of growers were listed as “unreachable.” The inadequacy of the list makes th e design vulnerable to selection bias that can seriously compromise the usefulne ss of the data. If the master list cannot be improved then these

limitations need to be considered in data anal ysis and interpretation of results and should be explicitly described whenever the EPA refers to these studies.

4. The Board also continued to recommend the se lection of Local Site Coordinators with demonstrable training and expertise in survey implementation to ensure optimal recruiting and thereby enhance the usefulness of the data.

Ethics

Charge to the Board

Is the research likely to meet the applicab le requirements of 40 CFR part 26, subparts K

and L?

Board Response to the Charge

HSRB Recommendation

If revised as suggested in the EPA review and as detailed in the spec ific points below, the research described in these three protocols is likely to meet the applicable requirements of 40 CFR part 26, subparts K and L.

HSRB Detailed Recommendations and Rationale

A. Clarifications Required (such clarificati ons would also be subject to IRB review).

1. The Local Site Coordinator, the Principal Field Investigator, the Field Facility, the Analytical Facility, and the Pr incipal Analytical Investigator must be identified in the protocol. Any key members of the research te am who will have contact with the research subjects or their identifiable data must rece ive and document their recent (not expired) training in human subjects protection.

Many training programs in human subjects pr otection issue certificates of completion indicating the date of issuance. Depending on the program, and the requirements of the relevant IRB, there may be policies relating to the freque ncy of training. Many cer tificates “expire” after two or three years, and in the U. S., the “best practice” standard is to require continual training or retraining at least every three years. It is impor tant for the certificati ons of all key research personnel to be current.

Page 12 of 28The specific identities of key research pers onnel have an impact on the assessment of the scientific validity of the research, which in turn relates to an ethical a nd regulatory assessment of

the reasonableness of risks in relation to the potential benefi ts of research.

2. Revise protocols to remove the inconsistenc ies in listing all three surrogate chemicals

that have been reviewed. Evaluation of risk-benefit must be informed by information on all surrogate chemicals involved.

3. Revise subject recruitment plan to specificall y address the probability that subjects may also be growers . Based on data from initial studies by AHETF, subjects can be workers or growers. The recruitment pl an is directed toward recruitment of workers. Information should be provided on whether any additional co nsiderations must be given to ethical recruitment of growers.

4. Remove risks of agricultural work from the listing of risks related to the research . The agricultural work itself is not part of the re search. Thus the risks associated with that

work are unrelated to research and should be removed from this and all future discussions

of research risks or ri sk-benefit relationship.

5. Identify risks of pesticide produc ts that are due to scripting. Working with the pesticide products is not part of the research. However the scripting that is done for the purpose of the research may produce exposures to higher concentrations or longer durations, which

are incremental risks of the re search. These are the risks asso ciated with the research.

6. Revise the IRB application to indicate expecte d ethnic/racial distribution specific to the location in which the study will be conducted. The ethnic/racial distribution indicated on all IRB applications is identical for all studi es submitted. This is unlikely as the research will take place at sites in widely dispersed geographic locations.

7. Answer question 17 in the IRB application, and submit a Data Safety Monitoring Plan Form as required by IIRB. Question 17 asks if risk is minimal or greater than minimal. This question is not completed on any of the applications. If greater than minimal, the IRB application requires attachment of “a Data Safety Monitoring Plan Form that includes procedures for monitori ng the progress of the trial and the safety of the subjects, reporting adverse events (AEs) and ensuring data accuracy and protocol compliance.” Because this study is greater than minimal risk (the major risk being heat exposure due to whole body dosimeters), such a form should be submitted to the IIRB, even if all of the items requested in the form are f ound elsewhere in the study protocols.

. 8. Revise the description of th e consent process to indicate how bilingual witnesses are going to be recruited and the amount of rem uneration, as referenced in the recruitment standard operating procedures. This information is critical to assess whether or not the consent process is conducted in a manne r to minimize potential coercion or undue influence of Spanish-speaking subjects. One suggestion is to recr uit a bi-lingual farm worker advocate or other community repr esentative to serve in this role.

Page 13 of 289. Revise the section of the recruitment SOP t hat relates to recru itment and enrollment of illiterate or low literacy subjects.

While an excellent attempt to address this issue has been made, there are aspects with

which the HSRB is uncomfortable. The Board r ecommended that the AHETF consult with farm worker advocacy groups on this issue. The SOP st ates that “reading abil ity ...will be ascertained by the person obtaining consent by asking the potent ial subject to read a portion of the consent

form out loud.” This can lead to embarrassment of a low literacy or illite rate person. In addition, subjects are asked to identify if they cannot read. Subjects may be he sitant to disclo se illiteracy, and may feel shame at their conditio n. By relying more on the consent process than the form , the ability to read competently becomes less impor tant, and then embarrassment and shame do not

become risks associated with the research.

Also, the recruitment SOP states that if the researcher is not comfortable with the potential subject’s level of literacy then “the Stud y Director will also verify that the worker has apparently understood the materials read to and discussed with them by asking specific questions to assess comprehension (see Sec. 7.10.a).” The Board recommended clarity how the test of comprehension will be used for those who are ju dged literate and non-l iterate. Sec. 7.10.a suggests that all participants will undergo tests of comprehension but earlier sections are unclear (e.g., Sec. 6.5a and 6.5c)

B. Clarifications needed prio r to study implementation

1. Explain why the IRB review of one prot ocol out of three was tabled, and why communication from IIRB to the investigator was not in writing. IRB communication includes a “note to file” from the principal investigator that IRB review of AHE57 was initially tabled, but not AHE58 or AHE59. The Board requested th at the IRB provide this communication in writing.

2. Describe how individual level data will be presented to the subject upon request.

Several issues are raised with this point. Ho w will the data be framed or translated to the worker? As an example, how will the AHETF wo rk to prevent workers from changing future

behavior to their own detriment if their individua l risk levels are lower than the average of all

workers? The HSRB felt that consideration must be given to the ways in which data could be used or misused by the individual subjects. For example, a worker who finds out simply that his/her individual exposure levels were less than the group average may feel that s/he can be less cautious in the future (i.e. behavioral disinhibi tion), thereby putting him/he rself at greater risk.

C. Modifications to informed consent form prior to study implementation (and subject to IRB review)

1. Harmonize enrollment criteria (inclusion, exclusion) between the protocol and consent form. Providing potential subjects with the mo st accurate and informative information

allows them to make the best decision about participation.

Page 14 of 282. In the consent form, replace “regular worki ng hours” with the specific hours for the time zone in which the research will take place. Since the research is being conducted in locations that may be in different time zone s than the IIRB, the term “regular working hours” is not informative to the subjects.

3. Revise the consent form with the underlined word: “you may refuse medical treatment.

However , you cannot refuse medical treatment if you get sick from too much exposure to pesticides.....” As is, these two sentences appear contradictory. Adding “however” corrects the apparent contradiction.

4. Revise the forms (consent forms, product risk statements, recruitment materials) that have been translated into Spanish. Spanish translations should be written in common, correct, simple Spanish.

5. Revise the consent form to id entify who makes the determinat ion that an injury is studyrelated. Providing potential subjects with the most accurate and informative information

allows them to make the best decision about participation.

6. Revise attestation statement for witness on consent form to eliminate subject’s understanding or accuracy of the consent process. A witness cannot hones tly attest to a subject’s understanding or accuracy of the consent process. The witness can only attest that the consent process was cons istent with the consent form.

7. Revise consent form’s attestation statement of person obtaining consent: to “ I conducted the private consent meeting with the worker named above and confirm that consent was given voluntarily after the participant was fully informed of all of the information stated above, including the procedures, risks, and benefits of the research.” There is more that

the researcher should have discussed with th e potential subject than benefits, risks and procedures. In addition, the pr ocedures and risks should precede the benefits in the

discussion.

8. Confirm and clarify in informed consent that compensation for rese arch-related injury includes any co-pay. Subjects in this type of study should not have to assume any out-ofpocket expenses related to treatme nt for research-related injury.

D. Points to Consider

1. Consider revising Product Risk Statements to indicate which sign and symptoms are due to use that follows the product label, and which are due to overdose or massive spills or excessive exposure beyond what is expected to occur in the research.

There was not consensus among HSRB memb ers as to whether or not signs and symptoms of overdose or massive spills or excessive exposure beyond what is expected to occur

in the research need to be included in the Pr oduct Risk Statements. Some members felt that since these risks are part of the risks of the agricultura l work rather than the research, they should not

be included. Others felt that th e additional information would be helpful to potential subjects, and that education about pesticid es and their exposure risks coul d be considered a benefit for individual study participants.

The Board agreed with EPA’s proposal to use generic product information sheets based on the active chemical(s) rather than specific products. This would simplify paperwork and decrease the probability of error.

Page 15 of 282. Define the term “sufficient” when used in th e inclusion criterion “sufficient experience”. Use of a subjective term in the protocol incr eases the probability of inconsistent subject populations.

3. Revise wording of eligibility criterion that states “Confirm that you normally wear the personal protective equipment (PPE) listed on the Product Risk Statement. Confirm that you will follow label directions.”

By asking potential subjects to “confirm”, it is unlikely that the subject will say that they

do not normally wear PPE or follow label directions . The inclusion criterion could be worded by deleting “confirm that you” and begin that criterion with “usually”. Likewise number 3 should delete “confirm you do”. Then in the screening pr ocess, potential subjects should be asked an open-ended question like “wha t types of protective gear do you usually wear?

On page 45 of the CCAB scenario design doc ument, there are clearly articulated program requirements for use of minimal PPE. The CCAB scenario design document, for example, states:

The desired PPE and clothing situ ation for this scenario is:

• Long pants and long-sleeved shirt

• Chemical-resistant gloves (new, pr ovided by AHETF) only when contacting

treated surfaces outside of the closed cab

• Any footwear that are require d by the label or that the workers choose to wear (as long as they are consis tent with the WPS)

• Any eyewear required by the label or desired by the worker (except full face shields that would prevent face exposure)

• Any respiratory protection required by the label or desired by the worker (except full face respirators which would prevent face exposure)

As these are exclusionary criteria, in orde r to collect exposure data for workers using minimal PPE, Task Force researchers should be car eful that they are not recruiting participants who agree to use less PPE than normal in order to receive payment. By asking open-ended questions such as “what types of protective gear do you normally wear,” researchers will be able to obtain an unbiased assessment of potential pa rticipant’s normal practices and exclude those who use PPE that would potentially bias the exposure data collected.

4. Add to the protocol some provisions for counting and reporting the number of potentially eligible workers linked to each grower, the number of potential subjects attending initial group meetings, number attendi ng individual consent interv iews, number consenting to participation, number subsequently withdrawing or being withdrawn (with the reason for withdrawal) and number co mpleting the study.

These data can provide evidence of equitabl e subject selection, a regulatory and ethical requirement. In addition, it is only through these numbers that any assessment can be made as to the representativeness of the study population, and to the generalizab ility of the data.

Page 16 of 282. Assessment of AHETF Pesticide Handler Pr otocols: Open-Cab Airblast Scenario

Overview

The three proposed field study protocols are si milar to those the Board reviewed for the closed cab airblast scenario, modified to mon itor additional exposure, es pecially to the head, resulting from use of open cab equipment. Th e Agency has concluded that a previous AHETF study, AHE-07A, conducted before promulgation of EPA’s human research rule, provided 15 monitoring units that met contem porary standards of scientific validity and then-prevailing standards of ethical conduct. The AHETF proposes to use the data from this earlier study in its generic database, and to supplement it with 15 more monitoring units, obtained through three

additional field studies. The HSRB has not been provided with deta ils or data from this prior study.

Charge to the Board

Science

If proposed open- cab airblast application field study protocols AHE62, AHE63, and AHE64 are revised as suggested in EPA’s reviews, and if the resear ch is performed as described: Is the research likely to generate scientifically reliable data, us eful for assessing the exposure of handlers who apply liquid pesticides using airblast equipment draw n by vehicles with open cabs?

Board Response to the Charge

HSRB Recommendation

If the proposed open-cab airbla st application field study protocols are re vised as suggested in EPA’s reviews, and data co llection and design weaknesses ar e modified as detailed below, then the research is likely to generate scien tifically reliable data, useful for assessing the exposure of handlers who apply liquid pesticides using airblast equipment drawn by vehicles with open cabs. However, the Board has not re viewed the procedures used for the pre-rule existing data and cannot evaluate whether co mbining these studies and existing data is scientifically justified. The Board concluded th at a more even distribu tion of monitoring units across the five proposed categories of active ingr edient handled would strengthen the design and provide greater insight into the question of proportionality. The Board recommended that once the study is completed the Agency formally ev aluate whether combining the datasets is appropriate. Finally, as the Board has stated throughout its review of these types of protocols, due to the limitations posed by the use of purpos ive sampling, small sample sizes, reduced range of exposures and representative ness of participating growers, the data will not meet the assumptions of most statistical analyses th at rely on mean scores or continuous data. Interpretations of the usefulness of the data should recognize these limitations.

Page 17 of 28HSRB Detailed Recommendations and Rationale

For the open-cab airblast protocols the Board reiterated its recommendations already put forward for the closed-cab protocols. The Board had two additional concerns.

1. The first concern focused on the intention to add the new data to existing data. The Board has not seen the pre-Rule open-cab ai rblast data that have already b een collected, nor has it seen the protocols used to generate these data. The Bo ard recommended that once the proposed protocols are completed, the data from the older and new studies should be evaluated to ensure that combining the datasets is appropriate. There ma y be unforeseen reasons why these data cannot be combined. If this were the case, the AHETF would need to collect additional open-cab airblast data to meet the sample size objective.

2. The second concern focused on the AHETF plan to distribute the 15 new monitoring units evenly across five categories of pounds of ac tive ingredient handled (5-9; 10-17; 18-30; 31-55; 56-100). The existing open-cab da taset consists of 15 monito ring units: one in the middle category, and seven in each of th e top two categories. The current plan will result in a monitoring unit distribution of 3, 3, 4, 10, and 10 across the fi ve categories. The Board was not able to

ascertain the rationale for this distribution. The Bo ard concluded that to ga in greater insight into the question of proportionali ty the final number of such units pe r scenario should be similar, and

that sufficient numbers of new MUs in each scen ario be collected to compare old and new.

Ethics

Charge to the Board

Is the research likely to meet the applicab le requirements of 40 CFR part 26, subparts K

and L?

Board Response to the Charge

HSRB Recommendation

If revised as suggested by the Agency re view and Board suggestions, the research described in these three protocols is likely to meet the applicable requirements of 40 CFR part 26, subparts K and L.

HSRB Rationale

The Board considered the comments and con cerns that had been provided for the closed cab protocols highlighted earli er to be applicable to th e open cab protocols as well.

3. Assessment of Completed Carroll-Loye Bi ological Research Picaridin-Based Mosquito Repellant Efficacy Study LNX-001

Page 18 of 28Overview of the Study

LNX-001 was a field-based study of repellen cy to mosquitoes of two conditionally registered products (one lotion and one pump spray) containing 20% picaridin; these two formulations are KBR 3023 All-Family Insect Repellent Cream (EPA Reg. No. 39967-50) and KBR 3023 All-Family Insect Repellent Spray (EPA Reg. No. 39967-53). It was conducted by Carroll-Loye Biological Research of Davis, CA between Ma y 14th and June 15th, 2008. The study was sponsored by LANXESS, Inc. of P ittsburgh, PA. The study was required by EPA to support registration of these two products.

As submitted to the EPA, the completed study consisted of two interdependent analyses: 1) a dosimetry study designed to determine the amount of lotion or spray th at typical users would typically apply; and 2) an efficacy study de signed to measure the effectiveness of each compound as repellent for those species of mosquito es likely to be vectors for West Nile Virus (WNV) in the United States. The efficacy study wa s conducted at two environmentally distinct field sites in Butte and Glenn Counties, CA. Each phase included 10 participants (5 female and 5 male). Two experienced participan ts (1 male and 1 female) serv ed as untreated controls to measure ambient mosquito pressure. Based on the findings of the dosimetry phase, it was determined that the margin of exposure (MOE) for dermal toxicity at the highest dose level (seen with use applicati on of lotion on the arms) was about 266.

The efficacy of each formulation as a mosqu ito repellent was determined by measuring the ability of the formulations to prevent mosqu ito landings (defined as “Lite with Intent to Bite”; LIBe). During the field study, treated participants and un treated controls exposed their limbs to mosquitoes for one minute at fift een-minute intervals, for 10 hours (40 exposure periods) post-treatment or until fa ilure of efficacy, whichever occurr ed first. Failure of efficacy

was defined as the two confirmed LIBes within a single exposure period, or a single LIBe within each of two consequtive exposure periods. Participants worked in pairs to facilitate identification of LIBe and to aspirate mosqu itoes during exposure periods. No actual bites were reported, and aspirated mosquitoes were stored for la ter identification and arboviral testing.

Statistical analyses performed included: Mean “Complete Protection Time” (CPT) for the pump spray formulation was 11.6 hours at both field sites; Mean CPT for the lotion was ≥ 14 hours at the Butte County site and 13.5 hours at the Glenn County site.

Science

Charge to the Board

Is the CLBR study LNX-001 sufficiently sound, from a scientific perspective, to be used to assess the repellent efficacy of the tested formulations against mosquitoes?

Page 19 of 28Board Response to the Charge

HSRB Recommendation

The data collected in the Carroll-Loye Re search study LNX-001 is sufficiently sound, from a scientific perspective, to be used to assess the repellent efficacy of the tested formulations against mosquitoes. However, the calculation of Mean “Complete Protection Time” is inappropriate for censored data and the Agency shoul d not rely on this aspect of the data analysis to assess the repellent efficacy of the tested formulations.

HSRB Detailed Recommendations and Rationale

1. Overall the study was conducted according to the approved protocol. There were some minor deviations, but these did not affect the quality or validity of the scientific findings.

One deviation was the use of historical limb measurement data (within the past 2 years) instead of taking new measurements on subjects who had previously participated in similar studies with Carroll-Loye Biologica l Research; since it is unlikely that limb measurements would have changed significantly in this period of time for those particip ants who indicated that they had not changed weight appreciably during the in terval since the previous measurements, the

historical measurements would have been accurate.

The second deviation was the reco rding of an average start time instead of a precise start time for each individual particip ant in half of the study; because the range of start times was such a small fraction of the total protection time, this average would not have affected the results substantively.

2. Improvements to the statistical analysis would enhance the value of the results.

When the data are heavily censored, as is of ten the case in arthropod repellent studies, the use of the Kaplan-Meier method is problematic. If censored values ar e replaced by the time of censoring, the estimated mean is biased dow nward, and the standard deviation is underestimated. The downward bias of the mean tends toward a more conservative result, but underestimating the standard deviation may lead one to assume more confidence in the results than should be given. It is not appropr iate to return to the power anal ysis conducted prior to the study as a foundation for drawing conclusions.

In its use of the data the Agency should c onsider the potential us e of either maximum

likelihood methods for estimation of the mean an d variance in the presen ce of heavy censoring or estimation of the proportion of the populatio n having protection times of at least a prespecified number of hours should be considered as alternatives to those currently used to analyze the data. The suggestions for statistical anal ysis provided in the June 2008 HSRB report would

enhance the value of the results.

Page 20 of 28Ethics

Charge to the Board

Does available information support a dete rmination that study LNX-001 was conducted in substantial compliance with subparts K and L 40 CFR Part 26?

Board Response to the Charge

HSRB Recommendation

The Board concurred with the Agency’s a ssessment that the study submitted for review was conducted in substantial compliance with subparts K and L of 40 CFR 26.

HSRB Detailed Recommendations and Rationale

The documents provided by Carroll-Loye (Ca rroll 2008a, 2008b) state that each study was conducted in compliance the requirements of the US EPA Good Laboratory Practice Regulations for Pesticide Programs (40 CFR 160). Additional regulations – 40 CFR 26 subparts K and L; FIFRA § 12(a)(2)(P); and the Californi a Code of Regulations Title 3, Section 6710 – are also applicable. The study was reviewed and approved by a commercial human subjects review committee, IIRB, Inc.. Documentation provide d to the EPA by IIRB, Inc. indicates that it reviewed these studies pursuant to the standards of the Comm on Rule (45 CFR Part 46, Subpart A) and found them in compliance.

1. The Board concurred with the conclusions and factual observations of the ethical strengths and weaknesses of the study, as detailed in th e EPA’s Science and Ethics Review (Carley 2008).

2. The Board concluded that this study met all applicable ethi cal requirements for research involving human participants, in acco rdance to the following criteria:

a. Acceptable risk-benefit ratio. The risks to study participants were minimized appropriately and were justified by the potential societal benef its, particularly data on the efficacy of these new formulations as personal insect repellents.

i. Minors and pregnant or lact ating women were excluded fr om participation, with pregnancy confirmed by self-administe red pregnancy testing on each “day of study”. The potential of stigma resulti ng from study exclusion was minimized by enrolling three ‘alternate’ participants, allowing volunteers to withdraw or be excluded without compromising confidentiality.

ii. Based on toxicological data currently avai lable for picaridin, study participants were unlikely to be at risk of adverse si de effects with exposure. One 28-year-old male study participant reported severe itc hing around the face and neck during a field efficacy trials, but this was a local ized reaction distance from the site of

Page 21 of 28repellent application, immedi ately treated, and later determined by the researchers and IIRB, Inc. as likely unrelated to product use.

iii. The study was designed to minimize the likeli hood of insect bites, but when they occur are usually mild and readily tr eated with steroida l creams. The study excluded individuals with a history of severe reactions to bites

iv. Finally, the field-based trials were co nducted only in areas where known vectorborne diseases like WNV had not been detected by county and state health or vector/mosquito control agencies for at least one month. Mosquitoes collected during the field studies also were subjected to molecular analyses to confirm that they were free of known pathogens.

b. Voluntary and informed c onsent of all participants

• The study protocol included several mech anisms designed to minimize coercive recruitment and enrollment. Monetary co mpensation was not so high as to unduly influence participation.

• Several minor protocol deviations occurre d. As reported to IIRB, Inc. and to the Agency, these appear to have been uninte ntional and ar e unlikely to have placed study participants at risk or to have compromised significantly the informed consent process. For example, Carroll -Loye researchers failed to countersign promptly two informed consent documents. In both cases, participants appropriately were listed as screen fa ilures and then re-screened, re-consented,

and re-enrolled.

• Contrary to the HSRB-reviewed (EPA HSRB 2007) and IIRB- approved protocol, Carroll-Loye researchers also used prev iously recorded limb measurements, rather than collect physical data from all trial participants. This deviation occurred inadvertently when a Carroll-Loye re searcher, acting upon an EPA suggestion

that use of archival limb measuremen ts was scientifically valid and would minimize study procedure invasiveness, implemented this protocol change without consulting Carroll-Loye management or IIRB, Inc. The likely result of an error in communication, this deviation agai n did not place study participants at increased risk or compromise the informed consent process.

Comments on Guidelines for Product Perf ormance Testing of Skin-Applied Insect Repellents

Overview

In order to improve the quality and reliabil ity of data submitted to the Agency, EPA issues non-binding guidance documents, referred to as “Test Guidelines,” describing the scientific methodology recommended by EPA to deve lop data required to s upport applications to register pesticide products. EPA’s test guidelines typically contain detailed information about

Page 22 of 28many aspects of the study design – for example, th e test material, the us e of control groups, the nature and number of data points, and the content of study reports.

The Agency has been working to revise its Product Performance Test Guidelines OPPTS 810.3700: Insect Repellents for Human Skin and Ou tdoor Premises since it was published as a “public draft” in December 1999. A revised draft addressing only repellents for human skin was presented to and discussed by the HSRB in J une, 2006. Since then the HSRB has reviewed and commented on numerous proposals for insect repelle nt efficacy studies a nd several reports of completed studies. Over the course of these re views the Board has made many suggestions for strengthening the scientific and ethical conduct of this kind of re search, and has encouraged EPA to further revise and publish its guidelines for researchers cons idering this type of study.

EPA has extensively revised its insect repelle nt efficacy test guideline in response to many helpful suggestions from the HSRB and ot hers. This new guideline of September 23, 2008 contains many new sections addressing the ethi cal considerations a ffecting the design and conduct of repellent efficacy studies. EPA has al so expanded and revised the sections dealing with scientific aspects of this kind of study.

EPA will soon announce in the Federal Register the availability of the new draft of the guideline. The Agency plans to designate the new version as an “interim guideline” for immediate use by investigators, bu t subject to further refinement in light of future comments from the HSRB and the public.

HSRB Evaluation

While the Board was not provided a charge for consideration on the guidelines, it did have several comments to enhance the utility of the document. The Board noted that improvements in insect repellent protocols would be derived from portions of the guidelines and

the document was well written and clear. The Board appreciated the inclusion of landings as well as bites as an endpoint. However, as noted prev iously by the Board, it encourages the Agency to consider landings as the preferred endpoint.

The Board expressed serious conc erns that if the erroneous assumptions and inconsistent statements regarding the statistical analysis pl an are not corrected, investigators following the guideline recommendations would develop scien tifically unreliable protocols. The Board underscored that it would evaluate protocol s submitted for review to the HSRB based on appropriate statistical assumptions and analyt ic plans and on that basis might recommend rejection of a protocol that follo wed those elements of the Guidelin es that were incorrect. Based on continued statistical concerns with the guide lines, the Board strongly recommended that a Board working group provide a review of the sta tistical portion of the guidelines, for subsequent consideration by the HSRB, prior to the final guidelines being released by EPA to the public.

Below are sections relevant to protocol de sign and statistical analysis that the Board recommends should be revised prior to publication:

Page 23 of 28a. On page 9, it was stated that “standard deviations around point estimates of relative protection (based on percent reducti on in number of b ites) are likely to follow a Poisson model.” The number of bites may be a Poisson distributed random variable, but neither the standard deviations nor the pe rcent reduction in number of bites would be anticipa ted to have that distribution.

b. Also on page 9, it is stated that the best manner to randomize is by use of a random number table. Although this is an acceptable method, it is not necessarily best. Random numbers can be generated on a calculator or computer. Some programs do this randomization. It would be better to stress the need for

randomization without di ctating the method.

c. The statistical analysis plan section as presented on page 10 raised a question by the Board. If the response is the comple te protection time, the distribution is unlikely to be normal. Although a transf ormation is one possible approach of accounting for non-normality, generalized linear mixed models could also be applied appropriately in this setting a nd should be included as a potential method of analysis.

d. On page 27, it is first stated that field tests should be conducted in two distinct habitats where the predominant mosquito species are different. Then it was noted that the study could be “repea ted in different locations within the same habitat, or in the same location more than once, on di fferent days, using the same subjects to minimize variability.” It should be clarif ied that repeating in the same location

does not remove the need to use two distinct habitats.

e. In these studies, a large proportion of the observations are censored, making the statistical analysis more challenging, and some guidance on appropriate methods should be given. If censored values are replaced by the time of censoring, the estimated mean is biased downward, and the standard deviation is underestimated. The downward bias of the m ean tends toward a more conservative result, but under estimating the standard deviation may lead one to assume more
confidence in the results than should be given. Thus, it is not appropriate to set a

confidence interval that uses the time at censoring to represent all censored responses, ignoring the censored nature of the data. The use of maximum

likelihood methods that account for the censo ring of the values to obtain estimates

for the mean and standard deviation is appropriate. These are iterative methods that must converge to obtain the estima tes of mean and variance. Convergence will not be obtained if none of the study pa rticipants have a confirmed bite before the study’s end. If one or two confirmed bites are observed, convergence may be obtained, but the estimates may still be unrel iable. An alternative to estimating the mean is to estimate the proportion of the population for which the complete protection time exceeds the study durati on. Some thought should be given to exactly what measure is most appropriate; mean protection time is unlikely to be the quantity that is of greatest interest.

Page 24 of 28f. “Round Robin designs” were also suggested by the Board as a potential design when testing more than one product. The Round Robin designs may have all subjects having the same order of treatments, which would not be an appropriate design. Replicated Latin squares or si milar designs might be useful ones to mention by name.

g. Although differences in location and date s hould be accounted for in an analysis,

this should not be referred to as bl ocking as occurred several times in the document. These may be referred to as st ratifying variables. If the same subject is used in different habitats, locations, da tes, or treatments, then the appropriate blocking variable is the subject. Because the efficacy for more than one mosquito species is to be evaluated, the potential differential effects of the repellant should

be considered.

h. Finally, in the field study guida nce, it is suggested that th e subjects work in pairs. Further, the subjects may engage in norma l outdoor activities during testing. Is it possible for the subjects to engage in normal outdoor activities during testing and to still be able to accurately identify landi ngs? Before this is accepted as part of the protocol, the effect of such pairin gs and activities on observation should be

studied.

The Board also made recommendations regard ing improvement of sections relevant to human subjects protections.

a. To improve the consistency and clarity of terms associated with bioethical principles

articulated in the Belmont Report , the Agency should consider reframing those portions of the document appropriately with three head ings: respect for persons, beneficience, and justice.

b. On page 11, the Agency downplays the importa nce of alternatives to research with human subjects by stating, “In general, the e fficacy of skin-applied repellents can only be tested in research involving human subject s.” The human subjects protection importance

and scientific value of methods that do not require intentional dosi ng of human subjects with appropriate examples should be equally emphasized.

c. The Agency should consider placing more em phasis on risk minimization for example: To minimize the risks posed by biting arthropo ds, the Agency may wish to require that any proposal to use bites as an endpoint in eith er field or laboratory studies be justified. On page 12, the list of proposed mi nimization procedures should read “ and have a physician on call during testi ng.” Also, the document should set aside and/or emphasize the need for stopping rules, monitoring, medi cal management and post-study follow-up to monitor for delayed adverse events, particul arly for studies that involved potential exposure to arthropod-b orne illnesses.

d. On page 13 “The target population to which th e results of repellent testing should ideally

be as generalizable as possible to the population of repellent users”, the Agency should

Page 25 of 28consider recommending that sponsors incl ude an explanation and justification recruitment strategies that will not include appropriate repres entation of adults of various ages, sexes and ethnicities. Convenience sampli ng, recruiting difficulties, etc. should not be considered valid justifications.

e. Consider changing the text on page 14 to r ead, “If it is proposed, study protocols should clearly justify transporting study, participants to distant locations and include a clear description of mechanisms to both prevent undue influence (i.e. offers of travel) and coercion (i.e. reluctance of participants to with drawal once they have traveled to a distant site).

f. On page 15, when discussing the issue of la nguage translation, it is important to use qualified translators and also en sure translations are at an appropriate reading level.

g. On page 21, the Agency should be explicit that any unanticipated adve rse event should be reported, even if it is eventually determined that it is not related to product exposure or study participation.

Clarification of Board Report Process

Precipitating factor. At the June 2008 public meeting the Board discussed a series of recommendations for improving the scientific value of the AHETF closed and open cab studies. Prior to the posting of and public meeting to fina lize the June 2008 report, the Office of Pesticide Programs (OPP) wrote a memo to the Board stating that the Agen cy had approved the implementation of the studies based in part on thei r interpretation of Board discussion at the June meeting and interpretation of the Chair’s minut es. The Board recognized the need for a more rapid turn around of its final repor t to avoid future confusion. Th e Board clarified its process for approving final recommendations and adopt ed a new report schedule and format.

Clarification of Board Report Process. Since its inception, the HS RB DFO has stated that

recommendations of the HSRB are not finalized un til formal Board approval of a final report is completed at a public face- to- face or teleconference meeting. While Board discussion at each meeting serves as an important foundation for final recommendations, no formal consensus is taken at the meeting. The Chair’s minutes reflect a summary of meeting discussions, but it is not approved by the Board nor is it a substitute for Board final consensus. Board members write the report after each meeting and take responsibilit y for integrating meeting materials and Board discussion into a summary of issues and recomme ndations. The draft report is then posted for public review. Additions, deletions, corrections and modifications to the fina l report are finalized at a public meeting that includes further opportu nity for public comments and Board discussion, review and approval of the document.

Improving Report Format. At the October 2008 meeting the Board adopted steps to complete its reports in a more expeditious pe riod of time while proving greater clarity of its

recommendations. In its deliberations and subs equent report, whenever possible the Board will clarify which recommendations are directed to: (a) modifications that would enhance a

Page 26 of 28scientifically sound design and analysis; (b) limita tions that need to be considered in data analysis and interpretation of a scientifically so und design and; (c) modifi cations that are needed to ensure that the design and an alyses are scientifi cally sound. The Board also agreed to make efforts to adopt similarly clarifyi ng language for its ethics reviews.

Page 27 of 28Page 28 of 28 REFERENCES

Carley, J.M. 2008. Ethics Review of Completed Carroll-Loye Field Mosquito Repellent Efficacy Study LNX-001. Dated September 23, 2008. Unpublished document prepared by Office of Pesticide Programs, United States Environmental Protection Agency.

Carroll, S. 2008a. Carroll, S. (2008) Efficacy Te st of KBR 3023 (Picaridin; Icaridin)-based Personal Insect Repellents (20% Cream a nd 20% Spray) with Mosquitoes under Field Conditions. MRID 47506401. Dated August 5, 2008. Unpublished study prepared by CarrollLoye Biological Research.

Carroll, S. 2008b. Supplementary Information for Mosquito Repellent Efficacy Report (Protocol LNX-001). Letter to John M. Carley transmitti ng supplemental correspondence between CarrollLoye Biological Research and Independent Investigations Revi ew Board, Inc., concerning LNX001, with enclosures. Dated September 26, 2008. U npublished letter prepared by Carroll-Loye Biological Research.

EPA HSRB. 2007. June 27-29, 2007 EPA Human Studies Review Board Meeting Report.