November 14, 2006

Minutes of the

United States Environmental Protection Agency (EPA)

Human Studies Review Board (HSRB) 

October 18-19, 2006 Public Meeting

Docket Number: EPA-HQ-ORD-2006-0798

HSRB Web Site: http://www.epa.gov/osa/hsrb/ 

Committee Members:  (See Roster – Attachment A)

Dates and Times:	Wednesday, October 18, 2006, 8:30 AM – 5:15 PM 

Thursday, October 19, 2006, 8:30 AM – 1:00 PM

			

(See Federal Register Notice – Attachment B)

Location:	EPA, One Potomac Yard (South Building), 2777 Crystal Drive,
Arlington, VA 22202

Purpose: 	The EPA Human Studies Review Board (HSRB or Board) provides
advice, information, and recommendations on issues related to the
scientific and ethical aspects of human subject research.

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

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

Board Members:	David C. Bellinger, Ph.D. 

Gary L. Chadwick, PharmD, MPH, CIP

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

Richard Fenske, Ph.D., MPH  

Susan S. Fish, PharmD, MPH

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

KyungMann Kim, Ph.D., FCCP 

Kannan Krishnan, Ph.D. 

Michael D. Lebowitz, Ph.D., FCCP 

Lois D. Lehman-McKeeman, Ph.D.

Jerry A. Menikoff, M.D.

Sean M. Philpott, Ph.D.

Richard Sharp, Ph.D.

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

Introductory Remarks and Meeting Administrative Procedures 

Dr. Celia Fisher (HSRB Chair) thanked the Board members for their work
in preparing for the meeting and called for introductions of Board
members.  Dr. Fisher commended the U.S. Environmental Protection Agency
(EPA or Agency) for its responsiveness to Board requests, adding that
the discs containing supporting documents provided to the Board by the
Agency were helpful. She stated that she was looking forward to a
positive meeting.

	Following Dr. Fisher’s introduction, Dr. Kevin Teichman (Acting
Deputy Assistant Administrator for Science, Office of Research and
Development, EPA) remarked that he had replaced Dr. William Farland, who
had recently left the Agency.  Dr. Teichman expressed appreciation for
the efforts of the Board members and their prompt submittal of reports. 
He welcomed Dr. Richard Sharp to the Board and introduced the Agency’s
new Human Subjects Research Review Official (HSRRO), Dr. Warren Lux
(Office of the Science Advisor [OSA], EPA).  Dr. Lux will provide
high-level leadership and guidance to the Agency on human subjects
research initiated and/or funded by EPA.  Dr. Teichman noted that at
this meeting, the Board would be reviewing a completed human study and
proposed protocols, evaluating draft EPA guidance for the submission of
proposed and completed studies for HSRB review, and discussing the
handling of Confidential Business Information (CBI) by Board members. 
Dr. Teichman stated that the Agency sought Board recommendations for the
submission of human studies and protocols, adding that the HSRB was an
instrumental example of  the Agency’s support of an open and
transparent process to ensure the use of sound science and informed
environmental decision-making. 

	Mr. Jim Jones (Director, Office of Pesticide Programs [OPP], EPA)
stated that during the Summer of 2006, OPP met a major statutory
deadline of the Food Quality Protection Act (FQPA) mandated by Congress
10 years ago.  He thanked the Board for its work at the previous HSRB
meetings held in the spring and early summer of 2006.  He recognized
that the Board expressed concerns at the last meeting related to how EPA
prepares for these meetings, including the preparation of the materials
for review.  He indicated that EPA took the Board’s feedback on this
matter seriously and made improvements for this meeting to allow for a
more effective operation of the Board.

	Dr. Paul Lewis (Designated Federal Officer [DFO], HSRB, OSA, EPA)
thanked Dr. Fisher and the Board, and welcomed Dr. Sharp to the Board. 
He explained that the HSRB is a federal advisory board charged with
providing advice, information, and recommendations on issues related to
the scientific and ethical aspects of human subjects research.  The HSRB
is subject to the Federal Advisory Committee Act (FACA) requirements. As
the DFO, Dr. Lewis serves as liaison between the HSRB and EPA.  Dr.
Lewis reminded attendees that meeting times would be approximate and
that public comments would be limited to five minutes.  

	Dr. Fisher reviewed the process for meeting operations, HSRB
responsibilities, the charter, Board process and major objectives.  She
stated that the Board seeks to clarify and develop criteria to evaluate
the science and ethics of different types of completed research and
protocols, allowing for consistency and fairness.  HSRB review would
begin with a presentation by EPA of the scientific and ethical
considerations on the studies under review.  Scientific considerations
would precede ethical considerations because if a study was not
scientifically sound, this would raise ethical deficiencies for the
study.  Both the risk-benefit analysis and ethics were dependant on
scientific validity.  Finally, Dr. Fisher introduced Mr. William Jordan
by stating how important it was to the Board and the public to hear how
EPA was considering the Board’s recommendations.

Update on EPA Follow-up of HSRB Recommendations

Mr. William Jordan (OPP, EPA) remarked that he valued the opportunity to
work with Drs. Lewis and Fisher, and the Board.  He thanked his
colleauges in the Health Effects Division, who assisted in preparing the
meeting materials.  Mr. Jordan reported that the Board addressed the
following four topics at the June 2006 meeting:  

(1) In regards to the completed intentional dosing study using
chloropicrin, the Board concluded that the acute inhalation study met
applicable scientific and ethical standards and that the results could
be used in EPA’s risk assessments.  EPA is using the results to derive
an acute Reference Dose (RfD) that will be the basis of a revised risk
assessment.  

(2) The Board recommended numerous ways to improve the draft insect
repellant efficacy testing guidelines.  EPA would consider the Board’s
suggestions as the draft guidelines are revised.  

(3) The Board reviewed research protocols for two insect repellant
efficacy studies and recommended revisions to address both scientific
and ethical issues.  Extensive revisions to the protocols were made, EPA
reviewed them and determined that the revised protocols were ready for
review and consideration by the Board.  

(4) The Board reviewed protocols submitted by the Agricultural Handlers
Exposure Task Force (AHETF) for five different scenarios of pesticide
application.  The premise of the AHETF research program was that data
could be used generically by various stakeholders (e.g., applicants,
registrants, EPA, and others) for calculating exposures for occupational
handlers of pesticides.  The Board recommended revisions of the
protocols, particularly with respect to scientific concerns.  The Agency
has referred these issues to the Federal Insecticide, Fungicide and
Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP).  Mr. Jordan
stated that the AHETF intends to develop revised protocols to address
scientifc concerns and regulatory issues; the revised protocols were
expected by the Spring or Summer of 2007.  

Dr. Fisher asked Mr. Jordan to explain the differences between the FIFRA
SAP and the HSRB. She remarked that her understanding was the HSRB
reviewed the scientific and ethical adequacy of specific protocols and
completed studies while the FIFRA SAP provides advice on pesticide
issues addressing human health and the environment.  Both Boards were
independent and the HSRB’s is committed to carefully consider, but is
not required to agree with SAP recommendations.  Mr. Jordan explained
that FIFRA required that EPA use the FIFRA SAP as an advisory committee
concerning pesticide scientific issues.  and EPA had worked closely with
the FIFRA SAP.  Several HSRB members, had served on the FIFRA SAP and
Dr. Lewis had also been associated with the FIFRA SAP as a DFO .  The
HSRB addressed scientific and ethical considerations for specific
studies and protocols for research involving human subjects.  While
there could be some subject matter overlap, Mr. Jordan indicated that
the focus of the two committees were different, wound not be duplicative
and would provide useful information.  

Introduction of the EPA Human Subjects Research Review Official

	Dr. Lux provided a brief introduction of his background and his role as
the Agency’s new Human Subjects Research Review Official (HSRRO).  Dr.
Lux is a neurologist who specializes in the treatment of frontal lobe
disorders, particularly traumatic brain injury.  He stated that his
scholarly interest had been in the area of the underlying methods of
cognitive capacities but that he had formal training in bioethics and
clinical medicine.  Dr. Lux explained that EPA was engaged in human
subjects research in several different domains.  His task was to further
develop the overall oversight of the different human subjects research
activities across the Agency.   He concluded by saying that he looked
forward to working with the Board in the future.

 

HSRB Review of Science and Ethics Criteria for Completed Human Exposure
Studies 

	Dr. Fisher discussed the Board-developed criteria for the review of
scientific and ethical issues for completed studies.  The following
questions were presented as criteria for the review of human studies
protocols:  

Did the research design and implementation meet scientific standards?

Do the data generated by the protocol have useful implications for the
Agency’s Weight of the Evidence (WOE) determination?

Is a valid scientific question addressed by the study?

Is the purpose of the study clearly defined?

Are there specific objectives/hypotheses?

Can the study as described achieve these objectives or test these
hypotheses?

Is there justification for the selection of the target population?

What is the sample size and how is it derived?

Can the findings from this study be generalized beyond the study sample?

Are participants representative of the population of concern? If not,
why not?

Are the inclusion/exclusion criteria appropriate?

Is the sample a vulnerable group?

What is the basis for the proposed dose levels and formulations in the
study?

Will the measurements be accurate and reliable?

Are measurements appropriate to the question being asked?

Are adequate quality assurance procedures described?

Can the data be statistically analyzed?

Are existing data adequate to answer the scientific question?

Are new studies involving human subjects necessary to answer the
question?

What are the potential benefits of the study?

What is the likelihood that the benefits would be realized?

What are the risks? Are they serious or irreversible?

Is there a plan allocating individuals to treatment?

Next, Dr. Fisher presented scientific standards for human dosing
studies, which included questions relating to the justification of the
study, dose selection, endpoint selection, study participation,
methodology, and statistical analyses.  

The Board’s ethical evaluation of existing human studies includes
compliance with the prevailing ethical standards at the time the
research was conducted.  If the study failed to meet the prevailing
standards, the Board looks for clear and convincing evidence that the
research intended to seriously harm participants or failed to obtain
informed consent (IC).  IC documentation must describe experimental
procedures, including a clear statement of the risk involved and the
voluntary nature of participation.  Additional ethics criteria to be
considered by the Board include the following:

Are risks justified by benefits?

Are risks necessary and sufficiently minimized?

Are subjects equitably selected?

Are there sufficient safeguards against coercion?

Are there procedures for assuring subject safety including adequate
monitoring?

Has the Principal Investigator (PI) provided sufficient and appropriate
documentation of the Institutional Review Board (IRB) review?

Chromium Repeat Open Application Test 

Scientific Considerations

Dr. John Liccione (OPP, EPA) reported that dermal exposure to hexavalent
chromium can cause a sensitization reaction leading to allergic contact
dermatitis (ACD).  Hexavalent chromium is a component of the wood
preservative known as Acid Copper Chromate (ACC, or commercially known
as CopperShield®).  There is a concern that the public may develop ACD
from exposure to hexavalent chromium left on ACC-treated wood.  Skin
sensitization reactions could arise after repeated exposure to treated
articles.  

ACD is characterized by two phases: 

(1) Induction following exposure of sufficient magnitude to activate
immune responses resulting in the acquisition of sensitization

(2) Elicitation or challenge, which is in response to the allergen in a
sensitized individual.  

ACD differs from an irritation response because ACD takes 24 to 72 hours
to develop and does not occur after the first exposure.  It also
requires immune memory.  ACD is recognized as a threshold phenomenon;
the thresholds vary but are generally higher than those for irritation. 
Hexavalent chromium and dermal sensitization issues have been reviewed
by the FIFRA SAP and the HSRB.  The Agency reviewed animal and human
data and found limitations to using animal data and deficiencies in the
human studies.  In 2004, the FIFRA SAP identified Nethercott, et al., as
the best available study based on human and animal data.  The FIFRA SAP
recommended that an open application test with repeated daily exposures
would be more appropriate for risk assessment purposes.  Nethercott, et
al., was reviewed by the HSRB in May 2006, and the Board concluded that
the study was sufficiently sound to be used to estimate a safe
hexavalent chromium level for dermal exposure.  The HSRB concluded that
the Nethercott study was properly designed, well-conducted, and
appropriate to determine a 10 percent Minimum Elicitation Threshold
(MET) (MET10).

Dr. Liccione reported that the Nethercott et al. study was recommended
by the FIFRA SAP to develop a MET10 for hexavalent chromium as contained
in ACC wood treatment solution.  The subsequent ROAT was conducted to
determine a safe level of hexavalent chromium in ACC and to determine a
cleanup level for potassium dichromate.  A total of 60 individuals
participated in the ROAT study; all were hexavalent chromium sensitive
based on patch test results.  Dr. Liccione described the study’s
inclusion and exclusion criteria, written consent documents, and study
design.  Participants were exposed to five concentrations of hexavalent
chromium or potassium dichromate for 6 hours per day for 10 days.  All
grading of allergic or irritant responses were performed by the
study’s PI, Dr. Joseph Fowler.  All skin responses were graded for
erythema, vesicle formation, papule, scaling, and pruritis.  Test sites
were examined daily and dosing was discontinued if a response was judged
to be an allergic reaction.

Two scenarios were modeled for the MET10 calculation: allergic responses
only (Scenario 1) and allergic responses plus irritant responses
(Scenario 2).  Due to the disproportionate number of +3 patch test
responders (most severe symptoms of allergic and irritant responses) in
the ROAT, both scenario results were normalized to the hexavalent
chromium-sensitive U.S. population based on the North American Contact
Dermatitis Group (NACDG) database.  Normalization was accomplished by
comparing +1, +2 or +3 patch-test reactions and the MET10 was calculated
for Scenarios 1 and 2 from the present study and patch-test normalized
populations.  

Study strengths included male and female test subjects, a large
population of sensitized individuals, good experimental design, and
repeated dermal exposure which is more realistic for risk assessment. 
The Agency reported no apparent weaknesses and concluded that the
Proctor ROAT study contained information useful to inform the selection
of a MET10 based on the elicitation of ACD from ACC-treated wood.

Dr. Fisher inquired how the dermal patch addressed the delivery of
hexavalent chromium through an open system like exposure to ACC-treated
wood and what benefit it was to the public.  Dr. Liccione responded that
the patch test was used for screening to confirm the ROAT was an open
system.  The proposed value of the study depended on public contact with
hexavalent chromium from treated wood.  He said that  the open
application test was the best way to investigate delivery of hexavalent
chromium on wood.  Dr. Fisher asked how exposure to hexavalent chromium
would occur if it was in the wood.  Dr. Liccione explained that the
hexavalent chromium was fixated.  However, since fixation took
approximately two weeks, contact with the wood prior to fixation would
result in exposure to the hexavalent chromium. He suggested that this
would most likely occur prior to shipment of the wood. For the Proctor
study, the lowest dose tested was the MET10 from the Nethercott study
and the highest dose was considered to be an extreme upper bound of
exposure to hexavalent chromium from exposure to ACC-treated wood.  Dr.
Liccione stated that the exposures were realistic and open.  He
concluded that the ROAT design was better suited to address delivery
through an open system because the test site was open. 

Dr. Gary Chadwick questioned why normalization was performed after the
study was conducted and whether there was an explanation for the high
number of responders.  Dr. Liccione explained that the study protocol
was revised to correct for high incidences of reaction among the test
subjects.  A high number of test subjects were weak sensitizers who may
have lost sensitivity over time.  False positives were minimized by the
strong concordance between the strong patch test and strong ROAT
response.  Dr. Liccione added that the study was conducted on an extreme
upper end population and normalization was performed to make the results
more meaningful.  Dr. Suzanne Fitzpatrick inquired if sensitization was
affected by skin type and whether dermal absorption was affected by
gender.  Dr. Liccione noted that gender can affect skin type; however,
it did not appear to affect dermal sensitivity to hexavalent chromium. 
Gender was a variable examined by the Nethercott study, with no
significant difference identified.  

Dr. Lois Lehman-McKeeman questioned the screening of subjects for
sensitization.  She asked, since there was evidence that some
sensitization appeared on the first day and there was a high rate of
reaction, if the comparison to historic data was relevant.  Dr. Liccione
explained that hexavalent chromium was both an irritant and an ACD
sensitizer.  Typically, irritancy was observed before ACD.  In some
cases, irritation occurred on the first day, taking longer in other
cases.  In all cases, irritant reactions were +1 or low-level reactions.
 Only one +2 irritant response lasted beyond the first day.  It is
believed that irritant responses did not confound the ACD results.  

Dr. Krishnan questioned the difference in pH of potassium dichromate
(which has an approximate pH of 7) and hexavalent chromium (which has an
approximate pH of 5).  Dr. Liccione explained that hexavalent chromium
tends to be more acidic than potassium dichromate.  Potassium dichromate
was studied for the purpose of determining soil cleanup criteria and was
not included in the ACC study; therefore, it did not effect the MET10
calculation.

Dr. Michael Lebowitz requested clarification of the definitions for
irritation and ACD.  He indicated that he did not know whether the FIFRA
SAP considered NACDG protocols when developing their recommendations,
but there was always the potential for scientific and medical confusion
when different groups were developing criteria and protocols.  Dr.
Liccione noted that the NACDG had a solid group of diagnostic and
clinical procedures on irritation; he recognized that there was a
contentious issue with the Hanson study using different criteria.  Dr.
Lebowitz remarked that he would like to see standardization of methods. 
He was concerned that the two control subjects were later included as
test subjects.  Dr. Liccione stated that the two control subjects did
react to hexavalent chromium.  Dr. Lebowitz felt that positive controls
should not have been included in the study.  He then asked if two weeks
had passed between the patch test screening and the ROAT study.  This
was confirmed; test subjects were asked if the area had healed.  The
issue of spacing between dose levels (two centimeter interval between
five doses) on the arm was standard and important for discerning excited
skin syndrome. There was no evidence of a bleed-out effect. 
Normalization with the NACDG distribution was an attempt to make data
represent the normal U.S. population.  The data set could be Gaussian or
skewed, but efforts are underway to make the data reflect a typical U.S.
population.  Dr. Lebowitz opined that the MET10 was a good point of
departure, but a NOAEL was not determined.  Dr. Liccione affirmed this,
but added that because the rate of hexavalent chromium sensitivity was
so low, the MET is considered protective of 99 percent of the
population.

With respect to the need for QA, Dr. Fisher asked if Dr. Fowler was the
only individual to evaluate responses.  It was explained that Dr.
Fowler, as the diagnosing physician, conducted the study, selected
subjects, hypothesized results, and was the only individual to evaluate
responses and decide when a subject should withdraw.  Therefore, he was
the attending physician and the principal investigator in the study. 
Dr. Richard Fenske asked if the study had not been performed by
Exponent.  Dr. Liccione responded that Exponent wrote the study protocol
with Dr. Fowler’s input.  The control group was treated with a copper
chloride (vehicle control) and CopperShield®.  Dr. Fenske asked what
the hexavalent chromium load was during the confirmatory patch test and
whether the same mass per unit area dosing was used for all the NACDG
studies.  Dr. Liccione stated that little detail was provided on this;
therefore, they did not know the load on the skin.  There were 495
individuals tested for hexavalent chromium sensitivity using a Finn
Chamber patch; the Nethercott study used higher doses to the skin.  The
methods used for the NACDG studies may have changed over time.  The
Board was surprised that the control group was all female.  While this
was not explained, the Nethercott study did not find a gender difference
for hexavalent chromium sensitivity.  It was noted that for the ROAT
screening, the percent of +1 response was higher for females but equal
for males and females at +2 and beyond.  Dr. Liccione did not feel that
there was a gender difference.  Dr. Chadwick interjected that the all
female control group participants were employees or associates of Dr.
Fowler.  Dr. Fenske said that while the test subjects were blind to
dosing, Dr. Fowler knew where the different doses were applied and who
the controls were; therefore, the study was not double blind.  The
irritant response data indicated that for 13 subjects it was determined
to be irritation rather than ACD.  For the control group, no irritant
response was noted.  Many of the people who had ACD experienced
irritation at the next lowest dose.  The investigators dealt with this
by modeling, using just ACD and ACD plus irritation.  Irritancy was
difficult to delineate from ACD.  

Dr. Sharp asked if the controls were exposed to CopperShield® and if
sensitization could have occurred with the level of exposure used in the
patch test screening.  Dr. Liccione reported that the controls had been
exposed to CopperShield® and that sensitization would have been a
possibility at higher doses.  Dr. Sharp inquired if hexavalent chromium
sensitized individuals were more susceptible to other T-cell mediated
responses.  Dr. Liccione responded that immune responses were specific
so that this type of susceptibility was unlikely.  .

Dr. Sean Philpott questioned the time lapse between the patch test
screening and the ROAT.  It was decided that sufficient time lapsed
between patch test screening and the ROAT.  Dr. Krishnan asked if any
effort was made to pool the new data with historical data before
normalization was performed.  Dr. Liccione indicated that the more
recent historical data (1998-2002) was used for normalization.  

To determine whether EPA’s new Human Studies (HS) rule would apply,
Dr. Fisher asked whether the last subject was tested after April 2006. 
Mr. John Carley (OPP, EPA) said the study ended in November 2005, and
that he would address this concern during his presentation.  Dr. Fisher
reported that the science presentation indicated no weaknesses; however,
the controls were all female and the study was not double blind.  She
recommended that the Agency’s presentations to the Board at future
meetings provide a more thorough critique of the study, including
strengths and weaknesses.  

Ethical Considerations

	Mr. Carley reported that three supplements to the primary ROAT study
had been received.  He said the study was transitional because it was
initiated prior to the effective date of the Agency new human studies
rule.  The study was not subject to 40 Code of Federal Regulations (CFR)
§26.1125 for prior review of the protocol, but the study was subject to
40 CFR §26.1303 requiring documentation for ethical conduct. 
Significant supplemental material was needed due to the timing of the
issuance of the rule.  The ROAT study was judged using the same
framework as for existing studies.  Most test subjects were former
patients of Dr. Fowler, the control subjects were employees of
Dermatology Specialists, and all who signed a non-coercion statement, as
well as an IC.  Preliminary screening was conducted by Exponent
employees without IRB oversight or IC.  To minimize risk, the total dose
used was below the RfD for hexavalent chromium and a small area of the
skin was treated.  Treatment was stopped at any dose level that caused a
reaction; medical oversight was provided throughout the study. 
Compensation ($1,215) was paid at the conclusion of the study, which may
have influenced subject’s willingness to participate.  

The IRB review was thorough but documentation of IRB approval was weak. 
The study claimed compliance with the Common Rule, the Declaration of
Helsinki, the Nuremberg Code, the National Academies of Science (NAS)
Committee guidelines, the Belmont Report and U.S. Food and Drug
Administration (FDA) regulations.  The IC process was described in
detail and conducted by Exponent, not the PI’s staff.  There was some
confusion about when final consent was obtained, but subject privacy was
maintained.  The Agency concluded that prevailing standards were met. 
The citation for prevailing standards was corrected because it did not
include the nursing women as an exclusion criterion.  This did not
impact the Agency’s conclusion.  One potentially noteworthy ethical
deficiency involved preliminary testing with Exponent employees.  This
testing did not appear to have involved IRB oversight.

	Dr. Susan Fish inquired why the IRB approval stamp did not include an
expiration date.  The IRB approval may have lapsed, but the IRB
continued to communicate as the study progressed.  Dr. Jerry Menikoff
interjected that the study provided little information on alternative
products and asked if the Agency considered alternative products when
evaluating benefits to society.  Mr. Carley responded that there were
practical limitations to the extent of protocol reviews and their
societal benefits.   Mr. Jordan indicated that the Board needed to make
a distinction between existing studies and new research.  Prior studies
presented a different case than protocols for new work.  Mr. Carley
chose not to dwell on societal benefits for existing studies.  For new
protocols, the Agency would have the choice of whether to evaluate
benefits to society.  Pesticides have risks and benefits; trying to
decide if a study would benefit society would be challenging.  This was
one of the challenges the Agency faced. 

	Dr. Krishnan remarked that copper was presented as an alternative to
ACC.  Mr. Carley said a benefit that the IRB and EPA would have
considered included significant usage changes for ACC.  A major growth
in the sponsor’s sales would not be considered a benefit of the
research.

	Dr. Fisher inquired about listing compensation as a benefit.  Another
benefit noted was that ACC could be used more broadly; however, but
while greater use of ACC is not a benefit to the subjects, it would be
to the Forest Products Research Laboratory (FPRL).  Dr. Fisher asked
about the protocol statement regarding the explanation of risks and
benefits of the treatment if a test subject needed a topical steroid. 
She stated that if there were experimental risks that required
treatment, the risks should be explained during the initial stages of
the study.  Mr. Carley interjected that this situation pertained to
clinical care and that the entire pharmacopeia of treatment options
would have to be explained.  Dr. Fish wondered if the fact that steroid
cream treatment might be needed was evidence that the study was
significantly deficient or fundamentally unethical.  Mr. Carley
indicated that this would be discussion for future protocols, not
existing studies.  A determination was necessary as to whether the test
subjects were fully informed of the risks involved in the study.  

Dr. Chadwick questioned to what extent the Board should be concerned
with Health Insurance Portability and Accountability Act  (HIPPA)
requirements and wondered why the IRB documentation had been retyped for
the report.  Mr. Carley explained that stamped originals were needed. 
The IRB documentation also stated compliance with FDA requirements. 
However,  disclosures were made to EPA.  He added that the IRB provided
the HIPPA form and the guidance.  The non-identifying photographs used
for clinical research only were submitted to EPA.  If the Agency thought
that HIPPA had been violated, it would be difficult for the Agency to
recommend the study.  Mr. Jordan remarked that preservation of subject
privacy was an ethical consideration for research, adding he would
confer with Dr. Lux to determine how to resolve the HIPPA issue.  Dr.
Lebowitz mentioned that the ethical guidelines were more restrictive
than HIPPA, but Dr. Fisher noted that if the Board believed a federal
law was violated they could not recommend the study.  In addition, Dr.
Fisher added that since the researcher and the PI was the same person,
this may be a concern.

Public Comments

Ms. Debra Proctor of Exponent, on behalf of the Forest Product Research
Laboratory  

	Ms. Proctor clarified that there was no documentation for the
preliminary Exponent screening because it was not conducted.  Initial
contact with potential test subjects was made by five Dermatology
Specialists nurses who solely conduct research.  Dr. Fowler was
sensitive to HIPPA requirements and would not allow Exponent to view
sensitive medical records.  The patch test was performed after the IC
form was signed.  Compensation for the ROAT study was somewhat higher
due to the inconvenience of participation (11 visits to the clinic in 15
days).  

Ms. Proctor stated that the test subjects experienced minimal risk in
this study because the study procedures were consistent with common
clinical tests.  Dermal responses were transient in nature and lasted
from 1 to 3 weeks.  The highest dose used in the ROAT was below the
clinical patch test dose; it was also lower than the highest dose used
by the Nethercott study, which the EPA and Board considered to pose
minimal risk.  The cumulative ROAT dose was 29 times lower than the EPA
oral RfD for hexavalent chromium.  A small area of skin was tested and
all study participants were closely monitored for responses.  If there
was an allergic response, further applications of test solutions were
discontinued for that dose and medical supervision was made available. 
Only one strong allergic response was noted; 17 of 60 people reacted. 
Ms. Proctor stated that the study was designed to facilitate risk
assessment.  Those who would benefit from the study included: (1) wood
workers in treatment plants; (2) other workers in occupations involving
hexavalent chromium; (3) consumers of treated wood, which included both
hexavalent chromium-allergic individuals, as well as the general
population; (4) and those exposed to hexavalent chromium in contaminated
soils.

	In response to a Board question regarding how exposure to hexavalent
chromium would occur, Ms. Proctor explained that exposure to
CopperShield®, a wood preservative containing hexavalent chromium,
could occur before the fixation process was complete.  Hexavalent
chromium was applied to wood during the manufacturing of CopperShield®
treated wood products.  During the fixation process, hexavalent chromium
was reduced to trivalent chromium, so trivalent chromium was present in
the final treated-wood product, but exposure to hexavalent chromium
could occur before fixation was complete.  Wiping freshly treated wood
could result in exposure to hexavalent chromium.  

Normalization was performed in hindsight; the data from the ROAT study
population was normalized to the U.S. population of hexavalent
chromium-allergic individuals because participants who were +3 reactors
to the patch test were more likely to respond during the ROAT.  The
patch-test-normalization of the MET10 values takes into account the
variable sensitivities of the allergic individuals.  

The Board asked Ms. Proctor about an irritant response to potassium
chromate noted in the control group.  Ms. Proctor could not explain the
differences; however, she stated that Dr. Fowler is a principle
contributor to the NACDG database and some of the subjects were probably
already included in the database.  Patch testing was conducted well
before the ROAT and subjects were asked if the test area had healed. 
The use of one PI allowed for greater consistency of graded responses. 
Dr. Janice Chambers inquired about the skin loading of hexavalent
chromium in the patch test.  Ms. Proctor stated that 8 mm Finn Chambers
patches were typically used for clinical patch testing, but this testing
typically involved simultaneous exposure to a large number of allergens.
 This study used 12-mm Finn Chambers patches, for easier discernment
between irritant and allergic responses.  The Board also asked if IRB
stamped approval documents had been submitted.  Ms. Proctor responded
that the original documents were re-typed to correct page numbers but
the originals had been submitted.  

	Dr. Philpott requested that Ms. Proctor clarify the role of Dr.
Fowler’s employees and Exponent.  Ms. Proctor explained that the
review of files containing personal information was handled by
Dermatology Specialists.  Dermatology Specialists employees were used
for control subjects because the ROAT required driving to the clinic
every day and it was convenient.  Dr. Chadwick inquired if Exponent was
separate from Dermatology Specialists.  It was noted that Exponent,
which is not part of Dermatology Specialists, is a consulting research
firm.  

Dr. Fenske questioned if the higher rate of response could be explained
by the load on the skin being higher during patch testing than during
the subsequent dosing and the mass per unit area greater than what was
in the NACDG database.  Ms. Proctor indicated that the load during patch
testing was higher than during the subsequent dosing and that there was
some variability in response over time.  Variability was an important
consideration when calculating the MET10.  Dr. Fowler adjusted the
results using the NACDG database; the NACDG has 14 members with
approximately 6,000 people in the NACDG database.  Sensitivity to
hexavalent chromium was relatively rare so the NACDG database was
invaluable.  Dr. Fenske commented that the NACDG web site was managed by
someone in Denmark and was last updated in 2001.  Ms. Proctor added that
the Occupational Safety and Health Administration (OSHA) had recently
updated its recommendations for hexavalent chromium, but she
acknowledged a gap in the database.  Occupational exposures could be
much higher without protective equipment.  

Dr. Krishnan inquired why the control group consisted of all females. 
It was explained that they were volunteers from Dr. Fowler’s practice.

Howard Maibach, MD of the University of California, San Francisco 

	Allergy, as defined by classical immunology, was a growing field.  One
estimate indicated that almost one-third of all chemicals submitted to
the European group that was re-registering chemicals, REACH
(Registration, Evaluation, Authorization and Restriction of Chemicals)
were allergens.  Clearly, all chemicals that can produce a type 4
immunological response must be separated.  The patch test was a
wonderful tool, but ROAT provided a more highly refined tool to
determine what levels were likely to illicit adverse reactions.  There
was a science behind identifying treatment sites; the greater the
distance between treatment sites, the less likely it was that excited
skin syndrome would occur.  

Dr. Lehman-McKeeman requested a distinction between irritant response
and allergic response, and asked what the most appropriate analytical
technique was for this type of data.  Dr. Maibach explained that there
was no simple answer to these questions.  Blood testing without human
subjects was not quantitative.  By including irritation responses, the
Proctor study had erred on the side of conservatism.  The NACDG recently
identified individual studies with positive patch testing in a normal
population with a group of subjects seeing dermatologists.  A huge
discrepancy between the two groups was not apparent.  Dr. Maibach added
that he was not involved in the research under consideration by the
Agency.  

Mr. Jay Feldman of Beyond Pesticides 

	Mr. Feldman stated that Beyond Pesticides believed that the ROAT study
was unethical and asked the HSRB to consider the following during their
review.  Beyond Pesticides was not satisfied with the societal benefits
of the hexavalent chromium study, which was unnecessary because
alternatives were available.  The HSRB did not review the protocol prior
to the study being conducted; therefore, the question of whether the
Board would allow the Agency to use a study with an insufficient review
of societal benefits was not considered.  EPA recently approved FPRL’s
application to sell hexavalent chromium-based wood preservative (ACC). 
The company that was previously registered to sell ACC requested to
cancel the registration; the wood preserving industry had moved toward
alternative products that did not contain hexavalent chromium or
arsenic.  Mr. Feldman added that the wood preserving industry could
function without hexavalent chromium.  Intentionally exposing human test
subjects to hexavalent chromium was unethical and a violation of the
Nuremburg code.  Hexavalent chromium was a known carcinogen via
inhalation and was associated with other non-carcinogenic effects,
including kidney and liver damage.  Mr. Feldman indicated that this
research may benefit FPRL but it did not benefit society.  He implored
the HSRB to obtain an independent review of the societal benefits of
this research in order to meet the burden of protecting human health.   

Board Discussion

Scientific Considerations 

	Dr. Fenske initiated the Board’s discussion explaining that the
purpose of the study was clearly stated, the sample size was based on
Nethercott study rather than power calculations, and that ROAT was more
realistic than patch testing.  Dr. Fenske added that the dose levels
were thoughtfully chosen, but there was concern regarding using all
female employees as control subjects as this was not representative of
the exposure group.  No allergic responses and one irritant response
were observed in the control group.  There was concern that the
distinction between the allergic and irritant responses was not clear;
controls showed no irritation yet there was a high percentage of
irritation in the exposure groups.   The patch test screening seemed to
indicate gender differences, but there seemed to be a generally held
belief that this was not the case.  Dr. Fenske concluded that from a
scientific standpoint,  a major problem was that one person, who was not
blinded, recorded all the observations, knew all the control subjects,
and knew where the doses were placed.  Further, the test endpoint was
subjective and there was no way to check for bias.  The use of the NACDG
database raised concerns because the loading of the subjects in the
database could not be correlated with that used in the study.  After the
fact, the data was normalized using the NACDG database.  Dr. Fenske
recommended that the Agency use the clinical data rather than normalized
results when calculating the MET10.

	Dr. Lehman-McKeeman agreed with Dr. Fenske  that using a single PI for
grading responses was a weakness but did not consider that it detracted
from the study overall.  In addition, she felt that a larger concern was
the uncertainty in the interpretation of the data.  She concluded that
the data from the irritation responses be included with the ACD data but
that the historical NACDG database, while providing a good qualitative
comparison, was inappropriate quantitatively and should not be used for
the calculation of the MET10.  

	Dr. Krishnan agreed with Drs. Fenske and Lehman-McKeeman and found the
study scientifically sound and suitable to convey information on the
calculation of a MET10.  He thought the rationale for the study was
clearly stated and agreed that  pooling irritation responses with ACD
responses was appropriate. However, he  did not think it was appropriate
 pooling the study data with historical data, as people’s responses
change over time.  

Board Discussion

	Ethical Considerations 

	Dr. Philpott led the ethical discussion, stating that the study did
present minimal risk to test subjects, which excluded pregnant and
immunologically-suppressed individuals.  The use of patch testing was
considered to pose minimal risk.  Dr. Philpott would like to have seen
escalating doses, but recognized that this would have been difficult to
accomplish.  He expressed concern regarding the equitable selection of
test subjects.  The control subjects appeared to have been selected for
convenience.  Dr. Philpott said that HIPPA compliance was a process and
that confidential information (i.e. immuno-suppression) was collected
without IC during pre-test screening activities.  Also, monetary
compensation was subjective and may be viewed as an undue influence.  He
considered non-coercion statements meaningless.  

	Dr. Sharp stated that the study was vulnerable to ethical concerns in
two places: collecting screening information without IC and IRB
assessment of monetary compensation.

	Dr. Menikoff agreed with his colleagues, adding that the consent form
was not clear regarding the probability of significant skin reactions.
He said that the study was designed to produce responses.  The intent
was probably to allow more use of hexavalent chromium, which should have
been conveyed to the test subjects. 

	Dr. Fisher summarized the Board’s scientific finding that this was a
high quality study even though there was no power analysis.  The sample
size was adequate and the ROAT study design was better than patch
testing design.  There was concern with recruiting all female employees
as control subjects and with one individual (who was not blinded)
recording all observations.  Also, the distinction between irritant and
allergic responses was questionable, particularly at low dose levels.  A
more conservative approach was taken by combining allergic and
irritation data and normalizing the data with the NACDG database.  The
Board recommended that the Agency use the clinical findings and not the
normalized results.  Also, the Board recommended that new data be
incorporated into the database before normalization was performed as
there was a difference in the patch test method used for this research
as opposed to what was historically used (12-mm Finn Chambers patches as
opposed to 8-mm Finn Chambers patches).  Since patch sizes were
different, pooling new and old data may not be appropriate.  Dr.
Brimijoin stated that pooling using old patch test data would be
inappropriate for calculating the MET10.  The Board considered the
historical data useful for qualitative evaluations but not for
quantitative use.  Therefore, the Board indicated that it was useful to 
pool irritant and allergic reactions data; however, it recommended using
the clinical findings that were not normalized with the NACDG database.

	Dr. Fisher summarized the Board’s ethical findings.  The study was
considered scientifically valid with minimal ethical risk.  Convenience
dictated recruitment of control subjects and IC should have been assured
prior to collecting screening information via the telephone.  The IC
document should have been explicit about potential reactions.  The
non-coercion statements were suspect. The risks and benefits needed to
be determined independently.  The Board’s ethical recommendation was
that there was no clear and convincing evidence that the hexavalent
chromium ROAT study was fundamentally unethical.  Furthermore, there was
no clear and convincing evidence that the study was significantly
deficient relative to the ethical standards prevailing at the time the
research was conducted.

IR3535 Insect Repellent Product Efficacy Protocols

Introduction

	Mr. Carley introduced the EMD-003 and EMD-004 protocols from
Carroll-Loye Biological Research, Inc.  The protocols submitted by Dr.
Scott Carroll (Carroll-Loye Biological Research, Inc.) described two
studies of repellent efficacy for three new formulations of IR3535.  The
protocols were revised versions of  those originally presented to the
HSRB in June 2006.    There is a California Environmental Protection
Agency (CalEPA)  requirement that a study be approved pre-registration
and post-Independent Institutional Review Board. This approval was
submitted to the Agency  to facilitate HSRB review of the revised
protocols.  Based on the presentations by the Board’s Ethics and
Science criteria subcommittees at the June 2006 meeting, EPA
substantially revised its framework for assessing protocols.  EPA
applied this revised framework to the resubmitted protocols, and
returned preliminary reviews to Dr. Carroll in late August 2006.  Dr.
Carroll made the required revisions.  Mr. Carley stated that the Agency
believed the protocols were now compliant with current EPA guidelines
for assessing repellant efficacy.

EMD-003

Scientific Considerations 

	Dr. Clara Fuentes (OPP, EPA) provided a review of EMD-003, explaining
that three different repellent formulations were proposed for
registration.  The revised protocol called for 12 subjects or
formulations; each one serving as his, her, or its own treated and
untreated control.  The rationale for the sample size was provided. 
Passive dosimetry would be assessed through skin surface area,
self-dosing behavior, and the weight of test material applied to skin. 
Dosage would be calculated on the basis of treated skin surface area;
test materials were closely formulated and controlled.  The revised
protocol included efficacy expressed as the average time to first
confirmed crossing (FCC) as an endpoint.  The study used
laboratory-reared, pathogen-free tick nymphs to test the efficacy of the
three repellents proposed for registration.  There were three treatment
groups; subjects would be selected randomly and blindly.  Results would
be analyzed using descriptive statistics; negative controls would not be
used.  

Principle changes to the protocol included the incorporation of a new
step to establish a typical consumer dose; expanded discussion of risk,
risk minimization and benefit; expanded discussion of sample size; and
the change in endpoint to the FCC.  The positive control was eliminated
and training materials for dosimetry and tick handling were added.  The
new dosimetry phase determined typical consumer dosage as the average of
the 12 trials.  The rationale for sample size was a compromise between
financial and ethical concerns.  Sample size was difficult to determine
without knowing the distribution of the findings.  Dr. Fuentes concluded
that this protocol was likely to yield scientifically reliable
information because the study would produce important data that could
not be obtained except through human research.  The study had a clear,
scientific objective and explicit hypothesis; the study design was
adequate to test the hypothesis.

Ethical Considerations 

	Mr. Carley stated that the proposed research would test the efficacy of
three new formulations of the active ingredient IR3535 as a repellent
for the deer tick.  Efficacy testing was an EPA requirement for product
registration; understanding the efficacy of these formulations was
important because consumers, who relied on repellents to avoid being
bitten by ticks, could not readily assess efficacy.  The question was:
did the product, as formulated, repel ticks?  Subjects would be
recruited from among friends, neighbors and scientists near the
laboratory.  None of the subjects were from vulnerable subgroups, but
this population may not be representative of the broader population that
was likely to use tick repellants, such as children, pregnant women,
etc.  

Risks were characterized as extremely low and included possible
irritation, headache, and dizziness from exposure to the test compound
and possible exposure to arthropod bites.  The test material had low
acute and chronic toxicity and the ticks would be disease free.  Mr.
Carley reported that the low increment of risk to subjects would be
offset by the benefit to society, which would be providing a new product
to repel ticks.  

IC materials were extensive and satisfactory.  The protocol included
methods to protect the confidentiality needs of subjects and stated that
medical care for research-related injuries would be provided without
cost to the subjects.  Mr. Carley concluded that EMD-003 met all
requirements of 40 CFR §26.1111, §26.1116, §26.1117, §26.1125 and
§26.1203, as well as all elements of NAS recommendation 5-1 and 5-2.

EMD-004 

Scientific Considerations

	Dr. Fuentes presented a timeline for revisions to EMD-004, stating that
the endpoint for efficacy was the average time to “first confirmed
landing with intent to bite” or “FCLIB.”  Test subjects would be
trained to aspirate landing mosquitoes before they bite in the
laboratory using laboratory-reared, pathogen-free mosquitoes.  There
would be three treatment groups; subjects would be randomly and blindly
assigned to treatment groups.  Each treatment would be replicated 10
times.  

To reduce risk, subjects would work in pairs and there would be two
untreated subjects present, experienced in field biology and entomology
to monitor biting pressure.  The untreated subjects would be attended by
two assistants, and exposed to mosquitoes for 1 minute every 15 minutes.
 Biting pressure would be quantified; the threshold being one landing
every minute.  Field testing would be performed in California’s
central valley with a wild population of mosquitoes.  Measured variables
 would include biting pressure, FCLIB, and time to first confirmed bite
(FCB). 

Principle changes in the protocol included a description of subject
recruitment and IC; the addition of a preliminary phase to estimate
typical consumer dose; and an expanded discussion of risk, risk
minimizations, and societal benefits.  The revised protocol had an
expanded discussion of sample size and statistical concerns; changes to
the frequency and duration of exposure to reduce risk to untreated
controls; and eliminated positive controls.  It also included training
materials for subjects in the dosimetry phase and on aspirating landing
mosquitoes.  The test results would be analyzed using descriptive
statistics and 10 replicates were recommended to improve the accuracy in
estimating the population mean.  

In conclusion, Dr. Fuentes stated that this protocol was likely to yield
scientifically reliable information because it would produce important
data that could not be obtained except by research with human subjects. 
The protocol had a clear, scientific objective and explicit hypothesis;
the study design should produce adequate data to test the hypothesis.

Ethical Considerations 

	Mr. Carley reported that the ethical considerations for EMD-004 were
similar to those for EMD-003, except for the possibility of exposure to
vector-borne disease.  Risk was minimized by fielding trained subjects
in pairs to reduce the likelihood of being bitten.  Applicable comments
and ethical standards were the same as for EMD-003.

	Dr. Chambers asked if the mosquito field study would be conducted in
California, Florida, or both, and how recruitment would be handled if
the work was performed in Florida.  Mr. Carley replied that Dr. Carroll
would address this question.  It was noted that an errata sheet was
provided for EMD-004 that addressed complete protection time.  This
sheet needed to be revised to address mosquito endpoints.  Dr. Brimijoin
stated that this was trivial and would be corrected.  

Dr. Lehman-McKeeman questioned whether dosimetry with 12 subjects could
be used for both studies because the EMD-003 dosimetry for ticks stated
that dosimetry would be conducted outdoors under specific atmospheric
conditions, whereas the tick study would be conducted indoors.  Mr.
Carley  explained that the dosimetry study was designed to approximate
the typical consumer dose; the presumption being that a typical consumer
would apply the repellent outdoors. He concluded that the dosimetry
phase was independent of the efficacy phase and that the procedure was
appropriate for the purpose which was to approximate the typical
consumer dose in terms of mass per unit area.

Dr. Bellinger requested clarification of the blinding of the studies. 
Mr. Carley explained that treatments would be applied blindly, thereby
preventing anyone from knowing who received each treatment formulation. 
The only untreated subjects in the field study were the two individuals
assessing biting pressure.  For the tick study, subjects would not know
to which treatment group they belonged.  The three formulations varied
with respect to level of IR3535 and non-active ingredients.  In response
to a question from Dr. Lehman-McKeeman, Mr. Carley  concluded by saying
that the dosimetry result would be impacted by the delivery method
(aerosol, pump spray, smearing) and dose applied.

Dr. Krishnan inquired why the presentation slide referred to replicates
rather than subjects.  Mr. Carley replied that the slide indicated
replicates because each limb could be counted as a replicate.  One
subject could constitute four replicates, one on each limb.  Dr.
Krishnan also asked, based on the available toxicological data, if the
safe dose would be approached, adding that this type of information
would provide clarification.  

Dr. Lebowitz expressed concern about the risks of vector-borne disease. 
The Agency responded that field studies would be conducted in areas
where no vectors were recorded for a month and mosquitoes would be
collected for follow-up screening, to be conducted in the laboratory. 
Dr. Philpott stated that the IRB documents indicated on page 6 that the
field study area would be monitored for disease.  Dr. Lebowitz also
asked how individual differences in attractiveness to mosquitoes would
be addressed.  Dr. Fuentes indicated that gender was the main factor for
different levels of attractiveness.  Since both genders would be used in
the study, this was not considered a problem.  

Dr. Sharp stated that there were references throughout the protocol to
previous testing of this product at lower dose levels; therefore, he
questioned the need for the study.  Dr. Fuentes responded that the study
was needed to evaluate the length of time the repellant was effective
since the formulations were different and specific formulations needed
to be tested to support label claims.  Mr. Carley concluded by stating
that formulations proposed for registration  needed to be tested.

Public Comments

Dr. Scott Carroll of Carroll-Loye Biological Research, Inc. 

	Dr. Carroll remarked that protocol development was an ongoing process
and that he appreciated the Board’s input.  He stated that ethical
oversight of his protocols  had not been as detailed as that are now
provided by the Board.  The generic protocol CL-001 was used and had
been approved by the University of California, San Francisco IRB several
times.  Data for monitoring insect-borne pathogens were becoming more
readily available.  The best approach was to conduct mosquito field
tests in the spring and early summer when the titers (viremic
populations) were lower than they were later in the year.  Sentinel
chicken flocks were also used to monitor pathogens.  Dr. Carroll said
that Dr. Krishnan’s comment regarding the NOAEL was cogent and the
studies would likely be well below toxic levels.  The studies would also
help define a margin of safety.  Dr. Carroll indicated that some test
subjects would be transported to Florida, and the tests would also
include professional vector biologists from the Florida Keys.  When
recruiting professionals in the Florida area, it would be emphasized
that participation was strictly optional.  

	Dr. Fitzpatrick questioned Dr. Carroll about measuring biting pressure
using two untreated subjects.  She felt that this was the weakest point
of the study design.  Dr. Carroll responded that to maximize safety,
biting pressure would be measured with two untreated subjects, who would
be attended by two observers.  The exclusion and inclusion criteria
would be submitted to the IRB and the same ethics criteria would apply
to the control and test subjects.  The two untreated field subjects used
to assess biting pressure would not be employed by Carroll-Loye
Biological Research, Inc., but would come from the university community.
 They would be subject to the same inclusion/exclusion criteria as
anyone else.  The Board was concerned that transporting subjects to
Florida might impact their ability to withdraw freely from the study. 
Dr. Carroll stated that transportation costs would be covered and
subjects would be compensated at their same hourly rate.  The Board felt
that the IC documents needed to be explicit about voluntary withdrawal
when subjects were transported to Florida.  In the past, Carroll-Loye
Biological Research, Inc. has primarily used subjects from Florida and
one or two other subjects.  This situation had not been formalized in
the protocol.  The new phase of research would require that more people
be transported so this needed to be clarified in the protocol.

	Dr. Carroll commented that with the new repellants available, there
were very few mosquito approaches; therefore, subjects may wait an
extended amount of time for mosquitoes to approach.  Dr. Lebowitz was
surprised at the long approach times encountered, stating that Dr.
Carroll must use different sites than those chosen by the Armed Forces. 
Dr. Carroll’s replied that he was now consulting for the Armed Forces
Pesticide Management Board  and was transferring the ethical insights
from his experience with the HSRB to his work there.

Dr. Lehman-McKeeman inquired how rearing ticks on quarantined rodents
would affect individuals with sensitivities to rodents.  Dr. Carroll
stated that after a blood meal, ticks metamorphosed into what appeared
to be a completely different organism so he didn’t expect them to be
tainted by the rodent. Dr. Sharp asked about medical monitoring for
anaphylactic shock.  Dr. Carroll stressed that this is very rare, but
the protocol stated hospitals would be notified in advance of studies
being conducted in the area.  Dr. Sharp suggested that a regional
physician could be contacted and assigned as the emergency contact for
the study.  Dr. Carroll indicated that this could be done.

Board Discussion 

EMD-003

Scientific Considerations 

 

	Dr. Lehman-McKeeman stated that the revised EMD-003 protocol showed
careful consideration of the Board’s concerns and that the study would
yield scientifically useful data.  The study objectives were clearly
stated; treatment formulations clearly defined; and the number of
participants was increased from 6 to 10.  Dr. Lehman-McKeeman added that
the study would quantify relative protection and protection time.  

The protocol suggested that since aerosols and pumps included the same
level of active ingredient, the same dosimetry could be used; however,
this was inadvisable considering that the volatility of aerosols could
affect dosimetry.  Better dosimetry was one of the strengths of the
revised protocol, which could be used to verify that no safety issues
were raised.  Detail on the use of gauze bracelets to assess aerosol
dosimetry could be improved. She suggested that the protocol would be
further improved if the lotion could also be tested, acknowledging that
this would mean an increase in the number of subjects to 30 instead of
20.   Dr. Fenske agreed and Dr. Bellinger  liked the dosimetry phase but
said he would be more interested in knowing what the effective dose was
rather than seeing what people routinely applied.  Dr. Krishnan
reiterated his comments on dosimetry and efficacy, suggesting that to
ensure the dosimetry and efficacy were conducted without compromising
safety it would be useful to indicate the known safe level, such as the
NOAEL.

Ethical Considerations 

	Dr. Philpott reported that the criteria of Subparts L and K were met
and he commended Dr. Carroll for his responsiveness to the HSRB’s
comments.  Dr. Philpott remarked that compensation was listed as a
benefit, but this is not appropriate and should be revised.  While the
IC authorized the release of medical records, this might not be
necessary for this type of study; Dr. Carroll indicated that this
authorization would be deleted.  The current IC form was vague but
provided more quantitative analysis of the risk of skin irritation. Drs.
Menikoff and Sharp concurred with Dr. Philpott adding that the IC would
be improved if a more detailed description of the possibility of
vector-borne diseases was included.   Dr. Sharp added that while the
study may be well-designed, he was concerned about whether it was
needed.  He offered that including someone familiar with the risks on
the field teams would improve the ethical considerations of the
protocol.

	Dr. Fisher summarized the Board’s conclusions: 

(1)  formulations were better characterized  

(2) the protocol was more complete and objectives were clearly stated
compared to the previous protocol reviewed by the Board

(3) the protocol appeared to generate more reliable data 

(4) there was an increased in the number of subjects tested with
subjects used as their own controls

(5) a more through analysis of data was provided 

Areas for improvement included the following: 

Dosimetry data

 

(1) separate dosimetry testing for the aerosol and  pump and the
inclusion of testing for the lotion

(2) dosimetry data were valuable but use of gauze bracelets outdoors
might need additional  information

(3) it would be helpful to include a comparison of the dosimetry data
with known toxicological reference points such as the NOAEL/LOAEL

Other - determination of the effective dose.  

	The study met the requirements of Subparts L and K.  Compensation
needed to be removed from the list of benefits on the IC form and the
request for release of medical records needed to be deleted.  The IC
should provide some quantitative assessment of the risk of irritation
and field teams should include someone who is familiar with medical
treatment of adverse effects.  

Board Discussion 

EMD-004

Scientific Considerations 

	Dr. Chambers reviewed the revised study and concluded that the risks
were better described compared to the previous protocol.  Risks would be
minimized by training subjects how to aspirate mosquitoes.  The study
design criteria were clearly defined and the sample size was increased
to 10, with 2 controls and no positive controls.  The justification for
the study was clarified and better QA measures established.  The
statistical methods were appropriate and a medical management plan was
included.  Dr. Chambers concluded that the PI had been extremely
responsive to HSRB concerns and that she welcomed this type of research
because 2006 was Mississippi’s worst year on record for West Nile
Virus.  New products for mosquito repellency were needed.  Dr.
Fitzpatrick requested clarification regarding expiration of the IRB’s
certification.  

Mr. Carley asked about the need to test in both California and Florida. 
Dr. Carroll responded that the EPA guidelines required testing in two
different habitats.

Ethical Considerations 

	Dr. Philpott felt that the revised protocol was sufficient and met
applicable ethical criteria.  He expressed concern regarding recruiting
subjects in California and transporting them to Florida in terms of
their freedom to withdraw.  Dr. Philpott requested additional
information on inclusion/exclusion criteria for control subjects.  Dr.
Menikoff agreed with Dr. Philpott, noting that the IC now included a
description of the signs and symptoms of West Nile Virus.  Dr. Sharp
suggested adding medical monitoring by a physician.   

	Dr. Fisher summarized scientific and ethical concerns for EMD-004.  She
stated that the EPA guidelines for efficacy testing required testing in
two different habitats.  If subjects were to be transported,
clarification about the move was needed and medical monitoring for
adverse conditions needed to be provided.  Dr. Fisher reflected the
Board’s view that Dr. Carroll had done an exemplary job of responding
to the Board’s initial recommendations for both EMD-003 and 004
studies and to providing in the revised submission explanations for each
of the scientific and ethical procedures that were revised.

Draft EPA Guidance to the Public Concerning Submission of Proposed and
Completed Human Research to EPA for Review by the HSRB  

	Mr. Carley discussed the Agency’s draft PR notice to communicate with
the regulated community and other stakeholders. PR notices were intended
for anyone planning to conduct human research involving intentional
exposures, including research intended to be submitted to the EPA under
pesticide laws or anyone who intended to submit the results of completed
human research for EPA consideration under the pesticide laws.  The PR
notice would be used to set the schedule for the next four HSRB
meetings.  Mr. Carley indicated that the PR notice explained how and
when to submit protocols for EPA and HSRB review and how and when to
document ethical conduct of completed human research to be submitted to
EPA.  EPA’s main concerns were that submitters be able to understand
the applicable requirements for their initial submission.  If submitters
complied with this guidance, EPA would be able to easily locate all the
information needed to conduct their assessments.  EPA requested feedback
from the Board as to whether it believed that this was an appropriate
avenue to submit information for review.  

	For the protocol submitter, the task was getting more difficult.  They
needed to develop a protocol and all supporting materials required by 40
CFR §26.1125, obtain IRB approval, develop IRB documentation, get State
approval (in some cases), compile and index all elements, and submit the
protocol package to the EPA at least 75 days before the HSRB meeting
during which it would be reviewed.  

EPA began with an assessment of the completeness of the package.  If the
package was deficient, the Agency notified the submitter.  If the
package was complete, the Agency would populate the framework and
complete an integrated narrative review of the science and ethics of the
protocol.  If the protocol was acceptable, the Agency review was sent to
the submitter and the protocol was scheduled for HSRB review.  The
“framework” was heavily adapted from the Emmanuel framework to
ensure that all critical questions were addressed.  

	The purpose of the framework was to assist submitters in organizing
relevant information from the protocol and provide supporting
documentation for EPA review.   The intent was that each subtopic in the
framework be addressed by inserting quotations or citations from the
protocol and supporting materials.  It was not enough simply to answer
“Yes” or “No.”  All direct quotations would be attributed and
paraphrases were discouraged when a direct quotation was available.

	Mr. Carley explained each of the framework criteria, including HSRB
suggestions provided at the June 2006 meeting.  For societal value, all
but three of the Board’s recommendations were captured.  The question
regarding QA was an oversight, to be corrected in the next iteration of
the framework.  The need for laboratory and field conditions to be
representative of the intended uses was omitted because they were only
relevant to certain types of studies. They may be better addressed in
discussions of guidelines rather than of specific protocols.  The
framework separated qualitative risks from the probability that they
would occur and the narrative review answered whether the risks were
reasonable.  The IRB review was explicit in the Emmanuel framework.  For
IC, several questions were added to address power discrepancies between
subjects and researchers, and to address language barriers during field
tests.  Mr. Jordan indicated that the document provided to the HSRB was
a draft copy and that additional information regarding confidential
business information (CBI) would need to be added.  

	Dr. Fisher remarked that the Board would discuss CBI but may not be
prepared to give specific recommendations at this meeting.   The PR
notice was not binding but could be helpful providing guidance to the
public.  The Agency did feel some urgency to disseminate some guidance
to bring consistency to the submittals and CBI concerns should not delay
issuance of the guidelines.  CBI guidance included how to label
information as CBI and how to package it.  Dr. Fisher said that since
the HSRB was constantly mentioned in the document, it needed to be
clarified that the HSRB had not drawn any specific conclusions regarding
CBI. 

	Dr. Lebowitz asked if CBI could be addressed separately so as not to
delay the framework.  Dr. Fenske indicated that this seemed like a
fairly comprehensive document that could be distributed independently of
the CBI or could be released separately but simultaneously.  Dr.
Lebowitz suggested that the framework review begin with Appendix B,
which covers the EPA submittal format, as well as respond to what the
HSRB recommended.  Dr. Menikoff suggested that risk minimization was
important enough to be included as a major heading with the appropriate
questions grouped underneath.  Dr. Fish suggested that the Framework 5
(Benefits) questions regarding remuneration be removed from risk benefit
and added under Framework 4 (Subject Selection) or Framework 8 (Respect
for Subjects).  Dr. Sharp felt that the Emmanuel framework was a
philosophical guide not intended to guide protocol design.  Dr. Lebowitz
remarked that the instructions specifically requested a paraphrase or a
specific reference from the protocol even though the submittal package
included all IRB documents.  He added that he would like to see a
section that reviewed potential limitations of the study.  Limitations
were an important part of understanding the research.  One question not
addressed dealt with field versus laboratory studies; however, this
might be ancillary.  General guidance was needed initially, but more
specific guidance might be added later.  

	Dr. Fisher summarized the Board discussion.  Risk minimization should
be a separate heading; remuneration should go under Framework 4, and
study limitations should be discussed. Guidance on specific types of
studies would come later.  Dr. Brimijoin indicated that if the Board did
not intend to strictly follow the review questions then the HSRB
framework should be different from EPA’s.  The framework should be a
guide to submitters and a tool for review.  Mr. Carley indicated that
EPA would like an annotated directory of submittal information, which
was key to reducing labor for both submitters and reviewers.  The Board
inquired why the Agency had not specified electronic submission to save
review time.  Mr. Carley responded that scanned files from hand-written
documents would be “read only” so electronic submissions may not
speed reviews.  Dr. Chadwick suggested that items d and e on Agency
slide 18 be moved to Subject Selection, and that item c on slide 20 be
moved to risk minimization.  He inquired what item c on slide 17 was
requesting.  Any IRB can register with the Office of Human Research
Programs (OHRP) but this was no guarantee of legitimacy.  Dr. Chadwick
suggested that the question be expanded to include information on
insurance or accreditation.  Dr. Krishnan asked if there would be a
question on QA/Quality Control on slides 12 and 13.  Mr. Carley
indicated that this would be added.  Dr. Krishnan also suggested that a
question be added regarding how the dose would be measured and how the
dose related to known NOAELs or known safe levels.  For Framework 5
(slide 15) the intent was to separate the nature of the risk from the
probability it would occur because there were several studies with the
remote possibility of serious adverse effects.

	Dr. Lehman-McKeeman suggested that the Board’s recommendations
against single dose studies be added.  The guidance should state that
EPA’s review would be based on the completeness of the responses to
questions in Appendix B and that the Board would only see a study if EPA
believed that the submittal met some minimal requirements for
submission.  Dr. Fisher suggested that the guidance might give
submitters the impression that if they answered all questions in
Appendix B that the HSRB would approve their study.   Dr. Krishnan asked
if Appendix B would have a title; the titles for Appendix A and C were
directly from the 40 CFR § 26, so Appendix B may not have a specific
title.

	Dr. Fisher inquired if the Board was fine-tuning EPA’s draft
guidance.  Dr. Sharp shared concern that the Board might get locked into
a specific review format.  

	Dr. Fisher further summarized Board discussion of the draft guidance as
follows: 

risk minimization should be a separate heading

remuneration should go under Framework 4

study limitations should be discussed

items d and e on slide 18 should be moved to Subject Selection

item c on slide 20 should be moved to risk minimization 

item c on slide 17 should specifically ask for insurance or
accreditation

a question should be added regarding how the dose would be measured and
how the dose relates to known NOAELs or known safe levels 

information should be added addressing the Board’s concern for single
dose studies.

The Board wanted to ensure that the framework was educational and
informative.  If registrants submitted a complete protocol, then
completed the questionnaire, it should not be a significant burden.  It
should be stated that these were the questions that the submitter must
answer before a protocol could be reviewed and that expedited reviews
required the brief summaries and specific references to the text. Dr.
Fisher complimented EPA for the work on this guidance draft and its
incorporation of previous HSRB criteria and discussions.

Public Comments 

	

Dr. Fisher invited oral public comment on the PR notice concerning the
submission of proposed and completed human research to the EPA for
review by the HSRB.  No public comments were received.  

Board Discussion

Dr. Fitzpatrick remarked that the 75-day HSRB review timeframe seemed
insufficient.  It was also noted that once a protocol was submitted to
the HSRB, it seemed that a step for resolving HSRB comments was missing
from the review process.  Mr. Jordan interjected that the draft guidance
was being updated, adding that the comment resolution section needed to
be revised.  Mr. Jordan referenced Dr. Carroll’s protocols as an
example of how the process should work.  Written comments from EPA and
HSRB reviews would be provided to the applicant.  The document
requirement included directions as to how discussions would be used. 
While the Board might want to review this discussion, the HSRB also may
not want to be privy to all discussions between the Agency and
registrants.  Organizing a formal review process may be premature.  Some
HSRB comments might highlight problems without proposing a resolution. 
Dr. Lehman-McKeeman suggested that it might be helpful for EPA to
submit a feasibility study to the Board as a learning tool.  If Board
comments could not be addressed, the situation might be discussed under
limitations.  

Dr. Kim reported that the FDA required a statistical analysis plan be
outlined before the data was interpreted to prevent bias.  This plan
could be a potential requirement of the package.  Mr. Carley commented
that the EPA already requested a statistical analysis plan in the
protocol.  

Dr. Fisher inquired about how the HSRB meeting discussions were
interpreted in relation to the  HSRB final report.  Mr. Jones indicated
that it was generally understood that HSRB reports were evolving
documents until the final public meeting on the report was held. 
Registrants were free to interpret what they heard at the public
meetings and move forward based on this understanding; the discussion
might also identify critical gaps in the protocols.  Dr. Fisher
suggested that language to this effect might need to be added to the
draft review guidance.  

Dr. Fenske speculated whether this information would be used as an
outline for future submittals and whether that was a cause for concern. 
Mr. Carley stated that if submitters followed the established framework,
information needed for IRB approval should not be omitted.  Mr. Carley
added that the framework would help present the information coherently. 
Dr. Krishnan inquired if new protocols sent to EPA would be available to
other submitters because the Carroll-Loye protocols could serve as a
useful guide for future work.  Mr. Carley replied that the protocols
submitted to the EPA so far are publicly available and in the EPA
docket.  Dr. Fisher commended Mr. Carley for the draft document.  Mr.
Carley concluded that EPA might  change risk headings, including risk
minimization, and change how questions were worded to ensure that the
process presented was adequate. Dr. Fisher added that the Board also
supported avoiding questions that would yield only yes/no answers.

Handling of Material Claimed to Be Confidential Business Information for
HSRB Consideration 

Mr. Jordan presented information on statutory requirements for how
regular government employees handle CBI.  Sponsors had indicated that
they would be making CBI claims for portions of future protocol
submissions.  Thus far, CBI had not been an issue; however, an
investigator indicated that CBI claims with respect to the identity of a
sponsor and test material should be expected.  Mr. Jordan indicated
that the Agency did not know the frequency of submitted CBI claims, but
this would likely not be the only occurrence 

Mr. Donald Sadowsky (Office of General Counsel, EPA) stated that CBI was
a sensitive area and that “constraints” was an operational term for
CBI because there were statutory and regulatory constraints.  CBI
statutes included FIFRA, Federal Food, Drug and Cosmetic Act (FFDCA),
and the Trade Secrets Act.  Once a product was registered under FIFRA,
the active ingredient was required to be listed on the label; however,
for a new active ingredient or significant new use of an existing
chemical.  This label identification could be considered CBI.  FIFRA
required the protection of trade secrets and commercial or financial
information that if publicized, could result in competitive harm. There
are criminal penalties for releasing CBI.  CBI could be disclosed to
Federal employees, including the HSRB, if they received proper training
and clearance.  Even when information was not considered CBI, it must
not be disclosed to multinational pesticide manufacturers.  Mr. Sadowsky
explained that safety and efficacy data, including information
concerning experiments performed on or with a registered or previously
registered pesticide or separate ingredients, must be publicized, except
during the pre-registration of a new active ingredient; safety and
efficacy data need not be disclosed.  Safety and efficacy data does not
cover a protocol if the test had not been conducted.  

Information claimed as CBI must be protected until a formal
determination that the information was not entitled to confidential
treatment was made.  Mr. Sadowsky said that the Agency could require
the applicant to clearly identify CBI and ask the applicant to
substantiate the CBI claim. It was noted that even an unfounded CBI
claim would take time to resolve.  Non-CBI material could be extracted
from a CBI document prior to releasing the document to the public;
however, proper care would need to be exercised.  Discussion of non-CBI
material that could lead individuals to identify the CBI information
should be avoided.  Mr. Sadowsky cautioned attendees to avoid
inadvertent discussions of CBI in public.  While instances were rare, he
reminded attendees that there were criminal penalties associated with
public disclosures of CBI.

Mr. Carley presented information on EPA standard practices for the
handling of CBI.  He explained that when a company submits its product
application and supporting documentation, anything claimed to be CBI
must be isolated in a confidential appendix.  In the case of a new
active ingredient or significant new use of an active ingredient, EPA
would publish an application receipt report in the Federal Register. 
EPA managed the confidential appendix and the remainder of the
supporting documentation separately.  There were relatively few CBI
claims for product registration because review of the application and
supporting documentation was generally not a public process.  Most
applicants do not make CBI claims on data and the Agency could check
with submitters before the public release of information.  Information
that was typically withheld from the public included inert ingredients,
manufacturing processes, and QA measures.  The Agency’s final human
studies rule affected planned activities because protocols must be
submitted a year or more before an applicant could conduct research. 
EPA had been advised to expect protocols claiming CBI for the identity
of the sponsor and the active ingredient.  

CBI claims were likely to increase because public HSRB review could
reveal a company’s intent to conduct research with certain pesticides
years before they could expect to gain registration.  This would
disclose their strategic business plans to competitors.  Mr. Carley said
that protecting the identities of the sponsors of proposed research or
the specific materials to be tested may not compromise the HSRB’s
role, which was ensuring the essentiality of the research, its
scientific soundness, and the protection of its test subjects.  The
Board inquired whether there was a clause in FIFRA indicating that CBI
could be disclosed when safety concerns overrode the need to protect
against competitive harm.  Mr. Sadowsky said that the Agency required
disclosure of List 1 inert ingredients if they were considered harmful
(such as formaldehyde), but it must be assumed that this would not be
the typical case.  

Companies submitted information to EPA in order to register their
products.  Everyone who viewed CBI must be authorized to do so.  In
order to access CBI, employees must sign a form verifying that they
understood the importance of securing CBI.  Training needed to be
provided; currently, no HSRB members were cleared to view FIFRA CBI.

Mr. Keith Matthews (Office of General Counsel, EPA) reported that FACA
and Government in the Sunshine Act did allow committees, such as the
HSRB, to discuss CBI in closed sessions but that the HSRB could not have
a public meeting and openly discuss CBI.  The requirements of holding a
closed meeting included publishing a Federal Register notice of the
closed meeting, and meeting minutes with and without CBI content. The
Board would maintain two separate sets of documents in case a Freedom of
Information Act (FOIA) request was received for the meeting minutes. The
CBI minutes would not be released, even under FOIA.

Mr. Jordan summarized that FIFRA and FFDCA noted that companies might
submit information to EPA claimed to be CBI.  EPA believed that some
parts of proposed protocols might appropriately be claimed as CBI and
EPA must protect this information.  Mr. Jordan explained that there were
at least three potential paths forward:  

(1) HSRB conduct its review without considering the CBI portions of
protocol submissions.  HSRB has already performed this with the review
of Carroll-Loye protocols without seeing the IRB review materials that
included CBI.  If the claim related only to the identity of the sponsor,
this may be a good way to proceed.  

(2) HSRB adapt EPA’s approach for handling CBI material: CBI contained
in a confidential appendix.  Once trained and cleared for access to CBI,
the HSRB would be allowed access to the confidential appendicies.  

(3) HSRB discusses protocols, including material claimed as CBI, in
closed sessions.  Access to the meeting would be limited to HSRB members
trained and cleared to review CBI and EPA employees FIFRA CBI cleared. 
Published reports would not contain CBI information.  If needed, CBI
material could be discussed in a confidential appendix to the report.  

 EPA contractors not FIFRA CBI cleared would be excluded from the closed
sessions.  

Public Comments 

	

Dr. Fisher invited oral public comment on the handling of material
claimed to be confidential business information for HSRB consideration. 
 No public comments were received.  

Board Discussion

Dr. Krishnan stated that the Carroll-Loye protocols included a table
specifying the three formulations of the active ingredient-and this type
of information submitted to the Board was sufficient to complete the
review.  If EPA kept this information because of a claim of CBI, Dr.
Krishnan suggested that the HSRB proceed with the review with access
only to the non-CBI claimed information.  Dr. Brimijoin voiced concern
that EPA would determine what the Board needed to see to complete their
protocol reviews.  The identity of a company may or may not be germane
to HSRB review, but he was uncomfortable categorically excluding some
information.  

Dr. Brimijoin supported the idea that HSRB members be trained and
cleared to review CBI, or that a subcommittee be established to
determine what the Board needed to see.  Dr. Fisher indicated that she
would be uncomfortable to serve on such a subcommittee.  She had no
issue with the EPA making decisions as to what were appropriate CBI
claims and what can be discussed publicly.  If the nature of the active
ingredient was held as CBI, the HSRB might be uncomfortable conducting a
review because of the resulting data gap.  

For Carroll-Loye, the IRB claimed that their review process was CBI. 
EPA encouraged the IRB chair to change this request but the Agency
accepted this claim without further substantiation.  Dr. Fisher stated
that she did not see the Carroll-Loye IRB/CBI decision as precedent
setting and also noted that the three proposed EPA options were not
exclusive.  A different approach might be applied to different
protocols.  Dr. Fisher did not feel that it would have been fair to Dr.
Carroll to further delay the review of his protocol considering this
issue with the IRB was not raised earlier in the process.  In addition,
Dr. Fisher stated that the IRB materials claimed as CBI was not critical
to the Board review responsibilities as long as EPA provided a detailed
assurance that federal regulations were met. Going forward, the Board
may not be as comfortable as it was for the review of the Carroll-Loye
protocols, as this had been a unique occurrence due to the first time
that the CBI issue had been raised. 

The Board questioned how frivolous CBI claims were handled.  Mr. Jones
responded that EPA was committed to an informal determination of CBI and
that some claims may not be substantiated.  To investigate every CBI
claim would slow the review process with little value added.  If CBI
were brought to the Board, it would be identified as such.  The FIFRA
SAP does not handle CBI material and EPA generally framed questions in a
format that did not disclose CBI.  Dr. Chadwick stated that the value of
the HSRB was that it operated in the sunshine and so options 2 and 3
were not applicable.  The Agency needed to advise its submitters that
CBI would be isolated.  Since a subcommittee would have the same
problems as identified in option 2, Dr. Chadwick recommended that
option 1 be adopted.  Dr. Fitzpatrick concurred with Dr. Chadwick and
raised the question regarding the adequacy of the 75 days allocated to
the review.  

If the HSRB determined that it did not have sufficient information upon
which to base a determination, the Agency would consult the applicant. 
The Board felt that it must be open and transparent, and that anything
that impeded this would affect the Board’s effectiveness.  EPA would
be asked to affirm that the missing information met Federal
requirements.  For science reviews, it might help to know the class of
an active ingredient (such as an organophosphate), but should the Board
feel more non-CBI information was needed, a delay could occur. 
Applicants should be advised of this situation.  The Board questioned if
the science reviewers could be cleared to access CBI to complete their
review.  It was noted that withholding the sponsor’s identification
could affect the ethics review; Board members may have a conflict of
interest with a CBI sponsor.

A concern was raised about CBI creating a loophole allowing an applicant
to circumvent HSRB review.  Anyone could claim CBI without
substantiation of the claim.  The Board was leery about becoming CBI
cleared because it might result in more closed sessions.  Dr. Menikoff
stated that the Board seemed to feel that CBI claims were often false,
but a significant new use of an active ingredient would be a legitimate
claim for CBI.  CBI protections were granted for legitimate business
claims and the Board should not subvert this.  Mr. Jones remarked that
the Agency used discretion to eliminate frivolous CBI claims.  The
Agency makes judgments regarding IRB reviews of protocols and felt that
more information was better than less.  The Agency was inclined to give
as much information as possible and eliminate as many frivolous CBI
claims as possible, but closed-door sessions might be needed.  He
encouraged the Board to take CBI training.  

Dr. Lebowitz stated that if he did not know the active ingredient, it
would be difficult to proceed with the review.  Just knowing a
compound’s class would be insufficient.  There might be cases where
the active ingredient was determined to be CBI.  Dr. Chadwick inquired
if the HSRB might review a protocol when CBI was claimed regarding the
data.  While this was conceivable, Mr. Carley stated that this situation
was hypothetical; resolving the CBI claim might go either way.  The EPA
final human studies rule changed the registration process by requiring
human study protocols significantly before registration.  If the
protocol was received five years and the data three years respectively
before final registration, the same market conditions may or may not
still exist.  The Board could approve a protocol and then not be allowed
to see the completed study.  Mr. Carley said that predicting whether or
how often this would occur would be difficult.  

A Federal Register notice would publicize that the HSRB was meeting on
an unknown substance from an unknown sponsor, and that a report would
not be publicly available.  The decision for the Board to be CBI cleared
precluded the Board from maintaining an open forum.  Dr. Krishnan
indicated that if EPA resolved CBI, that this might be sufficient.  Even
with a new substance, all the existing toxicological and safety
information would be available before a human study would be proposed. 
This might allow the review to go forward.  Dr. Chadwick added that he
was comfortable with the Agency making determinations about false CBI
claims.  Dr. Lehman-McKeeman was not in favor of the Agency’s second
option because inadvertent CBI disclosures were a definite risk.  She
felt that the Board must be cognizant of the issues, but must strive to
be open to the public.  If the Board could not make a decision because
of withheld CBI, this should be dealt with on a case-by-case basis.  The
Board could not change from open meetings into a closed session without
public notice.  If this was to occur, the subject would be tabled until
the next HSRB meeting.  

Dr. Fisher summarized the Board’s priorities with respect to CBI as
follows: 

(1) the HSRB wished to continue to be open and transparent

(2) EPA should conduct due diligence to determine the legitimacy of CBI
claims and provide justification for their decision to the Board

(3) EPA should inform the Board about the type of information being
withheld and provide redacted documents to the Board

(4) EPA should be prepared to answer questions, within legal limits, as
to the material being provided

(5) If a registrant was going to withhold the identity of the active
ingredient and the Board was asked to make some determination regarding
the toxicology of that compound, EPA should provide the Board with a
good critical scientific summary of the available information within the
data evaluation record (DER).  

(6) Registrants should be committed to providing EPA and the Board with
as much information as possible to permit the Board to make
recommendations that will be useful to EPA.

The Board requested improvement in the oral scientific reports provided
by EPA.  Summaries did not help with the deliberations.  The Board would
like to have more of an evaluative component and critique of the studies
before the HSRB conducted its review.  The Agency’s data evaluation
records tended to be summaries but were not evaluative.  The Board would
appreciate EPA’s feedback on the study.  

Dr. Fisher stated that the onus was on the registrant to restrict CBI
claims to the narrowest claim possible and the onus was on EPA to
provide the Board with the information needed to make a recommendation. 
Dr. Chambers indicated that when there was a historical context for the
usefulness of a study, such as the AHETF, that this information might 
be helpful in assessing the utility of the data.  Dr. Sharp clarified
that this was an interim position that would be further evaluated at a
later date.  EPA would describe the CBI claimed information, but not
disclose it.  This places the onus on EPA to defend the science and
ethics of the protocols.  Dr. Chadwick stated that the Board’s concern
about CBI was palpable.  Dr. Krishnan asked if options 2 and 3, as
stated above, were needed.  Dr. Krishnan commented that since human
studies were being proposed, toxicological information would be needed
for comparison to the doses proposed in the study to ensure human safety
and a complete protocol review.  

Mr. Jordan remarked that the availability of toxicity data might vary. 
Dr. Lux interjected that, as the person who would be ultimately
responsible for the protection of human subjects, the Board’s advice
would be useful only so far as it was fully informed and fully
independent.  If maintaining openness compromised the ability of the
Board to move forward, this might be a compromise worth taking.  

Mr. Jordan commented that he viewed that there were three distinct goals
of the HSRB: 

(1) to improve the science and ethics of human studies 

(2) to build confidence in the information gathering process;
transparency builds independence and confidence 

(3) the protection of legitimate trade secret information, including the
protection of certain types of information from public disclosure.  

Mr. Jones requested that these values be applied on a case-by-case
basis.  Dr. Brimijoin voiced concern that the Board would inevitably be
put into situations where, to make an adequate decision and to satisfy
the Board’s highest priority (which must be the protection of human
subjects) the Board must have access to CBI.  However, it appeared that
the Board was willing to try reviewing protocols and studies without CBI
materials present.  If the Board could not review the protocol without
the CBI content, then the Board would either fail to make a
recommendation, make a highly qualified recommendation, or decide that a
closed-door session was necessary.  The Chair could hold an
administrative meeting to decide whether the issue could be handled
during an open session; otherwise, if CBI was needed, the case would
have to be deferred to the next HSRB meeting.  Dr. Brimijoin recommended
proactively seeking a resolution before the next public meeting was
held.  Dr. Lebowitz was concerned that if the Board entered a closed
session to make the decision, the Board might not be viewed as
independent from EPA and the Board’s judgment might be questioned.  He
remarked that the Board made recommendations but the final decision was
with the Agency.  By being open, the Board served the public.  The Board
needed to decide how much independence would be sacrificed by conducting
closed sessions.  There were many things that would affect public
perception of the independence of the Board, including the Board
members’ reputations.  

Mr. Sadowsky indicated that if the Agency has not performed a formal
legitimacy review for CBI that EPA could not legally make a statement
about the legitimacy of the claim.  Dr. Fisher remarked that if she was
a member of the public and not a registrant, she would think that EPA
did not want to make decisions about CBI and did not want to delay the
process for registrants; that EPA would rather allow registrants to
claim anything as CBI.  EPA seemed to want the Board to become cleared
to review CBI, but the issue of whether the Board could improve the
science and ethics review could not be separate from being public.  The
Board may differ with respect to how to improve the science and ethics,
but Dr. Fisher was concerned that once the Board was CBI trained the
issue would become mute.  

Mr. Mathews indicated that the Board had tremendous discretion with
respect to moving in the direction that was most appropriate.  There
were legitimate reasons to enter into closed sessions, but the law did
not require closed sessions if the Board could deal with CBI in another
way.  Dr. Lehman-McKeeman suggested that the Board try handling a case
as an example.  If the Board is faced with a case where they cannot make
a decision because of missing information, the Board would need to know
decide how to proceed.  Dr. Fenske said priorities 2 and 3 both required
that the Board be trained in handling CBI.  The Board was being asked to
review proposed and completed human studies research, a different
responsibilities compared to the FIFRA SAP.  The nature and kind of
studies that EPA anticipated involved legitimate trade secrets which
would be viewed well ahead of product registration.  A new product would
be confidential.  The Board could schedule a meeting where the morning
session was open.  When discussion shifted to the CBI material, the
Board could enter a closed session.  

Dr. Krishnan said that in some cases the Board may only have access to
the basic data set.  Even if the Board was not concerned with product
formulations, he would be willing to be CBI trained to accomplish the
task assigned to the Board.  If the Agency  could not summarize the data
(as highly toxic, low-grade toxicity, etc.) in public, CBI training
would be necessary.  He was surprised that a summary of the basic
toxicity and safety data could not be extracted.  Dr. Fisher expressed
concern about how the Board would know whether something was in fact a
legitimate CBI claim.  Dr. Philpott expressed concern that if the Board
were to see the CBI claimed material and discussed the redacted material
in a public session and a Board member might inadvertently disclose
confidential information.  This could make the Board liable for
releasing CBI.  He was more inclined to retain access to non-CBI and
make the decision regarding the feasibility of the review, even if this
caused a delay.  

Dr. Lehman-McKeeman stated that the Board was grappling with deviations
from being a public entity and not fully appreciating what would be
considered CBI.  She thought an example might help.  In addition, it
would be helpful  and that it would be helpful for the public if the
Board were to indicate it could not render a decision based on
information being withheld.  The Board should strive to remain public
but must recognize the existence of CBI and the inevitability that it
would have to explain that it could not make a decision because
information was withheld.  Dr. Fish suggested that training on CBI
might be helpful, but Dr. Lehman-McKeeman added that training without an
example would not help.  Not knowing what the CBI was, it was difficult
to determine how it would affect the Board’s decision process.  Dr.
Lehman-McKeeman recommended that the Board remain open and public for as
long as possible, the CBI issue could be dealt with once a situation
presented itself.  Dr. Fisher responded that this recommendation assumed
that the Board could not review a protocol containing claimed CBI
without being cleared first; the idea of using an example could present
more challenges to overcome.  

Mr. Carley indicated that the Agency had an example.  A notice was
received for an insect repellant efficacy study claiming CBI for the
identification of the sponsor and the chemistry of the test material. 
The rationale for the claim was that this was a new area of product
development for the sponsor and knowledge of this initiative by their
competitors could result in significant harm.  Dr. Chambers remarked
that if a registrant made a CBI claim,  sufficient toxicity data needed
to be presented to the Board for the protocol to be approved.  The
identity of the sponsor might not be a problem but if the Board’s
scientists received insufficient toxicity data upon which to render an
opinion, they could not declare the science as valid and the ethics
discussion would be of no use.  It was in the sponsor’s best interest
to limit CBI.  

Mr. Gaynor (Insect Control and Research, Inc.) sent a letter to the
HSRB suggesting that the sponsor be identified by code and that test
materials be identified by product type (i.e., liquid, pump, towelette,
lotion).  For registered compounds, the chemistry could be described as
a percentage of active ingredient by application type; and for new
products, the active ingredient could be identified by chemical class. 
Masking chemistry was not as clear, especially with respect to
repellants containing few active ingredients.  If a new product was the
first member of a chemical class, this could be considered sensitive
information.  It was the registrant’s decision as to what information
to release.  Dr. Sharp suggested that a representative of the sponsor
could be invited to meet the Board to describe what they could or could
not disclose.

Dr. Fenske inquired about whether the Board would know anything about
the toxicity data for a new product if it was not CBI approved.  Mr.
Carley responded that this was unknown.  Most protocols included a
background section containing information about previous research.  This
might be presented but it would not be as complete as for an existing
compound.  The Agency would not bring a human study protocol to the HSRB
without sufficient information on the compound’s toxicity, but there
was a time lapse between submission of a data package and the CBI claim.
 This was when the Board would deliberate.  

Dr. Krishnan repeated his statement that if the Agency was considering a
human study, animal data should be available.  He wondered why this
information could not be presented in a manner that preserved CBI so
that it could be discussed in a public forum.  Dr. Lehman-McKeeman
indicated that the Board was struggling with what constituted CBI.  It
might be appropriate to determine the minimum amount and type of
information the Board needed to make a decision.  

With respect to conflicts of interest with an unknown sponsor, EPA would
conduct reviews to determine if a conflict existed.  Dr. Philpott stated
that ethically, the Board needed to identify connections between the
sponsor, the researcher, the IRB, and the research subjects; EPA could
handle this also.

Dr. Fisher suggested that an  approach to overcoming the challenge
associated with information availability could be a good will approach. 
The registrant could provide as much information as possible while still
protecting their business interests.  Having one or two Board members
CBI trained was another potential solution. She advocated that a good
will approach be taken and that the Agency work with registrants to make
decisions regarding CBI.  Dr. Brimijoin clarified that if everyone were
CBI trained, the Board could retain the options of whether to review the
CBI or discuss a sanitized document in a public forum.  Dr. Krishnan
suggested that a representative Board scientist and a representative
ethicist be CBI trained to advise the full Board on protocols and
studies without discussing CBI in public.  Dr. Lewis clarified that if a
working group were organized, it would have to report to the Board.  The
working group would not speak on behalf of the HSRB.

Dr. Fenske remarked that the next meeting was about 100 days away and
asked if EPA knew what the agenda items were for January 2007.  Mr.
Jordan responded that the agenda planning session for the January 2007
meeting had not yet been held; topics had not been determined. 
Potential topics included the insect repellant efficacy protocol with
CBI claims and some completed human studies without CBI claims.  As
noted by Dr. Lewis, no HSRB members were FIFRA CBI certified at this
time.  Dr. Fisher suggested scheduling the agenda planning meeting and
proceeding as needed.  Dr. Kim stated that for liability purposes, he
would rather not be FIFRA CBI cleared.  The Board also requested that a
sponsor from the registrant who could provide additional information on
the study background be invited to attend the January 2007 meeting. 
For the ROAT study this was very helpful.  

Dr. Lewis thanked the Board, adding that a report would be prepared
summarizing the Board’s recommendations.  A notice of the draft report
and schedule for HSRB review and approval of the report will be
published in the Federal Register.  

Dr. Lux took the opportunity to personally thank the Board for its
deliberations.  He noted that he had the same fundamental responsibility
as the Board:  to protect human subjects, and he was grateful for the
Board’s participation.

Dr. Lewis announced that the next HSRB meeting was scheduled to occur
January 23-27, 2007, at the Sheraton Crystal City Hotel in Arlington,
Virginia.  

Dr. Fisher adjourned the meeting.

Respectfully submitted:

Paul I. Lewis, Ph.D.

Designated Federal Officer

Human Studies Review Board

United States Environmental Protection Agency

Certified to be true by:

Celia B. Fisher, Ph.D.

Chair

Human Studies Review Board

United States Environmental Protection Agency

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

Attachment A

EPA HSRB Members

Chair 

Celia B. Fisher, Ph.D. 

Marie Ward Doty Professor of Psychology

Director, Center for Ethical Education 

Fordham University, Bronx, NY 

Vice Chair 

William S. Brimijoin, Ph.D.

Chair and Professor, Molecular Pharmacology and Experimental
Therapeutics 

Mayo Foundation, Rochester, MN 

Members 

David C. Bellinger, Ph.D. 

Professor of Neurology 

Harvard School of Medicine, Boston, MA 

Alicia Carriquiry, Ph.D. *

Professor, Department of Statistics 

Iowa State University, Ames, IA 

Gary L. Chadwick, PharmD, MPH, CIP 

Associate Provost

Director, Office for Human Subjects Protection 

University of Rochester, Rochester, NY 

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

Director, Center for Environmental Health Sciences, College of
Veterinary Medicine 

Mississippi State University, Mississippi State, MS 

Richard Fenske, Ph.D., MPH 

Professor, Department of Environmental and Occupational Health Sciences 

University of Washington, Seattle, WA 

Susan S. Fish, PharmD, MPH 

Professor, Biostatistics & Epidemiology 

Boston University School of Public Health, Boston, MA 

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

Senior Science Policy Analyst 

U.S. Food and Drug Administration, Rockville, MD 

KyungMann Kim, Ph.D., FCCP

Professor and Associate Chair, School of Medicine and Public Health 

University of Wisconsin-Madison, Madison, WI 

Kannan Krishnan, Ph.D. 

Professor, Département de santé environnementale et santé au travail,
Faculté de médicine Universite’ de Montreal, Montreal, Quebec,
Canada 

Michael D. Lebowitz, Ph.D., FCCP 

Professor of Public Health & Medicine 

University of Arizona, Tucson, AZ 

Lois D. Lehman-McKeeman, Ph.D. 

Distinguished Research Fellow, Discovery Toxicology 

Bristol-Myers Squibb Company, Princeton, NJ 

Jerry A. Menikoff, M.D. 

Associate Professor of Law, Ethics & Medicine 

Director, Institute for Bioethics, Law and Public Policy 

University of Kansas, Kansas City, KS 

Sean Philpott, Ph.D., MS 

Associate Director, Alden March Bioethics Institute 

Albany Medical Center, Albany, NY 

  

Richard Sharp, Ph.D. 

Assistant Professor of Medicine, Center for Medical Ethics and Health
Policy

Baylor College of Medicine, Houston, TX

* Not in attendance at October 1819, 2006 HSRB meeting

Attachment B

Federal Register Notice Announcing Meeting

Federal Register: September 27, 2006 (Volume 71, Number 187)

[Notices]

[Page 56527-56528]

From the Federal Register Online via GPO Access [wais.access.gpo.gov]

[DOCID:fr27se06-89]

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

ENVIRONMENTAL PROTECTION AGENCY

[EPA-HQ-ORD-2006-0798; FRL-8223-8]

 

Human Studies Review Board; Notice of Public Meeting

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

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

SUMMARY: The U.S. Environmental Protection Agency's (EPA or Agency)
Office of the Science Advisor (OSA) announces a public meeting of the
Human Studies Review Board (HSRB) to advise the Agency on EPA's
scientific and ethical reviews of human subjects research.

DATES: The public meeting will be held October 18-19, 2006, from 8:30
a.m. to approximately 5 p.m., eastern time on October 18, 2006, and 8:30
to approximately 2 eastern time on October 19, 2006.

    Location: One Potomac Yard, 2777 Crystal Drive, Arlington, VA 22202.

    Meeting Access: Seating at the meeting will be on a first-come
basis.  Individuals requiring special accommodations at this meeting,
including wheelchair access and assistance for the hearing impaired,
should contact the Designated Federal Officer (DFO) at least 10 business
days prior to the meeting using the information under FOR FURTHER
INFORMATION CONTACT so that appropriate arrangements can be made.

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

FOR FURTHER INFORMATION CONTACT: Any member of the public who wishes
further information should contact Maria Szilagyi, Designated Federal
Officer (DFO), EPA, Office of the Science Advisor, (8105R),
Environmental Protection Agency, 1200 Pennsylvania Ave., NW., 

Washington, DC 20460; telephone number: (202) 564-6809; fax: (202) 564
2070; e-mail addresses:   HYPERLINK "mailto:szilagyi.maria@epa.gov" 
szilagyi.maria@epa.gov .  General information concerning the EPA HSRB
can be found on the EPA Web site at   HYPERLINK
"http://www.epa.gov/osa/hsrb/"  http://www.epa.gov/osa/hsrb/ .

ADDRESSES: Submit your written comments, identified by Docket ID No.
EPA-HQ-ORD-2006-0798, by one of the following methods:

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

    E-mail:   HYPERLINK "mailto:ORD.Docket@epa.gov"  ORD.Docket@epa.gov
.

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

    Hand Delivery: EPA Docket Center (EPA/DC), Public Reading Room,
Infoterra Room (Room Number 3334), EPA West Building, 1301 Constitution
Avenue, NW, Washington, DC 20460, Attention Docket ID No.
EPA-ORD-2006-0798.  Deliveries are only accepted from 8:30 a.m. to 4:30
p.m., Monday through Friday, excluding legal holidays.  Special
arrangements should be made for deliveries of boxed information.

    Instructions: Direct your comments to Docket ID No.
EPA-HQ-ORD-2006-0798.  EPA's policy is that all comments received will
be included in the public docket without change and may be made
available online at   HYPERLINK "http://www.regulations.gov" 
http://www.regulations.gov , including any personal information
provided, unless the comment includes information claimed to be
Confidential Business Information (CBI) or other information whose
disclosure is restricted by statute.  Do not submit information that you
consider to be CBI or otherwise protected through   HYPERLINK
"http://www.regulations.gov"  http://www.regulations.gov  or e-mail. 
The   HYPERLINK "http://www.regulations.gov"  http://www.regulations.gov
 Web site is an “anonymous access” system, which means EPA will not
know your identity or contact information unless you provide it in the
body of your comment.  If you send an e-mail comment directly to EPA,
without going through   HYPERLINK "http://www.regulations.gov" 
http://www.regulations.gov , your e-mail address will be automatically
captured and included as part of the comment that is placed in the
public docket and made available on the Internet.  If you submit an
electronic comment, EPA recommends that you include your name and other
contact information in the body of your comment and with any disk or
CD-ROM you submit.  If EPA cannot read your comment due to technical
difficulties and cannot contact you for clarification, EPA may not be
able to consider your comment. Electronic files should avoid the use of
special characters, any form of encryption, and be free of any defects
or viruses.

SUPPLEMENTARY INFORMATION:

I. Public Meeting

A. Does This Action Apply to Me?

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

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

    In addition to using regulations.gov, you may access this Federal
Register document electronically through the EPA Internet under the
Federal Register listings at   HYPERLINK "http://www.epa.gov/fedrgstr/" 
http://www.epa.gov/fedrgstr/ .

    Docket: All documents in the docket are listed in the   HYPERLINK
"http://www.regulations.gov"  http://www.regulations.gov  index.
Although listed in the index, some information is not publicly
available, e.g., CBI or other information whose disclosure is restricted
by statute.  Certain other material, such as copyrighted material, will
be publicly available only in hard copy.  Publicly available docket
materials are available either electronically in   HYPERLINK
"http://www.regulations.gov"  http://www.regulations.gov  or in hard
copy at the ORD Docket, EPA/DC, Public Reading Room, Infoterra Room
(Room Number 3334), 1301 Constitution Ave., NW, Washington, DC.  The
Public Reading Room is open from 8:30 a.m. to 4:30 p.m., Monday through
Friday, excluding legal holidays.  The telephone number for the Public
Reading Room is (202) 566-1744, and the telephone number for the ORD
Docket is (202) 566-1752.  EPA's position paper(s), charge/questions to
the HSRB, and the meeting agenda are now available.  In addition, the
Agency may provide additional background documents as the materials
become available.  You may obtain electronic copies of these documents,
and certain other related documents that might be available
electronically, from the regulations.gov Web site and the HSRB Internet
Home Page at   HYPERLINK "http://www.epa.gov/osa/hsrb/" 
http://www.epa.gov/osa/hsrb/ .  For questions on document availability
or if you do not have access to the Internet, consult the person listed
under FOR FURTHER INFORMATION CONTACT.

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

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

    a. Explain your views as clearly as possible.

    b. Describe any assumptions that you used.

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

    d. Provide specific examples to illustrate your concerns.

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

D. How May I Participate in This Meeting?

    You may participate in this meeting by following the instructions in
this section.  To ensure proper receipt by EPA, it is imperative that
you identify docket ID number EPA-HQ-ORD-2006-0798 in the subject line
on the first page of your request.

    a. Oral comments.  Requests to present oral comments will be
accepted up to October 10, 2006.  To the extent that time permits,
interested persons who have not pre-registered may be permitted by the
Chair of the HSRB to present oral comments at the meeting.  Each
individual or group wishing to make brief oral comments to the HSRB is
strongly advised to submit their request (preferably via e-mail) to the
DFO listed under FOR FURTHER INFORMATION CONTACT no later than noon,
eastern time, October 10, 2006, in order to be included on the meeting
agenda and to provide sufficient time for the HSRB Chair and HSRB DFO to
review the agenda to provide an appropriate public comment period.  The
request should identify the name of the individual making the
presentation, the organization (if any) the individual will represent,
and any requirements for audiovisual equipment (e.g., overhead
projector, LCD projector, chalkboard).  Oral comments before the HSRB
are limited to 5 minutes per individual or organization.  Please note
that this limit applies to the cumulative time used by all individuals
appearing either as part of, or on behalf of an organization.  While it
is our intent to hear a full range of oral comments on the science and
ethics issues under discussion, it is not our intent to permit
organizations to expand these time limitations by having numerous
individuals sign up separately to speak on their behalf.  If additional
time is available, there may be flexibility in time for public comments.
 Each speaker should bring 25 copies of his or her comments and
presentation slides for distribution to the HSRB at the meeting.

    b. Written comments.  Although you may submit written comments at
any time, for the HSRB to have the best opportunity to review and
consider your comments as it deliberates on its report, you should
submit your comments at least 5 business days prior to the beginning of
the meeting. If you submit comments after this date, those comments will
be provided to the Board members, but you should recognize that the
Board members may not have adequate time to consider those comments
prior to making a decision.  Thus, if you plan to submit written
comments, the Agency strongly encourages you to submit such comments no
later than noon, eastern time, October 10, 2006.  You should submit your
comments using the instructions in Unit I.C. of this notice.  In
addition, the Agency also requests that person(s) submitting comments
directly to the docket also provide a copy of their comments to the DFO
listed under FOR FURTHER INFORMATION CONTACT.  There is no limit on the
length of written comments for consideration by the HSRB.

E. Background

    EPA will be presenting for HSRB review the results of a completed
human toxicity study, evaluating the allergic contact dermatitis
response in individuals with known sensitivity to hexavalent chromium to
repeated exposure to a wood treatment solution containing hexavalent
chromium.  In addition, the Board will be asked to review two revised
research protocols to evaluate the efficacy of new formulations of the
repellent, IR3535, against ticks and mosquitoes and to advise on a draft
guidance document explaining to the public how to submit proposed and
completed human research to EPA for review by the HSRB.  Finally, at the
Board's request, EPA will present the statutory and regulatory
procedures that EPA and its federal advisory committees are required to
follow when handling materials claimed to be confidential business
information (CBI) under FIFRA or other laws.  The HSRB intends to
discuss how it would like to operate in the event that EPA requests the
Board to review materials containing CBI.

Dated: September 22, 2006.

George Gray,

Science Advisor.

Attachment C

October 2006 Meeting of the HSRB

Meeting Agenda

One Potomac Yard 

Arlington, VA 

 

HSRB Web Site: http://www.epa.gov/osa/hsrb/ 

Docket Telephone: (202) 566-1752 

Docket Number: EPA-HQ-ORD-2006-0798 

Wednesday, October 18, 2006 

8:30 a.m.	Introduction and Identification of Board Members

Celia Fisher, Ph.D. (HSRB Chair) 

8:45 a.m.	Welcome

Kevin Teichman, Ph.D. (Acting Deputy Assistant Administrator for 

Science, Office of Research and Development, EPA)   

8:55 a.m.	Opening Remarks

Mr. Jim Jones (Director, Office of Pesticide Programs, EPA)  

9:05 a.m.	Meeting Administrative Procedures

Paul Lewis, Ph.D. (Designated Federal Officer [DFO], HSRB, OSA, EPA)  

9:10 a.m.	Meeting Process

Celia Fisher, Ph.D. (HSRB Chair)  

9:20 a.m. 	Update on EPA Follow-up of HSRB Recommendations

Mr. William Jordan (OPP, EPA)    

9:30 a.m. 	EPA Human Studies Research Review Official

Warren Lux, M.D. (Human Subjects Research Review Official, OSA, 

EPA) 

 

Chromium Repeat Open Application Test  

 

9:35 a.m. 	HSRB Review of Science and Ethics Criteria for Completed
Human Exposure Studies

Celia Fisher, Ph.D. (HSRB Chair) 

9:45 a.m. 	Chromium Repeat Open Application Test

John Liccione, Ph.D. (OPP, EPA) and Mr. John Carley (OPP, EPA)  

10:30 a.m.	Break   

10:45 a.m.	Public Comments  

11:15 a.m.	Board Discussion   

 

Hexavalent chromium is a component of a pesticide product intended to be
used as a wood preservative.  Members of the general public may
experience dermal exposure to residues of hexavalent chromium remaining
on wood treated with a wood preservative.  Because chromium has caused
allergic contact dermatitis (ACD) in occupational settings, EPA has
determined that it should assess the potential for ACD in the general
public resulting from exposure to hexavalent chromium on wood treated
with acid copper chromate (ACC). 

Scientific considerations 

The Agency has concluded that the study contains information sufficient
for assessing human risk resulting from potential dermal exposure to
wood treated with ACC, containing hexavalent chromium.     

 

Please comment on whether this study is sufficiently sound, from a
scientific perspective, to be used to estimate a safe level of repeated
dermal exposure to residues of ACC on treated wood. 

 

Ethical considerations

The Agency requests that the Board provide comment on the following: 

 

Is there clear and convincing evidence that the conduct of the
hexavalent chromium ROAT study was fundamentally unethical? 

Is there clear and convincing evidence that the conduct of the study was
significantly deficient relative to the ethical standards prevailing at
the time the research was conducted? 

12:15 p.m.	Lunch  

 

IR3535 Insect Repellent Product Efficacy Protocols  

 

1:15 p.m.	HSRB Review of Science and Ethics Criteria for Proposed Human
Exposure Studies

Celia Fisher, Ph.D. (HSRB Chair) 

1:25 p.m.	Science and Ethics of IR3535 Insect Repellent Product Efficacy
Protocols

Clara Fuentes, Ph.D. (OPP, EPA) and Mr. John Carley (OPP, EPA)  

2:15 p.m.	Public Comments  

2:45 p.m.	Break   

3:00 p.m.	Board Discussion  

 

1.	Study EMD-003 from Carroll-Loye Biological Research 

 

Does the proposed research described in Study EMD-003 from Carroll-Loye 

Biological Research appear likely to generate scientifically reliable
data, useful for assessing the efficacy of a test substance for
repelling ticks?  

b.	Does the proposed research described in Study EMD-003 from
Carroll-Loye Biological Research appear to meet the applicable
requirements of 40 CFR part 26, subparts K and L?   

2.	Study EMD-004 from Carroll-Loye Biological Research 

 

a.	Does the proposed research described in Study EMD-004 from
Carroll-Loye Biological Research appear likely to generate
scientifically reliable data, useful for assessing the efficacy of a
test substance for repelling mosquitoes?  

 

b.	Does the proposed research described in Study EMD-004 from
Carroll-Loye Biological Research appear to meet the applicable
requirements of 40 CFR part 26, subparts K and L?   

 

3.	Review format 

 

Please comment on the format used for EPA’s science and ethics reviews
of Dr. Carroll’s protocols in terms of:  

 

a.	Whether future use of this format is likely to produce reviews that
adequately explain the basis for EPA’s position regarding the ethical
and scientific acceptability of the proposed research; and  

 

b.	Whether presentation of future EPA reviews in such a format will
assist the Board’s review of proposed protocols.  

 

Draft EPA Guidance to the Public Concerning Submission of Proposed and
Completed Human Research to EPA for Review by the HSRB  

 

4:30 p.m.	Background

Mr. John Carley (OPP, EPA)   

5:15 p.m.	Adjournment   

Thursday, October 19, 2006 

8:30 a.m.	Convene Meeting

Celia Fisher, Ph.D. (HSRB Chair) 

8:40 a.m.	Follow-up from Previous Day’s Discussion

Mr. William Jordan (OPP, EPA)   

 

Draft EPA Guidance to the Public Concerning Submission of Proposed and
Completed Human Research to EPA for Review by the HSRB (continued) 

 

8:50 a.m.	Public Comments     

9:20 a.m.	Board Discussion   

Please comment on the approach, as described in EPA’s draft PR Notice,
to organizing materials submitted under 40 CFR § 26.1125 for EPA and
HSRB review.  In particular, please address whether this approach is
appropriate for anticipated types of studies involving intentional
exposure of human subjects, and whether EPA should provide different
guidance for various types of research. 

 

10:15 a.m.	Break 

 

Handling of Material Claimed to be Confidential Business Information for
HSRB Consideration 

10:30 a.m.	Introduction

		Mr. William Jordan (OPP, EPA)

10:40 a.m.	CBI Legal Issues

		Mr. Donald Sadowsky (Office of General Counsel, EPA) 

10:50 a.m.	OPP Process for Handling CBI

		Mr. John Carley (OPP, EPA)

11:00 a.m.	Federal Advisory Committee Review of CBI

		Ms. Marilyn Kuray (Office of General Counsel, EPA) 

11:15 a.m.	Conclusion

		Mr. William Jordan (OPP, EPA)

11:25 a.m.	Public Comments  

12:00 p.m.	Lunch 

1:00 p.m.	Board Discussion 

2:00 p.m.	Adjournment  

Please be advised that agenda times are approximate.  For further
information, please contact the Designated Federal Officer for this
meeting, Paul Lewis via telephone: (202) 564-8381 or email:
lewis.paul@epa.gov or Maria Szilagyi via telephone: (202) 564-6809 or
email:  szilagyi.maria@epa.gov. 

 

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