whether you use a topical steroid, or you decide this person needs to be
on IV steroids, that's a clinical issue but not an issue.  As Sean
points out, you need to provide for what happens if, but the what's
going to happen part is clinical, not research.

		MR. CARLEY: Essentially the entire pharmacopeia available to Dr.
Fowler could potentially have been used depending on what happened.
It's very highly contentioned, and I think that if you think of the
informed consent as the reasonably predictable effects sort of thing - I
just made a mess - that probably - I agree with Dr. Chadwick.  I think
that goes too far.

		DR. FISHER: Okay, Sue.

		MS. FISH: Also I just want to remind us that we're not the IRB here,
and we're not looking at a prospective study yet to be conducted.  But
is the fact that the risks of the steroid cream, even for some of us who
think it might have been appropriate, is it clear and convincing
evidence of noncompliance with the regulations or fundamentally
unethical in retrospect.

		And I think we could probably debate for a long time whether or not
the risks should be in the next study to be done prospectively.  We'll
probably get some debate.  But the study is already done.

		DR. FISHER: Right.  And just as a reminder, we are not limited to
fundamentally unethical, which is harm and no informed consent, but also
significantly deficient.

		But I think your point is well made.

		Let me ask one more question, and that is the unforeseen risks.  And
the unforeseen risks say there may be risks from participating in this
study that are unknown including an allergic reaction.

		I'm confused.  I thought this study was studying allergic reactions.

		MR. CARLEY: I understood that to be the risk of an allergic reaction
to something other than the hexavalent chromium.  And there were other
materials in the formulation

		VOICE: More a systematic reaction.

		DR. FISHER: Okay, Gary and then Richard.

		DR. CHADWICK: I guess I find myself in the role of IRB apologist
today.

		I think you perhaps can read that as an allergic reaction up to and
including antiphylaxis (phonetic), and maybe that's what they're trying
to say here is that it could be a really really bad allergic reaction.
I agree with you, that's the whole point of the testing is to get an
allergic reaction.  But I think that what they are probably trying to
say is that although we don't think this is going to happen you could
really go off the charts.

		I suspect that's what - you have to read between the lines.  But I
would agree.  It's not well written.  It's not clear.  And either it
shouldn't be there, or it should be better clarified.

		But as Sue points out, we are not an IRB, and we are not prospectively
giving them -

		DR. FISHER: Right, and what we do have to decide is whether or not the
information was significantly deficient that people who were making a
participation decision were in fact not informed.  That is part of the
charge for previously conducted studies, which is, to put it in my
question, I don't know how we're going to decide on it.

		Richard.

		DR. SHARP: I want to come back to a question about compliance with
privacy protections.  There is an inconsistency, at least I consider
this an inconsistency in what's said with regard to this preconsent
contact that takes place.

		In the protocol it's described as being the case that every contact
was made by research staff that did not work in Dr. Fowler's clinic.

		We also have the materials, the script, that was actually used to set
up that conversation.  And the very first statement in that indicates,
quote, I'm a research nurse calling from Dr. Fowler's office.  So it's
hard for me to reconcile how those two things could conceivably be the
case.

		So since that follow up call - or excuse me, that preconsent phone
call also includes the collection of significant medical information
including things like use of immunosuppressive agents and so forth, that
seems like that raises some issues that we need to sort out who made
that call.

		MR. CARLEY: The principal author is here in the room and may be able
to help.

		DR. FISHER: Gary.

		DR. CHADWICK: That actually raises a couple of questions that might
need some additional thought by the board in discussion.

		To what extent do we worry about HIPPA on this board and privacy
protections and potential violations or noncompliance with HIPPA and/or
other federal regulations.

		So that's kind of touching on what you are talking about there.
That's something that I think John raised.

		A question I had, and again I think this is maybe a policy issue for
the board picking up on John's comment about the IRB approvals being
weak, that they were retyped and reformated for the report.  I can
understand why a person would do that and not assign any nefarious
intent or whatever.  But I do think originals are needed, and if they
are not supplied they need to be obtained, and it is not acceptable -
this would be my recommendation that it would not be acceptable without
the addition particularly of these documents including the IRB approval
letters and the informed consent that was actually approved and stamped
by the IRB.

		And then my last comment, and again John pointed out the fact that
this talks about compliance with FDA regulations, and in the consent
form it does talk about disclosures and so forth, again touching on the
sort of HIPPA issue.  But it does talk about disclosures, and it only
states that disclosures would be made to the FDA.  And it doesn't
mention anywhere that this would be disclosed to the EPA.  And it makes
one wonder what was the IRB thinking, and should that have been edited
out.

		MR. CARLEY: In the IRB correspondence, they said, here are examples of
the sort of thing that you need to put into this.  You should adapt them
appropriately for the circumstances of this study or words to that
effect.

		So that's I think what the IRB was thinking.  You need to ask a
slightly different form of the question: why didn't they adapt it as
appropriate to this circumstance?

		DR. CHADWICK: Right, and you would think that if they were doing
something to be submitted to the EPA, they would at least mention that.

		Now maybe that's in the HIPPA documentation which may or may not have
been provided, whatever.  This certainly doesn't seem to include
anything about the information to the subjects that this is going to be
- this data is going to be given to the EPA, and in fact in the handout
here anticipating the next talk, we have pictures, colored pictures
which are - in the consent I assume qualify as nonidentifying photos,
which it says are only going to be used for medical publications.

		So potentially you have a violation of consent by giving this to the
EPA, although it's clearly something you would expect of this type of
study.

		So I think there are some deficiencies.  But again not clear and
convincing to that level.

		DR. FISHER: Sue, yes.

		MS. FISH: In the HIPPA documents, just to clarify Gary's question, the
HIPPA documents also relate to FDA, and don't mention EPA, but that goes
back to the original question is, whether HIPPA is a concern of ours or
not.

		And I would think that the question is, like EPA's comments on that.
Because certainly under the ethical standards it says, did the study
fail to fully meet specific ethical standards prevalent at the time the
research was conducted?

		Well, HIPPA has entire sections on research.  And how you implement an
informed consent authorization; all those kinds of things.

		I would think that it would be hard for us - if we thought a violation
of HIPPA was apparent, it's difficult to recommend as ethical a study
that did not adhere to that regulation.

		So I mean that's - a fault if you ask me.

		MR. JORDAN: This is Bill Jordan.

		It seems to me that in terms of ethical treatment of subjects that
protecting privacy is recognized widely as a legitimate consideration.
And HIPPA as best I understand it, and I'll readily confess my
understanding is pretty limited having only skimmed some forms and then
signed because I wanted the doctor to look at me, they set a set of
standards, relevant set of standards.

		Therefore it seems appropriate to me to think about HIPPA in terms of
these sorts of issues.  But frankly we have not discussed this at any
great depth with them.  The pesticide office, and I would want to confer
with Dr. Lutz and get his thoughts on it, and perhaps talk with our
colleagues at OHRP to see how they sort these things out.

		But in terms of that, it seems to me a relevant factor to look at.
Whether it rises to the level of being significantly deficient I don't
think we're prepared to offer any views.

		DR. FISHER: Jerry?

		DR. MENIKOFF: Yes, I guess my general take, just thinking aloud a
little bit, is that probably HIPPA, we shouldn't be enforcing HIPPA.  If
we look to the preexisting studies, the studies that were conducted
before this, yes, there was general language about appropriate ethical
standards.  But then on the more prospective studies, which
theoretically I assume are under stricter rules, it's actually enforcing
the actual regulations, the subpart K, L et cetera.

		DR. FISHER: I don't think that's true.  I think the question under
previously conducted study is, did the study fail to fully meet specific
ethical standards prevalent at the time the research was conducted.

		DR. MENIKOFF: Correct.  All I'm saying is in general I would have
thought by and large we were going to apply stricter standards to the
new studies as opposed to the old studies.

		DR. FISHER: I would just add, if we believe a study violated federal
law, whether we want to consider that as a significant deficiency.

		DR. MENIKOFF: The general argument on that is, let's ask ourselves
what standards we are going to apply prospectively and the ones that are
actually under these regulations.

		I think in general most people apply the Common Rule which has its own
language and subsection that deals with there being appropriate privacy
violations.  In general OHRP's view of that is that there are separate
privacy standards built into the common rules that are separate from the
HIPPA rules, and -

		DR. FISHER: Well, let me say that OHRP, and as part of SACHARP
(phonetic) we wrote an entire set of recommendations about OHRP should
handle HIPPA which was accepted by the secretary.  So OHRP does not - it
does include how to follow HIPPA recommendations as part of how it's
going to evaluate certain studies.

		And I'd also point out that HIPPA was in effect in April, 2003, so
that it is the law that covers this particular study.

		Suzanne?

		DR. FITZPATRICK: We don't have all the information here.  Because he
does a lot of research studies, he may have already asked all of his
patients if it's okay to be conducted to be in further studies.  So
therefore there is not any kind of violation if they have already agreed
that they would be willing to be in studies.  So I think that without
further information on what the data that the people are taking from
them, what their prior agreements were, you can't really say anything.

		DR. FISHER: I agree with you. And that's part of what I think Jerry
was pointing out in terms of post versus what we can require, but I also
want to point out that he cannot do it verbally.  It had to be a written
authorization, especially since he is both the investigator and the
researcher.

		And the extent to which we have those pre-participation authorizations
may or may not be something that we are going to pursue in a study that
was already conducted.  But it's always important to make a statement
about if we had the information or if it's a protocol, where we would be
going with that.

		If in fact the authorizations to provide the information in recruiting
was not signed, then that would be a violation of HIPPA.

		Any other comment?

		Okay, so I believe we have public comment.  And that's from Deborah
Procter of Exponent.

		And Deborah, could you come up.

		Ms. Procter, you are going to have to introduce yourself.  And also
we're going to be limiting you to five minutes.

		And in introducing yourself, give your credentials as well as who you
are speaking for.

		You have to stand up?  And if you are comfortable sitting down, so
that you could speak into the mike so we could hear it.

	PUBLIC COMMENT

		MS. PROCTER: I'd be happy to.  Thank you.

		I am Deborah Procter.  I am the principal toxicologist at Exponent,
and I am the project manager of this study.

		I am here with my colleague Jeffrey Thrudall (phonetic) who also
conducted this study with me, and Dr. Fowler.  And we are here on behalf
of Forge (phonetic) Product Research Laboratory which is the sponsor of
the study.

		My primary objective in coming here today is to make sure that the
board has an accurate understanding of the study to clarify any
misconceptions about what was done.

		We submitted to EPA 700 pages of documentation, so I'm not surprised
that there is some confusion on certain issues.

		I also wanted to briefly overview the risk-benefit ratio as we see it.

		Probably first and most importantly, the reason there was no
documentation about the preliminary Exponent employee study was because
it was not conducted.  We considered doing it.  However, and it was
referenced in a draft protocol that we had submitted to EPA that we were
hoping to get their input on the scientific information, sort of a draft
protocol that had not gone to the IRB.  We decided to remove it because
they thought that it was unnecessary.  So it was removed before the IRB
saw the protocol.  But there were typographical errors that IRB caught
and asked us about it, and we responded that it was not part of the set.
 And I'm sorry that there was confusion on that.

		With regard to the recruitment process I'll go over it specifically.
First over the telephone there - Dr. Fowler has a relatively large
practice.  And there are five research nurses who do nothing but
research; they don't work at all with the clinical practice.  So they
have a research operation and then they have a clinical practice.

		So all of the review of the finals and the contacting of the
individuals was done by his research nurses, not by his clinical staff
members and not by  Exponent.  Exponent did not go through his medical
files.  In fact Dr. Fowler was sensitive to HIPPA in saying, no, you are
not allowed to look through the files.

		These telephone calls were with an IRB-approved telephone script.  In
terms of whether or not people were interested; whether or not they were
eligible.  And then they were scheduled to visit the clinic.  Once they
were at the clinic for the first visit, again they were explained the
study protocol, and they were given the informed consent forms to sign
and review.

		After they signed the informed consent forms, Dr. Fowler examined
their skin.  They filled out a more detailed questionnaire, and then
attached samples were applied.

		So there weren't any chemical exposures until informed consent was
given.

		With regard to payment, what we did is a literature search to
determine what a reasonable payment would be for this study.  We found
that there was a range of about $25 per day to $125 per day for a visit,
so we decided to take the midpoint of this range, of $75 per day.  Dr.
Fowler thought in his experience doing testing that that was a
reasonable amount of reimbursement.

		The ROAT study involved coming to the clinic five days a week for two
consecutive weeks.  So it is considerably inconvenient.  And so we
increased the payment for a particular patient in the ROAT to $90 per
day.

		Payments were made for each visit at the end of each phase.  So after
patch testing payments again, after the ROAT payments were done.
Participants were free to withdraw at any point during the study, and
that payment on a daily basis we thought was just impractical, because
we would be writing more than a thousand checks with people coming and
going every single day.

		With regard to minimal risk to the participants, the exposure was
generally consistent with common clinical tests, specifically patch
testing.  Responses are transient in nature, lasting one to three weeks.
 The highest dose in the ROAT in this study was below clinical patch
test dose.  It's also lower than the highest dose in the Nethercutt
study.  And I note that the Nethercutt study was said to have posed
minimal risk.

		It's also as noted by Mr. Carley 2,900 lower than the EK reference
notes, and small areas of skin were exposed, responses were monitored.
Applications were discontinued for allergic reactions, and treatment was
actively made available.

		To give an example of the responses that we observed, just to give you
a visual, I gave you the pictures.  This is a mild, a moderate, and a
strong allergic response that we observed.  We only had one strong
allergic response in our study to Copper Shield, and only 17 of the 60
people reacted at all.

		With regard to the value of the research to society, most importantly
is the information that can be used for risk assessment.  Specifically
what we  is dose response data for application of Copper Shield, a
chemical that has not been tested before.  We also provide information
we believe can be a set of skin references technically on studies of
repeated open application tests which is more representative of
environmental exposures.

		Also our results generalize to the general population by normalizing
for the - with the patch data test for all the allergic people in the
U.S. and then we think it's applicable for projection of induction for
the general population.

		The distribution of societal benefits would be to workplace exposure
to hexavalent chromium, both in wood treatment and in the many other
occupations where there is hexavalent chromium exposure.

		Consumers with treatment wood who could potentially be exposed to
hexavalent chromium.

		And let's see, it's the wrong slide, it won't go back.  Okay I'll just
have to finish up.

		And then the benefit to the greater community would be that this data
could be used to set soil standards.  Certain states, Massachusetts and
New Jersey have already used patch test data to set soil standards for
hexavalent questions.

		And I'd be happy to clarify or address any questions.  There have been
some questions that were not quite correct, or confusing in what we
presented, and I'd be happy to try and address them again if I can.

		DR. FISHER: Thank you.  Before we go to questions, I have a question
myself.

		The next public speaker, Howard Mayback (phonetic), where is he, is
that about this study?

		(Off-mike voice)

		Oh, okay, then why don't we put questions to Ms. Procter.

		And I was wondering, Ms. Procter, I'd like to give you an opportunity,
are there specific points that you heard us questioning about that you
feel that you would want to --

		MS. PROCTER: I made a list as I sat in the audience so I could go
through it.

		First, on the scientific issue, and maybe some of this has been
covered, but I'll just make certain clarifications, no guaranty that I
got all of it, so please feel free to interrupt.  With regard to how
it's relevant to environmental exposures you can wipe wood with wipes
and measure hexavalent chromium when it is freshly treated with these
chemicals so a direct touching it would give you exposure to solutions.

		Why we had a disproportionate number of plus three more sensitive
individuals, we did a preliminary patch test at the beginning of the
study, Phase One, so did Nethercutt.  We didn't lose -- we lost 30
percent of the people who we thought we allergic did not have a positive
reaction.  Nethercutt lost almost 50 percent.

		So these -- when we go back and look at what these people's score was
historically, well the first time they were patch tested, they are
almost all plus ones.  So I think what has happened is that their
allergy has waned over time.  And they are no longer allergic or just --
not allergic enough to react to a patch test.  So I think that is why we
have more plus threes in our population.

		More of the males also were plus twos and plus threes.  And I don't
have a specific explanation for that.  Some research has shown that you
are more sensitive if you are sensitizing exposure was higher.  So of
the people who were sensitized by cement, which is classic for exposure
-- you know allergic contact dermatitis from hexavalent chromium, most
were men and had stronger responses so that could be a reason why we had
a larger number of plus two and plus threes that were men.

		We normalized the ten percent MET because we realized how very
sensitive the ten percent MET is to the makeup of your study population.
 And it was a hindsight that we did this.  And it actually came from a
comment that EPA made about how does our population compare with the
general population.  So we did that kind of as a hindsight.  But I think
it is pretty important because, you know, one additional plus three, one
less plus one really can create quite a bit of variability.

		And we looked for historical data on the Nethercutt population to do
the same with his data but unfortunately we couldn't find the patch test
scores.

		Why were the controls different with regard to irritant responses?
I'm unsure.  I will comment that in the potassium dichromate study, we
did have one irritant response to potassium dichromate.  That was to the
lowest dose of potassium dichromate.  But there was one response.  It's
unclear.

		The irritation that occurred, it occurred in nine individuals in our
study.  In four of the nine, all they had was a response that Dr. Fowler
deemed to be irritant.  The other five had allergic and irritant
responses.  The responses didn't occur on the first day.  The first
irritant response occurred on day four.  There was one on day five.  And
after that, the responses were in the second week of the study.

		With regard to the NAGDC database, Dr. Fowler is a member of the NAGDC
and has been contributing data to that database historically.  And
because he does more patch tests than any other physician in the United
States, you know, more data go into that database from him than from any
other physician.

		And it is reasonable to believe that any of the people who were patch
tested originally are already in that database although some of the
people had patch tests that were quite a bit older or newer so they
didn't fit the same time frame.  But otherwise they should have been in
the database.

		The two people who we didn't know if they were allergic to hexavalent
chromium or not and they were patch tested.  And in that patch test,
there was a response.  I think there was some question as to whether or
not they really were allergic, one had a plus three response.  The other
one had a plus one response.

		In the rote, the plus three reacted to very low doses just like most
of the plus threes did in the study.  The plus one did not react just
like the rest of them did.  So I think that they had been sensitized
previously.  They just weren't aware of it.  It surprised us as well.

		Patch testing was conducted between 1.5 and four months before any
rote testing was done so there quite a lot of time had gone by.  And Dr.
Goudrall (phonetic), who is here with me in the audience, recalls that
the nurses asked before the rote started whether the patch test site had
healed.  And the answer was yes.

		Exponent (phonetic) was the primary designer of the study.  Dr. Fowler
provided input.  And then with regard to the use of only one physician,
I have been involved in both Nethercutt study and there was a 1999
Fowler study in which we used multiple physicians and those studies,
though, weren't rote so they didn't have to be there every single day.
They just came in for patch test reading.

		And what we found was great consistency in the way the different --
two different physicians read the same result.  That was a patch test
and this is a rote.  So it's different.  But we just didn't think it was
feasible to get another physician to come in and do this at the same
time with the potential exception of other dermatologists that work in
that practice.  But we didn't include that.

		The loading of chromium in the Phase One patch test, we used the .25
percent potassium dichromate but we didn't weigh the Finn chambers
before they were applied because it was the standard patch testing
approach.  And so we weren't really thinking about that specific aspect.

		In researching Finn chambers, they make eight millimeter, 12
millimeters, and 18 millimeter Finn chambers.  Most patch testing, the
vast majority is done with eight millimeter Finn chambers.  Those are
much -- they are smaller, obviously, about half the diameter or half the
surface area as the 12.

		And in part because they test 65 to 100 chemicals all at the same
time, so they need not very much -- you know they use a little bit of
area.  And also I understand from Dr. Fowler they are a little less
expensive.

		We used the 12 millimeter because Dr. Fowler felt more confident that
he could judge the difference between an irritant and an allergic
response with a larger exposure area.  So that is why we did the 12
millimeter.

		With regard to the ethical issues identified by Mr. Carley, you know,
I guess I apologize for the confusion that was generated in those
reports.  We did submit the IRB stamps documents ultimately.  We had
included them for just typographical reasons.  We had retyped them so
the page numbers would be right of all things that now seems rather
silly.

		There were clearly things that needed to be revised in the draft
protocol that EPA reviewed in April.  And I believe that was rectified
by the IRB review.  They made a lot of changes in the important percent
that we wrote it completely.  So many of the things were modified by the
IRB with regard to ethical issues.

		And with regard to the benefits of society, you know, we did -- the
potential benefit associated with the less use of copper, less
introduction of copper into the environment was really portrayed as a
potential secondary benefit.  And, you know, there is about -- more than
50 million pounds of copper is used in treated wood in the United States
annually.  So there is a tremendous amount of copper that is put into
the environment in the form of treated wood.

		Some of these wood treatment chemicals contain 75 percent copper.  So
using a chemical that has half that much copper,, you know, potentially
could be beneficial.  Like I said, it is something that we put in there
for EPA consideration.

		Steroid cream was offered to all of the participants who had a
reaction but none of them wanted any cream.  So it turned out to really
not be a significant issue.  Perhaps maybe these are people that have
dermatitis so the small reaction that they observed was not anything
that significant.

		I know that Dr. Fowler is very sensitive to the requirements of HIPA.
And if there are specific questions with regard to whether or not HIPA
was violated as part of this study, I know he would like the opportunity
to reply to them and I won't attempt to do so because I'm not a
physician.

		So feel free to ask any questions.

		DR. FISHER:  Thank you very much for such specific responses.  I think
both your presentation and your responses were --

		DR. FISHER: Okay, and then Rich.

		DR. CHADWICK: Just sort of following on to what Sean was asking, what
is the relationship between Exponent and Dr. Fowler's practice?  Is
there any corporate entanglements?

		MS. PROCTER: None whatsoever.  They are a separate entity.  We hired
them as a subcontractor.

		DR. CHADWICK: So none of Dr. Fowler's research nurses or clinical
nurses or administrative people are part of Exponent?

		MS. PROCTER: Correct.

		DR. CHADWICK: Exponent is entirely separate as I understand then,
except I guess there are some relative relationships or not?  No?

		MS. PROCTER: There is no relationship other than the fact that we
subcontracted with them to work on this study.

		DR. CHADWICK: Okay.  So basically as I understand the role then,
Forest (phonetic) - if we come back to the FDA model in drug development
and so forth, Forest is the sponsor, Exponent is essentially a contract
research organization then, and Dr. Fowler and his practice are the
site, the investigative site and the investigative site investigator?
Would that be -

		MS. PROCTER: I think that that is a relatively accurate
characterization.  Exponent is a consulting firm that does engineering
and scientific consulting.  So we're not more of a traditional entity
that would manage research.

		DR. CHADWICK: Okay.  And then you said on about the second or third
slide that you had this in house study that you were going to do but
didn't do.

		Now as I understand it, that was really a sort of proof of concept, is
it going to work or whatever.  But that was not done at all?

		MS. PROCTER: Yeah, it was actually my idea.  I thought it would be a
good idea to see if we were administering the right amount of solution,
if it would run all over the arm, what were the practical implications
of this.

		But it turns out you can figure that out with water as well, so we
didn't need to do it.  And then we were going to try to administer
chrome, and then wipe it off with wipes, but the wipes were contaminated
with copper.

		So we just decided that it was a bad idea, and my boss encouraged me
that it was a bad idea.

		DR. FISHER: Richard.

		DR. SHARP: I'm going to just follow up on a couple of questions I
posed to the EPA group.

		The - it seems as if the load on the skin during the patch test was
higher than any of the open application loads, but we're not quite sure
what it was.

		MS. PROCTER: That's a correct interpretation.  The fin chambers are I
think the predominant way of doing patch testing in the United States.
An eight millimeter fin chamber holds I believe 15 microliters of
solution.  If you calculate the math that gives you a does on a typical
fin chamber that is administered somewhere around 25 micrograms per
centimeter square.  And this is patch testing that is done when people
come in with allergy all the time.  People who are not allergic to
chromium; common clinical practice.

		We use a 12- millimeter fin chamber which can hold more chromium than
an 8-millimeter fin chamber, and based on the manufacturer's
recommendation we calculate a dose from that that would be around 45 -50
micrograms per centimeter square.

		So the larger fin chamber would hold more chromium, and then the mass
per area would be larger.

		DR. SHARP: Okay, so if that is the case, if the match per area in the
patch testing for this study is greater than what is in the NACD
database, couldn't that explain why you had more two plus and three plus
reactions?

		MS. PROCTER: Potentially, yes.  We did examine that in detail in the
study, because what we did was, we went back and looked at what the
original patch test grade was for these individuals when they were first
patch tested with 8-millimeter fin chambers.

		The vast majority of them had no change; they had exactly the same
response as they did before.  Also keeping in mind that 26 people, or
approximately 30 percent, who were patch tested with an 8-millimeter fin
chamber, when repatch tested with a 12-millimeter fin chamber didn't
have a positive reaction.

		There is some variability with response over time, clearly.  Of those
who had a different response, who didn't have the same response with the
eight and with the 12, a few had a higher response with the eight, but
more had a higher response with the 12.

		So it's the situation where the data are not perfect, but if you look
in the report there is really detailed information on that.  But we
think of that, it's an important consideration when calculating that,
because of the great sensitivity to what, a 10 percent response level is
to the people in your population.

		So that was one element of the study that would be nice if we could
obtain it, but it was done.

		DR. SHARP: And a follow up to that then, since the adjustment to the
empirical findings of this study were done with this national North
American database, you obviously have that data base.  EPA said they did
not, but you must have it, right?

		MS. PROCTER: Actually Dr. Fowler being the president of the North
American Dermatitis Group calculated for us the percentage of each of
the responses, and he gave us that information, and he put it into our
report.  I don't have the database, but he has access to it.

		DR. SHARP: I guess I am just raising a kind of question about
representativeness.  The report refers to it as a representative of the
general U.S. population.  It in fact, doesn't it, the data collected
from a certain number of relatively small number of dermatologists who
do patch testing.

		MS. PROCTER: Perhaps Dr. Mybok (phonetic) can explain further.  But
there I believe are 14 members, and I don't know how representative they
are of dermatologists.

		I know that Dr. Fowler, a lot of patients that participated were, he
was not their primary dermatologist.  They were referred to him for
testing, so they came, some of them quite long distances, to be patch
tested by hand.  And then they returned to their regular dermatologist
for followup.  And that is one reason why he has a very large database
of information.

		But I'm not sure if it's representative.  I think there is about, I
know in the most recent publication there is almost 6,000 people who
were patch tested and their results incorporated into the database.
It's just that not very people react to hexavalent chromium.  There is
only less than 500 for that time period, that had a reaction to
hexavalent.  It's a relatively rare allergy in that regard.

		DR. SHARP: Have you visited the North American Contact Dermatitis
Group website recently?

		MS. PROCTER: No.

		DR. SHARP: It struck me as funny.  It's run by somebody in Denmark,
and it was last updated by someone in 2001.  So I guess they are not
really web people.  So I guess they are not really web people.  Anyway,
just an aside.

		You mentioned that you felt that this study would benefit workers.  I
wonder, given that workers have pretty different exposure experience,
what is the connection for you?

		MS. PROCTER: Well, for example, OSHA has updated the permissible
exposure limit, in fact the entire rule for hexavalent chromium.  And
they reviewed the dermatology literature, but identified that there was
a data gap in really understanding elicitation of dermatitis from
hexavalent chromium.

		And I think that what you could do for like a work environment is you
could measure levels of dust in a mass per are, or levels of liquid
chromium in different work environments, and then you could get an idea
as to whether or not direct contact with a piece of equipment could pose
a potential allergic response in individuals.

		So that's what I was thinking the potential application would be.

		DR. SHARP: Well, I guess we would expect those exposures to be much
higher than the dose range in this study.  So I guess you'd have to
extrapolate.

		MS. PROCTER: I guess it depends on the environment that it is.  For
most work I would assume you have to wear protective equipment.
Hexavalent chromium is well recognized to be highly irritating, so there
is a certainly amount of technical equipment that is required.  So I was
thinking more like secondary type exposure.

		DR. FISHER: I'm going to take one last question and we're going to
move, only because we're running so late.  I don't know why ROAT is so
exciting to us.

		Okay, Kannan.

		DR. KRISHNAN: The last question will be in two parts.

		(Laughter)

		DR. KRISHNAN: The control were all females.  Was it random,
intentional, or it doesn't matter?  You didn't comment on that.

		MS. PROCTER: No, they were all females, and it happened just because
those were the individuals who volunteered to participate from Dr.
Fowler's practice.  It would have been better to have a gender specific
match control.

		DR. KRISHNAN: And it's still not clear to me whether the original IRB
documentation or the untyped copies were provided to EPA or not.  I know
you addressed it and it wasn't clear to me.

		MS. PROCTER: They both were.

		DR. KRISHNAN: It was provided or no?

		MS. PROCTER: Yes, they were ultimately provided, they identified that
as well as several other things they wanted to review, including the
minutes from the IRB meeting.  And we hurriedly put that information
together and sent it in.  It would be  my team that I didn't include the
version with the stamp on it.  I was just trying to make the case
numbers.  So case numbers on these documents have to be 66 of 389, so
having it in the document allows you to do that, but it was not a good
choice in hindsight.

		DR. FISHER: All of the official IRB correspondence is scanned in the
supplement document.

		Thank you very much, and now Mr. Mayback - Dr. Mayback.  Were you a
doctor by the way?

		MS. PROCTER: No, I'm not.

		DR. FISHER: Okay.

		DR. MAYBACK: Madame Chair, colleagues, surely those of you who know me
know that I will be mindful of your gastrointestinal tracts and lunch.

		And also I think it is just fair for freedom of information and
equality to state that I am one of those five-day-a-weeker
dermatologists; not really, but I mean in theory I appreciated that
remark.  And I'm also one of those web impossibly disabled individuals
responsible but I will see that it is corrected.

		You know my young colleagues love the web, and they felt they had to
get it on the website, so we found some young guy in Denmark who really
wanted to do it, so that's why it's there.  But it's there; we will
update it.

		My point is very simple.  This panel and the agency has a very serious
responsibility.  I looked over my notes several months ago of the
extensive discussions of what allergic contact dermatitis is -- given to
the other group that has been referred to, and it was not as clear as it
should be.

		Point one: allergy as defined by classical immunology is growing all
around you.  The estimate which I cannot verify today is true but
probably is is that of all the chemicals submitted to the European group
that is reregistering reach one third of allergens.  What are we going
to do about that?

		Furthermore, now that we have even easier animal testing to work with,
the local lymph node assay, many chemicals that I deal with in my work,
and I have been a worker in the past, are allergens.

		Clearly we have to separate the left from the right hand part of the
brain, or the upper half and the lower half, a way of separating all
chemicals that can produce some type of an immunological type IV
response from those that can be appropriately and wisely handled to
subserve a function that one of the species on earth, the homo sapiens,
wants to do.

		The patch test is wonderful.  We've had it for 100 years.  We're still
advancing the science and the art, and it can be used for assessment of
what and how you are exposed to chemicals.

		But the open application test which we have been using slightly for 40
or almost 40 years in our first publication has in this particular study
as an exemplar for going forward, gives us a highly refined tool or
technique to determine what are the levels that are likely to cause
trouble.

		So I know all of you are tired, all of you are hungry.  But the
exercise that the sponsor of this idea, the agency staff working with
the sponsor, has really given us the largest and for all of its slight
flaws, the most elegant step forward to go to the hundreds of other
chemicals - fragrance chemicals, preservatives, you name it - will
eventually - because so many of them in the animal assays are
allergenic, gives us the chance to really refine how do you notify the
consumer of the chemical what is the level that is probably going to be
tolerated.

		That's all, have a good lunch everyone.

		DR. FISHER: Dr. Mayback, would you just name your affiliations and I
guess your tie to this database, because I am one of those people who
don't know you, and we need it for the record.

		DR. MAYBACK: Howard Mayback, University of California, San Francisco
Medical Center, San Francisco, professor of dermatology, long interested
in dermato-toxicology.

		DR. FISHER: Thank you very much.

		Yes, Dr. Lebowitz.

		DR. LEBOWITZ: I want to know what you think of the specific protocols
used by Dr. Fowler in terms of the - where the different doses were
placed, the intervals between the doses, and how they were read, et
cetera.

		Has that become a standard protocol that's used by allergic contact
dermatologists?  Or do you think that there are any questions about that
specific protocol that would affect our judgment?

		DR. MAYBACK: Well, Dr. Lebowitz, I really appreciate your asking me
the only question I might know something about.  That's a good feeling.

		Point one, it like so many other things that faces animal and man, is
a choice, and the science behind the choice is modestly well understood,
but the rationale of getting the job done, because we do some of this
work ourselves, is also understood.

		The further apart you spread them, the less likely you are to turn on
the hundreds of chemicals that circulate in your blood to produce what
we referred to earlier as excited skin syndrome.

		But if you really do only one level at a time the test goes on
forever, as far as I can see, which is as good a balance as I've seen.
The next time this is done I suspect that two years from now or whenever
it is, that people will probably randomize.  But compared to what we had
before, the Nethercutt study, we didn't have this data.

		So I'm sure the regulators who use that will be thrilled when this
becomes available.

		DR. FISHER: Lois.

		DR. LEHMAN-McKEEMAN: A question for you in regard to the
interpretation of the data in front of us.  And in particular, I'd like
to query your experience in the distinguishing of irritation and
allergy.

		Under this particular case where data were analyzed without the
irritation component considered, what is the most appropriate and valid
way to analyze these data?

		DR. MAYBACK: There again is no simple answer.  The simple answer will
be that it won't help us clinically that for 50 years now, the people
who preceded me and the generation going forward have received research
findings to simplify all of this.

		We get funding, and if I wanted to start another lab today I probably
could, to try to avoid using human testing.  Instead we do this all with
a blood test.

		And since 1963, that's the person publication you can occasionally
make it work.  But A, it's not quantitative; B, it's not clinically
interpretable; and C, even though we failed for 50 years it'll happen.

		But in the meanwhile the Procter family here chose to air on the part
- and I don't like to use the word conservative, radical, liberal any
more - but on a way that would give the regime, would make the chemical
look more allergenic than it is by including the irritation responses.

		But in the big picture, and looking at the data, it looks like that is
not a significant issue in the interpretation today.

		DR. FISHER: Gary.

		DR. CHADWICK: Just to clarify, are you part of the NAAB group?

		DR. MAYBACK: Well, for all of its horrible failures, including not
keeping its website up in Denmark, I am the father of it, and still a
member, yes.

		DR. CHADWICK: And as I understand there are 14 people?  How large is
this group?

		DR. MAYBACK: I think that is a good point.  I would like to say that
the country in which I have been raised and spent most of my time is the
most advanced country in the world dermatologically and in fact in a few
areas it's true.  But diagnostic patch testing and what you are trying
to do, setting rational levels of knowing what you are dealing with, is
a minor part of the American dermatological community.

		I would suspect that two little groups - one, the one that I founded,
the North American Contact Derm group, 12, 13, 14 people, you are
dealing amongst 300 million obviously a tiny microcosm.

		There is another group which was founded and is part loosely related
to this; there are about 300 of the 300 million people who do enough
diagnostic patch testing so that they belong to a little society that we
have.

		Now, when you compare that to Scandinavia, in Scandinavia, if I wanted
to be - say I was a real dermatologist, I have to have a year's
fellowship in learning how to do that.  We don't have this in the United
States.  Most of our people are just sort of self taught.

		However, and I know what you are driving at, we recently did an
exercise that nobody in this room unless they were the reviewers know
about.  We recently took advantage of the power of the computer to
identify isolated studies done in India and in Italy and ones that we
did in the United States to try to determine what is the proved
relationship of the frequency of positive patch testing in a normal
population, meaning not going to see a physician, to a general
population.

		It turns out that there are other institutional review boards of
various types, and there are now enough studies, enough bits of data,
doesn't help you with the sophisticated quantification in terms of dose
of a use test; it's just patch.  But there is not the - many people felt
for decades that you really couldn't use these specialized groups of
people that went in to see a physician to give you any hint of what goes
on in the general population.  But in fact when we tabulated all that's
available now, it's not a huge amount of data, there is not an enormous
discrepancy for many allergens.  Namely, the normal population has
within one order of magnitude the same level of patch test sensitivity
as the patients who see dermatologists or allergists.

		DR. CHADWICK: And then I think my last question can be answered
probably either yes or no.

		Do you have any connection with this study or with Exponent?

		DR. MAYBACK: No.  I know of Exponent's existence for many years.  Some
five or six years ago I shared with them all of the data we had on
chromate.  But I am not an active participant.

		DR. FISHER: Thank you very much.

		Are there any other public comments?  Yes?  Okay.

		MR. FELDMAN: Madame Chairman, members of the committee, thank you.

		My name is Jay Feldman.  I'm executive director of Beyond Pesticides,
which is a national nonprofit organization that works on review of
pesticide hazards and promotion of alternatives.

		We submitted a letter to EPA back in July that I hope you all have
seen, and then another letter on the 10th of October on this issue.

		I'd like to today address the issue of the societal benefit review
question which you heard about earlier.  In this case, in the case of
ACC, we're not satisfied with the discussion that you heard earlier, the
activities of EPA regarding societal benefits review, and we don't think
you should be either.

		This committee must answer the question we believe, is there a
potential societal benefit to the use of hexavalent chromium and ACC?
What is your process for evaluating this?  And where is EPA's analysis?

		In fact, based on the conversation or discussion we heard earlier, or
I heard earlier, I would say that EPA staff has an inherent conflict of
interest on this discussion and you the panel need an independent
assessment of the determination of societal benefit.

		And I don't say this lightly.  This is an agency or this is an office,
OPP, that is embroiled in controversy.  Nine thousand scientists have
challenged its process and substance on review under the Food Quality
Protection Act, including scientists associated with the American
Federation of Government Employees.

		The Inspector General issued a report back in August that raised
serious concerns about whether EPA's substantive review was adequate in
protecting human health as opposed to it meeting benchmarks for
timelines under the statue.

		And earlier a year or two ago the IG again issued the concern that
EPA's decisions were politicized.  That's why your role as an
independent outside committee is essential to this process, and we
submit going forward without an adequate societal benefit review, and
you did not get one earlier today, is a travesty, especially when we're
dealing with a chemical such as hexavalent chromium.

		Now our understanding is that the HSRB did not review the test
protocol prior to its execution, but is now in the process of doing that
ROAT study review, reviewing the analysis at this meeting.

		And I should mention, this issue of societal benefits is not an
existential question.  It is not an existential question.  This is not a
question fo when the study was done, but whether you , this committee,
this board, will allow EPA to rely on an unethical or ethical study - an
unethical societal benefits review process.

		This is not an existential question.  The question of whether the
societal benefits review process is an adequate review.

		I would like to note that from an ethics standpoint we believe that
the committee should also determine whether the study - or others should
determine whether the study - how and when there is disproportionate
risk in different population groups.

		I don't know what the situation is here, but if we're going to do a
full and fair review of benefits to whom, and who is tested, we need to
look at disproportionate risk to people of color, people of low
education, and people of low income.

		Human testing was never intended to be operationalized in a vacuum,
outside the context of societal benefit.  An outside panel such as this
cannot and should not rely - must rely on the highest ethical standards
which we believe have been violated in this instance.

		Now I say that turning to our October 10th letter in which we cite the
Nuremberg Code, as you know.  The scripts - quoting the experiment -
should be such as to yield fruitful results for the good of society
unprocurable by other methods or means of study, and not random and
unnecessary in nature.

		And as EPA stated earlier to you, believes that this process is too
complex, and that the factors are not easily equatable, then EPA is not
the entity to do this review, and certainly you cannot glean from a
statement like that that you were given earlier that the review is oh,
the best we can do, and therefore must accept it.

		Now, we are dealing with a situation where virtually all of those in
the wood preserving industry have withdraw the registration of chemicals
that include hexavalent chromium.  We have proven - we have proven, even
though EPA still after all these years of criticisms from the U.S.
General Accounting Office - or U.S. General Accountability Office - has
failed to adequately review benefits of pesticides, and in so doing
cannot come before this committee with a benefits analysis.

		But if you look at what the industry has said to you, the industry has
said to you this chemical has no societal benefit.  The wood preserving
industry can exist profitably, which is what EPA looks at, the benefits
to the industry.  The consumer can be served adequately.  And those -
somebody earlier referred to the marketplace determining societal
benefit, which I do not believe is appropriate for this committee to
embrace.  But be that as it may, let's say you take that position, the
marketplace has said we don't need hexavalent chromium.

		So alternatives exist and are widely used.

		We know already that hexavalent chromium is associated with adverse
effects.  We know it's a carcinogen for example, we know there are other
kidney and liver effects.  And certainly the data we have could suggest
when weighing the use of a human study, that this is totally
inapporopriate.

		The research may primarily benefit FTRL, but certainly does not
benefit society at large.   And again my closing comment on this is that
the process you've gone through and that I witnessed this morning,
hearing the discussion - I just saw the benefit review, and I have
certainly seen all the paperwork - does not constitute an adequate
societal benefit review.

		And I believe to meet the burden and the duty to protect human health
- my sister, my brother, my mother, my father, my wife, my cousins - the
people that might be engaged in these studies, to protect your family
and mine, you need to as a committee, as an independent committee,
receive an independent review, not from the EPA staff, but from an
outside reviewer.

		Thank you very much.

		DR. FISHER: Thank you.

		Are there any questions?

		Thank you very much.  Any other public comment?

		Now I have to figure out how long we should go for lunch.  Can we come
back in half an hour, 1:30?  I apologize for going through a long - and
I guess I will also suggest that when we come back, those who are the
lead - I think we've talked about this so much, I don't think we need a
summary from our primary and secondary, but to address the positive and
negatives, either one, and just get those points, because I think we've
really gone over this, for whatever reason.

		(Lunch break)

		DR. FISHER: Okay.  So we promise we are going to - I've asked anybody
who is commenting on the board, the primary and secondary reviewers, I
don't think we need a summary of the study.  We seem to have done that
pretty well.  And I think we should go over the strengths and weaknesses
and any recommendations that we might have.

		Then I think I will also suggest that we go with the science, we go
with the ethics, and then we have a discussion rather than asking each
other questions, because I think we did that also already.

		Okay, Richard?

		DR. SHARP: Okay, here are my thoughts about this.

		A clearly stated purpose of the study, a sample size was chosen as a
kind of - without a power calculation.  There was reference to the
Nethercutt study being about the same size, so I think it was an
investigator judgment that this would be adequate.

		It did seem to be adequate for their purposes of calculating MET 10.

		Repeat open application testing provides more realistic evaluation of
human exposures than does patch testing.  And I think that is an
important point that was underscored by Dr. Maybock.

		Use of mass per unit area rather than concentration is the appropriate
metric for dermal exposure study, so having - that is a good point of
this study.

		I thought that dose levels were thoughtfully constructed.  They
explained why they chose their doses and they provided a range.  I think
this was also - this was a very well written study by the way, whoever
wrote it.

		The first concern comes up with the recruitment of controls from
employees of the group doing the work.  And the fact that they were all
female, when it would have been very easy to have purposefully chosen a
control group that was representative of the treatment group.  I
consider that to be a deficiency in the study design.

		None of the controls had any allergic response, and only one had an
irritant reaction to potassium dichromate, so maybe it wouldn't have
made any difference.

		When I did look - I mentioned this already so I won't belabor it - but
when I did look at the data in terms of one plus ranking versus two plus
and three plus ranking on the sensitized group with the patch test, it
did seem that there was a difference between men and women, and yet
apparently the conventional wisdom is that there is not.  So I think
that is a point we should raise in our discussion.

		The distinction between allergic and irritant responses, I was
uncomfortable with because there were 22 percent of the treatment or
sensitized group had irritant responses and none of the controls did for
Copper Shield, and one did for potassium dichromate.

		While those numbers are small, so that could be by chance.  It wasn't
clear to me at this low level whether or not the distinction was made
effectively.

		Probably the largest issue that we should think about from a
scientific point of view is that all of the observations were done by
one individual who wasn't blinded, knew all the members of the control
group, knew all the people in the sensitized group, knew what doses were
placed where, and it's just human nature that some judgmental issues can
come in when you are using - particularly when you are using a
semi-quantitative or kind of a scoring system for these kinds fo
appearances on the skin.

		So I think that that is a major weakness of the study that there was
no independent way of spot checking even that work.  That was all done
by one person, and that person was very much involved in the study and
its outcome.  So I won't belabor that.

		And then I think that I have some - I have concerns about the use of
the North American Contact Dermatitis Group database for adjusting these
data.  We noted during the discussion earlier that the load on the skin
in the patch testing done for this particular study was perhaps about
twice as high as what would be done in the database data.  Can't say
whether that caused more three plus reactions or not.  Clearly Exponent
did a good job of trying to deal with this question, but I think in the
end there is enough uncertainty that the adjustment is - if you could
put confidence intervals around it, they would be awfully big.  So I
would probably not advise the agency to drop the actual empirical data
in favor of an adjustment of that kind.

		DR. FISHER: Thank you, Richard.

		Lois?

		DR. LEHMAN-McKEEMAN: In general I agree with much of what Dr.  Fenske
has already indicated.

		I think overall this is actually a fairly high quality study,
particularly in the open application design and the dose selection
rationale I think was indicative of reasonable judgment in study design.

		I also agree that the use of a single individual to review the arms is
potentially a weakness, but I don't see it as a major limitation to the
interpretation and use of the present data.  In some respects it does
provide some consistency, and with the caveat - and I'll digress for a
moment and say that my biggest concern with this study was the
investigators' inability to decide how to interpret the data.  That is
to say, seeing multiple METs calculated based on whether or not you used
irritation, it would seem to me that there should have been from their
familiarity with the data, a perspective on what was the most reasonable
thing to do.

		And so my recommendation is that the data including irritation should
be used in the final analyses, and if you do that, I'm less concerned
about the use of a single individual to lead all of this, because in my
own simple mind what I sense is that that means that anything from red
skin and up is actually being qualified as a response.

		So I think in that regard I tend not to feel that that is a major
weakness, again, withe the recommendation that the data from those
responses including irritation be used.

		And I would echo and actually reinforce the inappropriate use of the
historical database.  My own perspective in using historical databases
for things like spontaneous carcinogenicity rates in laboratory animals
is that they provide a very good qualitative comparison with which to
evaluate your present cohort.

		And so it's valid to use that data to say that the patients int his
particular study were seemingly showing more severe responses to
chromium.  But it ends there.

		It is really not appropriate to use those data in a quantitative way
to begin to normalize this data.  So it informs us as to the overall
responsiveness in a qualitative way, but it is in no way appropriate to
be used in the ultimate calculation of the MET 10.

		DR. FISHER: Thank you, Lois.

		Let's see, Kannan?

		DR. KRISHNAN: I guess I'm basically in line with what we heard from
our colleagues, and I may be repeating some of what we heard.

		In my reading it's scientifically sufficiently sound study to help
estimate a safe level for chromium six and ACC.  The current assessments
are the current MET 10 currently is derived from the Nethercutt study.
The present one uses the repeat open testing using the realistic
exposure scenarios, and these obviously enhance the scientific basis.

		And the rationale fo the study I thought was clearly spelled out.  And
the total dermal dose applied through this technique is much lower than
the RFD, and the dose selection was accordingly justified as well.

		I'm not so concerned about the pooling of the irritants with the ACD
response.  It think it's along the lines of what I learned as well.

		However I am also concerned about the treatment of the historical
data.  If with time people's sensitiveness or the response level has
changed, then lumping is not appropriate.  Because that is one of the
responses we heard.  I thought previously when they saw more of plus
one, now there is more of plus three, but then why compare one with the
other?  There kind of is a counter argument to that.

		If data do suggest a possibility of homogeneity, then maybe they
should be pooled before normalization instead of separating them out,
making the new data part of the old database if it's justified.

		And then do the normalization, rather than separating one and
comparing one with the other.

		I'll leave it at that.

		DR. FISHER: Thank you.

		Okay, if it's okay I'm going and ask Sean to start with the ethics.

		DR. PHILPOTT: Okay.  Of course one of the key aspects of whether any
study is fundamentally ethical is whether or not it is scientifically
valid to answer the question.  So I'm going to defer to my colleagues on
that part.

		I'm going to address just a couple of points.  I believe that Mr.
Carley's ethics review was quite in depth, and I agree with the majority
of the comments that you had.

		I just wanted to highlight a couple of key things.  I think with
respect to risk that really the study does represent minimal risk to
participants in terms of harms that may relate from exposure to the
compound.

		In particular you've got the exclusion of pregnant and nursing women,
even women who may not be aware that they are currently pregnant by
having them take an over-the-counter pregnancy test prior to enrollment.

		It also seems to me that excluding individuals for receiving
immunosuppressive or steroid medications, or have recent or concurrent
dermatological conditions helps also to minimize potential risks.

		Because you are using doses of hexavalent chromium for the ROAT that
are considerably less than is the standard exposure dose using patch
testing for skin allergies, and that the allergic response induced
really is as Dr. Liccione pointed out is similar to poison oak or poison
ivy.  And this really allergic contact dermatitis is generally mild,
particularly in  this case with limitation to one square centimeter
patches, and can be treated pretty easily with something simple like
calamine lotion or hydrocortisone cream.

		And the use of patch testing itself, I might point out, is considered
to be one of the generally accepted definitions of minimal risk for
contact dermatitis study.  So the fact that we are using doses
considerably below that should also qualify as minimal risk.

		It would have been nice as with the Nethercutt study they had used an
escalated dose approach to the testing, but I agree with Dr. Mayback's
comments that while that would have been ideal, that would probably be
pretty difficult to do and would definitely require some logistical
nightmares.

		I do have a couple concerns however regarding equitable recruitment of
subjects.  It appears to me as though the selection of the control group
was based primarily on a sample of convenience, and that should never be
used as a consideration when designing a study of this type.  It would
have been more appropriate since they had access to this data to contact
other patients of Dr. Fowler's who are known not to be sensitive to
chromium and invite them to participate.

		HIPPA concerns aside, I'd like to point out that informed consent
isn't a document.  It's not a period in time.  It's a process, and I
have some problems with the notion that there was this pre-participation
phone interview which collected some potentially stigmatizing medical
information such as immunosuppression, yet there doesn't seem to be any
documentation of verbal consent for the collection of that information.

		Ideally I would have liked to have seen at least documentation, the
people contacted by phone verbally consented to provide that information
prior to coming in for the initial screening by Dr. Fowler and his
colleagues.

		Another question that can be raised is whether or not the amount of
monetary compensation, which is up to $1,215 total, reaches the level of
undue influence.

		We could probably go around this table and everyone could come up with
a different answer as to what dollar amount would be undue influence.  I
don't think that there is any evidence to suggest that based on the fact
that you are asking individuals to travel to a dermatology clinic 13
times over a several week period implies that this level of monetary
compensation is - does constitute an undue influence, but some of my
colleagues my disagree with me on that.

		Regarding the idea of a noncoercion addendum for the control subjects
who were employees of Dr. Fowler, every time I see these they make me
laugh, because if the person can be coerced into entering the study,
they can be coerced into signing the piece of paper that says they
weren't coerced.

		So it would have been nice to have excluded the employees and once
again to have had a much more equitable selection of the control group.
However I don't believe that this particular deficiency makes the study
either fundamentally unethical, nor do I believe that there is clear and
convincing evidence that any of the deficiencies I've talked about could
have either resulted in serious harm or seriously impaired the informed
consent process.

		DR. FISHER: Thank you, Sean.

		Richard.

		DR. SHARP: Well, thanks, I don't have to add very much to that, so
I'll be very brief.

		My comments were twofold, that if you wanted to think about what were
the major places where the study might be faulted in some ways, or where
is it vulnerable to ethical criticism, I think that there are two
places.

		The first has to do with whether or not the researchers were
collecting some types of research information prior to having obtained
informed consent.

		There is still some ambiguities about whether or not that telephone
script was sufficient to qualify as a type of pre-consent or the first
step in that consenting process that Dr. Philpott is alluding to.  So
even though they may not have had that official signature on the form,
in some ways there was an implied or a presumption of consent there.

		The second question that came up for me was whether or not the study
might be vulnerable to critique on the grounds that it didn't have an
acceptable risk-to-benefit ratio for those control subjects.  And here I
think that different IRBs that might be asked to review a study like
this might actually reach different conclusions.

		So my own assessment of this is that there is room for considerable
disagreement, reasonable disagreements amongst IRBs that might be asked
to review studies like this.  I think that the IRB that looked at this
protocol clearly made decisions that were within the scope of what we
would call generally reasonable practices for IRBs.  So I don't think
that any of the ethical considerations reach the level that we would say
this was significantly deficient with regard to its treatment of ethical
issues.

		DR. FISHER: Thank you, Richard.

		Jerry?

		DR. MENIKOFF: I generally agree with the comments of my prior
colleagues.  I'll be very brief.

		Just in terms of informed consent, these are issues we've raised in
terms of other studies.  Firstly when it described the risk I thought
the consent form was sort of wishy-washy about you might, this might
happen to you.  In fact the study was designed in a way that they were
hoping that at least some of these people would have significant skin
reactions, and they should make that clear.

		And the second point - again we've made this earlier - the intent of
the study was probably the goal to allow more of this stuff to be used,
and the subject had a right to know that, as opposed to thinking that a
primary purpose of this probably was in fact to make it a stricter
standard.   That was highly unlikely to be the case.

		But by and large I think this study was relatively ethical, and
certainly doesn't meet the two standards for being declared unethical
that we are applying here with respect to retrospective studies.

		DR. FISHER: Okay.  So what I'm going to do is, I'll summarize what I
heard as the science, and then we'll discuss that if there are any
disagreements or amendments or corrections to how I said it.

		In terms of the strength of the study, it was a fairly high quality.
The purpose was clearly stated.  There was no power analysis.  The
investigators used their judgment, but the sample size did seem
adequate.

		The repeat open application is a better testing measure than the
patch.  They used an appropriate metric, and the dose level appeared to
be thoughtfully constructed and had a good range.

		With respect to the concerns, the recruitment of controls as
employees, and all female, was a concern, especially since the one plus
and two plus ranking seem to indicate a gender difference even though
the literature suggests there is no gender difference.

		The fact that all observations were by one individual who was not
blinded, knew the hypotheses, knew the doses, knew who was a control and
who was not, is not quality assurance, and could be problematic.

		This combined with the fact that there was - the distinction between
irritant and allergic response is questionable, especially since the
controls did not have the irritant response.  It is not clear at the low
level if this is a legitimate distinction, and a further concern was the
investigators' inability to interpret the data.

		So putting together the issue of a single experimenter observer as
well as the problems in distinguishing between irritant and allergic
response, then a more conservative and perhaps recommended way of
looking at the data is to combine the two so that as soon as there is
redness or something like that, that would be considered a sign of a
response or a potential allergic response.

		Another issue of concern was the use of the Northern database within
the normalization, how it was used.  The agency is advised not to drop
the actual empirical database based on this data.

		In addition there may have been an inappropriate use of the historical
database.  There was some argument that it is valid to use it
qualitatively to compare whether or not individuals are similar in terms
of cohorts, but not to use it quantitatively to normalize the data.

		And then was also the suggestion that maybe if in fact normalization
was desired, that the new data be incorporated into the older database
before normalization would occur.

		So that's what I think was said about the science.  Anybody have a
comment?

		Yes.

		VOICE: Just to reiterate that there was a difference in the patch test
method used in this study as compared to what was typically used in the
database, the 12 millimeter versus 8 millimeter, and it's arguable that
that didn't make any difference.  It's also arguable that it did.

		So I think it just raises the uncertainty associated with using that
database in a quantitative manner as an adjustment factor.

		DR. FISHER: Michael?

		DR. LEBOWITZ: My interpretation of combining the new data with the old
data was that if the old data were to be used at all what one could do
is add the new data to it, make it Gaussian, which is modeling and then
calculate the MET 10 percent from that.

		But that's just an option, and I'm not sure based on the other two
comments that you want to recommend it be used at all.

		DR. FISHER: I know there were suggestions for how to pool it, but it
does sound like because the patch dosing or whatever it's called that
maybe that would not be legitimate.

		Yes.

		VOICE: Dr. Krishnan will have the possibility of refusing these
databases, but I just think I lean much more strongly toward Lois'
suggestion that it's just simply not appropriate.

		You've got these data.  You did a study.  This is what it told you.
And if I do a study in my lab with a bunch of rats, and everything is
higher than it used to be, I don't go back to all my other lab studies
and mix - I'm talking about very objective data, which this is not.  I
think it's totally inappropriate.

		If the old data - I think we'd have to regard it as suspect even
though it's in a databank anyway.  If it's so reliable why did we need
to do this study in the first place?

		VOICE: May I?  Let me suggest that the wording should be that for
multiple reasons the old patch test data is not appropriate to use to
normalize the new data.

		VOICE: For the purpose of calculating a MET.

		VOICE: For the purpose of calculating a MET.

		Would that satisfy?

		DR. FISHER: Everybody?

		VOICE:   All of us are saying the same thing in different terms,
trying to look at the alternatives and so on.

		DR. FISHER: Okay.  So from what I gather, then, this is our
recommendation.  If we were to answer the question, the agency has
concluded that the study contains information sufficient for assessing
human risks resulting from the potential dermal exposure to which,
treated with ACC, containing hexavalent chromium.  And our response is
that it could be - our recommendation would be that it could be useable,
but we're recommending that the irritant and allergy - allergic
responses be combined as first evidence of a reaction because there is
no way to know when one began and the other ended; and that the data be
taken as is and not be subjected to normalization based on the old
database, because for various reasons it's inappropriate.

		Okay.  All right.

		DR. KRISHNAN: Again, we haven't really seen the old database in the
context of this report.  For the value.

		DR. FISHER: From an ethics perspective it seems that the study is
scientifically valid for the scientific benefit.  The risks appear to be
minimal to participants in terms of harm from the compound exposure.

		The exclusion factors were good and protective.

		The dose of hexavalent chromium was less than usual doses, and
allergic contact dermatitis can be usually treated.

		An escalating dose might have been ideal but difficult to do.  And
while people might disagree there is no evidence that the compensation
was an undue influence.

		Some of the ethical concerns were subject recruitment.  This was a
sample of convenience that was employees, and it might have been better
to have other patients of Dr. Fowler's for more appropriate controls.

		Prior to consent, we are unable to determine whether or not the
telephone script was appropriate to appropriately inform individuals for
the type of information that they were providing over the phone.  The
informed consent could have been more straightforward with respect to
risks.

		And to risks given that risks were anticipated - not risks, but
reactions were certainly anticipated.

		I don't think we place much value in the noncoercion addendum as
evidence of lack of coercion for reasons that Sean spoke about.

		And there is some concern about a lack of risk-benefit independent for
control studies and for the other studies, which I think is something
that is becoming more popular in terms of the component analysis that we
might recommend more protocols that are going to be coming out, that the
risks and benefits to both groups need to be evaluated separately, and
not just combined.

		So based on that it appears that the ethical recommendation would be
that there is no evidence that the study was either fundamentally
unethical, nor that there were significant deficiencies that could have
resulted in harm to the participant or deficient informed consent.

		Any discussion?  Okay, that's our recommendation.

		VOICE: May I just make one slight change to the recommendation?  I
don't think it's that the control might have been chosen differently; I
think it should have been chosen differently.

		It's not clear that given that we have the study before us it makes a
demonstrable difference in the outcome.  But if it were to be designed
now I don't think it would be acceptable.

		DR. FISHER: Right.

		VOICE: In other words would you want to say that there should be more
controls?  And better gender or demographic mix or something?

		DR. FISHER: Well, I think we've made it as a criticism.  Whether it
should be better, it's a study that was already done.

		I think the criticism is there, I think the ethical issue part of it
is really the issue of coercion, because they were employees, and we're
not saying they were coerced.  But there certainly was the potential
there that is not remedied simply by asking them also to sign a
noncoercion form.

		I don't think we take a vote.  What do we do?  Are we done?

		Okay, so any other comments?  We have a consensus.  Yeah.  Okay, very
good.

		We're on to insect repellent, and I don't think I'm going to give my
little spiel -- is over so we're not redundant either, if that's okay.

		But clearly if there is an important question, something you think you
want clarification right away, then just let me know.

		All right.

	SCIENCE AND ETHICS OF IR3535 INSECT REPELLENT

	PRODUCT EFFICACY PROPOSALS

		MR. CARLEY: Thank you very much, Dr. Fisher.

		My colleague, Dr. Clara Fuentes, and I will present these two
protocols.

		These - I will kind of wrap up what's happened since the June meeting
where you saw them before.  The subtitle of that is how Scott Carroll
(phonetic), John Carley and Clara Fuentes spent their summer vacation.

		And then we'll do the - present the science and ethics reviews of each
of the two protocols and for the first time in our presentations to you,
this time we have done an integrated review, where we both used the same
framework and resolved any differences, so that we didn't have to both
characterize the design of this study and things like that.

		In that way the review framework no longer simply defers on the
science questions as you have seen and the ones that I've done in the
past.

		Ah, Dr. Clara Fuentes has officially arrived along with her name tag.

		Bottom line: the protocols that were submitted by Dr. Scott Carroll,
of Carroll-Loye biological Research describe two studies of repellent
efficacy of three new formulations of IR3535 which is an already
registered active ingredient of demonstrated repellent properties.

		These are the protocols that you saw in the June meeting, but they
have been very substantially revised since that meeting.  EPA now thinks
they meet the appropriate scientific and ethical standards, and we seek
your advice.

		What's happened since June?  Well, immediately following the board
meeting in late June, Dr. Carroll substantially expanded and revised the
protocols based on what he heard at the meeting, and resubmitted them to
us and to the IRB informally a couple of weeks later.

		Then while he was working on that we took what we'd gotten from the
presentation of criteria, and we substantially revised the framework
that we were going to use for assessing protocols.  So we asked a lot
more questions in within the same basic headings that we had adapted
from the Emanuel (phonetic) in the first place.

		And what we've gotten to with this expanded framework is quite distant
from the Emanuel original, because we've done a lot of adapting and then
further adapting.

		So I think it is best thought of now as EPA's current iteration of the
framework for assessing protocols.

		We applied that revised framework to the resubmitted protocols and
turned around the preliminary reviews that we got back to Dr. Carroll in
August.

		We used as I say the new framework for these reviews.  We will discuss
with you tomorrow the framework itself in the context of the draft PR
notice.  So we should defer that discussion, if you've got some issues
with the framework, until we're looking at it tomorrow.

		After we turned our preliminary reviews of the revised things back to
Dr. Carroll, he made some more changes and then formally resubmitted the
protocols to the IRB and to the California Department of Pesticide
Regulation.

		As you will recall from the discussion in June, there is a California
state regulation that requires that any pesticide exposure study
conducted within the state of California has to be approved in advance
by the California Department of Pesticide Regulation after IRB approval.

		The IRB then reconsidered the protocols that were submitted, and
responded to Dr. Carroll's request for all of the documentation of the
IRB business by sending all of the records of the meetings at which the
protocols were considered, but they sent their procedures, which are
among the requirements of 1125 for documenting your work, they submitted
their procedures directly to us under a claim of confidentiality.

		And we will discuss that, the general phenomena of claims of
confidentiality, in more detail now.  I don't want to digress to address
it now.

		Then Dr. Carroll pulled together all the information required by
261125 except those IRB procedures subject to the confidentiality claim;
resubmitted the packages to us; we updated our preliminary reviews,
considered the last stuff, and tried to get all of this in by the
deadline for submitting stuff for your consideration on the CD.

		There was about a week there in early September that was so busy we
may have overlooked some details.  We don't really think of your as
proofreaders, but you may have caught some things we didn't.

		So that's how we got to where we are now.  And we're now going to talk
first about the study labeled EMD-003, which is a laboratory test of
tick repellency, and here's what we sent you, and here is what our
review is based on.

		There is a transmittal document.  It happens to be addressed to me
personally, but it was the one by which Scott Carroll sent the bundle
in.  Then the protocol.  Then a few corrections to typographic mistakes
a day or two later.  Then we have in this package training materials for
subjects covering tick handling, and how to spray your arm kind of stuff
so they could figure out what a typical consumer does was.

		We have the IRB review documents of this revised protocol.  We have
the IRB's correspondence record.  In every case both protocols were
submitted, both responses returned at the same time, so there is only
one correspondence record that applies to both protocols.

		And then we have our science and ethics review of the study.  And
Clara is now going to continue with a discussion of her science
assessment.

		DR. FUENTES: Good afternoon.

		This test is in the revised protocol, this test is a preliminary study
to determine the amount of drug that will be applied for the efficacy
testing both the studies, the tick and the mosquito studies later on.

		The safety - I want to point out that the safety and composition of
the test material is known, and the composition is confirmed by
analytical methods prior to and following the efficacy studies.

		The active ingredient is of low toxicity.  The inert ingredients are
in the 4A and 4B EPA list, which are considered relatively safe
ingredients.  Other ingredients are cosmetics.

		The protocol also includes MSDS documentation.

		The products are produced under good manufacturing practices, and the
ingredients are not pre-active.

		The materials are kept in Dr. Carroll's lab with a chain of custody
documented.

		The repeated applications during the dosimetry study are of short
duration, and the test material has been tested on animals for toxicity.
 This data will be submitted to EPA for registration later on.

		The sample size of 12 subjects, replication for three rips (phonetic)
per treatment is justified, and I will be talking about that later on in
the presentation.

		Each subject is his own or her own control.  The variables measured in
this study would be the forearm skin surface; self dosing behavior of
the subjects; and the weight of the test material that is applied.

		The dosimetry data will be analyzed using the Freedman (phonetic) to
weight analysis of variance test.  The dose will be calculated on the
basis of treated skin surface area.

		The objective of this laboratory study is to measure the efficacy of
three formulations proposed for registration against Ixodes scapularis,
ticks, which are a vector of Lyme Disease.

		The end point will be the average time to repellency break down
expressed as the average time of complete protection from application of
the formulation to the first confirmed crossing, with the purpose to
fulfill EPA's registration requirements for new products that claim
repellency against human health tick pests.

		The study now includes an initial training and steps to determine the
average amount of material applied, and that's what I just said about
the dosimetry study.  And this calculation of dose tries to estimate the
typical amount that will be applied by consumers.

		The sample size in this study, 10 replications for treatment, and the
sample size as I said before is justified, and I will be talking about
it later.

		The protocol also discusses the rationale for controls.  Positive
controls are eliminated from the study design, and the negative controls
are replicated to 10, and they are used mainly for prescreening of the
tick (phonetic) questing behavior.

		The negative controls are an untreated arm of the same treated
subject.  It's treated identical  to the same way as the treated arm is
treated, except that the negative or untreated arm does not have the
formulation present.

		And the negative control having no formulation matrix without the
active ingredient is not used because the protocol also explains that
it's beyond the scope of the study, and so basically the negative
control is just an untreated arm.

		The negative control in this study are not used for statistical
comparison of treatment needs, because that is not the objective of the
test.  All treatments are randomly and blindly assigned to subjects.

		The statistical analysis for estimation of dose rate in dosimetry
study and for data determination of the complete protection time in this
study, it's the data is analyzed using the descriptive statistic, the
mean within 95 percent confidence interval.  It will be reported also
with the associated standard deviations as a measure of uncertainty.

		So the principal changes in the protocols are, in the revised
protocols, are, the incorporation of the general description of
recruitment and informed consent which was formerly in a supplemental
protocol, CL 001, now is part of the revised protocol.

		The revised protocol also adds a new preliminary phase to establish a
typical consumer dose in the dosimetry study; expands discussion of
risk, risk minimization, and benefits.  The protocol also expands
discussion on sample size and the statistical concerns.  Change primary
end point to time to first confirmed crossing; eliminates positive
controls; and incorporates training materials for subjects in the
dosimetry phase and in handling ticks.

		So in response to the comments made by the board originally,
specifically they revised the protocol as to the following points.

		The inadequacy of controls: for that the positive controls have been
eliminated; the number of untreated arms is a rate identically the same
as the treated arm on the same subject.  This type of design reduces
among subject variability.  And the use of the matrix formulation with
the active ingredient as a negative control is not used but it's also
explained why in the protocol.

		The negative arms are used for preselection of the active ticks prior
to their exposure to the repellent, and the untreated arms are not used
for the study because it's a difficult comparison of treatment means.

		The results are summarized, and expressed, as a mean protection time
within 95 percent confidence interval with the associated standard
deviations as measures of uncertainty.

		The rationale for sample size, which is explained this cost and
justifies the revised protocols, is that the sample size reflects a
compromise between financial and ethical concerns.

		The sample size is hard to predetermine without knowing the
distribution of the outcome values.  EPA guidelines recommend six
replications based on adequate performance of most products.  Six
replications have been widely regarded as sufficient to show statistical
significant difference between means, at a P value probability of 5
percent significance level.

		That replications does likely improve accuracy in estimation of the
population mean, and each additional subject beyond 10 increases
precision of the mean progressively.

		The upgraded protocol provides justification for this and also cite
literature supporting this argument.

		In compliance with the scientific standards, this protocol is likely
to yield scientifically reliable information, because it satisfies the
following scientific criteria from the framework recommended by the
board.

		The study would produce important information that cannot be obtained
except by the amended research, and also because the formulations being
tested have not been tested before.

		The study has a clear scientific objective, and explicit hypothesis,
and the study design, subject selection, sample size, dosing, quality
assurance and quality control should produce adequate data to test the
hypothesis.

		And this study is conducted under good laboratory practices, and it
would be audited by an independent quality assurance unit.

		And that concludes my presentation up to this point.

		MR. CARLEY: Continuing with the ethics assessment of the same
protocol, which is the lab study of tick repellency.

		The proposed research would test the efficacy of three new
formulations of the previously registered active ingredient, IR3535.
Effifacy testing is, as Claire pointed out, an EPA requirement for
registration of these products, and the requirement applies to the
product as formulated and sold.

		The changes in these formulations from previously registered
formulations are to make the products cosmetically more appealing to
users, and therefore, to make users more likely to use the product.  So
the efficacy question is not about the active ingredient.  And therefore
there is no reason to test the efficacy of the matrix exclusive of the
active ingredient.

		The question being investigated is whether the product as formulated
works to repel ticks.

		It's important to understand the efficacy of these new formulations,
because consumers rely on the fact of EPA registration to inform them
that it's likely to be effective.

		Subjects were recruited among communities of friends, neighbors and
scientists near the laboratory, and that gave us all some concern when
we looked at these protocols before.  This is an area that has been
heavily beefed up.  There are explicit exclusion factors applying to
children, pregnant or nursing women, those in poor health or physical
condition; those unable to speak in English; and particularly important,
students or employees of the principal investigator.

		Anyone who is dependent on him either academically or for employment
is excluded as a candidate to be a subject.

		Bottom line assessment from our side is that none of the subjects who
met these criteria would be from vulnerable populations.

		Now the same is, because of these factors, not perfectly
representative of the broader population that is ultimately likely to
use tick repellents.  There is not much that can be done about that,
because the broader population that will use tick repellents is going to
be likely to include, children, pregnant and nursing women, people who
are compromised in some other respect.

		So as far as we can tell a more perfectly representative sample would
be neither practical nor ethical to use for this sort of research.

		The risks were characterized qualitatively - remember this is a lab
study with ticks - as possible irritation, headaches, dizziness or
temporary stomach distress from exposure to the test materials.  That is
risk category one; it is the materials themselves.

		And the other characterization was possible exposure to
arthropod-borne disease.  There were three general categories of
exposure characterized - or of risk characterized in the mosquito study
which I - the third one being exposure to arthropod bites.

		And I was interested that in this presentation the qualitative risk of
disease was identified but not the risk of bites.  And that seemed to me
like maybe that was backward.  These are lab-reared populations of ticks
that are disease free, but then it doesn't make much difference either
way because the probability of these risks is characterized quite
accurately as extremely small.

		Skipping over the first bullet, what we know about the materials is
that they are very unlikely to cause effects.  But going to this
question of the risks of bites or disease, there is - we're using
disease-free ticks, and the design of the research is such that the
ticks are going to be gone long before they have time to embed
themselves.

		So the probability of either of those two categories of risk is
negligible.

		The risk-benefit ratio, there is no direct benefit to subjects, and
there is - I agree with the characterization in the protocol that there
is a low increment of risks to subjects.  And that it is offset by the
potential societal benefits of adding an appealing and effective
repellent to the means available to consumers to protect themselves from
tick bites.

		The ethics review, the IRB, this is the same IRB, Independent
Investigational Review Board incorporated at Plantation Florida, it is
the same one that had previously looked at the earlier generation of
these protocols that you saw in June.

		They reviewed and approved the protocol in the informed consent
materials.  They are independent of the sponsors, EMD, and the
investigators, Carroll-Loye and the IIRB is registered with OHRP.

		I will mention in passing that their registration lapsed in June, and
according to the OHRP website there is nothing to indicate that it's
been renewed.  I haven't been able to verify exactly what the status of
that is.

		The protocol includes a very extensive, and I found it entirely
satisfactory, description of the recruiting and consent processes.  As
Clara mentioned, this is based on the material that was formerly in the
supplemental protocol.  It's now been incorporated into the specific
protocol, and considerably expanded and clarified.

		All of the IC materials which used to be separated have also now been
incorporated into the protocol as approved by the IRP.

		The methods proposed for managing information about the prospective
and enrolled substances, by subject, will ensure their privacy is not
compromised, and that includes information about the results of the
screening pregnancy tests.

		Subjects will be free to withdraw at any time, and will be reminded of
this at several points in the course of their initial discussions and
recruitment, and then when they come in for the dosimetry study, and
again when they come in for the actual efficacy study.

		And medical care for research related injury will be provided at no
cost to the subjects.

		The applicable ethical standards for this protocol, it's a proposal
for third party research involving intentional exposure of human
subjects to a pesticide with the intention of submitting the resulting
data to EPA under the pesticide laws.

		Therefore the primary ethical standards applying to this research are
40 CFR 26 subparts K and L.

		K of course includes the characterization of everything that needs to
come in with the protocol.  It also is the part that extends the
provisions of the Common Rule to third party data.

		L is the prohibition against intentional dosing research with children
or pregnant or nursing mothers.

		A point by point evaluation of how this protocol addresses each of
their requirements in subpart K, section 1125, and L, section 1203, and
the additional criteria that were recommended by this board in their
June meeting appears as attachment one to the EPA review of this
protocol.

		In summary we concluded that all of the requirements of 26.111
concerning the basis for the IRB judgment that it was acceptable; 1116
addressing the requirements for the elements of informed consent; and
1117 concerning documentation of informed consent; all those
requirements are satisfied.

		We concluded that the submission to us was complete in the sense that
all of the requirements of  26.1125 were met.

		You have seen everything that we got on this with the exception of the
one item, the procedural package that was claimed to be confidential.

		At the June meeting the ethics subcommittee recommended specific
attention to NAS recommendations 5.1 and 5.2.  We reviewed this protocol
against the specific elements in those items, and concluded that they
were satisfied as well.

		Charge questions, which I think we will skip for now, because we are
going to keep going and run through the other protocol.  The charge
questions are the same except for the substitution of the names of the
protocols.

		I do want to say at this point, be sure to understand that subpart M
does not apply to the review of protocols.  It concerns only the
requirements for documenting conduct of completed work that is submitted
to us in the form of a report, such as the red study that we were
talking about this morning.

		K and L are the only subparts that apply to protocols.

		And now we'll move on to the mosquito study.  This is what our review
reflects.

		It's a similar set of data, differing only in the penultimate bullet,
the California DPR approval of the EMD-004.  This was in hand at the
time that dr. Carroll sent us this package in early December, and the
CDPR approval for the other study was not yet in hand.  It's come in
since.  I think he sent it to the docket, and it is in any event while
it's a requirement of California that that approval be in hand before
the work begins, it's not specifically a requirement of our rule or
something that you have to have to have a complete data set.

		And now Dr. Fuentes again.

		DR. FUENTES: This is a field study for testing the repellency of three
formulations against wild populations of mosquitoes.

		The test sites are in California, central valley; and Florida Keys.

		The end point is the average duration of complete protection time,
from time of application of the test materials, to the first confirmed
bite.  The first confirmed bite now has been modified.  The concept of
biting has been changed to landing with intent to bite in order to
reduce risk from being bitten in the field.

		The study includes preliminary training in the lab for test subjects
to learn how to handle mosquitoes prior to exposure in the outdoors.
Subjects will be randomly and blindly assigned to the treatments.  There
will be three treatments replicated 10 times.

		The subjects will be arrayed in pairs in order to facilitate
observations.

		Negative controls are not replicated beyond two.  These are not used
for a statistical comparison of treatment means, and as a way also to
reduce exposure in the field.

		These two untreated subjects are experienced in field biology and
entymology, and they will quantify the biting pressure in the field.
There are no negative controls using the problem matrix, as John already
explained.  And the exposure to mosquito is limited to one minute every
15 minutes.

		The threshold for biting pressure is one  landing per minute as
recommended by the EPA guidelines.

		The test site, as I said, of California central valley and the Florida
Keys.  The expected wild population of mosquitoes found in these areas
are the species Aedes vexans, Ochlerotatus melanimon, Ochlerotatus
taeniorhynchus, and Culex pipiens  whatever, I know who they are, but I
can't pronounce them.

		The variables that will be measured are the biting pressure, the
number of landings with intent to bite per minute, and the first
confirmed bite, and the time to first confirmed bite, which is also the
protection time or complete protection time.

		The test results will be analyzed using discrete statistics, then
treated controls are not used for comparison with treatment means, just
for measuring the biting pressure in the field.  And the measurement of
uncertainty at a 95 percent confidence interval of a mean, and as
associated with standard deviations.

		The principal changes in the protocols, the revised protocol now, are
also the incorporation of the general description of equipment and
informed consent, which formerly was in supplemental protocol CLCS01.

		The revised protocol adds a new preliminary phase to establish a
typical consumer dose.  This is the dosimetry study explained before.

		It expands the discussion of risk, risk minimization, and benefit.

		It expands discussion of sample size and the statistical concerns like
the power of the test.

		It changes the frequency and duration of exposure to reduce risk of
untreated controls; eliminates positive controls from the design; and
incorporates the training materials for subjects in the dosimetry phase,
and also in aspirated (phonetic) landing mosquitoes, before going into
the field, the subjects will be trained in the lab using mosquitoes that
are free from pathogens, for them to learn how to handle them and how to
aspirate them before the subjects go outside in the field for the field
test.

		So in response to the comments made by the board before, the revised
protocol addresses the following points:

		The positive controls in terms of inadequacy of controls, the positive
controls now have been eliminated, and most of the relative protection
time measure of repellency has been eliminated.

		Two untreated subjects are used to monitor the biting pressure
following the EPA guidelines' recommendations.

		The dose supply is predetermined through the dosimetry study.

		The results are presented as an average period of complete protection
from time of application of the test material to the first confirmed
landing with intent to bite, which indicates the break down of
repellancy.

		The mean will be reported within 95 percent confidence interval, and
it's associated standard deviations for measurement of uncertainty.

		The rationale for sample size in this study is the same as the other
dosimetry and EMD-003.  The sample size represents a compromise between
financial and ethical concerns.  It's hard to determine without knowing
the distribution of the outcome values.

		EPA guidelines recommend six replicates based on the adequate
performance of most  products.  And six replicates have been widely
regarded as sufficient to show statistical significance at a P value of
less than five percent significance level.   Ten replicates is like an
improved accuracy in the estimation of the mean, and each additional
subject beyond 10 increases precision of the mean progressively.

		And as I said before the protocol includes citations from literature
supporting this argument.

		In compliance with scientific standards, this protocol is likely to
yield scientifically reliable information because it satisfies the
following scientific criteria, and these are taken from the framework
recommended by the board.

		It would produce important information that cannot be obtained except
by research with humans.

		It has a clear scientific objective and explicit hypothesis.  The
study design, subject selection, sample size, dosing, quality control,
quality assurance, should produce adequate data to test the hypothesis.

		And again I want to add that this study is also conducted under good
laboratory practices and standards.

		MR. CARLEY: And we're rounding the final turn.  This is going to go
fast.

		And this level of detail that's in this presentation there are very
few differences between the presentation for 003 and 004.

		There are no differences in this area: we require testing.  People
rely on our regulatory reflection of the results of that testing.  And
this is a well designed test to serve those purposes.

		Again the exclusion and inclusion factors are good, and they address
the concerns about people who might have been dependent on the
investigator.

		But one of the results of this is that we don't have a perfectly
representative sample, but it would be either or both impractical or
unethical to include a fully representative sample.  I think this is a
good enough one, a typical enough one, to use for the purposes of a
study.

		On the qualitative risks, there were three listed for this study,
including the one in the middle, exposure to biting arthropods, which
was not listed for the lab tick study.

		Again, the really significant point is that the probability of any of
these risks is extremely small.  Appropriate steps have been taken to
minimize both exposures and accidents.

		One of the things that Clara mentioned was that the untreated subjects
in the field used to verify biting pressure would have two attendants.
What those two attendants are going to be doing is making sure there
aren't any landings that nobody notices so that those bugs get aspirated
before they bite.  So there's been some really good work done here in
reaction and response to your discussion in June to make appropriate
changes in the design to minimize the risks to all the players including
those who are not actually testing the material, but are just doing -
verifying biting pressure.

		There has been a new expansion with this training on aspirating
landing mosquitoes in the lab, so that they can expect to be good at it.

		Something that I forgot from time to time and had to remind myself of
when I was reviewing this is that once you get out there in the field,
the exposures are so short that you are not talking about having to
aspirate a flock of mosquitoes really fast.

		You are also not assuming that there is some efficacy to the
repellent.  Most of the time you are going to have no landings with or
without the intent to bite.  And it's only as the repellancy breaks down
that there are going to be any landings, and by putting the subjects in
the field in teams to watch each other with only just the treated
forearm exposed, there is a very low probability that people are going
to get bit.  And if they don't get bit they are not going to get West
Nile or whatever other dreadful disease these mosquitoes might be
carrying.

		Same calculus here, there is no direct benefit to the subjects, but
there is a very low risk to them, and a potential significant benefit to
society if we have another effective attractive repellent in the armory.

		These comments are unchanged from the ones I made for the previous
study.  These are also unchanged from the ones on the previous study,
and so are these.

		So we're getting down to the standard, same thing.  It's a proposal
for third party research, intentional exposure, pesticide, intent to
submit under the pesticide laws, so it's subject to subparts K and L but
not M, and we ran down everyone of those requirements in the appendices
to the review and concluded that all of the applicable requirements were
satisfactorily addressed, including all of the elements of the two NAS
recommendations, which now brings us to the charge questions, and you
can in your mind's eye read the same thing only changing all occurrences
of the character - no, not all occurrences - all occurrences of the
string, 004, to 003.  Then you'd have all four charge questions.

		Does the proposed research appear likely to generate scientifically
reliable data useful for assessing efficacy of the test substances?  And
does the proposed research appear to meet the applicable ethical
requirements of 40 CFR 26 subparts K and L?

		Oh, there is - please, back up, that one.  I had forgotten about this
one.

		This is something that we want your feedback on, how much of it comes
in this context, and how much of it comes when we talk about the PR
notice tomorrow, it doesn't really matter.

		But what we were trying to do is figure out how to meet both our needs
and yours by using this structure to pull bits together, and we want
some feedback from you on how well it worked.

		DR. FISHER: Thank you, John.

		Just so you don't leave, I think we may be getting to the PR guidance
today and combine those two questions.

		MR. CARLEY: I wouldn't dream of leaving before you all do.

		DR. FISHER: I know.

		Any questions?  Yes, Jan.  Jan and Lois.

		DR. CHAMBERS: Do you want to do 003 first?  Because my question is on
004.

		DR. FISHER: I don't think it matters.

		DR. CHAMBERS: Okay, I had two questions about the protocol.  One, this
is the mosquito protocol, and the study sites will be California and
Florida.  And the recruiting is really only described as I can tell for
California.  And I was just kind of curious as to how are they going to
recruit in Florida?  Or are they going to transport the California
people to Florida to test them?

		MR. CARLEY: I could speculate, but I'd rather not.  Is Dr. Carroll
going to comment?

		DR. FISHER: Carroll's here, so we'll leave that for his presentation.

		MR. CARLEY: If you would save that for him.

		DR. CHAMBERS: The other question I have, and there may have just been
a typo, there was a little confusion on correcting, on page 37 where you
describe complete protection time about the first confirmed light with
intent to bite, followed by another one within 30 minutes, and the
numbers just don't seem to make any sense in the example.

		And I'm kind of confused as to how this is going if those numbers are
accurate.

		So for example, light with intent to bite, one 20 minutes following by
another at 35 minutes is not confirmed.

		MR. CARLEY: That is corrected by one of the errata at one of the items
in -

		DR. CHAMBERS: The errata on this one was for ticks.

		MR. CARLEY: There was a correction sheet for each of the two studies.
And I spotted that same thing after we got the protocol.

		DR. FISHER: Can somebody just point it out so we have the answer?

		MR. CARLEY: Dr. Carroll, can you step forward?

		DR. FISHER: I don't need him to step forward.  I just want the
document that corrects this.

		VOICE: It was in the bundle that we sent to you.

		DR. FISHER: These are the corrections that came with -

		VOICE: Yes, the errata sheet for EMD-004 which is dated 14 September
speaks to the -

		DR. FISHER: The errata on the -

		VOICE: Let me read you the text as it should read on page 37.

		Complete protection time, CPT, is measured as the length of time from
initial application to the first confirmed crossing.

		DR. FISHER: Yeah, that's the thing.  It refers to ticks.

		MR. CARLEY: Dr. Carroll sent the correction labeled AMD-004, and he
corrected the tick study.

		DR. FISHER: But the errata and the tick study is also for ticks.  So I
think I know what it means, but it's inaccurate.

		MR. CARLEY: It needs to be fixed.

		DR. FISHER: Okay, let me ask, do you have something written, Dr.
Carroll?  Do you have your addendum that's written and the one we need?
No, I know that, and we don't seem to know where it is.

		Those are the errata on 003 and 004.

		DR. CARROLL: Well, there is a 6 October 2006 letter that says summary
revisions, mosquito repellant protocol EMD-004.  In the form of a letter
to Dr. Fisher.

		VOICE: What we have here, to the best of your knowledge, there is no
correct correction in the files.  There still needs to be a correction
of the original blunder, but it hasn't been fixed yet.

		DR. FISHER: Well, is it going to be possible to have that information?

		VOICE: This is really not important.  It's really procedural.  It's
already been defined for us.  This is only an example that happens to
have one wrong number in it.  So it's trivial.  Let's insist that it be
corrected.

		DR. FISHER: Jan, it is not going to be essential for your delivery?
Oh, okay, thank you.

		VOICE: I just want to make certain that I understand the dosimetry
link.  So this is going to include 12 subjects.  Are they different than
the subjects who will then be used in the efficacy leg of the study?

		DR. FUENTES:  Protocol said that it could be the same.

		VOICE: Okay.  And is it the intention that those same 12 would
actually serve for the dosimetry for protocols 003 and 004?

		DR. FUENTES: Well, the studies on dosimetry will apply to both.

		VOICE: Right, so you're effectively doing it once and it will provide
the dosimetry for both studies?

		DR. FUENTES: Yes.

		VOICE: That wasn't clear.

		There is, and this is perhaps a bit trivial, but in looking at the
dosimetry, I had a couple of questions particularly as it related to the
tick study, because the tick study is intended to be a laboratory study
understanding that the use is in the environment.

		But the way the dosimetry reads is, it says that it will be conducted
out of doors with a temperature greater than 57 degrees, and no more
than a 7-mile-an-hour wind, and so on and so forth.

		So from your vantage point is that adequate for interpretation of the
tick dosimetry given that that's a laboratory study?

		MR. CARLEY: Remember that the actual dosing in both studies is not
going to be done by spritzing from a can or pump spray.  It's going to
be done by pipetting a measured quantity and then smearing it around.

		The dosimetry study is designed to approximate the typical consumer
dose.  And the presumption is that a typical consumer applying repellant
whether against ticks or insects, is going to be outdoors with
temperatures above whatever, and not do it in a gale.

		So in that sense yes, we think that testing the - doing the dosimetry
phase which is entirely independent of the efficacy phase, doing the
dosimetry phase under those conditions is appropriate for its purpose
which is to approximate the typical consumer dose in terms of mass per
unit area.

		DR. FISHER: David, and then who is it - David, and then Kannan and
then Richard.

		DR. BELLINGER: I just had a question of clarification about 003.  The
phase two, where you and protocol say that the treatments will be
applied blindly.

		I wasn't clear on what blinding meant since everybody is getting the
same dose applied in the same way, what is blinded?

		DR. FUENTES: It explains in the protocol that nobody knows what is
being applied to them.

		DR. BELLINGER: Which of the three?

		DR. FUENTES: Yeah, which of the three formulations are applied.  There
is a coding of those, but it's not - the subjects don't know.  They
won't let them know.

		DR. SHARP:  You said they are all being applied.  They are not being
applied by the pump or the aerosol in phase two, but by someone with
latex gloves smearing on the skin?

DR. FUENTES: Yes.

		DR. SHARP:  What does it matter if they're blind?

		DR. FUENTES: No, blind to what treatment they are receiving.  You
know?

		MR. CARLEY: Your specific question: what does it matter?  Not much.

		Dr. Sharp asks if some of the subjects are getting none, the only
subjects who are untreated in the field study are the two that are used
to verify biting pressure, and they know who they are.

		In the tick study the circumstances is entirely different, because
everyone is testing the questing behavior of each tick on their
untreated arm before they put the tick on their treated arm for the
trial.

		DR. FISHER: Sue, did you want to follow up on this?

		MS. FISH: It is my understanding that the dosimetry studies are
informing the laboratory study as to the dose, and therefore, is it
possible in fact, or probable that the aerosol spray for example may
have a more consistent or a higher dose let's say than a pump spray, or
vice versa, a lower dose, so therefore the blinding is really around
dose levels and possibly some degree of formulation.

		Is that correct?  Or am I wrong here?

		MR. CARLEY: You are on the right track.  There are qualitative
differences in the three formulations that contain different
nonpesticidal ingredients and in different proportions.  So that's one
of the things that people don't know.

		And the other thing is that there may be different results from the
dosimetry phase in the actual dose.  The effective quantity of IR3535
that is  what it is in a typical consumer dose when they spritz it with
an aerosol, when they use a pump spray, or when they smear on a lotion.

		So both of those factors could vary from individual to individual in
the test, and they would not have any idea which of the three recipes
was being applied or whether it was in effect stronger or weaker
solution of repellent than the guy next to them.

		DR. FISHER: Thank you.  Kannon?

		DR. KRISHNAN: A clarification and a question.  Clarification relates
to the statement that I saw more than once that EPA historically
required a minimum of six subjects.  Was that the case?

		MR. CARLEY: The slide said replicates.  The reason it doesn't say
subjects is that historically if you recall from the discussion of
guidelines at the last meeting, some of these studies are run where each
limb is considered an independent replicate.  So I could go out in the
field and be four replicates all at once, depending on how each of my
extremities was treated.

		(Laughter)

		DR. KRISHNAN: My question relates to -

		(CD Change)

		DR. CARROLL:  - which is to suggest that I am open to any specific
questions you may have.

		I don't have a PowerPoint presentation, which to me feels like a
relief.  Hopefully to you too, but you may have to retune your nervous
systems over the next several seconds to deal with that.

		As John suggested this has been a rich summer for all of us, and I
very much appreciate the input on that from you in June, and the input
from EPA staff.

		In a sense to me this is an ongoing process.  It's been a melding of
cultures.  For many years I have been trying in a sense, and I use the
word loosely, sneak somewhat better science into this deal that
parallels the science that I practice more in my basic research
programs, and I've had some success with that, but this has allowed me
to formalize that more thoroughly, and I appreciate that very much.

		In addition the ethical oversight has been, compared to what I've
experienced, with this group very minor.  Some of you may recall there
were some adjunct protocol, called the generic protocol, called TL-001.
That was the protocol used in subsequent years that was approved several
times by the UCSF IRB, their in-house IRBs, and as I've come to
appreciate your discipline more thoroughly, when I began thinking about
it intensively for the first time this year, I realized that for
whatever reason that oversight was not up to contemporary standards.

		But that was the only feedback I've ever had, and I certainly know
that UCSF Med School is a famous place.  So to me it was sort of well,
this is easy, piece of cake.

		So I appreciated their willingness to rely on my goodwill or good
nature to the extent that I possess it to treat my subjects well, and I
tried to comport my research responsibly in the context of my home
community.

		And the additional oversight has allowed me to make the process much
more transparent and be more thoughtful about it myself, and I do
appreciate that very much.

		Why don't I just go on to a couple of questions that came up at the
end.

		One was the monitoring of pathogens in insects.  That is something
that is continuing to develop.  Those data are becoming more and more
available throughout the nation with the concern about West Nile.  The
only things we're doing with respect to that is consulting with mainly
our university and stage vector biologists to find better ways to
collect those data.

		Our very best approach is to conduct tests against mosquitoes
currently in the spring and early summer, because then the titers of the
viremic populations are very low compared to what can happen later in
the summer.  Specifically we'll take approaches like that.

		In addition to sentinel (phonetic) chicken flocks being used, which
have been used for many years, there is now much more trapping and a
much denser grid throughout the state of California, and other states as
well.

		So we have access more and more up to the week date, and my notion is
to incorporate those things further into the protocol once I'm sure of
their reliability.

		I thought Dr. Krishnan's comments about the dosing relation to the
Noel (phonetic) was very cogent.  It was something that is an obvious
thing to include.  Our approach is simply - what is included is based on
discussions we had this year and in previous years with EPA
toxicologists.

		A function of the efficacy data isn't just to show whether the product
works or not.  We anticipate that it will work.  We know from
discussions with EPA toxicologists that we are likely to be well below
the limit unless reapplication is necessary every 15 minutes or so.

		So a very important adjunct, or some would say principal function of
such a test - and I understand this even better now having thought about
it more this summer - is to - when calculating the labeling information,
based upon the duration of the reported efficacy, what we are doing is
really defining the margin of safety as well.  We know how often a
person is likely to have to reapply and therefore that tells us more
about what an actual dose is likely to be.

		DR. FISHER: I think there was a question about Florida and California
recruiting you might want to answer.

		DR. CARROLL: That's also a good point, because that's something that's
not addressed as specifically.  We do have subjects move to remote field
locales with us, but also sometimes we use professional vector
biologists.  And many times when we tested in Florida we have had help
specifically from the Florida Keys mosquito control division from their
staff.  And we use the same consenting procedures, and use the same
consent forms.  And even though we are given permission by supervisory
personnel there to have access to their personnel - this is typically in
the winter when there aren't many mosquitoes in California, and they are
not very busy in Florida, but there are still mosquitoes in the Keys.
So they have staff that don't have a lot to do.

		But I'm not sure how I should write this more explicitly in the
protocol.  I imagine I might be able to.  But we make it clear to the
supervisory personnel that we want to present ourselves to their staff
providing - presenting a situation that is entirely optional, it's not
part of their work experience.  It's not part of their job
responsibility.

		DR. FISHER: So just to clarify you are recruiting in Florida with
people who are professionals or experienced in that area; you are not
transporting individuals from California to Florida, or you are?

		DR. CARROLL: The seasonality on these tests that we do conduct some of
them in Florida.  We would have both types of subjects present.

		DR. FISHER: Okay.

		VOICE: I thought you did a very good job, and I want to commend you
for replying to all of the concerns that the HSRB listed last time.

		There was one concern that you didn't respond to.  There was a
suggestion that another investigator, outside of the study, screened the
control investigators.  And you didn't in your - that the control
investigators would be there too, the investigators that are part of the
study, and that they should be screened by someone who is not in the
study, do you remember that?  They would be screened a little bit
differently maybe than the participants?

		DR. CARROLL: These are control investigators?

		VOICE: The investigators who are going to serve as controls might be -
make sure they are not screened by the study director, he's serving as a
control, he's screening himself, or someone - to make sure that there is
an independent person who didn't really have a relationship with the
persons being screened to make sure they actually make a decision.

		DR. FISHER: So at this point there are no controls, but there are two
people out in the field who are going to measure, the two people who are
employees are going to be measuring pressure bite or something>

		DR. CARROLL: Measuring ambient bite.

		DR. FISHER: Right.  So I guess the question is, how is the screening
of these two individuals, so they're appropriate, they're not
vulnerable, they're not at risk, going to be handled?

		DR. CARROLL: I've left that objective, because I did not devise a way
where I felt personally as comfortable in ensuring safety if I was
relying on the judgments of another person to do it.  There just aren't
many professionals who have this kind of experience.  I do have people
who worked with me for many years who are mosquito afficionados and know
how at a professional level comport themselves very safely.

		And I also have preexisting subjective knowledge that they seem to be
rather typical, not far from the average in terms of attracting - and
scientifically this is the very weakest point of this general study
design, where we, to minimize risk, and maximize safety, we are using
such a low intensity of data collection to measure ambient biting rate
that my preference is to maintain - as a scientist maintain more control
over the quality of data based on my experience with particular
assistants.

		DR. FISHER: I guess the issue is, maybe you've handled this, or maybe
this is something you could do, but one thing we suggested in the report
was that those two investigators who serve as subjects are treated just
as any other subject; therefore, their exclusion inclusion criteria and
procedures are submitted to the IRB, and reviewed.  So that was one form
of quality control.

		I guess I don't remember if you were explicit in terms of - in another
words, what I think you should do if you haven't done it is describe the
inclusion-exclusion criteria that you would use for anyone who would be
subject to what these two individuals will be, and demonstrate that
these two people meet that inclusion-exclusion criteria.

		I assume what you're saying is, they don't have some horrible reaction
to mosquitoes, and whatever else your inclusion-exclusion criteria would
be, but it's important I think what Suzanne was raising, how important
we felt it was to apply the same ethics and inclusion-exclusion criteria
to people that are employees or experts in the study as not.

		DR. CARROLL: I agree with that.

		VOICE: And also to add to what you just said, to document that the
control subject had methods, inclusion-exclusion criteria, just as you
do with the test subjects.

		DR. CARROLL: I agree with that, and frankly it hadn't occurred to me
to treat them any different.