But Dr. Gupta tells us that you can't predict anything, and then Dr.
Strickman presents some very compelling evidence for using laboratory
based studies.  And, you know, as a scientist, the reason I'm not a
field biologist is that you can get the precision in the laboratory.
You can control the species.  The species obviously can be disease free.
 You can control the humidity, the temperature, all of these factors
that Dr. Gupta says makes a difference in the overall thing.

		And so the way to get data that you can compare amongst these various
products to put labels that the consumer can have some confidence in I
would think would be through the laboratory studies.  And that would be
my conclusion at this point.

		CHAIR FISHER:  Sue Fish.

		DR. FISH:  Picking up on what Jan said, I would like to ask Bill
Jordan or John Carley or someone about this.  What I think I understood
about how labels are generated, how the labeling is generated, and what
it means.  And I don't remember which of the previous meetings, but I
remember hearing that what the label says, this product is good for four
hours, came from the average complete protection time in the field
studies, and that that is not intended to inform the public that the
protection time is four hours, but is only helpful when used in a
relative basis to compare which product to purchase.

		And if that, in fact, is the case, and what I have heard today, is
making me less and less and less comfortable with any of the data that
we have seen in the experiments because of the tremendous variability
among the mosquitoes, among the people, among the conditions, I'm
wondering why -- if what I understand the labeling to mean, why the
labeling isn't -- this has a short, medium, and long protection time, or
one star, two star, three star, because to say four hours, to me, as a
consumer, suggests four hours, kind of like on a clock.

		And I would be concerned about reapplying, if I'm getting bitten, I
would be concerned about reapplying it in less than four hours, so I
need some help here to clearly understand where the data from the
experiments goes to inform the label writing.

		MR. CARLEY:  We are going to respond with a kind of a tag team effort
here, but I get to go first.  First, your memory is pretty good.

		We take these studies and, as Bill mentioned in an earlier response to
the question, we don't always do it precisely the same way, or in ways
that are equally defensible, but generally speaking, yes, we take the
mean complete protection time from the various tests that have been
done, and we permit that to be incorporated into claims on the label.

		But I refer you to the slide that is still up there from Dan
Strickman's presentation.  He talks about two different purposes, one of
which is this index permitting product to product comparisons, and the
other of which is, think of them as advertising claims, marketing
claims.

		The label serves both purposes, and this is one reason why this whole
area is kind of muddy.  We have been permitting claims for the duration
of protection that serve both the purpose of expressing the results of
testing, and the purpose of marketing claims.  		So the question of
whether you should think of four hours merely as twice two, or half
eight, or as clock time, is what emerges from this conflation of the two
different purposes.  So I think Dr. Strickman has suggested a way of
clarifying or thinking about that, that there are two different
purposes.

		The other point I want to make is that there is more than just the
number of hours on the label.  There are also, on typical repellent
labels, specific directions about reapplication.  Sometimes there is a
safety concern that says, "Reapply as needed, but not more than X times
per interval."  Or, "Keep it away from your eyes, or keep it away from
children under the age of X."

		There are all sorts of things like that that also come out of the
whole array of testing that we require on repellent products before we
approve them. So there is more than just the one number, but we are
certainly thinking in terms of separating the index.  Your small medium
large, or your one two three start from any number of hours.

		MR. JORDAN:  I'll add a little bit to what John said.  The agency has
been in the business of evaluating repellents for a lot of years, since
we were created, in fact.  And the understandings have evolved over that
time, but I think we have not revisited or updated our approach taking
into account the latest information.

		As we have said in past meetings, and again this time, we are in the
process of doing that, and some of the ideas that you all have suggested
have also occurred to us, and we are pursuing them.  I think we are not
quite ready yet at EPA to say we are going to switch from field tests to
laboratory tests, although that is certainly under consideration.

		We have not said that we haven't reached for sure a position on
whether to shift from labeling products in terms of hours of protection
to relative merit, but that is also under consideration.  We have not
figured out whether we want one day and one site, or one day and two
different sites, or two days in two different sites if we were to go
with the field testing.

		We haven't decided whether we want two different labs, if we were to
do it in different labs.  So there are a lot of questions that are still
open. And as I tried to indicate in introducing the third charge
question, these things connect in that we have to think through what are
the expectations of consumers, how best to communicate that information
to them, what level of certainty or uncertainty can we tolerate in terms
of understanding and analyzing the data.

		How does all of this play out in terms of cost, and how are we going
to make the transition if we do decide to adopt a dramatically different
approach, given that we already have a large existing universe of
registered products with registered labels.  And how do we -- you think
your workload is heavy now, just imagine retesting all of these
pesticides using a more standardized approach.

		And can we, as Dr. Schofield, I think it was, pointed out, can we
group products together, and what are the characteristics that permit us
to group products, say, by concentration, or perhaps formulation types,
and the carriers that may affect dermal absorption.

		So we are working on it.  As John's boss said, it does take time, and
we haven't sorted those things out, but we are learning a lot from both
these discussions, and others that we've had.

		CHAIR FISHER:  I want to use Lois' imaginary guide, and just point
out, I do want to kind of begin to go to a summary of this morning,
because we have a very long day.  And so I guess what I would like us to
discuss, and maybe only give five minutes to this, I think we've learned
a lot.

		It seems to me what we are hearing is that, in terms of questions two
and three, two being intermittent versus continuous, that is something,
obviously, that is going to be in the realm of EPA to be considering,
and then they are considering this, this new kind of multiple versus
single landing is another issue that I think ends up to be beyond what
we can be thinking about, because it has so many implications for the
way that products will be, and have been in the past evaluated.  So I
guess what I would like us to talk about is what are the implications?
There were a lot of variability issues that we learned about when we
talked about question 1.

		We do now have some information on intermittent, continuous, and on
multiple versus single, but is there anything that this means to us as a
committee in terms of, not criteria, but the type of information and
justifications that we would be requiring, or is there not enough there
that we are kind of in the same position?

		Jan.

		DR. CHAMBERS:  I think things are in enough of a state of flux right
now that I don't --

		CHAIR FISHER:  I'm sorry.  We can't discuss this yet.  I forgot the
public comments.  Thank you.  Sean reminded me.  We shouldn't make any
conclusions until we hear the public. So save your response to my
question.  I'm sorry.  Thank you for reminding me.

		Please introduce yourself.  Tell us who you are affiliated with, and
also remember there is a five minute.  And I assume you're together.

		DR. OSIMITZ:  We are.

		DR. CHAMBERS:  Okay. So five minutes.

		DR. OSIMITZ:  My name is Tom Osimitz, consultant to the DEET task
force.  And this is Keith Kennedy, entomologist, also a consultant to
the DEET task force.  And I wanted to just spend a few minutes.  I think
this is very relevant to what you were talking about this morning.
First of all, thank you for the opportunity, and we enjoy the
conversation very much.

		One of the most important things that we see -- next slide, please.
The DEET task force, by the way, consists of the major manufacturers and
marketers of DEET.  The project team we have here that is working on the
whole issue of learning from experience of what we know about DEET and
insect repellency includes the DEET task force, myself and Keith, Larry
Holden, and Bob Sielken from Sielken and Associates.

		Next slide, please.  The key element I want to mention today is that
we have put together a program over the last six months to look at,
comprehensively, the literature, both publicly available, the Gray
literature, industry studies, etc., as they relate to DEET repellents.

		The focus is on DEET repellents, but still, what we are finding in our
initial efforts, is that there is a lot we can learn.  And I think they
can inform, not just the EPA with regard to repellent guidelines, but
also some of the considerations that you are undertaking with regard to
human subject protection.

		Next, please.  Actually, back up one more.  Okay, next please.
There's three questions that we are looking at in this analysis, and we
don't have answers yet, but I wanted to at least get in front of you
today and let you know that this is where we are headed, and give you an
idea of how we are focusing this effort.

		Again, as manufacturers of DEET containing products, the DEET task
force is focused clearly on data that can help, not only the EPA decide
what should and shouldn't be registered, but the associated claims and
communications to the public.

		So this is not a basic research effort, but really is taking a look at
studies.  Some of them are basic studies that have been published, but
also studies that have been submitted over the last 15 to 20 years
specifically to support registration of actual products.

		Three questions.  What is the relationship between DEET concentration
and protective time, and is it possible to develop some predictive
model?  Second of all, assuming there is a simple relationship, is there
a variation, and how can we characterize that variation?

		One of the things we heard today, when you're talking about two hours
or four hours of protection, we clearly know there is no such thing as
two hours of protection.  Not even for one individual.  Over time, that
is going to vary.  We are trying to characterize that variability both
per individual, if possible, but certainly across individuals.

		And finally, can the protection time versus DEET concentration that we
obtain in laboratories actually be used to predict some kind of a
relationship -- don't know what that is going to look like yet --
between what you see in the field, especially, at least for some of the
more common species that have been tested extensively.

		The outcome of this, we would like to see something similar to what
Dr. Schofield mentioned takes place in Canada where there is essentially
a monograph or a generic approach that says, if you have certain
concentrations of DEET products, DEET or other repellents, but again, we
are focusing primarily on DEET here, because that is where the richest
data are, is there a way, then, to generalize about what protection
times would be, again, given a range as opposed to a point estimate.

		The value of this, I think, especially from a human subject standpoint
is obvious, because I think we could reduce or eliminate the need for
the extensive human testing that might be required if the agency moves
to new guidelines, and essentially wants to reset the system.  And
second of all, we think from an overall efficiency of resource use,
besides humans, both EPA resources and industry resources, this could be
valid.

		What have we done so far?  We have reviewed over 800 abstracts
relating to the efficacy.  We have actually looked at 49 papers in great
detail.  We have collected over 500 industry studies, reviewed about 370
laboratory studies, and now it's over 50 field studies.

		Next.  Keith will make a couple of observations about what we have
seen so far.  Again, we don't have statistics, but our initial
impressions at least we can comment on.

		DR. KENNEDY:  In the interests of time, I'll just hit the highlights.
One thing I would note is that arm-in-cage testing is remarkably -- is
conducted remarkably similar across a lot of different studies.  There
may be some variation in number per cage and cage size and whatnot, but
it was surprising how consistent that was across all the studies that
we've looked at so far.

		Certainly in the last 10 years there has been more inclusion of
additional species besides Aedes Aegypti, which is the standard test
model insect for lab studies, and I think that's been a good thing.  But
it was surprising how similar it was. Next slide.

		The field test, as you've heard today from the consultants here, there
is incredible diversity of how field tests are carried out.  And I have
read papers, but trying to tease out information on how a researcher
conducted a certain study, and did they list the biting rate, and where
did they list it, and how did they do it, and what was the control -
extremely frustrating, which says something about need to standardize
how we report our field test data, I guess, in the literature.

		Not a lot of similarities. Given that we have looked at about 50
studies, I was shocked, frankly.  And the issue of how they report the
data, whether it's complete protection time, or percent repellency was,
in some cases they calculated both, and in many cases, they only
calculated one.  So a lot of discrepancy there.  Let's just go to the
next -- go to the last slide.  We just did.

		But just on testing, though, I would say standardization of some type
of field methodology, at least from guidelines, is definitely in order.

		DR. OSIMITZ:  Just as far as the next step of our analysis, we are now
currently working through the criteria to stratify the data, meaning the
criteria we are going to use to look for differences, and if we can
develop any models that are predictive, we'll do that according to study
type, laboratory versus field, methodology, genron species, of course,
and then we'll look across formulations, as well, and particularly
looking at lotions, sprays, wipes, water based versus solvent based, and
regular and slow-release formulations.

		So this is going to be taking place probably over the next three to
six months.  It's a monumental task, but we think the information from
here can one, give you we hope more confidence in understanding the
difference between field and lab studies, whether there really is a lot
to be gained by trying to hone in on what is really an imperfect test
system, and probably always will be.

		And I think more important, when it comes to informing EPA's view of
how they should approach future testing, we might be able to realize
tremendous efficiencies, and especially reduce the need for human
testing.

		DR. KENNEDY:  Just one more comment, Tom.  One thing I would like to
second that Steve mentioned, and if you look at all the data that has
been accumulated on DEET that has been published or not published, it is
remarkable how similar, from a macro view, the protection times are.  It
is a fairly robust molecule, actually.

		CHAIR FISHER:  Thank you.  Questions?

		Jan.

		DR. CHAMBERS:  I applaud that effort.  I think it will be very useful
in the future.  That last statement that you just made, would you
elaborate on that just a little bit, please?

		DR. KENNEDY:  If you look at -- we have a question in there about
relationship between DEET concentration and protection time, and
without, we haven't completed the analysis, but just a cursory look
would tell me what I already suspected, and that there is a pretty
strong relationship.

		DR. OSIMITZ:  And part of what we hope to do, Dr. Chambers, is
characterize how uncertain that is.  So even though we know there are
differences in similar formulations, and some of these studies have been
done at different times, in the end, when it comes to communicating to
the consumer, is something such as protection from two to three hours,
or 90 minutes to three hours, that may be as good as this system will
ever do.

		And if that is acceptable from a consumer and EPA standpoint, then the
need for additional testing probably doesn't make sense.  We don't know
that at this point.  The one thing we have learned from a lot of
statistical analysis, and working with Sielken and Associates in
particular, is that these systems are not perfect.

		But to say that is not enough.  We really have to characterize how
imperfect they are, so it can give you an idea of the kind of precision
that couldn't be derived from additional testing.

		The last comment, just to let you know, we do plan on sharing this
with the EPA in great detail in whatever format they want, and the
eventual intent is to peer review and publish this, too.  So thank you
very much for the chance.

		CHAIR FISHER:  Thank you.  Are there any other questions?  Okay.
Thank you.  We are looking forward to seeing your products.

		Are there other public comments?  Dr. Carroll, please introduce
yourself and your affiliation.

		DR. CARROLL:  This is Dr. Scott Carroll from Carroll-Loye Biological
Research in Davis, California.  And I reserved this slot in case I had
something to add based upon board commentary.  I wasn't certain there
would be a lot after the expert commentary today, but a few things have
come up that, based upon my very practical experience, I may be able to
contribute.

		One is that, as I indicated in one of my first appearances before you,
when I came to the field of repellent science, I discovered, as was just
alluded to, that it is, in general, not a very strong body of work.  The
brain power aimed at the questions right now is greater than it has ever
been convened before in this room this morning.

		And I think three of the five major quantitative scientists in the
field in the last half century are sitting at this table with us here.
So I think there is prospect for gain, but issues have come up about
sponsor motivation, and about difficulty in controlling what happens in
the field that I would like to address.

		And let me do that by focusing on the question of relative protection
versus, which comes from continuous sampling, or at least in the studies
that have mainly been performed and recorded, comes from continuous
sampling, versus the intermittent sampling, the interval sampling that
is present in my protocols and others that are presently being put
forth.

		As of five years ago, I argued before an SAP in this subject convened
by EPA that doing continuous sampling and using the relative protection
measures was much stronger scientifically, much stronger statistically.
There was a great deal of information that was being lost by relying on
CPT.

		And we didn't even talk that much about intermittent sampling because
it seemed a much weaker approach.  And I commented at that time that I
could only see its relevance for studies in which disease concerns were
either major or paramount.

		So all studies that I did before the new era - we need a name for this
new era, probably a logo - were always continuous exposure, and looking
at relative protection.  My very strong impression from speaking with
various EPA officials at the federal and state levels was that such
protocols would no longer be permissible given the renewed, or the new
emphasis on risk to subjects.

		And so I crafted, for the first time in this new era, protocols that
use an exposure interval that I thought was relatively precise if we had
10 subjects, for example, giving us data points every 15 minutes.  But
some of the limitations there, especially statistically, I think, are
obvious.

		There was a suggestion, both implied by Steve Schofield's
presentation, and by a comment from a board member that, "Gosh, that's a
neat way for a sponsor to design a study if they want to maximize what
they generate as the summary data for complete protection.

		Two things there.  One, just from my practical experience -- well,
both from my experience.  The first is that, I know sponsors are very
concerned about what they get to put on the label.  I have never had a
single discussion, in the 15 years since I initially drifted into this
field as an adjunct to my primary field, with the sponsor where there
was any -- it has never been a point of discussion regarding study
design.

		No sponsor has ever brought that up.  And almost all my sponsors have
been very keen to know whether or not the study would show that the
product didn't work.  That has been the emphasis.

		Also, since adopting the one minute per 15 minute exposure regimen, we
require an ambient biting pressure for the study to continue, of one
bite on an untreated control arm during that exposure interval.  Or I
think the protocol now says in 90 percent of those exposures.

		To achieve that, especially for a test that may last 10 hours or more,
we are actually working at higher ambient biting pressures in the
environment than ever before.  Does that make sense?  In order to -- if
you are standing out there all the time, we have always wanted one bite
per limb per minute, and what I used to do was do summations every five
minutes.

		And if you are present in the environment, and we are always active,
we are moving, and there are enough mosquitoes around, you will find
five bites on a limb within a minute.  That's our criterion for
sufficiency.  But if every 15 minutes you are just putting your arm out
for a minute, it may -- well, mosquitoes move around you, they are
attracted to your body.  You may have several mosquitoes on your Tyvek
suit, but not one on your arm.  They are getting closer to it.  I find
it requires a higher ambient biting rate, so it does not necessarily
result in a longer measured mean complete protection time.

		I don't know how it does influence it.  Your back-of-the-envelope
model was interesting, but that is a countervailing factor that I am
experiencing.  We have to work at higher ambient biting pressures.

		So just to return to a focus that Dr. Strickland brought up, I think
the question is what we have to emphasize.  And Dr. Chambers also
brought up that it is out-of-control in the field, and how can we
predict anything.  And it has to do with effect size, as Dr. Kim raised.
 If we are looking at treatment versus nontreatment, control versus
treated, that effect will be very, very strong.  Site effects, data
effects, conditions, all of those will be important. They may be
relatively inconsequential in terms of their impact on relatively
nonambigious results from treatment effects, so whether we label
something for seven, eight, 10 hours of protection, as in the DEET
studies we are looking at today, site effects, data effects are
relatively inconsequential.

		CHAIR FISHER:  Thank you, Dr. Carroll.

		Any questions?  Okay. Thank you very much.

		Any other public comments? Okay. Thank you.  Now to resume our kind of
conclusive discussions, Jan, and then Rebecca also wanted to --

		DR. CHAMBERS: Well I think what I was going to say earlier, if I
remember, was that this obviously is in a state of transition right now,
and it looks like EPA is going to come up with some new guidance
sometime in the future based on all the available evidence.

		It seems like what we have to do as a board right now is just deal
with the things that are being presented to us, and look at the science
and the ethics of those particular things.

		I don't think we need to be making a whole lot of suggestions about
future directions and everything, as much as we may feel like we want
to, because I think that is being handled in the best way possible by
EPA, with the advice of your expert panels, for instance, not this naive
group who has to  bring in experts to find out about this particular
subject matter.

		CHAIR FISHER:  Rebecca.

		DR. PARKIN:  Thank you.  I wanted to go back to the issue around
purpose.  And I am, again, totally new to this issue, so I need a little
bit of education here.  Is the purpose clear in the regs as to why these
studies are being done?

		MR. JORDAN:  I'll take a shot at trying to answer the question.  EPA
has regulations which are focused on data requirements, and it specifies
that we require appropriate data -- it does not say what those data are
-- to support claims regarding the efficacy of insect repellents.

		And we do that because consumers really can't evaluate that in
advance, and we think it's important for consumers to be able to
understand something about the efficacy of the products they are buying,
so claims on those products must be supported by data.

		Guidelines are not regulatory requirements.  They are suggestions. But
operationally, people give them considerable weight, and very frequently
cue quite closely to the methodologies described in the test guidelines.

		The test guidelines themselves, in the latest version that was
reviewed by the board, indicate that we are interested in protection
time measured from point of application to efficacy failure.  The
guidelines, as currently drafted, specify bites, but we have been moving
in response to the board's direction toward landings as an indication of
failure of efficacy.

		That's what is said, and out there in the public domain.  In our
explanations and our discussions with companies, with you, and in other
settings, as well, we have emphasized that what we are trying to do in
terms of pesticide labeling is to give consumers a sense of the relative
protection that they will get from buying one product versus another
product through putting on the product claims related to the data
derived protection times.

		DR. PARKIN:  That brings me then to my next question, which perhaps
will be more of a comment than a question, because I think I already
know the answer to the question. And that is, when you talk about this
domain, I'm hearing appropriate data to support claims, to help
consumers understand -- this goes back to that document we looked at
yesterday -- without doing empirical research on what consumers want to
understand, and how they need to get that information so they can
understand, to make the appropriate decisions between products.  That's
a different domain of research than I believe your office is involved
in.  Is that correct?

		MR. JORDAN:  That's correct.

		DR. PARKIN:  So I'm wondering if there is some value to considering,
as you move forward in this process of deciding what kind of outcomes or
what kind of labeling changes you'll be making, whether it would be
reasonable to conduct some research that would be appropriate to these
labeling issues, which other agencies have done, and other researchers
have done, so there is a body of literature you could build from.

		MR. JORDAN:  We will certainly think about that.

		DR. SHARP:  Returning to the question that you raised about sort of
what does this mean in terms of what the board might do differently in
the future, or how that might change our request of investigators
submitting protocols and so forth.

		Personally, I would find it very helpful if there was a section of
these protocols that was more specifically focused on the rationale for
conducting field studies, and essentially made that case that there is
some needed data here that can only be generated through that particular
study design, as opposed to a more laboratory based study design.

		I think it effects, not only our interpretation of the science that we
talked a lot about today, but also our interpretation of some of the
ethical challenges imbedded in some of these protocols.

		Because if you can generate more or less the same types of data in a
more controlled environment, a safer environment for subjects, I think
that's important.  So my recommendation, I guess, would be to have some
section of those protocols explicitly address the need for a field
study, as opposed to a laboratory based study.

		CHAIR FISHER:  Mike.

		DR. LEBOWITZ:  A major conclusion for me given our responsibilities to
look at studies from a scientific and ethical perspective is that the
discussions we've had today provide the very important framework for us
in which we can actually understand and judge the studies that have been
completed in terms of their methodologies, results, etc.

		This is the most critical thing in terms of providing advice to EPA
vis-a-vis what is appropriate in terms of design and data that can be
used for their purpose to protect the human population vis-a-vis these
repellent products.

		I think the discussion we had this morning has, in fact, for me
provided that basic framework so that I can use now in assessing and
evaluating all the future studies that we have to look at starting with
those that we have to look at today in this field.  I am very glad we
have had that discussion.

		CHAIR FISHER:  Jan.

		DR. CHAMBERS:  I have two questions, one for Bill.  Really you were
addressing Richard's comment.  In the current time is our field test
required by the guidelines?

		MR. JORDAN:  In the sense that guidelines are guidance they are not
required, but operationally companies always do them and we pretty much
always expect them.

		DR. CHAMBERS:  The other question is for our three consultants because
the question I've had for months now, and I don't think I still have a
precise answer is do landings necessarily result in bites?  I'm getting
the impression from you all that it's not.

		DR. STRICKMAN:  No.  A mosquito can land without biting obviously.

		COL. GUPTA:  That assumption is correct.  Most of the time when
mosquitoes land they are probably going to probe multiple times before
starting to bite.

		DR. CHAMBERS:  But, again, not being an expert in mosquito behavior
and trying to avoid them as much as possible, I don't really look at
them closely.  In the context that we are seeing here if it looks like
it's going to probe and bite, then it will?

		DR. STRICKMAN:  Mosquitoes are like any other fly.  At these high
densities we're talking about you can have a mosquito land on you just
because it's landing on you and it's quite common to have like a gravid
mosquito that is not going to take a blood meal land on you, you know,
just appear with no intention to bite.

		As far as determining whether it had an intention to bite or not, I
mean, I wouldn't want to have that task myself without actually being
bitten.  I mean, that's usually what you see is the mosquito starts to
probe and you can see in the mouth parts.

		I don't know if you want this but the sheath separates from the
styletes that are actually inserted and you can see that at the very
start of the probe so there is the ability to do that but that is more
than landing.

		That's a probe and in terms of risk to the subject, that's as much
risk as a blood meal, at least for viruses.  That is in the literature
that the virus is transmitted at the first probe.  I don't know if
that's helpful.

		CHAIR FISHER:  Okay.  So just to conclude, the thing that I think we
could perhaps be looking at, which we are, but I think have come -- in
some sense it's questionable about whether we should look at is some
rationale for the sample size including the outcome measure that's used
as well as how many treatment groups and control.  I think we are
interested in that and sponsors could be providing that information.

		Why a field study?  I understand there's also constraints and
requirements for field study but if there is information about contrast
with lab studies, it seems like something that would be helpful for us
and feasible for us to hear about.  Why the specific environment was
selected and how the two environments differ and why two different
environments were selected I would be interested in hearing.

		How one is controlling either statistically or methodologically for
environmental shifts in temperature and daytime and things like that,
these are things that we know.

		We understand that there is a smaller sample size and some of the
procedures that are being used lack the power we would like to see
because of this balance with subject protections but it still is
important to understand which of these kind of extraneous factors that
affect mosquito behavior are going to be looked at, controlled, or at
least considered.

		Whether or not there is a balancing in terms of expertise between the
control group and the treatment group because we were presented with
some evidence that the better trained you are the more likely you are to
be able to detect the landing and also the activity of the subjects
appears just the information that would be important for us to look at.

		Those are just some of the things without providing the types of
guidance on some of these other issues that we really don't know what
there is and I don't know if there is anymore that people are thinking
about.

		Okay.  It sounds like we can --

		DR. JOHNSON:  Can I ask one of our consultants one more question?

		CHAIR FISHER:  Sure.

		DR. JOHNSON:  Still don't know that I understand exactly -- this is
for Dr. Gupta.

		CHAIR FISHER:  Dr. Gupta is not here.  Let us do move on because we
are so packed and we really do have to get to the next phase where your
question may come up at that point.

		John.

		MR. CARLEY:  Before I proceed, I would like to point out that today is
the 253rd anniversary of the Charge of the Light Brigade.  With their
example in mind, we are going to charge prudently forward into this next
topic which is EPA's review of two completed Carroll-Loye field tests of
mosquito repellency, one comparing three slow release DEET repellents to
the U.S. military standard and another testing all by itself a
repellent, the active ingredient of which is oil of lemon eucalyptus.

		This presentation is unusual as compared to those we have done before
because we are combining our discussion of the two studies.  The
organization will be a little more complicated.  I'll go first.

		When we get to the science assessments most of you are pretty familiar
with the Carroll-Loye designs but there are two new members of the group
and we've got the three consultants.  With them in mind we have prepared
to review with some detail the objectives and design of the study.

		We won't do that again when we get to the protocol for a new proposal
when we discuss that later on today.  For those of you who are already
very familiar with this protocol, please bear with us.  We are just
trying to make sure everybody is on the same page.

		First a brief history of the SCI-001 study.  You reviewed this
protocol in January.  Scott Carroll executed it this past July.  The
results of field testing were recorded separately for each of the three
test formulations, two of which were registered products and a third of
which was neither registered nor the subject of an application.
Although there was only one protocol and although it was only executed
once, the results were submitted in three separate volumes each one
reporting on only one of the three products and each relying on the same
positive control data and on any given day on the same untreated
controls.

		On September 18th EPA asked for a supplemental description of the
composition of the third test material, the one that was substituted
just before execution and an explanation for how it came to be
substituted for the material described in the protocol.  We included Dr.
Carroll's response to that inquiry in your background package and we
take that into account in this presentation.

		Our assessment was that the study reports taken together with that
supplemental material meet the standard of completeness defined in the
rule at 26.1301.  Because this study was initiated after the effective
date of the rule, the completed study has to be reviewed by the HSRB so
here we are.

		For the other study, WPC, this was reviewed by the HSRB in April of
this year and executed also in July.  Reports testing of a single
conditionally registered repellent product containing oil of lemon
eucalyptus.  In this case on September 13th we got back in touch with
Dr. Carroll and asked for an accounting of which subject signed which
versions of the consent document and when they did it.

		That is the supplemental material that we are referring to in the
third bullet.  Again, we think that the report plus the supplemental
material meets the standard of completeness in 2613.03.  Again, this is
post-rule research that has to be reviewed by the HSRB.

		The two studies were conducted by the same laboratory and used
essentially equivalent recruiting strategies, tapped the same pool of
subjects.  Many of the subjects participated in both studies.  Both
studies had very similar objectives and followed essentially the same
experimental design.

		Perhaps most important both were executed concurrently at the same
sites sharing the same untreated controls along with some of the other
data involved in the study.  That is why we are presenting them
together.  We have posed separate charge questions for each of the two
studies but you will see that fully understanding the conduct requires
that you appreciate the interdependence of their execution.

		There are some important differences between the two studies.  You
need to keep these in mind.  First, on the dimension of complexity.
SCI-001 was a little like some of the studies Dr. Gupta described
earlier.  It involved multiple materials, one positive control, if you
will, the military standard product, and three test materials.

		WPC-001 had only a single test material.  With respect to recruitment
of controls and consent forms the differences are really a reflection of
the different times at which these protocols were drafted and reviewed
by this board.  The earlier one, SCI-001, does not have an expanded
description of the recruiting process for untreated controls and uses
one consent form for both classes of subject.

		The more recent one, the WPC protocol, was amended after the HSRB
meeting to expand the discussion of the recruiting process for untreated
controls and it does use separate consent forms for treated and
untreated subjects.

		Looking at the calendars, first a caveat.  There is a lot more detail
in my ethics review about the calendars.  I'm just getting high points
for this presentation.  The SCI protocol was revised in the December and
the EPA's review was done a week later.  		Then in response to that
review there were some further revisions made by Dr. Carroll to the
protocol and consent document.  Those revisions were approved by the
IIRB in early January and the protocol was reviewed by this board in
late January.

		This board had the December 14th version of the protocol, our review
December 20th, and the further revisions as reviewed and approved by the
IIRB.  Our presentation to the board in January reflected those
revisions.

		It was essentially the December 29th version of the protocol that the
board considered.  The report of the January meeting didn't come out
until mid-April and there were no other events in that intervening
period.

		For the other study the early history was a little more
straightforward.  There was only one generation of the protocol that
came in in mid-January.  We reviewed it in mid-March.  It went to the
board in mid-April and a couple of months later the HSRB issued its
report.

		Then immediately in the wake of the HSRB report a round of amendments
to the protocol and revisions to the consent documents was conducted and
went forward to the IIRB.  Those amendments were approved on 19 January
but with some calls by the IIRB for further changes.

		That resulted in further change to the consent documents on the 4th of
July, approval by the IIRB on the 10th, but with still a little bit left
to go.  Final revisions to the consent for untreated subjects on the
12th of July approved by the IIRB the following day.

		Now let's look at the calendar for the execution phases.  I have put a
calendar strip at the bottom of this slide, a few selected dates in
June, all of the days in the first half of July.  It reads kind of from
the bottom up.

		On the 30th of June the sponsor asked for a change to the list of test
materials substituting LipoDEET 3434 for the previously proposed
material that we had reviewed, that you had reviewed that was stated in
the protocol and described in a consent document.

		The protocol was amended to make this change on the second of July.
Then the study is reported to have been initiated on the 3rd of July.
On that same day subject limb measurements were begun.  They went on for
10 days.  Dosimetry testing was begun and that lasted for three days.

		Then the field testing phase began on the 7th of July and ran through
the 15th six different days in two different sites, three at each.  For
the other study the pattern is a little bit more complicated largely in
this presentation because I have included more information about the
consent documents that is relevant to this study.

		June 13th the HSRB reported the next day amendments to the protocol
and consent documents.  A week later -- five days later approval by the
IIRB but with a call for some further refinement.  Then we see the
further amendments on the 4th and the 12th and IIRB approvals on the
10th and the 13th.

		The treated subjects are reported in the supplemental materials to
have signed the consent of July 10th during the time range from the 10th
to the 12th.  The control signed the consent of July 10th on the 11th
and the consent form of July 13th on July 16th.

		Now it gets a little bit unclear.  Subject limb measurement extended
from the fourth to the 11th but the study wasn't reported to have been
initiated until the 10th, the same day dosimetry testing began.  Then
there were three days of field testing on the 12th, 13th, and 15th.

		If you put these two together, you can see that the study initiation
was staggered by a week attributable to the delays in approval of the
revised consent documents.  The subject limb measurement overlapped
almost completely.  The dosimetry was completely independent and three
of the six field days overlapped.

		The discrepancies in the dates with respect to the signing of the
consent is something I'll talk about more later when I present my ethics
review.  To really understand what happened we have to look at the level
of individual subjects.  In this presentation each column represents a
specific subject.

		The days are July 7th for the top row, the 8th for the next row.  Then
this little white line is the reminder that the days were not continuous
between the 8th and the 12th.  Then we have four more days during the
second week of testing.

		The color indicates whether people were untreated controls or which of
the four materials in the SCI-001 they were treated with or the dark
blue is the WPC-001 study.  This shows all of the six days of field
testing.  It was in Butte County on the 7th, 8th, and 15th and Glenn
County on the other three days.

		The four materials in SCI-001 were tested on all six days.  OLE was
tested on only three days.  Looking at July 12th and following across,
this and these two subjects were treated with LipoDEET 302.  The four in
green were LipoDEET 3434.  The light blue four is Coulston's Duranon.
The four yellow ones are the Ultrathon and the four dark blues are the
oil of lemon eucalyptus.  The purple is the controls.

		Note that on two of the six days the controls were identified only by
function and not by subject numbers so there are sum analyses that we
can't follow all the way through because we are not sure which subjects
those actually were.

		Where there is a stack of different colors on different days that is
an indication that the protocol exclusion of subjects who used the
repellent on a previous day was violated.  Wherever that pattern occurs,
as long as it doesn't cross this white boundary line, there is the issue
of violation of that provision of the protocol.

		The day on which it was recorded as a violation of the protocol that
the subjects failed to maintain interpersonal distances prescribed was
this day.  It was the most complicated day where all five materials were
being tested.

		There are two key questions that come out of this.  These are the
protocol specific questions associated with the methodological issues
that we discussed earlier this morning.  The first of these is the
exclusion factor that I have already mentioned.  The second one has to
do with the amendment to add this material that was not previously
described through an amendment that was not reviewed by the IIRB.

		Depending on how one interprets the significance of that issue, you
can see by how many green spots there are how many different subjects
were affected that it could potentially have a broad impact on what is
left.

		Looking at the next frame, this is just for people who like numbers
better than pictures.  We've got the two sites, Butte County, which is
the sum of the three unshaded days, and Glenn County, the sum of the
three shaded days.  We have the repellents across the top and this shows
the number of subjects treated with each material on each date.

		The total number from the day ranged from 13 on July 8th to 23 on the
15th with the exception of oil of lemon eucalyptus on the 15th.  In
every other case in order to reach the sum of the design sample size of
10, you have some smaller samples from different days.

		That led us to another protocol specific question which has to do with
whether you can sum partial results across multiple days in the same
habitat to comprise the design sample size, what implications this might
have, and is it likely to affect the results.

		Now, to illustrate the impact of the question concerning the violation
of the protocol prohibition on testing people who had been used the
previous day, on this slide I subtracted all of those stacked instances.
 The only case where there is a stack is the untreated controls and here
where there is a gap of several days between the two test days.

		What happens?  This is illustrative.  This is not a recommendation but
if we were to drop out the data points, the treatment days that violated
that protocol constraint, we would have left only 54 of the original 100
treatment days.  That is 20 for each of the five materials.

		In summary form you look across these stacks here and we still have
the problem of pooling partial results from multiple days to comprise
the sample size but the overall number of samples left for each case is
quite a bit smaller.  We've got -- they are marginal at best.  I'll just
leave it at that.

		A different illustration here.  What I did here you will see there is
still the salmon and it disappeared because of the columns in this Excel
spreadsheet that I suppressed.  I didn't notice it until this morning
but there should still be a pink key down here but there is no green.

		What I did here was I dropped out all of the subject columns that had
a green square.  Those are the people who were treated at least once
with the LipoDEET 3434.  What happens here is that you lose 66 of the
100 treatment days.  There are two days, or three days rather, where
there is only one untreated control left, although we can't be quite
sure about that because we are not sure who these two guys were.

		Those are the ones that were identified by function rather than by
subject number.  Moving on to the next frame, we've got really tiny
numbers down here.  Still the issue about cooling results across days.

		If you put both of these factors together depending on the sequence
with which you delete things, you can get some interestingly different
accounts.  This is, again, just illustrative but if you exclude all of
the subject days, the treatment days that were affected by either of the
two conditions of concern, there is not much left at all.

		When that is summarized numerically, this is what you get.  The
biggest sample size is three and they are unacceptably low and there is
still some cooling of data across multiple days in a couple of cases.

		On the 19th of this month Dr. Carroll responded to our science and
ethics reviews, my ethics review of both studies and there were separate
science reviews done by Kevin and Clara.  You should have those letters.
 They are in the public docket.

Dr. Carroll will make some comments of his own later on.

		To summarize our general concerns, the two studies were very deeply
entangled in their execution.  Many subjects were treated on successive
days violating the protocol exclusion criterion that was in both
studies.  The unreviewed amendment to SCI-001 to change the test
material potentially affects about two-thirds of all the data.

		We are not sure what to do about the issue of pooling partial data
from different test days at the same site.  We did not expect that when
we looked at the protocol. Kevin will talk about that more in a bit.

		Forty-six of 100 treatment days violated the exclusion criterion.
Sixty-six of 100 involved subjects who were treated with LipoDEET 3434
and 86 of the 100 treatment days involved one or the other of those
problems.

		Here we are.  That is the stage setting.  Kevin is going to begin with
this.  Kevin and Clara will take turns telling you about their science
assessments.

		CHAIR FISHER:  John, I wanted to thank you for that remarkable
analysis both verbally and visually.  Just really very appreciative and
impressed.  Thank you.

		MR. SWEENEY:  Okay.  I guess Clara and I are going to first describe
the general methods that apply to both protocols, or both studies in
this case.  Then we will both present separate science assessments on
each study.  I'll start this off and then Clara will follow.

		First the study objectives are similar to what we have seen in other
studies before.  I don't know that I really need to read this slide but
essentially we are looking at the study objectives here to test each one
of these materials in the field against mosquitoes in this case.  Then
we had a section and both studies were determined typical consumer
doses.

		The dosimetry phase, of course, is quite similar to what we have seen
before.  In this case, though, lower legs were measured and skin area
was calculated and there was some variation of those measurements as you
can see from the data.

		The symmetry phase established a typical consumer dose of each test
material for use in efficacy testing.  In SCI-001 each of the 10
dosimetry subjects applied to each of the four test materials three
times to each leg.  In WPCO each of the 10 dosimetry subjects applied
the OLE pump spray three times to each leg.

		Brand mean of subject mean was calculated for each test material and
that was used as the standard dose rate for material in the field.  Then
the standard dose rate was converted to an individual dose for field
testing by adjusting it to the individual subject leg area.  The leg
areas were different for each subject.

		In terms of the subject design aspiration mosquitoes.  Again, this is
a standard part of the protocols that we have been looking at,
especially in Dr. Carroll's protocols.  Before participating in the
field studies all the subjects were trained or the subjects that were
going to aspirate were trained in the laboratory to aspirate landing
mosquitoes before they bite using lab-reared pathogen-free mosquitoes
and handheld electric aspirators.

		Subjects in the field testing were equipped with aspirators and worked
in teams of two to watch each other for landing mosquitoes.  Untreated
subjects were attended by two technicians to assist in aspirating
landing mosquitoes.

		The field efficacy phase.  The way the treatments were described and
the way they were allocated was 10 subjects were treated with each
formulation and two untreated control subjects participated in the field
trials in each two habitats.

		Because of the expected long duration of efficacy the subjects were
treated with test propellants before traveling to the site.  That is,
they were pretreated and there was a time span before they were actually
exposed to mosquitoes in the field at the sites.

		Untreated subjects were monitored for mosquito pressure and treated
and untreated subjects were exposed to mosquitoes for one minute every
15 minutes until efficacy failure.  I think Dr. Carroll elaborated on it
a little bit more this morning.  I think John talked about the actual
outlay of the study design in the chart shown previously.

		In terms of the sample size considerations, sample size was 10
subjects per treatment at each site for a total of 20 with two
concurrent untreated controls.  This was just protocols with arguments
considered previously by the board in reviews of Dr. Carroll's
protocols.

		With the board's comments from the previous meeting, and I elaborated
on this to some extent in my own review, EPA is reconsidering this
matter in a general case but our current position is that the sample
size of 10 was adequate and exceeded the general recommendations of the
guideline.  That is, therefore, what was done in this particular study.

		I think I'll turn it over to Clara at this point to talk about --

		DR. FUENTES:  The variables that were measured in this study were the
skin surface area of the subjects, the legs that were used for applying
the repellent.  The weight of the test material applied to subjects by
dosimetry.

		The mosquitoes landing pressure at least one landing per minute on
control subjects, the time of all landings and time of first confirmed
landing and the efficacy that was expressed as the average time to first
confirmed landing which is the standard deviation and was in 95 percent
confidence interval.  The median was also calculated using the
Kaplan-Meier Survival Analysis.

		The next slide, please.  The field sites.  The test was conducted at
two different sites, field sites, representing different habitats
according to the EPA guidelines to have the opportunity to test
different species of mosquitoes.

		One site was the lake-side grassland in Butte County, California.  The
other site was a forest habitat in Glenn County, also in California.
The sites were numbered in reverse order for the two different studies,
SCI and WPC.  That is a little bit confusing.  It's better to refer to
the sites by habitat or the county instead of numbers.

		The species of mosquitoes encountered in the field were those that
were listed at the last bullet, aedes melanimon, aedes vexans,
freeborni, and culex tarsalis.  The distribution of the species that
were encountered in the field by site and by date are represented in
this table.

		The percentages of a species encounter by day and site changed as you
can see in this table.  The predominant species in Glenn County was the
aedes vexans and in Butte County grassland site was the aedes melanimon.

		The counts show the average percent of a species found per site close
to three days put together.  In the population and the distribution of
the mosquitoes varied quite a bit from one day to another.  For example,
in the aedes melanimon at the Glenn County site you see a 3.7 percent
changing to 13.9 percent.

		Also in the aedes vexans in Butte County there is a 3.3 percent
changing to 15.8 percent.  Also keep in mind that from July 8th to July
15th when this occurred there is not one day to the next.  There is a
seven-day difference there.

		This is the study to test the efficacy of a product containing oil of
lemon eucalyptus.  The study was conducted according to changes that
were incorporated in the protocol.  The dosimetry test, for example, was
conducted outdoors because it was a pump spray.  The data captured forms
were modified to allow recording of the exact placement of the
dosimeters on the legs.

		The statistical procedures were revised and incorporated and the
Kaplan-Meier survival analysis was incorporated in the protocol.  Also
it was used in the study.  The rationale for simple sites was not
revised and the premature withdrawal of subjects in case that would
occur was addressed in the protocol in Amendment Section 9.1.312,
exclusion criteria for subjects.

		Post-testing consisting of monitoring of collected mosquitoes was also
incorporated in the protocol and was also performed in the study.

		The dose that was -- this table represents the dose that was applied
to the subjects.  The standard dose was determined for the pump spray
product and it shows that it was only 26 percent of the long-standing
standard of 1 grams per 600 square centimeters for deep lotions.

		The dose of active ingredient applied per square centimeter of skin
was 0.13 milligrams.  The mean total dose of active ingredient was 135
milligrams.  The first row shows the standard dose of the product that
was applied per square centimeter.

		This active ingredient that is contained in the product and the dose
that is applied per milligram per square centimeter.  Then the mean
total of active ingredient that was applied was by multiplying that dose
of active ingredient per square centimeter by the outreach,
approximately 1,000 square centimeters of skin area that was used for
applying the repellent.

		Then the dose that is applied to outreach 70 kilograms adult is 1.93
milligrams per kilogram.  The MOE is based on the dermal LD-50 of oil of
lemon eucalyptus which is higher than 2,000 milligrams per kilogram.

		The landings with intent to bites that were collected and reported in
the study are broken down into different categories in this table.  The
unconfirmed landings were a total of seven.  The confirmed landings were
20, one per subject.

		The confirmed landings were more than that.  They were 24 because
sometimes more than one mosquito landed simultaneously on the same
subject.  The total landings of all that was 51.

		The reported protocol deviations, these are deviations that are
reported in the study, are the ones listed here.  The subjects didn't
cover untreated limbs between exposures because they moved to a screen
house that was available.  The practice rounds for the dosimetry phase
was reduced from three to one for most subjects.  Three replications of
he same applications was deemed unnecessary so it was reduced to only
one.

		The experienced subjects assisted in treatments of the other subjects.
 At the time of application of the repellent on the subjects, other
subjects helped out to apply the repellent and that, in fact, helped to
synchronize the application.

		The treatments were applied before traveling to the test sites so the
treatments were applied in advance to the test.  The prescribed
distances were not maintained on July 12th and that has a significant --
it's important.  This observation led to our fourth protocol specific
issue identified earlier by Bill Jordan that if a minimal intersubject
distance is not maintained, could this affect the results.

		The next deviation is the temperature data that was recorded
accurately for three hours on July 12th but it only occurs at the first
two hours of the test when most mosquitoes were not really landing on
subjects.

		The dose for subject 13 was miscalculated by 0.01 milliliter.  All
these deviations were explained except the -- well, they were reported
in explaining the study report not to be relevant in compromising the
accuracy of the data.

		In this next slide there are some unreported protocol -- a couple of
unreported protocol deviations and these are the concurring execution of
the two studies, WPC-001 and SCI-001.  That was not acknowledged and the
exclusion criteria that was violated by testing subjects who had used
repellent on the previous day and different repellents, too, on the
previous day.

		The complete protection time, the  result of the test, appear on the
table, the mean complete protection time for each site and the mean
protection time for the two sites pooled together.  Also the median
complete protection time for each site and for the two sites pulled
together.  The median was generated by the Kaplan-Meier survival test.

		The study limitations are an experiment deviated from the revised
protocol by testing more than one formulation simultaneously.  Different
repellents were tested on the same leg the day before testing the oil of
lemon eucalyptus-based repellent.

		The data for different days was pooled for analysis without accounting
for additional sources of liability due to different dates.  The data
from Glenn County site was collected during two separate dates, July
12th and July 13th and pooled together for analysis.  That introduced an
additional source of liability associated to different days.  That has
not been acknowledged in this study report.  Finally, a clarification is
needed to verify the accuracy of the data generated by this study.

		Now I will pass it to Kevin.

		MR. SWEENEY:  And I will present the science assessment for SCI-001.
This is a field mosquito study with four slow release lotions all
containing DEET.

		Next slide.  First of all, in terms of test materials I think we have
talked about some of them before so I will make this brief.  This
protocol was reviewed by the HSRB in January and proposed the testing of
four materials listed on the slide.  We have data of course in the study
from three of those materials and I'll talk about that for a second.
They are all D formulations and they are all lotions.

		Next slide.  At the request of the sponsor, as John has already
mentioned, insect R2 was replaced as test material by LipoDEET 3434, an
unregistered repellent product.  The initial submission was inadequately
characterized in the report of its testing and the substitution was not
acknowledged in the reports for the other two test materials.

		In response to EPA's request LipoDEET 3434 was described as similar to
LipoDEET 302 but containing DEET at a slightly higher concentration.
This was for the purpose of comparing it to 3M Ultrathon product which
also had 34 percent DEET.

The rationale was also explained and I'm talking about the first one.
Insect-Guard was no longer going to be marketed.

		Next slide.  In terms of dosing regime, I went through this in more
detail in my science review presented in table form and I'll present a
summary of that here.  Essentially I'll go row by row.  These are the
four repellent products that were tested.  First one a 30 percent, 34
percent, Duranon is 20 percent and then Ultrathon again 34 percent.

		The standard dose in milligrams per centimeter score is listed here.
They are pretty much the same for the first three or fairly similar with
LipoDEET 302 being the highest and Ultrathon now being the lowest.

		In terms of the amount of DEET expressed in milligrams per centimeter
squared, again the lowest DEET application rate was with Duranon at 20
percent formulation compared to the highest for 302 which was also
fairly close to Ultrathon.  Excuse me, 3434 was the highest.

		In terms of the mean dose of AI in milligrams, again the dosages here
vary quite a bit between these three and Duranon again with Lipo 3434
being the highest and Ultrathon only being 500 and Duranon being as
expected, a much lower dose.

		When you look at this in terms of the amount applied with 70 kilogram
adult we see significantly less DEET applied, Duranon formulation.
Slightly less than what you see with these two apply for Ultrathon.

		Just to make a mention about the formulation.  I'm familiar with
Ultrathon.  I mean, this is a fairly viscous formulation and goes on
pretty easily but it doesn't take quite as much material.  I think also
in the table I talked about as well as Dr. Carroll talked about the fact
that there's only three-quarters the amount of Ultrathon was used
generally compared to these other three repellents if you look at it on
a 600 square centimeter basis.

		Next slide.  In terms of distribution, landings by repellents, I think
John presented an overview of this already.  I think what is really
important here is that we saw unconfirmed landings at all these and
especially with Duranon No. 14.

		Confirmed landings as expected would be 20 and, of course, we saw even
more bites with these confirmed landings.  Essentially you have a
situation where you've got a total of 55 -- u p to 63 bites, excuse me,
over 20 subjects for this formulation and 55 for these two and then 49
for this one.

		I think in my mind the thing that is really important is that we have
bites that are not confirmed and the testing is continuing.  I think it
is probably something that we talked about before.  Landings, excuse me.
 Landings.

		Next slide.  In the science review I did I separated these out.  For
the purposes of just the illustration here I'm pooling everything and
that made this slide a little easier to read versus a much larger table
as presented in the review.

		Essentially when we look at these products, and here is the active
deconcentration, when you look at the CPT time with the standard
deviations, you can see it is fairly similar for these three DEET
products.

		It seems significantly lower, although not greatly lower when you look
at the standard deviation values.  It's much more pronounced with the
median CPT values with Duranon being significantly less than these
others.

		Essentially, I mean, I think I pointed this out in my review, the
results are fairly similar between these three with the 20 percent being
significantly different, although not that significantly different
depending on the overlap between these confidence intervals.

		Next slide.  In terms of the study limitations, and I would point
these out, too, and I think Clara made some mention of this.  In terms
of some of the comments from the board on this protocol, the random
selection of treated limbs was mentioned.

		In here the method used to chose which leg to treat was not reported.
The data suggest the subjects who participated on more than one day were
treated on the same leg each time.  We did this just from evaluating the
data sheets themselves.

		Many subjects were treated with different repellents on consecutive
days and this has already been mentioned so I'm not going to elaborate
on that.  Or the same repellent on multiple days.  Then data for the
same repellent from the field site but at different times on different
days were pooled for the analysis.

		I guess this is a fairly significant point, of course.  I pointed this
out in my review and I think a little bit of discussion came up already
about this this morning and also in the tables presented.  What we see
here is we have four different treatments at least in this study.  We
have two different sites.

		We have 10 subjects per site for a total of 20 per treatment but the
data collected up to multiple days.  Then the data were pulled and then
pulled again to present the analysis.  I think that is significant
compared to say doing the treatments all in one day and then replicating
them on consecutive days at these same sites just as another method.  We
also see it submitted to us over time.  Thanks.

		Then potential for dropouts.  This was mentioned by the board in the
analysis plan although there were no dropouts and the subjects that
received confirmed landings with intent to bite.  Everybody actually in
the study who participated the repellent applied to them actually went
to the failure time.

		The distribution was not analyzed for normality.  In this case the
sample size, as Dr. Carroll points out in the study, are fairly small so
he did not apply the assumptions or normality to these data and
conducted multiple analyses.

		One other thing I mentioned, and Dr. Carroll addressed in his reply,
is that the potential impacts of data affects or time affects were not
assessed.  I think the argument could be also mentioned this morning
whether the side effects were really adequately assessed.

		Again, Dr. Carroll addresses this in his reply and I'll let him speak
to that in his public comment if he chooses.  He reports for only one of
the studies where he had the discussion and I think this was Duranon if
I remember correctly.

		Next slide.  Then at this point I'll hand it over to John for the
ethics assessments.

		CHAIR FISHER:  First I think we will take science questions if there
are any.  Remember for the purpose of time, let's limit board comments
here to questions rather than comments that we might make in the
discussion and critique of the study.  Are there any questions for EPA
about the science aspects?

		Dr. Kim.

		DR. KIM:  It was described that the patients at location each day was
randomized method according to randomization.  I see on July 8th of 2007
the distribution of the number of patients are two to three to five to
three.  My question is what kind of randomization method was used to
look at the subjects?

		MR. CARLEY:  That was identified as one of the limitations of the
study that was not reported.  There was a slide that Bill didn't get a
chance to present earlier, the one that listed protocol specific
questions.  		The question that came from that was does it matter how
the limb to be treated is selected and, if so, how should it be
selected.  That is something that we would welcome comments from the
consultants about.

		DR. JOHNSON:  You made a point of the Lipo 3434 taking some of that
data out.  I didn't see the rationale for why you were doing that other
than it wasn't part of the original protocol.  Was that the reasoning
behind it?

		MR. CARLEY:  First off, what I did was illustrative of the effect of
one possible response to ethical concerns.  This is an ethics issue
about whether the study should have gone forward with this change in the
design that was not reviewed by an IIRB and it was not reflected in
revised information provided to the subjects so it is not really a
science issue.

		All I was doing was saying here is a picture that shows you how few
spots are left on the page when you drop out the green people.

		DR. KIM:  I just want to mention that there is also science issues
with the interpretation of the data because of the potential carryover
effect of one treatment to the next day.

		DR. SHARP:  In the earlier review of this we got a chance to look at
the specifics of the other three formulations but we didn't see anything
about Lipo 3434.  Can you say a little bit more about that product and
how it compares in particular to Ultrathon?

		MR. SWEENEY:  I mean, well, first of all, the deconcentrations are the
same.  In terms of the carriers, I mean, they are different and that is
proprietary frankly.  But, I mean, the carrier are similar to what is in
the LipoDEET 302 product.

		DR. PHILPOTT:  On that same sort of line of questioning, I'm just
curious are there other Lipo formulated products out there because one
of the things that I keep seeing in protocols is simply that
justification for a particularly concentration is based on the notion
that there are other products with the same concentration.

		I'm curious about what is known about the risk associated with the
formulation in liposomes or in the case of the other products, the
protein capsules.

		MR. SWEENEY:  I'm not a toxicologist but I'll attempt to answer your
question.  I mean, in terms of there's acute toxicity data for that.
There has been data collected on liposomes.

		I mean, that's a -- I don't know if it was really developed only for
-- I don't want to get myself in any hot water -- only for the use of
repellents.  I think the original patens are actually held by Johns
Hopkins if I'm not mistaken off the top of my head.  I think that has
been looked at.

		Have we conducted -- I guess if you're asking have we conducted a
separate toxicological evaluation to just look at that part of the inert
ingredient, I think we have considered that as part of our regular
analysis.  I think we have determined it's not that different from
anything else we've seen.  Does that answer your question?

		DR. PHILPOTT:  I think my question was more are there other products
that use this technology for delivering insect repellents, either
liposomes or protein capsules?

		MR. SWEENEY:  There are slow release formulations out there.  The
liposomes, though, are restricted pretty much to these products, I
think.  I don't know if there are any other registered off the top of my
head that are LipoDEET specific.  I'm not sure.

		CHAIR FISHER:  Dr. Gupta, did you want to enlighten us?

		COL. GUPTA:  Yes.  Just for information on the Lipo 3434 and
Ultrathon.  They are two different delivery mechanisms as far as I
understand.  Ultrathon is a polymer-based formulation.

		In that case what happens is there are about two different polymer --
the DEET is sandwiched between two polymer layers.  Whereas the
liposomes the active ingredient is actually inside it in a small bubble.
 Liposomes could be complete or incomplete.

		Earlier, 10 years ago, the reason the DEET wasn't -- liposomes were
not considered as the ideal delivery mechanism for DEET because it was
very expensive.  Since the advances in the technology, now you can
manufacture that liposome formulation DEET as cheap as the other ones.
Basically what you are trying to do in both formulations is trying to
control the release rate of DEET.

		CHAIR FISHER:  Okay.  Thank you.

		Jan.

		DR. CHAMBERS:  Does EPA have any information about the kinetics of
these formulations or how quickly they dissipate over time once they are
applied to the skin?

		MR. SWEENEY:  These particular formulations themselves for these four
products you mean?  Probably for Ultrathon we probably do.  Whether we
have the exact kinetics for the other three I'm not aware that we do but
I think as far as how fast, basically we're looking at -- we use a --

		I guess we use the bioassays really to determine as to whether these
things fail or not.  We do know what the vapor pressure is of the
formulation itself.  We know the densities of the formulations and the
other physical chemical characteristics.  Does that answer your
question?  Okay.

		CHAIR FISHER:  Okay.  Let's move on.  This is for everybody because we
are behind schedule.  Let's try to --

		MR. CARLEY:  I'll talk just as fast as I can.  In addition to the
studies themselves I reviewed our EPA protocol reviews and the HSRB
reports of the two meetings at which these protocols were discussed and
carolized responses to our specific questions on each study that I
referred to before.

		The same six deviations were reported for both studies and there was a
seventh one for WPC-001 involving the miscalculated dose.  Two of them I
thought had potential ethical significance.  One was the use of
experienced subjects to assist in application of repellents to other
subjects.  		The second was the failure of subjects to maintain
prescribed distance, dismissed, I think, and somewhat misleadingly but
with a statement that all subjects were wearing the same repellent.
This occurred on July 12th.

		That was the date that all five repellents were being tested.  In the
supplemental material Dr. Carroll said that the people treated with oil
of lemon eucalyptus were physically apart from the ones treated with
DEET.

		Unless I missed it, there hasn't been any clarification about whether
the people treated with different DEET products were isolated or whether
they were intermingled.  But the ethical points about that is that this
may have been mischaracterized as distinct from what the potential
scientific implications of the distance were.

		There were a bunch of unreported deviations.  These are quite
specific.  Subject limb measurement in WPC-001, as I showed you on the
calendar slide, was begun almost a week before the reported data study
initiation.  It was done well before -- it was initiated well before the
subject's signed WPC-001 consent forms.  I'll address all of these
points further in later slides.

		Subject No. 29 participated in limb measurement for WPC-001 on July
7th, four days before signing the consent.  Subject 60 participated in
dosimetry testing for WPC-001 on the 10th of July, two days before
reportedly signing a consent form on the 12th.  		The untreated control
signed the final version of the appropriate WPC-001 consent form after
all field testing had been complete.  Then this point that I made
earlier, 46 percent of the treated subject days involved subjects who
had used the repellent the day before violating the exclusion factor in
both protocols.

		In terms of responsiveness to EPA with respect to SCI-001, this
section of the presentation addresses only comments that were made in my
ethics review or under the ethics heading in the HSRB review with
respect to either of these protocols.

		I commented that the protocol inadequately described recruiting of
experienced subjects.  There were changes in this respect made in the
version of 29 December which preceded HSRB review but there were no
further changes made after the meeting.

		I said that the consent forms should be corrected to delete references
to alcohol in the test repellents since there isn't any and that was
acceptably addressed in the 29 December version.  I said the consent
from should be revised or split to better inform untreated controls of
what they would face as it differed from the treated ones.  That was
acceptably revised on 29 December.

		The HSRB made some similar and some different comments on this
protocol.  Suggested collecting mosquitoes for subjection to analysis to
confirm the absence of known pathogens.  The protocol was amended on the
2nd of July to incorporate the same viral assay of the collected
mosquitoes that had been written into the amendments to the other
protocol.

		That protocol occurred -- that amendment occurred on the same day as
the amendment to change the material to LipoDEET 3434.  Neither of them
was reviewed by the IIRB.  HSRB said the protocol should clarify how
untreated controls will be recruited.

		As I mentioned, this wasn't addressed further after the HSRB meeting
but I think this comment from the board actually may have been in the
earlier version of the protocol, the December -- well, I don't want to
go there.  It's too complicated.  There were a bunch of different
versions of this protocol.

		The board commented that they would like to see some -- that it was
hard to judge the abilities of the IIRB.  They would like to see some
evidence of member training accreditation.  No additional information
about the board member qualifications or accreditation has been
provided.

		There were three points made about the informed consent in the HSRB
report in April.  It said it mischaracterized the test materials as
containing alcohol.  That was already fixed.  Structured so that it
doesn't apply to untreated controls.  There were changes made in the
December 29 version.

		And the comment was made that it should say up to 48 subjects would
participate whereas it already said up to about 40.  The actual number
of subjects was somewhere between 37 and 41 depending on who those
unidentified controls were.

		The change wasn't made but understand that there were not two controls
per arm of this study.  There were two controls per day in the field so
the arithmetic doesn't add up to 48.

		On the other study we asked that the data collection forms be changed
to refer to subjects only by coded number.  That was done.  We said they
needed to better characterize how experienced subjects would be
recruited.  This was done in the June amendments.

		We called for description of recruiting in Florida in comparable
detail to the description concerning California.  The amendments deleted
all references to testing in Florida making that point moot.

		CHAIR FISHER:  John, I'm really concerned about time because we are
supposed to go to 6:00 something today and I do think that most of what
you are saying, first of all, your first presentation covered a lot and
overlapped with this.  Also a lot of this was in the beautiful report
that you wrote for us.  I know it's difficult and I'm going to ask
everybody the same thing.

		MR. CARLEY:  I will do my best.

		CHAIR FISHER:  If you could just highlight, that would be great.

		MR. CARLEY:  The only major point on this slide is that the informed
consent was split in the June 14th amendment so it went two ways.  There
were two completely different reports.  Thereby, I should add
necessitating preidentification of controls, a topic that came up from
the consultants earlier today.

		The investigator was generally responsive to our suggestions.  There
were a couple of exceptions.  The applicable standards are the usual
ones.  I'll skip over this and explain further to Drs. Parkin and
Johnson if they have questions about it later.

		My findings.  The completeness standard for documenting ethical
conduct was met for both studies.  All subjects in both studies were at
least 18.  None were pregnant or nursing.  There is not an issue with
26.1703.

		FIFRA Section 1282P has been in the law for 35 years and it says that
you can't use people in a test with pesticides without their being fully
informed and without their participation being fully voluntary.

		There is some question about whether they were fully informed because
of the failure to acknowledge the change in test materials and change in
the description of materials in the consent document for SCI-001.

In the case of the other study, there is this issue about the date
sequence for all of the consents which technically may fall into a
problem with 1282P.

		Then with the tricky question about whether it was in substantive
compliance with the rules in Subparts A through L of which K and L are
the only ones that apply to third-party studies.  We thought about this
problem before.

		The rule requires that the IIRB have procedures that will ensure that
changes in approved research aren't initiated without IIRB review and
approval.  The rule does not forbid making the changes or implementing
them without IIRB approval.  It says that the IIRB has to have
procedures that will ensure this doesn't happen.

		The procedures from the IIRB, which we do have under a claim of
confidentiality were in this case not effective in insuring that
amendments to approved research, changes in approved research, were not
initiated without IIRB review and approval.

		DR. PHILPOTT:  I'm sorry.  I hate to interrupt but can you elaborate
by what you mean because we haven't seen these.  When you say not
sufficient, I mean, do they say you have to submit?

		MR. CARLEY:  No.  The relevant part of the rule is right there on the
wall.

		DR. PHILPOTT:  I'm talking about the IIRB's rules.  You have seen
their procedures.  We have not so you are stating that their procedures
were not effective in ensuring that amendment.  Do you mean that the
IIRB screwed up here or did Dr. Carroll violate their procedures?

		CHAIR FISHER:  Are the procedures you're talking about written in
their document or not so they don't even have those procedures or did
Dr. Carroll not follow the procedures that are written in the document?

		MR. CARLEY:  There's another question to which I'm not certain of the
answer which is whether the board has -- to what degree has the IIRB
shared their procedures with Dr. Carroll, what did they tell him in the
approval.  We have seen the approval letters.  This is kind of an
unclear area.  I am simply pointing out --

		CHAIR FISHER:  It didn't work.

		MR. CARLEY:  -- that this protocol -- that whatever this was it didn't
work because --

		CHAIR FISHER:  It didn't work and let's put it there.

		MR. CARLEY:  -- we know that it was amended without oversight.

		CHAIR FISHER:  Yes.

		DR. MENIKOFF:  Do the IIRB procedures allow amendments to the protocol
to be effective without the IIRB being told about those amendments?

		MR. CARLEY:  Not except for this exception that is in the rule where
it's necessary to eliminate immediate hazards.

		CHAIR FISHER:  Okay.

		MR. CARLEY:  That is the only exception in the IIRB rules.

		DR. MENIKOFF:  That clarifies it.

		CHAIR FISHER:  So the IIRB has a policy and the policy wasn't
followed.

		MR. CARLEY:  The IIRB policy such as it is is consistent with the
requirements of the rules which are spelled out here.

		CHAIR FISHER:  The IIRB policy in order to be consistent shouldn't
just be written but also the IIRB should carry out its policy and
whether or not it informed Dr. Carroll, etc., etc., is a question.  I'm
sure the rule was not intended to say just have this written but ignore
it.

		MR. CARLEY:  I'm sure that was not the intent of the rule but the
trick of the rule is that it doesn't direct --

		CHAIR FISHER:  Let's move on because there are issues.  Informed
consent wasn't taken so I think we can move on because there are other
issues here.

		MR. CARLEY:  Okay.  Next point has to do with the consent.  I won't
repeat all of this stuff but I do want to explain a little bit.  The
limb measurements that began for WPC a week before the stated initiation
date, in general that is not a very big problem because the same
subjects and the same limb measurements were used for both studies and
with one exception everybody whose limbs were measured before the
initiation of the second study was also part of the other study and had
presumably done a consent before they started in there.

		There is only one anomaly and this was the subject 29.  Then the case
with subject 60 as mentioned by Dr. Carroll in his supplemental
materials.  If that is not clear, he can explain it better than I.  And
the untreated control signed their consent form after completion of
field testing but the last generation of changes had to do solely with
pregnancy risks and all of these subjects were males so there was no
substantive effect of that change or that delay.

		CHAIR FISHER:  All right.  I think we really have to move on.  Is
there anything you haven't said before?

		MR. CARLEY:  Yes.

		CHAIR FISHER:  Okay.

		MR. CARLEY:  There is at least technical noncompliance summarizing all
of this.  The question is how far does it rise on the scheme of the
criteria.  I want to say a little bit more about the change in the role
of the experienced subjects to serve as assistants to the investigators.

		That was not reflected in the protocol or the consent forms.  It was
not considered by the IIRB and that strikes me as a fairly significant
topic that deserves some careful attention.

		The explanation by Dr. Carroll of his understanding of his discretion
to determine what amendments have to be reviewed seems to me to be in
direct conflict with the plain language of the rule.  If the IIRB
decides that they are not interested, they can say so but it should be
their call and not his.

		The summary of concerns, there are two of them here.  Just take a
quick look and I won't read them allow and waste your time.  They are
listed in the study.  Next slide.

		CHAIR FISHER:  Excellent and we appreciate that.

		MR. CARLEY:  And so there were plainly shortcomings in the conduct of
the studies.  In my judgment they didn't put the subjects at greater
risk for different reasons depending on a specific exception.

		Taken all together with the other deficiencies noted they may have
compromised the studies a little bit.  They are at least technically out
of compliance with Subpart K.  I defer to the board about whether they
rise to the level of substantial noncompliance.

		CHAIR FISHER:  Okay.  Only questions if it's a technical question.
We'll save our discussion for after.

		Yes, Jerry and then Sean.

		DR. MENIKOFF:  Two points.  Do we know did the IIRB get informed of
the various changes like changing the test compound?  If so, what action
has it taken?

		MR. CARLEY:  I don't know the answer to that.  Dr. Carroll probably
does.

		DR. MENIKOFF:  Secondly, I take it it was probably intentional on your
part.  You don't characterize the change in the test compound as a
protocol deviation.  Was that because he amended the protocol?

		MR. CARLEY:  Yes.  I'm not sure.  That is an important distinction.  I
think the important point is that the protocol was changed without IIRB
oversight and without reflection of that change in the consent
documents.

		DR. MENIKOFF:  It might reflect in terms of how you then characterize
this.  I would assume normally protocol deviation would be related to
the approved protocol.  There was a deviation from the IIRB approved
protocol.

		MR. CARLEY:  I wasn't making that distinction.  I was just saying yes,
he amended the protocol, perhaps improperly.  If he was consistent with
the amended protocol, it wasn't a deviation but it was a different kind
--

		CHAIR FISHER:  Sean and then Sue.  Sue.

		DR. FISH:  One quick question, John.  Did you find any evidence that
any of these protocol deviations had been reported to the IIRB?

		MR. CARLEY:  I did not.

		DR. KIM:  Short question.  Has the informed consent form indicated
that subjects may be tested with more than one product?

		MR. CARLEY:  The consent form for the SCI-001 study describes the
study has we know it.  This is going to be a test of several different
repellents and you are going to get one or another of them.

		Your odds of getting any one of them on any given test day are such
and such and so forth.  The consent document for the WPC study makes no
reference to any other materials.  I should add that neither consent
document makes any mention of LipoDEET 3434.

		CHAIR FISHER:  Kannan.

		DR. KRISHNAN:  One of you presented some of the MOEs based on
compression of the LD-55s.  Since there were some repeated applications
on the same individual, was any attempt made at all to compare NOAEL
from any repeated demonstration studies?

		MR. CHARLIE:  We did one calculation.  I assume you have seen Dr.
Carroll's response to that of the multiple washings and all.  The
changes that there was some interference from day to day of significance
there are pretty slim.

		CHAIR FISHER:  All right.  In an effort to catch up, and we're not too
bad but we are going to break for lunch.  I remind the board we have an
administrative meeting so everybody get right into the room and then
we'll come back at 1:45.  It's a little less than an hour but we'll come
back at 1:45.

		(Whereupon, at 12:53 p.m. off the record for lunch to reconvene at
1:52 p.m.)

	A-F-T-E-R-N-O-O-N  S-E-S-S-I-O-N

	1:52 p.m.

		CHAIR FISHER:  Okay.  We're going to get started.

		Dr. Carroll, I believe we're ready for public speakers.

		Okay, Dr. Carroll.  For the record, please introduce yourself, your
affiliation.  You have five minutes.  We did all get your response
letter, and we've read it.

		DR, CARROLL:  Thank you.

		This is Scott Carroll from Carroll-Loye Biological Research.  And I'm
here today to make comments on the Ethics and Science Reviews of our
insect repellent efficacy studies of SCI-001 and WPC-001.

		By way of context, I'm sure you remember this at some level, but I'd
like to say that these protocols and the conduct of these studies in
terms of human protection greatly exceed, as far as I know, anything
that's previously been conducted in the field of insect repellent
testing.

		The science of these studies is basically very sound.  And I'll give
you a quick overview of that in a minute.  I'm just going to show a few
slides to highlight, I think, some of the main points that Mr. Carley
brought up.  It's a bit like playing three dimension chess with a
computer, but I'll just skip over these things in a way as I best can.

		To give you context for why these studies were conducted together, and
I think this is very relevant to the Board.  Each spring what I do now
is to map the spread of mosquito numbers from south to north in
California and West Nile Virus and other potential pathogens from south
to north.  And in contrast to all the rest years and since we've had
West Nile Virus in California, as the mosquitos moved north to where we
conduct our studies and began to appear in sufficient numbers to conduct
one of these high intensity botany studies that we do, West Nile Virus
was very close on its heels.

		We've had previously a window of several weeks to conduct such
studies.  But in analyzing the data through June, it became apparent
that we might have as little as a week to conduct all of our 2007
testing.  At that point I made the judgments that we would need to
complete both studies as quickly as possible. Hence, we ended up with a
lot of temporal overlap in their conduct.

		One of the first things we came up with was a question of spacing.
Mr. Carley also brought it up because he was concerned about misleading
statements in our reports saying that when spacing protocol was violated
that all subjects were testing the same active ingredient.

		And this just gives an idea of what it looks like.  Here on the left
we have pairs that are too proximate.  This happened on the 12th.  We
had quality assurance personnel present and they engaged me and a couple
of technicians simultaneously, and that meant we had less monitoring
going on briefly.

		And these subjects are clumping, the ones farther away but still too
close, are testing the OLE.  All the people in the foreground are
testing DEET.  There are also people in back of the photographer.  So
this was ephemeral, the kind of distribution we prefer.  It gives you a
picture of how these tests are conducted, what a proper distribution
looks like, at least in my eyes on the right.

		And in this case what you see there is, those are DEET subjects, all
these subjects are in this case on the right in back of the
photographer. So we kept them spatially segregated.  And the untreated
controls worked in the appropriate proximity then to both treatment
groups.

		The questions about how we -- well, let me go to the amendment.

		I'm sorry. I advanced my slide with that button.

		The most serious error, other than that, that I made and this is very
interesting to me in terms of how I tried to learn about proper
consenting, et cetera, how to run one of these studies.  Had to do with
not seeking approval for the two amendments I made, one to include the
virus screening and the other to substitute the very similar DEETs
formula, and that's the I-001.  I did not understand that all amendments
require IRB approval.  Obviously, that's very basic to this process and
once that was made clear to me, many things fell into place.

		I have been conducting studies with IRB oversight since 1996.  No one
ever mentioned that specifically.  It might have been assumed that I
would know that.  I have taken the online CITI courses in this  conduct.
 And in conducting these studies it's not mentioned in any of the
materials I've studied for that.

		And in approaching IRB, it's not the current one the IIRB and state
and federal agencies I've heard time and time again we only need to know
about things that influence subject safety. I hear that all the time.
And the reason I hear that a lot is because I frequently volunteer
information or make inquiries about do you know this or that or this or
that.  I'm not trying to ask them about trivial things.  And so I've
always felt I had surprising latitude to make these judgments.

		And it's not uncommon for there to be confusions among the -- and less
experience between deviations and amendments.  And I think that was
probably not clear in discussions I've had with people about this in the
past.  And so those were frank errors.  They've been reported to the IRB
and along with what I regard as minor consenting errors on a couple of
subjects that I don't have time to give you the details on right now.
And those are in process at the IRB currently.

		So again, the last thing is simply to talk about the distribution of
treatments across days and across sites.  Obviously we have multiple
sites to improve generalizability.   Having multiple days within the
sites probably does not decrease generalizablity.

		The results of these studies are relatively unambiguous.  Even though
there are site effects, the major effects, the major differences between
treated and untreated subjects.

		Here the treatment effect is the third one down.  And it's lower here
because we're testing DEET products again.  DEET products principally.

		If we're interested in the effect of previous treatment, previous
treatments falls out as highly nonsignificant.  This sample is
structured in a way that makes it very easy to determine that.  For
those of you who didn't noticed in my written comments, the exclusion of
previously treated subjects was originally introduced, I mean long ago
when I was trying to keep people from uncontrolled backgrounds with
respect to participating in the studies.  At this point we know that
anyone previously treated has gone to failure.  They've washed two to
three times between exposures, between different treatments.  And these
data corroborate the fact that there wasn't an impact.  So my intention
was not to exclude this kind of study conduct based upon that exclusion
criterion.

		And next slide.

		Likewise we see no effect to previous treatment in the WPC study.

		That's all.  Thank you.

		CHAIR FISHER:  Thank you.

		Now are there any technical questions for Dr. Carroll.  Just technical
questions?  Jan?

		DR. CHAMBERS:  Dr. Carroll, a couple of questions.  One is what do you
know about the ability of soap and alcohol to wash either the DEET
preparations or the OLE preparation off the skin?

		DR, CARROLL:  We don't have quantitative data about that.  You can
certainly tell that the smell disappears and the skin sensation
disappears, especially with the -- well soap and water does a very good
job.  Alcohol, I think, enhances that.

		I do know in terms of the response of caged mosquitoes to recently
washed arms, I think there's a little reduction in avidity immediately
after washing and the alcohol stripping.  Maybe just the attraction cues
that are normally present on the skin are reduced.  Certainly the
effectiveness of the product disappears with that cleaning.

		DR. CHAMBERS:  And the other question I have is what do you know about
the distance that the smell, or whatever the insect would be repelled by
that's volatilized, how far away from the person does that aura go?

		DR, CARROLL:  It varies by treatment.  It's been quantified in a few
cases, but I don't know of any studies that quantified it in anyway
that's very generalizable.  You know, people know how far they can smell
repellents on one another; mosquitoes, you know, they experience a
similar universe.

		DR. CHAMBERS:  And then one further question.  In light of one of the
comments that one of our consultants made this morning, I guess there
are repellents that are contact repellents and there are others that are
volatile repellents. These two are?

		DR, CARROLL:  These would be volatile repellents.  Yes.

		CHAIR FISHER:  Kannan?

		DR. KRISHNAN:  When the participants were treated more than once, I
mean it could literally on subsequent days and so forth, were those done
on the same limb?

		DR, CARROLL:  Yes, those were on the same limb.

		DR. PHILPOTT:  I have a series of rather quick questions.

		The first is I do not or at least cannot find in the thousand pages of
documents that we have an MSDS for LipoDEET 3434.  Was one available and
was it available to study participants?

		DR, CARROLL:  Yes, it was.

		DR. PHILPOTT:  Okay.  My second question is in your letter you
mentioned that different personnel managed the subjects for each study
during simultaneous efficacy testing.  Now it's a little unclear to me
exactly how many study personnel were on hand, and particularly for a
day like July 15th in Butte County where you have 26 study participants
including 14 that were involved in the SCI-001, 10 in the WCP-001 plus
two controls.  How were these personnel divided up and how did they
manage and oversee the participants?

		DR. CARROLL:  There were two people per untreated control. And then
there was a group leader for each of the two studies.  And then three
additional personnel that provided support, assist in keeping the groups
segregated and provided food, water, shelter.

		DR. PHILPOTT:  So about nine?

		DR, CARROLL:  Seven total.

		DR. PHILPOTT:  Seven total?

		DR, CARROLL:   Eight.  Eight.

		DR. PHILPOTT:  Let me just go through my list here.  Informed consent
documents have specific study titles on them.  The controls, the
untreated controls crossed studies on three days.  Did they sign two
consent forms?

		DR. CARROLL:  Yes.

		DR. FISH:  Dr. Carroll, were any of the protocol deviations that were
listed in Appendix five, I think, were any of those submitted to IIRB?

		DR, CARROLL:  I can't recall at the moment.  I think they may not have
been.

		CHAIR FISHER:  Any other?  Yes?

		DR. JOHNSON:  Could you put up the previous screen with all the tables
that you had on the previous screen?  Thank you.

		The treatment included the controlled or uncontrolled --

		DR, CARROLL:  No, it does not include the untreated control.

		DR. JOHNSON:  The active ingredients?

		DR, CARROLL:  Yes.

		DR. JOHNSON:  And period within site, was that the comparing days?

		DR, CARROLL:  Yes, it is. Yes.

		DR. JOHNSON:  And how come we have six degrees of freedom for that?

		DR, CARROLL:  Because of the number of sites and days.

		DR. JOHNSON:  There's three sites.

		DR, CARROLL:  Two sites.

		DR. JOHNSON:  Two sites, three days so there should be two degrees of
freedom within one site and two degrees of freedom within the other
site, making four degrees of freedom.

		DR, CARROLL:  I'll have to review that.

		CHAIR FISHER:  Any other questions?  Yes.  Did you want to clarify
something, John?  Okay. So John and then KyungMann.

		MR. CARLEY:  In response to the earlier question, you said that the
subjects did get an MSDS for LipoDEET 3434?

		DR, CARROLL:  Yes.

		MR. CARLEY:  The one that was included in your response to our request
for additional information which you sent to us on September 24th --

		DR. CARROLL:  Yes.

		MR. CARLEY:  -- was dated September 24th.  Was there a different one
that the subjects saw when they signed consent?

		DR. CARROLL:  I don't think there's a different one.  I can double
check that.  Dated by the --

		MR. CARLEY:  The MSDS itself was dated September 24th. that you sent
to us on September 24th.

		CHAIR FISHER:  KyungMann and then Susan and then Kannan.

		DR. KIM:  I had this question to Mr. Carley earlier.  But the study
involved four treatment.  And I believe protocol said  randomization of
subject among four treatment.  And what method of randomization was
used?

		DR, CARROLL:  What we've normally used in the past was a random number
generation system.  And assignments based upon -- well, I'll tell you
what we did in this one because I have, as you might imagine, newer
technicians in my laboratory when we were ready to assign the intended
randomization table was not available. And so what I simply did was I
had people -- I had a technician that morning put name -- put subject
numbers in a hat, okay.  And then I actually filled one material -- one
test material at a time with lots needed sequentially from that hat.  As
simple as that.

		It wasn't actually a hat, but you know what I mean.

		DR. KIM:  Yes.  But that doesn't seem to make any sense knowing that
on the day July 8th of 2007 there's a total of 13 subjects tested.

		DR. CARROLL:  Yes.  Yes.

		DR. KIM:  And if you want a randomization, you probably like to do it
close to three tags, say, three DEET, L302, 30L3434, 30--

		DR, CARROLL:  Yes, that would have been a better way to do it.

		DR. KIM:  Right.

		DR. CARROLL:  I didn't do it that way.

		DR. KIM:  Then how did you do it; that's what I'm asking?  I mean,
because you had two, three, five, three and that raises the entire
question about whether the randomization was appropriate.

		DR. CARROLL:  You saying the number of subjects, two, three, five and
three?

		DR. KIM:  Yes.

		DR. CARROLL:  Yes.  Well, I structured that because my goal was to
have on any -- throughout the -- over the five exposure days to have to
the extent possible  the same number of subjects within a given
treatment compared to Ultrathon across all those days.

		DR. KIM:  Right. So that --

		DR. CARROLL:  So it's very close to a symmetrical design based upon
that goal.

		DR. KIM:  Well, your explanation doesn't seem to jive with the numbers
you had.  The natural thing would be to do equal randomization each time
you --

		DR. CARROLL:  Randomized within a given treatment.  But I already
decided how many of each treatment would be present on a given day given
the number of subjects I had available to work with.

		DR. KIM:  Well, I don't quite understand when you say "within a given
treatment."  Randomization is done --

		DR. CARROLL:  Which subjects were assigned to a treatment.

		DR. KIM:  Right.  So that's across treatment, right?

		DR. CARROLL:  I'm talking about within a treatment.  Oh, yes, well who
is going to end up in which treatment, yes.

		DR. KIM:  Right.  So if you want to balance the allocation evenly each
day, the natural thing would be to do equal randomization.

		DR. CARROLL:  To have the same number for each day?

		DR. KIM:  Right.

		DR. CARROLL:  Yes.

		DR. KIM:  And so your explanation and the number that we see just
doesn't seem to jive.

		DR. CARROLL:  Yes. Given the number of -- given the ways in which I
had to distribute subjects among these two tests that I had not
originally planned on running simultaneously, I was not able to for each
day use the same number of subjects across treatments.

		DR. KIM:  But I believe your reason of protocol said that you were
going to test for treatment randomizing subjects to these four
treatment?

		DR. CARROLL:  Yes.

		CHAIR FISHER:  Well, it sounds like he didn't do that and he knows
that that was in the protocol, right?

		DR. CARROLL:  Yes.

		DR. KIM:  Your explanation doesn't seem to jive with the protocol
there.

		CHAIR FISHER:  I'm not sure. I mean, I think he's answered that he did
not do it.  And we have the protocol to know if it was in there or not.

		DR. KIM:  All right.  The next question is earlier this morning Dr.
Gupta mentioned that a typical exclusion of the substance takes between
30 and 48 days.  And the problem with the multiple treatment given to
the same subject consecutively is the whole issue of a washout.  And
with the biological inflammation of about 30 to 48 day sort of --

		DR. CARROLL:  Hours.

		DR. KIM:  Hours.  Thirty-eight hours.  Okay. All right.  I withdraw
that question then.

		DR, CARROLL:  It's still relevant, I don't think it influenced of this
study.

		DR. KIM:  So there is an issue of whether there is a sufficient
washout period to ensure that previous treatment doesn't effect the next
day's outcome?

		DR, CARROLL:  This data set can be used to analyze that.

		DR. KIM:  But as was pointed out, I think there's some fundamental
issues usually in the analysis --

		CHAIR FISHER:  I think these questions are -- I'm not an expert in
this, but I don't think we should be discussing with Dr. Carroll
methodological issues in terms of whether or not we agree with the
methodology or think it's appropriate.  I think if there was specific
questions that we need to inform decisions about it.  So let's keep it
to whatever the specific question is, not whether he kept to this or
that.

		DR. KIM:  So I'm sort of getting at the sort of validity of Dr.
Carroll's argument that the period didn't affect the outcome.

		CHAIR FISHER:  Okay.

		DR. KIM:  Because I have a question about that analysis.

		For example, can you tell me what kind of error models that was using
these-- there's four types of errors one can generate.

		DR, CARROLL:  Well, type three sums of squares and subject was random.
 But I can't tell you beyond that.

		CHAIR FISHER:  Okay.  Suzanne, Kannan and Lois.

		DR. FITZPATRICK:  I had a quick question.  I was going to ask you if a
person was in the experimental group and then was in controlled the next
day.

		DR, CARROLL:  No.

		DR. FITZPATRICK:  But I see that it didn't. So you must have picked
the controls out.  At randomly you might expect that some of those would
have become a control the next day when they were an experimental person
before.  So did you specifically pick the controls out to make sure they
hadn't been in treatment in a group the day before? Do you see what I
mean?

		DR. CARROLL:  Yes. None of the controlled subjects were ever treated.

		DR. FITZPATRICK:  Right.

		DR. CARROLL:  But that was really for other reasons.

		DR. FITZPATRICK:  Okay.  Subject 13?

		DR, CARROLL:  Not that I recall. But I don't anticipate that would
have an effect anyway.

		CHAIR FISHER:  Remember if it's in the data -- if it's in the
materials, you know, if it's problematic that's something for us to
discuss.  But not the --

		DR. CARROLL:  Things without correction, yes.  But the control
subjects were chosen in advance as a segregated body, which is relevant
to the conversation earlier this morning.

		CHAIR FISHER:  Kannan?

		DR. KRISHNAN:  I see that the same number of subjects were involved in
both protocols.  But is that also true between locations?

		DR. CARROLL:  Twenty subjects per -- total of ten per treatment per
site.

		DR. KRISHNAN:  So in those two locations was the same set of subjects?

		DR. CARROLL:  No, no.

		DR. KRISHNAN:  Okay.

		DR. CARROLL:  There was some overlap, not complete overlap in subject
constituency between the sites.

		DR. KRISHNAN:  And one of the exclusion criteria was that the subject
did not use the repellent within 24 hours?

		DR. CARROLL:  Yes.

		DR. KRISHNAN:  But when that was not respected, was it communicated to
the IRB, was there any communication there?

		DR. CARROLL:  No, that wasn't.  That was simply the fact that I was
not thinking bearing that exclusion criterion in mind I hadn't initially
intended it to apply to this kind of case.  But that is how it reads.

		CHAIR FISHER:  Okay.  Lois and then Richard.

		DR. LEHMAN-McKEEMAN:  Very detailed question.

		DR. CARROLL:  Yes.

		DR. LEHMAN-McKEEMAN:  What was the time of day that these studies were
started?  And what I'm asking is when studies were run on successive
days and a subject was treated with one agent on one day and a different
agent on the other day, what was the actual duration of time between
those actual treatment periods?

		DR. CARROLL:  Twenty-four hours, you know give or take probably an
hour maximally.

		DR. LEHMAN-McKEEMAN:  Give or take an hour?  So they would start in
the morning?

		DR. CARROLL:  Yes, 7:00 a.m.  Yes.

		DR. LEHMAN-McKEEMAN:  Okay. And how long were they in the field?

		DR. CARROLL:  Usually until early evening.  So, you know, 7:00 p.m.

		DR. LEHMAN-McKEEMAN:  Okay. And I noticed, again to Kannan's question,
part of the informed consents does say you haven't used repellents
within a 24 hours period.

		DR. CARROLL:  Exactly.  Yes.

		DR. LEHMAN-McKEEMAN:  What was the basis on which that parameter --
what was the rationale for having that stipulated?

		DR. CARROLL:  When I first included that criterion in my protocols,
which must have been quite a while ago, it simply seemed like a good
idea to exclude people who had been using repellents where I didn't know
what they would have been using, or you know might not have been
familiar with the product or how it was applied, or exactly when they
had applied it. I wasn't thinking in terms of a situation at all where a
repellent would have been monitored to failure and then washed two or
perhaps three times subsequently.  So a failed repellent removed and
then a reapplication the next day.

		DR. LEHMAN-McKEEMAN:  Okay.

		DR. CARROLL:  Okay.

		CHAIR FISHER:  Richard?

		DR. SHARP:  I think we already had this, but we had a hard time
hearing Dr. Krishnan's question.  So the change with regard to the
protocol allowing individuals that had received some form of treatment
within a 24 hour period to be eligible was that deviation actually
reported to the IRB or not?

		DR. CARROLL:  No.  Was not.

		DR. SHARP:  Okay.  And a question about the control subjects. You
mentioned that there were two members of the research team who were
overseeing the two controls.  Were members of the research team actually
serving as control subjects?

		DR. CARROLL:  No.

		DR. SHARP:  Okay.

		DR. LEBOWITZ:  One quick question.  You talk about one minute periods
of exposure in 15 minute intervals.  Did that period of exposure occur
at the beginning in all subjects during all such 15 minute periods?

		DR. CARROLL:  I'm not sure what you mean by "at the beginning?"

		DR. LEBOWITZ:  Well, you have a one minute period of exposure during
15 minute intervals.  So in a 15 minute interval it could occur at the
beginning or anytime in the middle or at the end?

		DR. CARROLL:  Well, the interval between all exposures was at or very
close to 15 minutes.  Does that help?

		DR. LEBOWITZ:  Okay. So they were exposed to one minute --

		DR. CARROLL:  And then 15 minutes later they were exposed another
minute.

		DR. LEBOWITZ:  Okay.  Thank you.

		DR. CARROLL:  Or 14( minutes or --

		CHAIR FISHER:  Anybody else?

		Okay.  Thank you very much, Dr. Carroll.

		DR. CARROLL:  Thank you.

		CHAIR FISHER:  Any other public comments?

		Okay.  So now we will go to Board discussion.

		John, I just wanted to make sure; I don't remember if you presented us
with the charge questions?

		MR. CARLEY:  No, I did not.

		CHAIR FISHER:  Okay.  So I guess should we do them one-by-one because
it seems like we divided people one-by-one?

		MR. CARLEY:  There are three pieces here.  One is this quick recap of
the split protocol specific issues that had come up. And then there's
the charge question for SCI-001 and then the charge question for
WPC-001.

		I think the Board needs to think about whether you want to talk about
those studies together for a while and then look at the specific charge
one at a time or what.  I don't know what the best way for you to think
about it is.

		At the end of the day you have to think about them separately but you
may want to start by discussing them together.

		CHAIR FISHER:  I think I'll leave that.

		Jan, what is your recommendation, because you're on many of them here?
 And then anybody else who has a recommendation.  How did you organize?

		DR. CHAMBERS:  I tried to write them up separately like you had the
questions.

		CHAIR FISHER:  Okay.

		DR. CHAMBERS:  So I think I'd rather pursue it the way I'm going to
try to get through my write up here.

		CHAIR FISHER:  Okay.

		DR. CHAMBERS:  Are we ready for that?

		CHAIR FISHER:  I think he has to read them.

		DR. CHAMBERS:  Okay.

		MR. CARLEY:  Back up one.

		The specific issues that we raised, which are pretty much embedded in
the charge questions, but just a quick recap:

		Is sequential testing of different repellents by the same subject on
successive days likely to have effected the results?

		Can partial results testing the same repellent in the same habitat on
different days be polled to comprise the designed sample size?  Is this
likely to have effected the results?

		If only one limb is treated, does it matter which one or how it is
selected?

		If a minimum intersubject distance isn't maintained, could this effect
the results?

		And then the ethics related question:  If one arm of a study is deemed
unacceptable by virtue of not having been in substantial compliance with
the rule, what are the implications for other arms of the same study?

		Bill reminds me that there's also the specific question of
substitution of materials LipoDEET 3434, which I inadvertently omitted
from that last.

		The specific charge question for SCI-001, is that first on your list,
Dr. Chambers?  Is this study sufficiently sound from a scientific
perspective to be used to assess the repellent efficacy of the
formulations tested against mosquitoes?  Please comment specifically on:

		First, whether participation in field study testing by several
subjects on the day after they had been treated with a different test
repellent is likely to have effected the validity of the results for
those subjects on those days;

		Second, the effects of changes to the experimental design resulting in
evaluation of repellents using fewer than ten subjects per treatment per
day followed by pooling of results by site for a statistical analysis.

		Next.  Does the available information support a determination that
this study was conducted in substantial compliance with subparts K and L
of regulations at 40 CFR Part 26?  Please comment specifically on:

		The decision to use a different test formulation in place of one of
the test materials described in the protocol reviewed b the IRB, EPA and
the HSRB;

		And how to assess the ethical conduct of an insect repellency study
involving multiple test formulations when there is an ethical deficiency
in the conduct of the study with respect to one of the test
formulations.  If the ethical deficiency warrants not relying on the
results of the testing with regard to one test formulation, under what
circumstances, if any, does the ethical deficiency affect the
acceptability of the results from testing the other formulations?

		CHAIR FISHER:  Thank you.

		Jan?

		DR. CHAMBERS:  I think this is the most complex issue you've presented
us with yet.  Testing our stamina, I think.

		I'd like to start out with one editorial comment.  And it is for me,
but I do believe others on the Board concur, is that I'm wondering
seriously if this not premature to be bringing to us.

		I read Dr. Carroll's responses on the plane, because we got them
really, really late. I don't know whether you guys have actually had a
chance to look at those and whether that has changed your analysis any
or not. But if it does,  I think it would be better to present that to
the Board in terms of a modified analyses, if that's the case. But I
don't really know at this point. So take that for what it's worth.

		My question was A1, and that was with respect to the consecutive days
of treatment.  So if I can find my notes here.

		This deviation -- this is what I wrote up before.  So let me pretty
much go over what I wrote up before and then I'll comment based on what
I read with Dr. Carroll's responses.

		The deviation of not allowing a day of non-repellent use before
testing may or may not have had an influence upon the results.  There's
insufficient information available to the Board to make a judgment about
the impact of this experimental result on the results. Certainly this
testing strategy may have been more efficient in terms of getting all
the products tested, certainly this testing strategy of not having days
in between would have been more efficient for getting everything done in
a set period of time with a suitable group of subjects.

		I've noticed that some of the other protocols we've gotten from other
people do not have this specific one day of non-repellent use as an
exclusion criterion would suggest that the one day probably is really
not necessary, at least it's not necessary in their protocols.  So that
implies that the effects of the repellents dissipate over the course of
the night following testing.

		However, on the other flip side of that these products were designed
to improve durability. One of them was designed to improve durability
and another was designed to inhibit evaporation. So that suggests that
there might be a more prolonged effect. So there might have been
residual effects; it's really kind of hard to say.

		Let's see what makes sense here.

		If there is information available on the length of time that there is
still some residual efficacy, such as a laboratory test, this
information was not provided.  And I gather from the answer a little
while ago that's not known.

		I'm going to be a little random here because I've had to change my
write up.

		I guess it appears that with these particular products the complete
protection time was at nine to ten hours, which suggests that if they're
starting them all at 7:00 in the morning, nine or ten hours later the
efficacy is gone.  Waiting the rest of the 24 hours to dissipate the
rest of it; they've taken a bath, they've washed twice wit Neutrogena
soap, they've washed once with alcohol suggests to me that probably the
residual effects are gone.  And so my gut feeling, not based on any
science or anything, but my gut feeling is that probably the results on
consecutive days are valid because I think the residual effects of the
previous day's repellent would have been gone.  But, again, there's not
a lot of information to conclude that.

		Let's see.  A couple of the other things that you had as your
preliminary questions above that is:  One limb or the other.  I cannot
see as a biologist why that would make any difference. So I can't see
that testing on one limb is invalid in any way.

		The minimum distance between the pairs of people?  Again, if the are
solarization doesn't extend very far, then it shouldn't make any
difference. But, again, we don't have very much information. So my gut
feeling is that that probably didn't make a whole lot of difference.
But, again, there's no information.

		I am sympathetic -- well, let's see, let me just say this first.  One
of our consultants, I think if I got it right a little while ago this
morning, suggested that testing over several days was probably more
desirable than testing all on a single day.  And so this protocol that
was supposed to be done all on one day that ended up being over several
days may have actually provided more information.

		Again, I got the impression from our consultants that these data,
regardless of how you run them in the field, are not going to be
terribly accurate anyway.  So you know, I'm really not sure that those
little deviations make a whole lot of difference.

		Also, I have to question, I am sympathetic to the reasons that Dr.
Carroll gave for comprising all of this and that the West Nile Virus was
moving up the state and they really didn't have much choice in trying to
get it done quickly.  And you don't want to wait and put the subjects in
danger of infection. So how much flexibility does anyone at EPA allow in
the protocols like that to allow for changing environmental conditions?
Again, this is not a white rat in a cage study where you can control
those sorts of things.  You have to depend upon the environment and
adapt to it.  So is it reasonable to go ahead and allow deviations like
that in light of the changing environmental conditions?  That's a
question I can't answer.  You all have to answer that.

		So I think I was a little more random than I usually am here.  But it
seemed like it was just too much information here at the end.

		I guess bottom line in my opinion is that I think the consecutive
days, in my mind, are probably not impacting the results.  And the one
limb, in my mind, doesn't impact the results.  And the minimum distance
that was mostly maintained correctly, probably did not impact the
results.

		CHAIR FISHER:  Thank you, Jan.  And I think you've said that clearly,
as usual.

		Who?  Michael?

		DR. LEBOWITZ:  Now I know why we sat next to each other.

		Mine's going to be a little bit disjointed, although I didn't think
Jan's was.

		There was definitely some straits to the study, including
predetermining dosimetry in the lab and reaching a predetermined dose
therefrom to use in the field.

		The statement that then differed from former industry standard was
probably correct.  And the fact that the repellent was applied in the
field by techs was a good idea.

		Now there's an argument in my mind whether the differences in
temperature, relative humidity and light intensity within a day was
pertinent or not to the investigation.  The fact that they were similar
among days and between sites, which appears to be the case, is probably
a strength.  And if they had been accounted for within days given the
wide range each day, then it would have been a good attribute for
repellency testing.  The same is true of the question about extending
the starting time so that dusk was included in one page. But I didn't
find any indication as to what impact that had on any of the results;
the days in which dusk was included.  So in the end, I guess, I had
questions about the variability and impact of the invariability in
temperature relative humidity  and light intensity.

		I was pleased that no mosquitoes pools are sent -- no chicken flocks
and neither of the counties in which testing occurred were positive for
West Nile Virus.

		I did like the fact that the corrective mosquitoes were identified and
tested by RT-PCR for both West Nile Virus and equine encephalitis types
and at QCD, which I think was good.

		It was interesting that Culex tarsalis is one of the primary viral
carriers  did not land on any of the treated sites, so that was nice.

		The number of samples, actually, corrected from treated limbs and used
in pooled specimens for testing was good.  And, in fact they weren't
positive was good.

		I thought exclusion criteria were appropriate.

		And let's see.  Okay.  The fact that the untreated control subjects
experienced a minimum of one branding was intensified per exposure and
448 of the 450 periods was good.  I didn't actually check whether there
was, indeed, 450 periods.  But certainly if random over the number of
days and number of sites it would indicate an adequate amount of
mosquito landings. I guess it's called mosquito pressure or what I call
density in each site at each time was sufficient.  And I was pleased
that the Kaplan-Meier test was performed and give similar results.

		Going on to some of the other criticisms. It still bothers me that
different test materials were applied on the same day in each test site
and ending up with insufficient number was tested for each repellent
during each day in each site to determine day-to-day affects.  And I
don't think the ANOVA was calculated correctly or was powered
sufficiently to look at all of that.

		And I think Mr. Carley has gone over that in great detail, I don't
want to go over it any further length.

		Applying the repellent 150 to 210 minutes before first exposure and
the effects of travel I don't think are fully known.  And I'm a little
bit concerned about that as well.