Okay.  And comparisons between all of the three test materials may not
be appropriate if environmental conditions differ for one of them.
That's actually an expansion of one of my other comments.

		I still would have to see confirmation. We had some discussions from
consultants, but I'd have to see more confirmation for the
investigator's statement that the LIVE is identical to that of an FCB
classically used to measures of repellency by insects.  Okay.  So that's
still a question in my mind.

		And then in response to the charge, I'd like to read that last,
although I've come to some tentative conclusions based on the fact that
protocol criteria were not followed very well in terms of randomization,
attempts at pooling, testing on subsequent days given potential for
effects.  It might not have been visible given the numbers of subjects,
et cetera, tested repeatedly on different days.

		And we're going to talk about pooling, et cetera, next.  So I'm going
to  leave that for now before I decide whether one can conclude or not
that the study was sufficiently sound from a scientific perspective.

		CHAIR FISHER:  Thank you, Mike.

		Steve?

		DR. SCHOFIELD:  I think Jan almost exactly summarized my point of view
on this.  I mean, I sense a certain tentativeness in her conclusion.  So
I guess for me the key question was the potential for a residual
repellent on the limb 24 hours later to influence the response of
mosquitoes.  And like Jan, I think it's probable that it didn't because
these things largely their repellent efficacy or they have substantially
have lost it within eight hours.  There was an overnight rest period and
there were frequent washing.  So I think that it's probable that there's
no accumulation.

		And I think I captured from Dr. Carroll's presentation that the ANOVA
failed to pick up, although it was probably not adequately powered,
failed to pick up any signs of cross interactions.  In other words, it
found some differences among the treatments which would have been
blurred if there had been a great deal of carryover back and forth. That
would have been a much more powerful internal evidence of independence
if instead of using preselected controls, if there were untreated
controls on one day who became treated subjects and other days and so we
were actually able to see whether someone was a control on day two but
had been treated day one responded differently from a control who had
never been treated.  But at the end of the day I still think it's likely
that the influence would have been below the limit of detection by the
relatively inaccurate methods that even if you had perfect precision in
this matter, you will still have a great deal of imprecision in your
final conclusion.  So, actually, I'm just lending my support to Jan
Chambers' view on the scientific aspects here.

		CHAIR FISHER:  Dallas?

		DR. JOHNSON:  Thank you.

		I don't think I have too much to add.  Many of you may be aware that
I'm a co-author of a three volume set of statistic books called Analysis
of Messy Data.  And this experiment would qualify. But it's there are
some experiments that are too messy to know how to analyze, and this
experiment may actually fall in to that category as well.

		But I think it does give you some general ideas that are probably --
the good thing about statistics is if it looks pretty good and it looks
obvious, it's probably okay even though you may not be analyzing it
exactly the right way.

		I did do a back of the airplane calculation on the way out as to try
to get at the question as to whether there was a difference due to
having a treatment on a previous day, whether it would have any effect
on the results on the following day.  And so what I did was I tried to
go through subject-by-subject and see whether the time to first bite, or
whatever criteria they were using, whether that changed very much
depending on whether they had gotten a treatment on the day before.

		So, for example, subject A in Butte was a 7.5 on day one and a 9.75 on
day two. And so there was a change there of 2.25 hours in terms of that
particular thing.

		And so I did that for every subject assuming that the four days in
between the testing that there was sufficient time to not worry about
whether the treatment had been received on the previous day or not.

		And I sort of said in my mind that if the change was no more than a
half an hour, that I would call it a tie.  And if the change was more
than a half an hour, I'd say I got an increase.  If it was less than a
half an hour or if it went the other way a half an hour more, then I
would say I got an increase.

		And so in doing that, there were 19 data points in which the subject
got a treatment on the previous day.  Twelve of those the following day
had an increased hourly rate, seven had a decreased hourly rate and four
sort of tied.  And so there was a little bit of evidence there, 12
versus 7.

		I tried to get on the web here a while ago to see if I could get the
sign test and get the P value for that, but I couldn't.  And so I kind
of did another back of the wall normal approximation, knowing I don't
satisfy all the requirements. And it doesn't appear that it's large
enough to be statistically significant.  But there is a bit of evidence
that maybe there is an effect.

		I think any other comments that I have will wait until the next charge
question.

		CHAIR FISHER:  Thank you, Dallas.

		I think it sounds like we should go on to the next charge question
about the pool, right?  Because they're all interrelated.  Okay.

		So KyungMann, I believe. So the charge question, the effects of
changes to the experimental design resulting in evaluation of repellents
using fewer than 10 subjects per treatment per day followed by pooling.

		DR. KIM:  When I first saw that question, I mean the thought that came
to my mind immediately is that generally if you have more observations
available for your analysis, generally better.  But that requires
certain assumptions to be satisfied. And so I started to go over the
data points, how they are distributed in terms of treatment sites and
dates, much in the way Mr. Carley presented.

		I came to the realization excluding the negative control observations,
we had only 33 unique subjects representing 80 data points.  And then I
started to look more deeply into the distribution of the subjects across
dates, sites and treatment.  Then I started to realize that perhaps the
subjects may have not been sort of properly allocated using
randomization mechanisms.  Again, putting some limitations as to what
kind of analysis one may be able to perform.

		So in order to combine results from different sites, for example, you
would require statistical independence of the observations.  And so if
you go down to each of the tables of the list of data points, you see a
fair amount of overlap between sites.  And so, I mean,  it's something
that you can do it.  But in the way that it is presented, it completely
ignores the dependency of overlapping subjects.  So the error estimate
would be wrong, for example.

		And in terms of there being less than the originally specified number
of subjects per day and having the experiment spread over five days,
again when I first saw that I was kind of delighted.  Because by having
the experiment conducted over multiple days you will be able to account
for the potential confounding by the difference in the wind and the
temperate in the different date. But then I realized that there's a lot
of overlaps of subject from day-to-day, standard analysis of combining
the results across date will not work.  So that sort of created sort of
a problem for me.

		Another point that I would like to make is that the study, at least
according to the protocol, was going to randomize three test material
along with the positive controlled treatment with Ultrathon.  So when
you randomize subjects into four treatment, the appropriate analysis
would be to look at four treatment together.  And after that you may
want to go into what we call parallelized sort of analysis of comparing
-- I mean looking at positive control to each of the three test
material.  But that was not done sort of in an appropriate way.  And I
found that sort of somewhat troubling.

		And, I mean, we had lengthy discussion about the first confirmed LIVE
versus just first LIVE. I don't want to get into that. We have said
enough of that issues.

		The other point that I would like to make is that after I have seen
the data set, in this case there is 80 data points from the treated
subject. And for 80 data points there was not a single censoring noted.
So  every data point had an event.

		So I went back to the earlier data from EMD-00123.  I have the numbers
to quote. In the EMD-004.1 there were 40 percent censoring.  EMD-004.2
there was 10 percent censoring in site one, 30 percent censoring in site
two. And then in EMD-004.3 that we reviewed in January there was 100
percent censoring in one site and 90 percent censoring in the other
site.

		Now we come to SCI-001.  From two sites four treatment there is zero
censoring.  And that was so troubling to me because I understand that
there is sort of a natural variability of the mosquito pressures and
difference in the temperature and the site selections.  But precisely
because of the reason the investigator confirmed the mosquito pressure
at the beginning of each day, and I'm wondering how could we have such a
stark variability from experiment-to-experiment?

		And let me stop with that?

		CHAIR FISHER:  Jan?

		DR. CHAMBERS:  If I'm recalling what the censor data was, and correct
me if I'm wrong here, but isn't that people that went to the time when
darkness hit and they had to quit?  And they got no complete protection
time because it lasted longer than the experiment could run?  So I
don't--

		MR. CARLEY:  Yes, that's what happened.  And the difference in this
case is that the function of the pretreatment and then just planning for
a longer test date.  Because they started off thinking that these were
going to be potentially 12 hour repellents.  So they pretreated before
they traveled, then they had the delayed start and then they did it at
high summer. They designed it to keep going to breakdown, and they got
there for everybody.  EMD was a shorter period. I think the field time
was eight hours.

		DR. KIM:  The EMD study had a field time of more than ten hours each.

		MR. CARLEY:  Okay.  But they didn't do the pretreatment and they
hadn't planned for as big a window.  And if I'm not mistaken, those were
done in the mid-fall when day length was much shorter. And so it was
harder to keep running. It got dark sooner.

		DR. BRIMIJOIN:  That's my recollection, too.  It was a false --

		DR. LEBOWITZ:  Well, I'd like to be corrected.  But my recollection is
that some of the censoring occurred because some of the participants got
tired and quit.  And that's just because it got dusk.

		MR. CARLEY:  What the censoring instances had in common was that a
particular subject did not go to the point of repellent failure.  And
the reason why that stopped doesn't change the fact that the time that
they used was the time that they went off test rather than the time of
repellent failure.

		DR. KIM:  Not all of them.  There were subjects who actually dropped
out before reaching the day end.

		MR. CARLEY:  Yes.  That's right.  There were some that they didn't
analyze because they dropped out too soon.

		CHAIR FISHER:  This study or the past study?  The past study?  Okay.

		Where are we here?  Dallas?

		DR. JOHNSON:  Yes.  I'm still here.

		I want to talk a little bit about these Kaplan-Meier things.  I
haven't done the Kaplan-Meier analyses before, but I've heard of them.
I have no doubt that they're appropriate things to do.

		But the analyses that are done here I assume is assuming that they
were different subjects on each group.  And the analysis of variance
that we saw a little while ago sort of took into -- I think, although I
have some doubts about the analysis, it apparently takes into account
the fact that some subjects were used more than once.  And so it didn't
treat them all as being independent since subjects was a random effect
in the model.

		And the conclusion in these three studies here, if I'm reading it
right, seemed to be that there's no difference in these treatments.  And
yet -- said there was a difference in the treatments.  So I'm a little
bit confused about that.

		The other thing, the other comment that I wanted to make is in
statistics it's always a lot easier to prove things are different than
it is to prove things are not different.  And so it takes a lot bigger
sample sizes to show things are equivalent than it does to show things
might be different.  Because once you can show they're different, it
doesn't matter what sample size you have. But in trying to say that
they're the same, then that often takes a much bigger sample size.

		And I don't know whether it's possible or not, but I guess I would
like to see some -- if we're going to claim these are the same, I'd like
to see some confidence interval for the difference between the two means
and to see how wide and how big that confidence interval is.  If that
confidence interval ends up being very wide, then they're really saying
we don't know anything at all.  If the confidence interval ends up being
very narrow, then we can probably say we know a lot.

		And so I guess right now that's my comments for this particular --

		CHAIR FISHER:  Can I ask a question, and then Jan wants to ask a
question?

		The ANOVA, that was on the treatment groups and the control?

		DR. JOHNSON:  No. I asked that question, he said it did not include
the control.

		CHAIR FISHER:  Okay.

		DR. JOHNSON:  So it was only the four active --

		CHAIR FISHER:  But why do we care if they were different?  Was the
point of the study not to compare to each other, but to compare them to
the control?   No?  It was to compare the efficacy of each to one
another?  No?

		DR. JOHNSON:  Well, in the reports that we have here, the three
reports are comparing each of the others to Ultrathon.

		CHAIR FISHER:  Right, to the Ultrathon.  Not to one another?

		DR. JOHNSON:  Yes, they're comparing each --

		MR. CARLEY:  Each test material was compared to the positive control.
None of them were compared statistical to the untreated control.

		DR. JOHNSON:  Right.  But the ANOVA, as I understood it, compared the
four active treatments to one another.

		CHAIR FISHER:  Well, that's what I didn't understand why does it
matter whether they're alike or difference?  I mean, I understood your
analysis --

		DR. JOHNSON:  Except in their conclusion.

		CHAIR FISHER:  Well, yes.

		DR. JOHNSON:  Here it seems to be that they're all the same and the
ANOVA said that they were different.

		CHAIR FISHER:  But not for the outcome.  The purpose of the study is
not to compare those, but to compare those to the controls, supposedly,
the positive and negative controls?

		DR. JOHNSON:  Well, I didn't see the protocol so I'm not sure that I
know the purpose.

		CHAIR FISHER:  Okay.  I'm just confused as to why it matters, other
than something interesting about whether there's something there in
day-to-day. But I'm just not sure.

		Okay.

		DR. CHAMBERS:  Yes, just continuing that same point, Celia, I think
our perspective is not whether you can make a valid comparison amongst
the various products or not.  That's for somebody else to be interested
in.  But this is, can you trust the complete protection time that were
calculated from this particular protocol for each one of the compounds
independently.  And that was the point that I got out of it.

		CHAIR FISHER:  And can I just ask, so the smallest -- the shortest
interval in which there was a bite was what?  Time period?  I guess my
question is I'm trying to get it-- I think it was Dr. Strickman who was
talking about there's always that odd mosquito that nothing bothers.
And I'm wondering why wasn't that odd mosquito around.  I mean, I don't
think we saw the odd mosquito.  Yes. Yes.  And so like is that realistic
not to see that.

		I mean what you were saying just changed everything and it really
questions, you know, complete protection time.  Because really what
you're saying is there should never be complete protection time if
you're counting every single.  Because there is always some oddball
mosquito around that doesn't care about repellency or something.  So did
we see that oddball mosquito in the data?

		DR. CHAMBERS:  Well, there were some unconfirmed landings that
occurred earlier in the study that would not confirmed within half of
hour. So those would have been some of the earlier ones.

		DR. LEBOWITZ:  But that's also site specific. And the example he was
using was an extreme site.  So the oddball may only occur in the extreme
sites.

		But let me go on since Paul asked me since Alicia wasn't here, to also
review it.   My review is very quick.  I agree entirely with what Kim
said.

		CHAIR FISHER:  Okay.  I like that kind of review.

		DR. JOHNSON:  To answer your one question, it looks like the shortest
time was 6.25 hours.

		CHAIR FISHER:  But that's for the confirmed.

		DR. JOHNSON:  Right.

		DR. LEBOWITZ:  There was an unconfirmed bite at --

		DR. JOHNSON:  That's the date --

		DR. LEBOWITZ:  I'm sorry. I think it was five hours.  The first
confirmed bite was about 6(, 6.45 depending  on --

		DR. JOHNSON:  That was confirmed, yes.

		DR. LEBOWITZ:  -- which stack you look at.

		CHAIR FISHER:  Thank you.  Because I was thinking something different
after Dr. Strickman's talk.  So thank you.

		COL. GUPTA:  No, that's not ordinary.  I think Dr. Strickman and I
both emphasized that when you're looking for the complete protection
time, there's some mosquitoes which are on the either end of the normal
distribution can bite anytime.  So it's farther out.  So it's expected
all the time.

		DR. SCHOFIELD:  It's a probability game.  I mean we say it's a 100
percent protection.  Maybe it's 99.999 percent protection and we just
don't encounter that one.

		So I think it's fairly representative and we see it all the time.  And
it's not unexpected.

		CHAIR FISHER:  No.  I guess my question was is it unexpected not to
find that?  To have the outside be five hours until a confirmed bite if
that's a --

		DR. SCHOFIELD:  It's a question of the size of the population that
you're exposed to.

		CHAIR FISHER:  Okay.  So it's not out of the ordinary?

		DR. SCHOFIELD:  It's not -- absolutely no.

		CHAIR FISHER:  Okay.  Dan?

		DR. STRICKMAN:  Yes. I think five hours is actually pretty impressive.
That's half the protection time.

		CHAIR FISHER:  Thank you.  So that helps me a lot.

		Okay.  I'm a little confused here because we still have -- I'm truly
confused. Then we do ethics and then we would be finished with 001 and
then we'd go to -- right, then we do --

		DR. LEBOWITZ:  Celia, we haven't summarized the scientific.

		CHAIR FISHER:  No. That I know.  That I know.

		DR. LEBOWITZ:  Okay.

		CHAIR FISHER:  I just didn't know if there was more science to
summarize.

		DR. JOHNSON:  I guess I'd be interested in whether the consultants
have any input with respect to these charge questions.

		CHAIR FISHER:  Well, I think what we might want to do is maybe if
there are questions that we have for them, I don't know if Kannan wanted
to say something.  But at least what I'm hearing up to now is that the
study was messy, but there's no evidence -- and this is I guess maybe
the feedback from the consultants.  I'm just trying to summarize what
I've heard.

		There's no evidence that there were residual effects.  So that closing
the time period, there's no evidence it would matter and they also had
washings and there's an eight or 12 hour, something like that, that
would have been done anyway in terms of effectiveness.

		There's no evidence that one limb versus another limb would have made
a difference.

		There's no evidence that the proximity would or would not have made a
difference.  Differences in the temperature, humidity may or may not
have been a factor, but because it was on two Mondays or something like
that, there's a little more confidence in I guess the temperature or
weather control.

		There's something about the

ANOVA and something about whether or not the test materials were
different from one another.  But that wasn't the primary issue of the
experiment, nor was there enough power to really have that ANOVA mean
something.

		In terms of pooling, here I'm not sure what we've concluded or what
people have been saying.  The subjects were not properly randomized.
Right.

		No, I know. He can correct me.

		The subjects were not properly randomized.

		You didn't have the statistical independence and the error estimates
were wrong.

		All experimental statistically tested against the control together.
But that wasn't done before the pair testing was accomplished.

		So maybe, Dr. Kim, if you could say how -- I wasn't clear how strong
that was in terms of questioning the results?

		DR. KIM:  Well, as was presented, I mean I cannot take stock in the
results that was presented because it's completely ignoring the
dependence within the summary.  I mean, when you combine site one and
site two there's up to like three subject overlapping.  That has not
been accounted for.

		CHAIR FISHER:  So what you're saying is that the overlap and lack of
independence makes the results uninterpretable?

		DR. KIM:  Right.

		CHAIR FISHER:  Okay.

		DR. LEBOWITZ:  Yes.  Actually I'm going to amend that and say because
of the attempted pooling and the number of subjects per day, and the
limitations, the avoidance of following the protocol and the lack of
appropriate randomization et cetera, et cetera, one goes beyond -- one
has to reach the question of whether we could conclude that it was
scientifically sound.  And a number of us -- I mean at least I have
reached a decision because of the pooling et cetera that it was not
scientifically sound.

		CHAIR FISHER:  So the first question in terms of the residual time and
all that kind of stuff, there's no evidence that it wasn't
scientifically sound?  But the pooling questions the scientific
interpretability and validity of the results.  That's what I'm hearing
so far.

		Richard?

		DR. BRIMIJOIN:  I want to interject here.  So this is -- so we're
virtually on the brink of essentially trashing the whole study on the
basis of the statistical -- flawed statistical analysis.

		So my question is granted that the design is not optimal and it was
not analyzed or it was analyzed in ways that would require assumptions
which cannot be confirmed.

		Are you also saying that going back to the raw data there is no way to
extract any meaningful scientific information from this study?  Because
that's what you seem to be saying, and I want you to say that flat out
if that's your opinion.  Or is there some way that this data set could
be reopened and examined, messy though it may be, and to draw some
reasonable conclusions?

		DR. KIM:  In answer to your question, if the experimental controls
were in place in terms of a distribution over a date, control of a site
this is something that we do all the time by proper control.  But what I
see in the presented data is that there was no control of this critical
experimental conditions such as allocation of subject to site,
allocation of subject to treatment and allocation of the subject over a
date.

		I mean, you can analyze the data, I mean whatever you like.  I mean,
but can you trust that analysis?  Because all the assumptions that we
need is not met here.

		CHAIR FISHER:  So I think that he's answering your question as no, it
can't be analyzed based on its design, at least from what you're saying,
right?

		DR. KIM:  Right.

		CHAIR FISHER:  Okay.  Mike?

		DR. JOHNSON:  Yes.  Let's back off the pooling for a second.  I mean,
I think Mr. Carley did a wonderful job of going over the number of
subjects per day and each treatment arm, et cetera, et cetera.  Even
forgetting whether they randomized or not.  Just the getting to the
number of subjects per day in each treatment arm and any confounding
that may have occurred day-to-day, et cetera, or within treatment arm,
from treatment arm to treatment arm, is basically the reason why I feel
that I cannot say it's scientifically sound.  Not the analysis per se.

		CHAIR FISHER:  Thank you.  That's helped.  Because I think I did not
phrase it appropriately.  And I'm glad you asked the question, Steve.

		Richard, is yours a different or is it related to this?

		CHAIR FISHER:  Okay.  We'll stay with the statistics and then we'll go
to Richard. And I also see Dr. Gupta and Jan.

		DR. JOHNSON:  Well, I think that what the consultants told us this
morning is that there's a lot of variability from subject-to-subject.
And I also heard from Dr. Gupta that he tends to use it -- sounded to me
like he tends to use Latin square type treatment structures, which also
fits into what could be called cross over designs that Susan mentioned.

		And part of the reason I think to do that is to control for that
difference among subjects.  And so if you have -- oh, it's not so bad
that they have the subject experiencing both treatments or three
treatments or all four treatments, it's just that it's not balance in
anyway.  And if it were balanced in some way, then the fact that we used
the subject over and over it wouldn't be a problem.  We know how to take
care of that in the statistical analysis.  But it's the unbalance here
that really gives us a lot of trouble in terms of whether the analysis
means anything or not.

		DR. CHAMBERS:  I think Steve and I, Steve Brimijoin and I are, I
think, on the same page.  Is that this is a field study.  And, you know,
it's not ideal, it's not a white rat in a cage study where you can
really control things.  But if it were redone, would it come out any
different if it were designed properly?

		I'm not at all convinced that it would be.  Our consultants have
pretty much said that things are going to vary day-to-day, site-to-site,
time of day-to-time of day and everything.  So what you look at here is
you've got four products, one of them came out a little bit lower than
the other three.  You've got the other study we haven't even gotten to
yet, and it's two or three hours lower than this one.

		So the study design, even with its flaws, was able to make some
discrimination amongst the various products.  So I have confidence that
it's about as accurate as you're going to get for a field study on
mosquito repellents. And to say that it's flawed because it wasn't set
up statistically quite right, I mean that is true. I will agree to that.
 But whether that makes it unusable and requires that it be redone, I
don't think so.

		CHAIR FISHER:  Dr. Gupta?

		COL. GUPTA:  It's a very interesting discussion I'm hearing.

		What happens is in the -- your point is well taken.  When you're in
the field there are multiple factors, variables which are out of
control.  If a study is done as is mentioned, the location of the
treatments and all there it is done appropriately, the analysis can
help. Like in the study where we only had a partial data. You can use
statistical methods to calculate the missing points.

		See, I have done personally a lot of studies where we could not get
all the observations in the experiment, but you can use statistical
methods if the study design is sound.  You can use the statistical
analysis to predict or calculate the missing points, and thereby
validate your studies.  So maybe in this case what is needed is maybe go
back and do a different statistical analysis to account for the
variables which we are having discussion on.

		CHAIR FISHER:  So I guess the question raised by Jan and also others,
and maybe Steve and Dan would comment on it, is there's a problem with
the design in terms of they didn't use a balancing randomization, Latin
square, appropriate ways of controlling for those kinds of things was
not put in.

		So there are two points going on.

One is Dr. Gupta has suggested well is there a way to extrapolate for
that error, which is different from missing numbers.  I mean a pooling
is different from empty cells. But is there a statistical way to account
for that?  Jan's question is does it matter?  Is there macro evidence
there enough that we might have gotten the same -- that one might feel
confident you'd get the same thing if you balanced the design?
Something like that.  Okay.

		DR. SCHOFIELD:  First off, I'm a big bar little bar kind of guy, so I
think I need to state that caveat.

		I think it's a very valid point.  I think my expectation would be that
we would not necessarily see substantial difference in the estimates,
even were we to have a more robust statistical algorithm.  However,
that's just an expert opinion in terms of what we typically see.

		My concerns would be more focused on whether or not the environmental
parameters were different.  Whether or not, for example, some of the
discussion we had earlier in terms of intermittent sampling would have a
more profound impact on things.  In all likelihood the relative sort of
performance for these products is probably would you would expect to see
in a more robust design.

		DR. STRICKMAN:  It comes down to one of the comments that was made; if
you're trying to make a comparison between the products which was the
way it was designed, apparently, then it's not robust enough to do that
for the reasons that the statisticians are saying.  But if you're just
trying to get an estimate of duration for each individual, then you have
something to talk about.  But the part of the design that worries me the
most is the way that it was carried out throughout the day.

		And these mosquitoes in general, although they bite during the day all
day, they bite more vigorously toward the evening.  And so if anything,
they probably have a bias to underestimate the duration.  And, you know,
that's a real bias there.

		So, I don't know if that helps.

		CHAIR FISHER:  I don't know why if they -- I'm sorry, I'm just
confused. But they started out in the beginning of the day and
mosquitoes bite more at night, why would that be an underestimation of
how long?

		DR. STRICKMAN:  Because the population is more avid at the time that
the repellents are starting to degrade.  So if they were avid --

		CHAIR FISHER:  I see. I see. Thank you.

		DR. STRICKMAN:  -- then it might go on a little longer.  Your average
might move out there.

		CHAIR FISHER:  Okay.  Thank you.

		Richard and then Jan and then -- wait a minute.  Kannan. I missed him.
 Kannan. I also missed Rich.  So I'm totally confused.  But Kannan,
Rich, Jan and then KyungMann.

		DR. KRISHNAN:  Mine is going to be somewhat general, the specific one
to myself unless we -- because I don't want to talk about some of the
issues that we already touched upon.

		CHAIR FISHER:  Well, wait a minute.  Are we done with this?  Was
anybody going to address this particular issue.  Okay. So let's stay
with that.

		So Richard, Jan and KyungMann.

		DR. SHARP:  And this a question, actually, directed for primarily Dr.
Kim, actually.  And that's I think there's agreement that the data came
up a bit short.  But what I'm confused about is why you think the data
came up short?  Because this was a study that the Board actually
reviewed just a short time ago.  And so I think from my point of view
there are three explanations as to why things might have went wrong.

		First is that we looked at the study designed and we got it wrong;
recommendations we made were sort of short.

		Another explanation is that perhaps that Dr. Carroll fielded this in a
way that didn't make a lot of sense. He sort of operationally got it
wrong.

		The other possibility I think is just that it was bad luck.

		And certainly there are other possibilities.  But I'd be interested in
hearing from you whether you think the Board is acting consistently in
saying now that this data came up short given the fact that we did
endorse the project earlier?

		DR. KIM:  In fact at the other January's meeting Dr. Alicia
Carriquiry, who was a reviewer for this study, had a lengthy discussion
about proper design of the experiment.  None of them was taken up by the
sponsor.

		And then there was the operationally issues of not being able to
essentially, in my view, enough volunteers to be able to conduct the
study as originally planned.  So what happened at the end of the day is
not design, sort of the spread of the subject over days site, but
occurring in a haphazard way.  At the end of the day you cannot do the
proper analysis.

		Getting to Dr. Gupta's comments when you have a properly designed
experiment, and as Dr. Chambers pointed out, with a field study I come
from a human clinical trial sort of field, there's all kinds of
deviation.  That's given.  But if you have the proper experimental
design and if there's logistical issues, some data points do not get
filled, then you can use the imputations, the kind of Dr. Gupta makes
and carry out the proper analysis.  But if you don't have that plan in
place and you just follow along haphazardly, you have no statistical
basis to do analysis.

		Another point I want to make is that perhaps estimation itself.  If
you are looking at the biasness, probably this results give the proper
-- I agree with Dr. Chambers if you do carry out the proper performance
study in the same setting, probably your predictional time will come out
the same. The question is you cannot estimate the errors associated with
your mean because of the way the experiment is done.  You cannot
estimate the variance.  Mean is okay.

		CHAIR FISHER:  Right.  But I have a couple of questions, but one to
follow what Dr. Strickman was saying.  When you're saying you can't rely
on the mean and you're talking about the comparisons among the products
or -- he was saying there it's too small and you can't do that. But what
about the estimation of duration?

		DR. KIM:  That's what I'm talking about.

		CHAIR FISHER:  That's what you're talking about.  Okay.

		DR. KIM:   I think probably this will give you the proper data.  But
the problem is you cannot estimate the variability of the estimated
mean.

		CHAIR FISHER:  He's agreeing with you?

		DR. STRICKMAN:  Yes.  I think that's very clarifying.

		DR. JOHNSON:  Another way I think to say what Dr. Kim is trying to
say, is you get an estimate plus or minus numbers.  He says it's the
plus or minus stuff that you can't estimate right.

		DR. CHAMBERS:  But I thought the duration was what this was all about,
right?  That's what you're trying to get; complete protection time.  And
the variability isn't really part of the label, right?

		And just to go back, I guess was to Dr. Strickman's point a few
minutes ago.  If this ends up being a conservative estimate of complete
protection time because of the evening more activity and everything,
then your amount will be more protective of people if that's what your
estimate was to be.

		CHAIR FISHER:  Okay.  Yes, you may.

		DR. BRIMIJOIN:  Just take my own take on this again.  Is I'm starting
to think of this, and the one that follows, as a bunch of disconnected
studies. Each one is a separate study on a separate compound.  Had
nothing to do with each other.  We're not going to compare one with the
other.  It's just by an accident that these studies happen to involve in
some cases the same subjects or overlapping subject populations.

		And it's also an unfortunate fact that each of these products was
examined in two sites.  And some of them were examined more in one site
than the other site.

		And from each of these studies, then we've got some estimate, we've
got a report back about how long it lasted.  That's data.  It's field
data.  And it has this variability in it.  Same kind of variability we
might have if we did an agricultural study and extend it over days.  And
some of the things were done on -- you know, nothing is ever quite the
same.  So if there's an uncontrolled variable in there, which we know
might influence things, probably did a little bit.

		So we have these numbers. And so EPA knows. So my bottom line is that
these numbers have to be taken with a grain of salt, but they're not
worthless numbers.

		And it's true.  It's true that we just do not know how precise they
are, and there's no way of extracting that information.

		CHAIR FISHER:  Before Kannan speaks, I did want to clarify in response
to Richard's question it sounded like what you were saying, Dr. Kim, was
that the pooling issue was brought up by Dr. Carriquiry  last time the
issues.  What wasn't done was -- it was not that Dr. Carroll was
following what we told him to.  It was that some of what we recommended
was not incorporated and some of what was in the protocol was not
conducted, is that what you were saying?  Okay.  So it's not our
inconsistent.  So I'm glad you asked the question and clarified that.

		Yes?

		MR. CARLEY:  I don't have the report from the January meeting in front
of me.  But my memory is that several of the issues, the specific issues
that have arisen in review of these completed studies were not addressed
by the Board in the January meeting.  They were not among the point in
Dr. Carriquiry's list.   One specifically that wasn't mentioned, for
example, was this pooling across days.  I'd have to go back to that--

		DR. SCHOFIELD:  That's my recollection also.

		CHAIR FISHER:  Right.

		DR. BRIMIJOIN:  What she really harped on was the sample size.

		CHAIR FISHER:  But I thought the pooling was not in the design to
begin with.  So there wasn't a plan. When we reviewed it, was there a
plan to pool?  No.

		So the issue really here is whether or not we're giving conflicting
advice.  And it doesn't sound like we are.  That the issue of pooling
was not raised because that was not in the protocol.  And so to suggest
that Dr. Carroll shouldn't pool was really not presented to us because
we didn't assume he was pooling.

		So Paul had asked me, and I just wanted to make sure that we clarified
that.

		DR. LEBOWITZ:  But I thought we had told him -- I mean, we had
accepted that he would use ten subjects per treatment on per day,
basically in order to test it.  And  then -- okay.

		DR. PHILPOTT:  I actually do have it on my computer.  And I mean our
scientific considerations explicitly say that we raised several comments
in terms of the statistical design.  And that if the recommendations
provided by the EPA and those suggested by us were followed, then the
protocol would be likely to generate scientifically valid data.

		So I think it's both what Dr. Kim has said and what Mr. Carley has
said that we're not being inconsistent.  We did make a number of
statistical recommendations, however a lot of these were issues that we
expected to come up.

		CHAIR FISHER:  Yes.

		MR. CARLEY:  But I think we can also say that if we looked at another
protocol that had several substances, some specific questions about
pooling, about Latin square designs and so forth, would be on our
agenda.  We would have to think about those another time.

		CHAIR FISHER:  Absolutely.  Absolutely.

		DR. KRISHNAN:  One thing that is underlined is that there is no
feedback loop here. I mean, we do make these recommendations.  The
protocols don't come back to us.  That's not how it's intended.  But if
some level of exchange happened between EPA and on this, maybe if they
just update their protocol or something and provided the EPA something,
that probably would be useful.  Because there is no communication
occurring after we make the recommendations.

		CHAIR FISHER:  Well, they're not supposed to -- right.

		DR. KRISHNAN:  So maybe that's a part of the problem.

		CHAIR FISHER:  Okay.  We have got to finish.  We've got to go home
tomorrow.

		DR. KRISHNAN:  Yes.

		CHAIR FISHER:  Yes?

		DR. KIM:  I'm looking at Dr. Carriquiry's comment about the
experimental design.  She used italicized expression indicating that if
the attached studies replicated in two locations using  different
subjects.  It's right there.

		CHAIR FISHER:  Okay.  I think it's clarified.  We are not
inconsistent.

		I'm going to rush through.  Maybe where I think we might be agreeing.
So, Kannan, are you going to destroy that.

		DR. KRISHNAN:  I'll speak fast.

		I just had a couple of things to say.

		Okay.  (1)  It's only as some of the protocol deviations are
attributed to -- you know, unanticipated environmental conditions it
says here, West Nile Virus, virus issue as the other deviations clearly
are not related to that.

		A general suggestion or question that I have is that shouldn't there
be a place for a contingency plan, particularly for field studies such
that certain deviations could occur but still be ethical?

		CHAIR FISHER:  Let's save that for the ethical.  The ethics
discussion, which is going to be very different.

		DR. KRISHNAN:  Yes. I mean still be scientifically valid and ethical.

		CHAIR FISHER:  Yes.

		DR. KRISHNAN:  And finally, back to the protocol deviations on the
scientific part.  EPA, you know, listed a few questions for specific
issues, five or six of them. When I look at those if those issues
existed during our review, if that's how the study was going to be done,
I think there would have been hesitation on request of additional
information before letting it roll.

		CHAIR FISHER:  Okay.  So now we have to -- Michael, don't leave.
Don't leave yet. We're just trying to conclude on the basis of the
science.  Okay.

		So the study was messy.  And we know all the problems with it.  Some
of the messiness -- there is no evidence that the messiness itself
changed the data with respect to legs and time and how close people were
to one another. But the overlap and pooling in the design makes any
comparison of products not legitimate. There's no way to legitimately
compare products.

		The data might be useful for an stimulation of duration, but the
standard deviations, right, I think that's what you were saying, Dallas,
one can't really be secure about the standard deviations.  There might
be a macro -- it might be useful to EPA as a macro estimate of hours
that in fact, as Dr. Strickman was saying, going into the night, in
fact, ends up to be conservative in terms.  Because it becomes more
dense potentially. I don't know if I'm using the right language.

		So I guess if we were going to have an answer to this question, for
the first question, we have no evidence that all of these factors would
have changed the results one way or the other.  And that's the only way
that we can answer them, right?  Jan, that was your -- right.  Okay.

		The second one is that pooling did present problems.  That the major
problems are in comparison of the -- we don't recommend using this data
to compare the products to one another.  We only recommend the data for
some kind of global estimate of the number of hours, but not individual
differences vis-a-vis the standard definitions.  And we're not happy
with studies that aren't performed as planned.

		So is that about our consensus here?  Okay.  All right.

		Let's go to ethics.

		DR. PHILPOTT:  Okay.  Do we have the first question up.

		Yes.  So I'm actually going to start by answering specific comment to
first in the context of the studies that we're looking at here.  It is
my opinion and my colleagues may agree or may differ and I'll leave that
up to them to comment, that because of the way that these studies were
conducted and were so -- that the different compounds were tested
simultaneous and that essentially we've got three or four substudies
here that are integrally related. If we find that the conduct of one of
them was conducted unethically and it is our recommendation that you
can't use the data, that applies to the whole data set.  You can't
cherry-pick data on the basis of -- well, let's not talk about WPC-001
just yet.  Let's focus on SCI-001.  And that if we find that these
protocol deviations reach a level of leading us to recommend that you
not the use data, I would personally say you have to throw out the whole
data set.  You can't cherry-pick.

		Now, let me just start by saying Mr. Carley did an incredible job of
summarizing and bringing together what was a huge amount of vary
disparate data spread across multiple studies.  My only regret was that
I did what I always do, which was I read the protocols first and started
trying to draw my conclusions before I read his review.  So I ended up
wasting a lot of my time trying to trace who did what when he so nicely
did that all for me.  And, actually, did a better job than I did.  But
thank you very much. I mean that was an incredible amount of work and I
think you deserve a lot of kudos for your review.

		In general I agree a 100 percent with your conclusions.  And for the
purposes of time, I am going to only focus on I think what is the big
issue for the ethicists with regard to this particular set of studies,
and that is the serious protocol deviations.

		In particular, I'm going to focus on three of them.  That is the
conduct of the serological or molecular analyses of mosquitoes, the
change of the exclusion criteria and then the substitution of 3434 for
Insect-Guard II without notifying the IRB of these changes.

		And I'm going to start with the serological testing of the mosquitoes
-- no.  It was molecular testing of this PCR.

		I personally should that protocol change, have been submitted to the
IRB and reviewed?  Absolutely. I don't consider it a big deal, though.
And my rationale for it is this.

		It increased in all likelihood protections for the subjects.  And if
you considered those analyses done separately and independently; if Dr.
Carroll has collected the mosquitoes and then a few years later had
decided to look back at whether or not they were infected with any
arthropod-bourne pathogens, it wouldn't have been a big deal for us.  We
would have even expected it to go to an IRB.  The fact that it was
conducted sort of in conjunction and those data would have been used to
inform participants of potential exposure does require IRB review and
approval. But I don't consider that to be that serious of a deviation to
warrant any other mention other than don't do it again.

		Now, the second is the change of the exclusion criteria. That is a
bigger deal.

		The third is the substitution of a different test compound. That is a
huge deal.  I would have liked to have known with the IRB's response was
when Mr. Carroll informed them of these protocol violations.  And I have
not seen that information.

		The question that we have to really ask ourselves is does the serious
nature of these violations in any way either put the subjects at greater
risk or did it somehow compromise the informed consent process to the
point that the study is so deficient that we cannot recommend the data
be used.

		I am going to use my prerogative as to lead discussant not to answer
the question yet myself, but to wait and see what my colleagues say.  I
have an opinion, but I'm doing five of these studies.  So I'm taking a
little -- I do have to say, though, that I am horribly disappointed that
this level of protocol violation occurred, particularly this is not the
first time that we've had a serious protocol violation involving the
failure to inform an IRB of changes prior to their initiation.

		And once again, it really raises questions about whether or not the
study investigator in this case is cognizant of exactly what is required
with respect to human subjects, regulations and protections.  And so I
would strongly recommend that before a single additional subject is
enrolled in any trial, that those once again be reviewed.

		CHAIR FISHER:  Thank you.  Richard, thank you.

		DR. SHARP:  Someone once said to me I know who I am.  I later married
her.

		I also want to say that I'm quite disappointed with what's going on
here, too.  And my disappointment comes from a very different source,
though, and that's that were a number of subjects that volunteered their
bodies in the service of science here.  They believed that they were
doing something that was going to actually yield results that would
serve some higher purpose.  And I think that the way in which the study
was operationalized here compromised the ability of the stated to have
any value.  So in that sense I think that this a serious ethics issue
because it raises broader issues of public trust and the ways in which
we may have inappropriately asked these individuals to make some level
of sacrifice in a manner which simply wasn't warranted here.

		But the two issues I want to come back to are the two that Sean has
already alluded to.  For me I think the two important protocol
deviations are two of the three that he highlighted.  And, actually,
they're not quite the same ones that Mr. Carley highlighted.  So let me
just reemphasize that point.

		The first issue is an issue that's an IRB issue.  Right?    There was
this departure from the stated exclusion criteria for the study.  I
really strongly say again I think that that is something that ought to
have been reported by the IRB.  Dr. Carroll reported to us this
afternoon that that had still not been reported to the IRB.  That is a
substantial deviation that needs to be reported.

		My own sort of personal assessment on that level is that this may not
actually be a matter that changes the risk to benefit assessment.
Right?  There may not be any additional risk incurred to subjects
because of that change or the fact that they may be enrolled in sort of
the same study in multiple arms and so forth coming back again and
again.  But that's not my decision to make. That is simply the IRB's
decision to make. Pure and simple.

		It's very clear what their charge is.  It's not our charge. It's not
Dr. Carroll's charge. It's something that the IRB should have been
informed about and they should have made that determination as to the
implications for what needed to be relayed to subjects and so forth.  So
that's a major issue here.

		The second big deviation here has to do with the change in formulation
of product.  And here I think that this is really a complete no-brainer
when it comes to the implications for the HSRB.

		The regulations clearly state that before studies that involve these
intentional exposures can take place, subsequent to the issuing of the
rule, right, the rules that we operate under here require that the study
be reviewed by this Board and some approval issued in advance.  A
product that we did not hear about was deliberately given to these
subjects.  For me it seems absolutely obvious that none of that data
having to do with LipoDEET 3434 can be used by the EPA.

		And so those are the two major issues.  Whether or not that by
extension then implies that all the other data points can't be used from
this study as well, I'm less convinced of that.  But surely the data
that has to do with that particular formulation of product is not
consistent.  The way in which it was obtained is not consistent with the
rule.

		CHAIR FISHER:  Thank you, Richard.

		Jerry?

		DR. MENIKOFF:  Yes.  I basically think my colleagues expressed it very
well.  In terms of showing three points, I'm actually less troubled
about the serological analysis and the exclusion criteria. But as has
been noted, the change in the test compound is huge from an ethical
viewpoint.  The only reason that this Committee is in existence is
because Congress passed a law and EPA imposed regulations that are about
intentional exposure. It's not about mosquitoes biting, it's not about
all these other risks we're often reviewing.  But being exposed to
particular types of compounds.

		And I must admit, my personal sense of many of these compounds is that
actually they're pretty benign.  I spend my day job usually dealing with
drugs, which seem like a lot, lot riskier. But nonetheless, Congress
choose and EPA backed it up in terms that there have to be certain types
of reviews of intentional exposures to these types of compounds.  This
study was changed in a way that it changed a compound that the person
was being exposed to. It did not get the reviews, as Richard has noted,
that are required.

		I mean, it is huge that the IRB did not review this.  I mean, I think
what would happen if an IRB in another context that was reviewing drug
studies and somebody changed a drug, changed from one antibiotic, could
be improved to another antibiotic; I can't imagine how people would
respond to that.  And that's basically what happened here.

		So we talk about substantial compliance.  There's no way in my opinion
you could conclude that this is in substantial compliance with the
appropriate regulations.

		I think there are obviously concerns in terms of a huge amount of the
data, just in terms of the group that were exposed to this compound. And
as Mr. Carley has noted, that's like two-thirds of the data points. But
even beyond that, I think you're going to have issues, and I guess we'll
get to it in a moment, but in terms of even the other data points
because the extent that people were randomized between this compound and
others, I think you have serious approval for any of those data points.

		CHAIR FISHER:  Sure.

		MR. CARLEY:  In my presentation I said that if this effected 66 of the
100 data points across the two studies, but that was assuming that all
data on a subject who received LipoDEET 3434 was dropped out.  If you
dropped out only the data points, it would effect only the 20 data
points, the 20 treatment days for that compound.

		CHAIR FISHER:  Okay.  Sue?

		DR. FISH:  I would just like to point out for the record that in the
IRB application to IIRB the investigator signs an investigator
acknowledgement which includes a statement that says "I agree not to
make any changes in the research without IRB approval."  And so I think
that that states that should not have been done, and that just supports
everything that my three colleagues about how important this issue is.

		CHAIR FISHER:  Okay.  Are you going to give us your opinion now, Sean?
 We've been waiting.

		DR. PHILPOTT:  I am.  And it's exactly what Rich and Jerry have
already articulated.  That while this may not seem to outsiders as such
a big deal because this is a compound, as Dr. Carroll argues, where it
was only slightly increased formulation, it's similar to other
formulations that are already out there.  The fact of the matter is that
we are in serious violation of both the letter and the intent of the
regulations here. And because of that it is my opinion that ethically
you cannot use these data.

		MR. CARLEY:  Could you please clarify the extent of the data that
you're saying we can't use?

		DR. PHILPOTT:  I've clarified my opinion of the extent of the data.
Because, as has been pointed out both in our science discussions and
everything else, because of the randomization and the integration of all
of these compounds into a single protocol that to me means that you
cannot use the data.  Any of the data.

		Yes, I'm not referring to WPC-001.

		MR. CARLEY:  Any of the data in SCI, in any of the three subreports
for SCI-001?

		DR. MENIKOFF:  We haven't had the panel addressing the second of the
ethic, right?  You have a separate panel for the second question.

		CHAIR FISHER:  Yes.

		DR. MENIKOFF:  Which is what I think you're asking about.

		MR. CARLEY:  All right.  We started with the second question.

		DR. PHILPOTT:  We have that charge question.

		DR. MENIKOFF:  But Sue, isn't Sue in charge of that?

		DR. PHILPOTT:  No.  So do you want to go back to that question, Jerry?
 So I had sort of touched upon it and beginning as to my opinion that
the --

		CHAIR FISHER:  Wait.  Before you do this, let's be clear about what
study are we talking about and whether in fact we should be talking
about both studies.  Are they the same issues?  Are they different
issues?

		Jan, do you have a question?

		DR. CHAMBERS:  Well, they're written up as three independent
compounds, plus the Ultrathon and all.

		DR. PHILPOTT:  It was a single protocol that we approved and reviewed
that had all three compounds plus Ultrathon and individuals are
randomized as to which compound that they receive.

		DR. CHAMBERS:  Yes.

		CHAIR FISHER:  The ethical issue, Jan, is the randomization.  In other
words, it wasn't as if one group in their informed consent says you're
going to receive this fourth chemical that I've added, or whatever.  But
that the randomization itself that we approved was that one of these
three compounds or the control.  So the randomization from an ethical
perspective and an informed consent perspective, and what the subject
was prepared to face as risk or inconvenience is the issue from an
ethical perspective.

		But can you answer my question now or everybody's question, are we
talking about both protocols or one protocol?

		DR. MENIKOFF:  Yes.  I'm just talking about I guess whatever this is
as --

		CHAIR FISHER:  Right.  But is that the case --

		DR. MENIKOFF:  Any of the subject from my viewpoint, I think I'm
saying the same thing as Sean.  Any of the subjects who were basically
-- had the chance of being randomized to that unapproved compound, that
compound that was not part of the protocol --

		CHAIR FISHER:  Okay.

		DR. MENIKOFF:  -- none of the data relating to their exposures to any
of the four compounds should be able to be used in my viewpoint.
Because again, the wrong was that that protocol was not an approved
protocol.  They had one of the arms they were being assigned to was not
approved, and therefore it was improper for them to be exposed to
these--

		MR. CARLEY:  So this would then apply to any data from any subject who
was consented into SCI-001?

		DR. MENIKOFF:  Yes.

		CHAIR FISHER:  Right.  Okay.  And some of those ended up to be in the
other one.  Got it.

		Okay.  Okay.  So any comments on this, the three --

		DR. BRIMIJOIN:  A clarification, please.

		CHAIR FISHER:  Yes.

		DR. BRIMIJOIN:  So basically I guess we're trashing SCI-001 totally.
Since there's overlap of subjects in the other protocol, which involved
a separate consent form, so some of those people signed the contaminated
consent form, the compromised consent form.  So are we encroaching on
making inroads on the data in the second study by that standard?  The
same subjects, but a totally different protocol through which so far, we
haven't heard the ethics review, but so far no complaints about whether
that's an ethical study?

		DR. PHILPOTT:  Correct.  But keep in mind that I did ask a very
specific question of Dr. Carroll regarding signing of consent forms.

		CHAIR FISHER:  Which was?

		DR. PHILPOTT:  Which was that if the people that participated in both
studies did sign two different consent forms.

		DR. BRIMIJOIN:  And he specifically answered yes.

		DR. PHILPOTT:  Yes.

		CHAIR FISHER:  So then we may make a conclusion about this one study?
Okay.

		So the ethicists are unanimous in their recommendation that I don't
know which federal regulation this -- you'll quote it.  Both?  Both?
No, no. I knew it was K and L, I just didn't know which part of it.
Okay.

		Are we in consensus?  Are there any other comments?

		Okay.  So now we move on to the science of the W-1.  But we're going
to take a break.  Okay.  We're taking a break.

		It's ten to 4:00.  And so let's come back at five after 4:00.

		(Whereupon, at 3:50 p.m. a recess until 4:05 p.m.)

		CHAIR FISHER:  Did you want to read us the charge?

		MR. CARLEY:  WPC-001 charge questions.

		A:  Is the research conducted under WPC-001 sufficiently sound from a
scientific perspective, to be used to assess the repellent efficacy of
the formulation testing against mosquitoes?  Please comment specifically
on whether participating in field testing by several subjects on the day
after they had been treated with a different test repellent is likely to
have affected the validity of the results for those subjects on those
days.

		And question B:  Does available information support a determination
that the research covered by WPC-001 was conducted in substantial
compliance with subparts K and L of EPA regulations at 40 CFR Part 26?
If the conduct of any part of SCI-001 is deemed not to substantially
comply with the requirements of subparts K and L, please comment
specifically on how to assess the ethical conduct of research conducted
under WPC-001 in light of the fact that it was conducted at the same
times and at the same places as the research covered under protocol
SCI-001.

		CHAIR FISHER:  All right.  Jan?

		DR. CHAMBERS:  All of the arguments and opinions that I would have on
this I already expressed earlier this afternoon.

		The only reservation that I really had on any of this stuff was
whether there was residual effects from one day to the next in the
subjects that were repeated the next day.

		For this particular one, the complete protection time came out four to
six hours.  It was shorter, and also that suggests that there even less
residual effects.  So I have even less concern with this one than any of
the others.  But the same bottom line on this is that I think it's
useable.

		CHAIR FISHER:  Okay.  Mike?

		DR. LEBOWITZ:  Agreed.

		CHAIR FISHER:  Okay.  Lois?

		DR. LEHMAN-McKEEMAN:  Ditto.

		CHAIR FISHER:  Okay.  Discussion?  And so the consensus is the data is
useable for the purposes it was purposed for?  Lois?

		DR. LEHMAN-McKEEMAN:  I was trying to be brief, although not quite
that brief.  But I just wanted to point out that I really appreciate the
organization of the data that John Carley did for us.  Because if
facilitated my review tremendously.

		And the one point that I would make, just to add to Jan's perspective
and I'll step back for just a moment because I think that it's not
intellectually satisfying to say that these people were treated on
successive days and it raises some issues.  But I think what we rely on
is our common sense and practical instinct more so than empirical data
to the contrary.  So that's my first point of view.

		And the second is that based on the organization of subject treatment,
for this particular study from John's slide what is number 13, it
appears that the second arm in this study all ten subjects were actually
treated on the same day.

		MR. CARLEY:  In Glenn -- in one site but not the other?

		DR. LEHMAN-McKEEMAN:  Yes.  Site number two.  And what's interesting
is that that site, and I realize there are lots of factors that can
contribute to that, that that site has the shortest CPT of any of the
days trials.  So, again, I think when I put that together my sense is
that there's really not an experimental bias that's built in in light of
the compendium and composite of data and how this particular compound
looked when it was tested.

		CHAIR FISHER:  Thank you.

		Any other comments?  Okay.  So I think we have consensus on that.

		Let's go to the ethics discussion. Sean?

		DR. PHILPOTT:  It would help to have a mike.  I'm sorry.  I have bring
my brain back to the issue here.

		So even though these studies were conducted on at least on three days
in the same location and we have a lot of subjects who participated in
both the study that we just reviewed and have recommended not be used on
the basis of a serious ethical violation, on this study I think it's
useful to try to separate the two in our minds and come back to the
issue covered in the charge question about how now that we've concluded
from an ethics perspective that the research conducted under SCI-001 can
not be used, how to deal with the research here.  So I'm going to focus
solely on the ethical issues associated with WPC-001 first and then
we'll come back to the question of if we then conclude that the data can
be used, how to deal with the issue of the unethical conduct of the
concurrent study.

		And once again, I think that with respect to all of Mr. Carley's
comments in his nicely detailed review to quote Lois, ditto.

		And now I think that we can focus on just a couple of key ones.

		There were a number of consenting issues involving questions about
consent forms that were dated unusually.  And for the vast majority of
these, to me they're sort of one of the things that happens when you're
conducting these studies.  I don't think that in any review of research
that I have done that any investigator, no matter how ethical and no
matter how organized, has not made some little tiny mistake where they
didn't realize the subject walked off with both copies of the consent
form, or they performed one aspect of the investigation prior to having
them sign a consent.   And I think it's important to sort of ask
yourself is there a consistent pattern, and also what extent do those
violations have with respect to the rest of the participants, and also
the informed consent process itself.

		And so to me the only real serious one here, most of the other ones I
think have been nicely explained by Dr. Carroll, is simply the limb
measurements of the one participant several days before he signed the
consent document.

		Once again to quote myself, don't do it again.  But I don't think that
this rises to the level of such a significant deficiency to preclude the
use of these data.

		The real big issue here I think is the protocol deviation involving
the change in the exclusion criteria.  And we've touched upon lightly in
our discussion of SCI-001 the fact that this should have been reported
to the IRB before it was initiated for their review and approval.  But
also in response to questions that we had for Dr. Carroll this
afternoon, I'm very disappointed that this protocol deviation has not
been discussed with them since it has happened.  And I would have liked
to have seen what IRB's response to it would have been.

		The question then becomes whether or not this serious protocol
deviation rises to the level where it either compromised the informed
consent process or where it put the subjects at risk.

		And I tend to think in this case that it probably did not increase the
risk to the subjects, so the real issue here is whether or not the
informed consent process, particularly because the informed consent
document still includes the clear exclusion criteria of no repellent use
in the 24 hours prior to field testing, whether or not we have a serious
compromise of the informed consent process.

		DR. SHARP:  Again, I would echo a lot of that.  I do think it's
important that we distinguish the two protocols, the one that we just
finished discussing and the one that's here.  Because in terms of the
major deviation having to do with the change of formulation of product,
that does not exist in this second study.  So that, obviously, is the
single most important difference between the two studies in question.

		The departure from the statement exclusion criteria, I think I agree
with Dr. Philpott that that is a major issue, and it's a major
unresolved issue.  And I think until Dr. Carroll submits that deviation
to the IRB and we get some indication from the IRB as to how they
envision this and what they see as necessary steps, if any, in terms of
remediation I'm not sure that we can really fully evaluate this
particular protocol.

		So for me I would like to, again, as at least to be cautious with
regard to taking a strong judgment on this protocol in the absence of
having heard from that IRB.  Because, obviously, in terms of the system
of regulations that exist in the United States the authority with regard
to some of these judgments it really is at the local level, at the level
of the particular IRB that's charged with reviewing the study.

		So I don't know quite what to do with that in the absence of having
heard back from that IRB.

		CHAIR FISHER:  Sue?

		DR. FISH:  To quote some of my colleagues, ditto.

		And I was just looking in the consent form, the approved form for this
study to see if I could tell whether or not subjects were told that they
would refrain for 24 hours before.  And I'm not finding it.  So I don't
think it compromised the informed consent process.  But the issues that
Rich raised and that Sean raised I completely agree with.

		CHAIR FISHER:  So it sounds like at least Richard and Sue -- I think
Richard -- it sounds like everybody's in the agreement in the sense if
in fact 24 hours was not in the informed consent --

		DR. PHILPOTT:  I did see it.

		CHAIR FISHER:  Okay.

		DR. PHILPOTT:  It's there.

		CHAIR FISHER:  Oh, it is there. It is there.  Okay.  So that's
problematic because they were asked to do something once they were
already in the study that they had not consented to.  And I assume -- I
don't think we need the IRB to make a judgment about that.

		And then Richard raises an interesting point, and I guess maybe we
should just discuss this.  Is there's -- I'm not sure. It's an
interesting question.  It was not submitted to the IRB, it still hasn't
been submitted to the IRB even though the investigator has been well
aware for a couple of weeks that this was a violation based on feedback
from OPP.  And so on that basis it seems to me that we an make a
judgment about that.  So I'm not sure that in terms of what our
responsibility is that we have to wait to see what the IRB says.  I'm
just not sure of that.  Because I think we can make a determination that
it should have been sent to the IRB.

		Richard?

		DR. SHARP:  I guess the question I would have is if we made a
determination that it ought to have been sent there and that that's
sufficiently troubling for us to lead us to say that this is
substantially out of step with the normal ethical practices in this
context, does that sort of prevent us from revisiting that issue at
another meeting where perhaps after Dr. Carroll does go back to the IRB,
explores that issue with them and receives from them an indication that
they believe that this was not an ethically troubling event, can we then
revisit that or does that now preclude us from doing so?

		CHAIR FISHER:  Well, I guess the question is an IRB is important but
it doesn't dictate our judgments.  We have been in disagreement with
IRBs before.  So I think that it's important for us and also in terms of
sponsors and everybody else to know where we stand on issues in terms of
regulation.

		And so I would hesitate to make our judgments always dependent upon an
IRB.  Because I think, as many of us have noted, there have been
inefficient IRB evaluations.  We see IRBs that are approving informed
consents that have nothing to do with the study.  So, you know, I don't
want to go down that road, I guess.  So, you know, that was just my
general concern.

		So on that basis then so we have two things.  And I guess the
question, as everybody has raised, that we need to discuss is whether or
not this raises to the level of substantial noncompliance that the
informed consent told them there'd be a 24 hour wait period and then
there was not.  They were asked to be in something the next day without
a renewed informed consent.  And the other was that given this change in
exclusion, not only was it not reported to the IRB before it was done,
but it still hasn't been reported to the IRB.

		So discussion?

		DR. PHILPOTT:  And I think if we as a Board are going to make a
recommendation about the deficiency, we need to ask ourselves
essentially what we have defined as criteria since the first meeting in
April 2006, which is risk and the informed consent process.

		I mean, it may be a little surprising given what we just talked about
maybe 20 minutes ago.  But I guess my feeling on this one is this is a
major violation, however do I think that changing that exclusion
criteria and the fact that it wasn't noted in the document but we don't
know what said to the participants, did that effect their understanding
of the risks and the benefits to their participation in the study?

		CHAIR FISHER:  Let me just ask it a different way to get your feeling
about this.

		DR. PHILPOTT:  Yes.

		CHAIR FISHER:  I think we're in agreement about the level of risk.

		DR. PHILPOTT:  Yes.

		CHAIR FISHER:  We have no evidence that it's more risky 24 hours
versus not 24 hours.  However if people were told they were going to
have a day in between --

		DR. PHILPOTT:  Yes.

		CHAIR FISHER:  -- and then told -- and I don't know what the pay
schedule was or whatever, but to me that's the issue.  I agree that it's
not risk in the sense of harm.  But I do think they agreed to have at
least a day in between.  And so they did not.

		MR. CARLEY:  No, I don't think so.  		CHAIR FISHER:  Oh, okay.

		MR. CARLEY:  The way this was presented in the informed consent was to
be eligible to participate in the study you mustn't have used a
repellent during the day before testing.

		CHAIR FISHER:  I understand that.  But if you weren't going to be
repeatedly tested?  I thought you couldn't be tested the next day.

		MR. CARLEY:  I think there is a plausible interpretation of that
language that says before you start working with us on this testing
under our supervision and control we don't want you to have been using
repellents outside our supervision and control.

		CHAIR FISHER:  I see.  But it didn't say that every other day you're
going to be in the study.  Okay.

		MR. CARLEY:  Right.  It said nothing about days off between days in
the field.

		CHAIR FISHER:  Okay.  I got confused when you said 24.

		MR. CARLEY:  That plausible interpretation seems to me to be
consistent with what Scott Carroll told us he was thinking about when he
originally put this into his protocols.

		DR. PHILPOTT:  And that was sort of the interpretation that I was
working with this.  I thought about this.

		So my general feeling is that I don't think that this violation
effected the informed consent process to such a level that we cannot
recommend that the EPA use the data if it's scientifically valid.

		CHAIR FISHER:  Discussion?

		DR. SHARP:  I'd like to separate out two questions.  There's the issue
of his compliance with the IRB approved protocol, which I think we're
all in agreement that he was out of compliance with that. And then
there's the question of his compliance with 40 CFR 26 which requires
that he submit a protocol to the IRB and have it approved, and then
there's presumably other language in there.  And I think that in the
absence of looking at that specific language at that section of the
regulations, it would be difficult for me to make a hard call as to
whether he's in compliance with that regulation.  Again, as distinct
from his compliance with the terms of his protocol.

		DR. PHILPOTT:  Well, and to add another layer of complexity, the
regulations say "substantially complaint," if I recall.  So good enough
for government work.

		MR. CARLEY:  Let me clarify that a little bit further.  The
regulations address the idea of changes to approved research only in the
context that I put up on the wall during my presentation in saying that
the IRG has to have procedures to ensure that it doesn't happen; that
changes without approval don't happen.

		And then as Dr. Fish pointed out, this IRB gets a signature from the
investigator that says I understand that I can't change anything without
your approval.

		That's kind of the points of leverage to decide what to do, how big a
deal this is.

		CHAIR FISHER:  I'm discomforted.  So I'll just say that.  It's just
taking two together, I don't -- you know, I conduct so many studies.
And, by the way, I've never tested a subject without giving them
informed consent.  I have never had an assistant who has done that ever
in 28 years.  So I'm just saying maybe in other kinds of studies or
field studies it's harder or something like that.  But I have never ever
done that. I just wanted to point that out.

		But I am just discomforted by the combination, I guess, of these two
things.  And I'm discomforted by the fact that we have discussed this
issue with this particular investigator numerous times.  That we even
recommended an ethics course.  That I'm concerned:  What do we say next
time?  I mean, it just seems like we're constantly saying "Well, okay,
that was all right.  You know, you didn't know."  But this would be
something that would not be approvable in an IRB or, you know if it came
to us beforehand.

		So I have a certain level of discomfort.  And I also look to balancing
the data.  I know the regulations speak to, and I agree with it, that if
there are some ethical violations but the data is so important that it's
going to protect the public, I think that there's a weight to be given
to that.  But I don't see that here.  I don't see this data as
critically important.

		So it's just I'm not saying where we should go with it, but I am very
uncomfortable.

		Yes?

		DR. PHILPOTT:  We originally started this conversation and I guess I
was still thinking of it in terms of considering there'll be a PC-001 in
isolation.

		CHAIR FISHER:  Yes.

		DR. PHILPOTT:  And so now, you know, we have to address the issue of
okay now the interrelation with SCI-001.  And I share your discomfort
once we bring them back together.

		If I was to look at WPC-001 in isolation without, that would be my
recommendation. Now we've got some broader issues to talk about.

		CHAIR FISHER:  I just want to point out too, because I do this all the
time, anytime I make a change I e-mail the IRB immediately. Immediately
before I implement the change.  So I'm saying this is not a big deal to
inform your IRB, especially when it's expedited and it's minimal risk.

		Suzanne?

		DR. FITZPATRICK:  Well, I don't share the discomfort because I think
Dr. Carroll's interpretation of what that exclusion criteria meant was
he'd used a foreign repellent.  But the fact that once he realized that
other people interpreted differently and he didn't inform his IRB, that
yes it could have been interpreted in a different way and I've done
this, that's the part that bothers me.

		But we are auditing our studies and we do find problems with consents.
 A lot of problems.  Troubling, it's troubling to us but I think it's
common.

		DR. PHILPOTT:  Yes, and that's what I was trying to imply.  No one's
perfect.

		CHAIR FISHER:  Except for me.  But then, again, I have a super charged
conscience because of this field.

		Yes?

		DR. LEBOWITZ:  I wonder if we can just treat this one on its own merit
with the concerns and with the advice to EPA maybe that before they go
ahead with approval they have to get assurance from the IRB, et cetera.
And come back to the issue of instruction to Dr. Carroll after we were
done with Dr. Carroll's studies, including the proposed studies.  So as
not to take the time much further in WPC-001 and be able to proceed, but
not to ignore the concern we have.  I mean, I think part of our mission
is also to advise, you  know to give better advice to the investigators.
 But I think we still can finish this issue now and then come back to it
again when we deal with the proposed studies.

		MR. CARLEY:  We really do need clarification with respect to the
overlap across the two studies.  And I've asked Leshawna to put my slide
13 up on the wall, which is the one where you can see the spread.
She'll have it there in a minute.

		What it comes down to there were only four subjects who participated
exclusively in WPC-001.  And there are only two data points at each site
that are not touched by the concerns about SCI-001.  And two data points
at each site isn't a whole lot to go on.

		So we've got to figure out how broadly that stain spreads.

		DR. PHILPOTT:  Right. But one of the key issues here, of course, is
that participants were individually consented for the two studies. So
that does, in a sense, create a wall between them in that regard.  So
even though only four participants were in WPC-001 that weren't also in
SCI-001, I think that we can consider their participation in the two
different studies separately, even though there is overlap as to when
they were conducted.  Because there have been many times when I've known
people who were involved in multiple research protocols that were being
conducted concurrently.

		MR. CARLEY:  With shared data?  Remember that all the limb
measurements or all but one of the limb measurements for WPC preceded
the first consent form for that study.

		CHAIR FISHER:  Sue?

		DR. FISH:  Going back to this in this current protocol about what the
consent form says about the 24 hours prior, the only thing I can find is
that in the consent form it says you must not have used repellents
within a day prior to the start of the study. And if the start of the
study is dosimetry, then the fact that they were dosed day after day
after day from a subject's point of view is completely consistent with
what they were told.

		I understand the enrollment criteria-- I mean the protocol.  But from
the consent form as far -- I'm still on the compromised consent process.

		DR. PHILPOTT:  Not everyone participated in the dosimetry, though. But
some--

		DR. FISH:  But even day one, I mean even if you just participated in
the field part of the study, if you didn't use before day one, then if
you were dosed on day one and day two and day three as a subject reading
this, I think it would be fine.  I would have assumed it were fine.

		CHAIR FISHER:  And let me just summarize, because I don't want to beat
a dead horse if everybody's on the same track.

		So it sounds like it's not clear that there was a violation of
consent.  It's just not clear.  Because given it could be interpreted
and Dr. Carroll thought it was interpreted in that way, I don't see that
it's a clear consent violation based on what Sue was describing.

		In terms of the overlap between -- the constant issue of the overlap
between 001 and the WP, that doesn't seem to be problematic on the basis
that they were independently consented for this study, whether or not
they were in that other study or not.  I believe that's the conclusion
of the ethics panel.

		And with respect to the exclusion criteria, I think as Suzanne pointed
out, Dr. Carroll did not think that that was increasing risk which was
how he interpreted informing the IRB.  So that aspect of the initial
misjudgment was not substantial.  The fact that he didn't report it once
he knew it, I don't know why that.  But it doesn't seem to rise in
people's mind to the level of a substantial noncompliance.

		So is that where we are, or am I mistaken?

		DR. PARKIN:  I just have one other question for the efficeces to help
me remember.  John raised one thing on one of his slides that hasn't
been discussed yet. And I wondered if it was a concern or we have just
forgotten about it, or it was so minor that you'd not worry about it.
But the point was stated that there was a change in role of the
experienced subjects to include service as assistants to the
investigators. And it was listed only under WRC-001, not SCI-001.  And I
can't recall exactly what that change was, and I wonder if somebody
could help me remember and we could decide whether that was significant
or not.

		MR. CARLEY:  The first thing to remember is that there was this
special class pre-identified experienced subjects who were used as
candidates for the untreated controls.  From within that group, and I
think this applied equally to both studies.  I'm not absolutely certain
of that.  But from within that group of experienced subjects the
controls were asked to help with dosing the other subjects so that more
of them could be treated equally all at once kind of thing.  That was
the rationale that was offered was that this allowed more consistent
timing of the dosing.

		The concern that I had about the change in role is partly based on the
fact that the dosing by technicians, by skilled, trained technicians was
identified as a risk reduction, risk minimization step in earlier
discussions.  And while we're told that these people are experience, for
all I know they participated in scores of these studies and they may be
very, very familiar with them and very highly skilled at applying
repellent, I noted that there was nothing in the consent document about
their helping treat other subjects.

		They had a special consent document for WPC, but there's nothing in
there about treating other subjects.  And this is a significant change
in role, to my way of thinking anyway.

		Is that clear?

		DR. PARKIN:  That was very helpful.  And I would then say, obviously,
there was nothing in the consent form telling anyone that they might
have a role of dosing one of the other subjects in the study. To me
having a subject dose another subject, to me that's a real serious
concern.  Even if they've been through other studies.

		CHAIR FISHER:  I don't see it as much, only because I've heard about
these studies for quite a while.  But it's very interesting because are
they still participants when they're dosing?  I mean, it raises a lot of
very kind of interesting and complex issues.  But the question of
whether-- I assume they're paid no matter how long they're there. And
the issue really rests on voluntariness and things like that.

		You're absolutely right. It should have been included in the informed
consent form.  But the issue becomes, as Sean put it, did it increase
risk and did it violate their consent.

		DR. PARKIN:  As somebody being dosed by another subject, I would have
had concerns that my risks may have been increased.

		DR. FISH:  Were they control subjects and working in the dosing at the
same time, John?

		MR. CARLEY:  That's my understanding.  But I can't be absolutely sure
of that.

		DR. FISH:  So might it have been possible that the control subjects
might have been exposed themselves to the repellent and there might be a
scientific compromise here?

		MR. CARLEY:  I assume they did not apply the repellent with their
lower legs.  I believe they were probably wearing gloves and using a
gloved finger to apply it, and that it would not have confounded the
control testing of their untreated leg.

		DR. FISH:  Contaminate?  Okay.  Okay.  Thank you.

		And just to add and since we've been told previously they're all
people working in this area.  They might have been skilled technicians
that happened to also be in the study but weren't employees of Dr.
Carroll, employees of somebody?

		CHAIR FISHER:  Jan?

		DR. CHAMBERS:  This is not an invasive form of dosing.  Rebecca, this
is not an invasive form of dosing.  It's just applying lotion on the
skin so it seems pretty trivial.

		DR. PARKIN:  Yes.  I'm just looking at it from the viewpoint of
another participant and whether I was not informed in the informed
consent that somebody other than the staff or the PI was going to dose
me.  And then I find out that my partner in the field is going to dose
me, I might have a different decision about whether I was willing to
participate or not.

		CHAIR FISHER:  Okay.  Well, I think that in principle is a very valid
concern.  I think at least for this context, the fact that it's rubbing
a little cream on the foot, or the leg, you know I think many of us feel
it doesn't rise to that at least.  But it gets back to the fact that we
would like to see these much -- you know, it doesn't rise to substantial
incompliance, but it does raise all the problems that we've spoken
about.

		Have we answered all your questions, John?

		MR. CARLEY:  I'm unclear about the answer to this one.  Are you saying
that to have some subjects treat other subjects without saying that in
the consent documents for either the treated or untreated subjects is a
change that's within the discretion of the investigator and doesn't need
to be reported?

		CHAIR FISHER:  No. Within the context of this particular study where
it's rubbing cream on a leg.

		MR. CARLEY:  Isn't that the same argument that Dr. Carroll made that
said to switch LipoDEET 3434 wasn't a big deal because it doesn't change
the risk profile?

		DR. PHILPOTT:  I think it's more along the lines of it is a violation.
 The question is what level of seriousness does that deficiency rise to.
And I don't think it rises to the criteria that we've established
previously about risk and informed consent.

		MR. CARLEY:  The risk and informed consent criteria, which I agree the
Board did set early on, my memory is that those were in the context of
pre-rule studies where the significance of deficiencies had to be
assessed by the standard of clear and convincing evidence of a
significant deficiency. And here we have a different standard. We have
the substantial compliance standard with all of the provisions of K and
L, which it's a very different context for applying that standard.

		My view is that this change in role is at least as significant a
change in the terms of consent then the point about the violation of the
exclusion factor.  So I'm puzzled.

		DR. PARKIN:  And I would think that it's also in the same ballpark of
needing to be reported to the IRB.

		CHAIR FISHER:  William.  Bill and then Rich.

		MR. JORDAN:   At the risk of wading into waters over my head, what I
see as common to the change in the role of the untreated controls and
the exclusion criteria is that the protocol has described one particular
process, the IRB has reviewed it and blessed it, EPA and HSRB have
reviewed it and said go ahead.  The subjects have consented to it.  And
then the investigator says, yes, here's your consent process but I'd
like you to something a little different.  And the dynamic of changing
that sort of agreed upon review process is what I find troubling.

		In the particulars it may not have altered the risk very much, but it
reflects a difference in the relationship between the participants and
the investigator that sort of departs from the IRB process. And the
review process is intended to ensure that the investigator doesn't do
something at odds with the best interests of the participants. And it's
undermined that relationship.

		CHAIR FISHER:  It gets harder and harder.  Thank you.

		Rich?

		DR. SHARP:  So I think your reasoning is right, Mr. Carley.  At least
I'm inclined to agree with that that each of these things are, by in
large, on pair with each other.  These are a series of relatively minor
compliance issues, all of which should have been reported to the IRB.
But any one of those individually doesn't rise.

		I think what we're here as sort of a matter of consensus here is that
none of them rise individually to a level where we would say that there
is substantial lack of compliance with the rule.

		Now the question that I think Dr. Fish was raising earlier, though,
was whether or not sort of collectively there are so many of these
things together that they sort of make us all feel a bit uncomfortable.
But I think we're moving away from that point, unless I'm wrong here.

		CHAIR FISHER:  I'm seesawing.  I have to say, you know I don't see the
-- I would prefer -- you know we've been doing this for 18 months now or
two years?  How long have we been doing this?  April 2006.  We've sent
the same message over and over again, whether to this particular
respondent or all respondents who read what we say.  And in terms of the
integrity of the Board process, you know I think that the first six
months to a year we were sympathetic of the newness of this process and
saw ourselves in an educative mode.  But I don't know why we're
continuing to see ourselves in that mode.

		Jerry?

		DR. MENIKOFF:  I guess I would just say in terms of getting back to
what the specific deviations that we're talking about here, to what
extent are some of them perhaps just misunderstandings or confusion, for
example in terms of the 24 hour thing that it really was maybe just a
misunderstanding in terms of what they thought was going on.  In terms
of, for example, the technician applying the thing, I guess my viewpoint
which it sounds like similar to most of the other ethics people, is that
it's sort of a de minimis thing.

		I mean, whoever applies some compound to your skin, it's not if that's
a skilled technique that is going to dramatically alter, particularly
dealing with the compounds we're dealing with here.  If it was somebody
doing a spinal tap on somebody else, that would be a big deal.  But it's
that plus the other thing -- now, I guess again you could add them
altogether.  But, by in large, I could see whether there are extenuating
circumstances or whatever in terms of some of these things, there are
explanations there are explanations for why they happen.

		I take a different take of the notion of changing the compound that is
being tested.  I have seen no explanation of why you wouldn't know,
particularly again in terms of the series point of the history of this,
that you should let the IRB know what's going on here.  So that's why I
do see a difference there.

		CHAIR FISHER:  Gary?

		DR. CHADWICK:  Finally provoked.

		I mean basically what we're talking about here is science that's
equivalent to a high school project.  And, you know, we would anticipate
for things that are being submitted to the EPA for registration purposes
that they would be some higher standard.

		I think the swamp that we are wading into on this one is that it is
not within the investigator's call to determine what the effect on the
risk profile is when a change is made, regardless.

		I agree with absolutely everything that's said.  I mean, we're talking
about off woods DEET here, whatever it is.  I mean, it's no big deal.
People spray this stuff on, put it on their peanut butter sandwiches and
everything else.

		So, you know, I think there's an argument that we can make around this
table and should have been discussed at the IRB, but was not.  And I
think that's the problem here. And it does equate to the one that we
have talked about before.  It is the same ethical deficiency, is that a
change that was made, wasn't approved, wasn't sent to the IRB and it may
or may not have had a change in the risk profile.  But the IRB, who is
our ethical overseer on these in the United States, didn't get an
opportunity to exercise their appropriate oversight.

		So, you know, how small is small?  Well, I don't think that's our
issue to debate.

		DR. FITZPATRICK:  But in looking at the protocol in the consent form
it doesn't say who will apply it to the person. So I don't--

		DR. CHADWICK:  Yes, I know.  But don't you think the IRB when they
approved this assumed that it wasn't being applied by "oh, you're
walking through the park, take my picture sort of thing."  That happens
all the time.  Okay.

		DR. FITZPATRICK:  Well we don't know how technically skilled the
person was that applied the -- all I'm saying -- I don't see that as
really a violation of protocol if that protocol doesn't say who put it
on.

		CHAIR FISHER:  But it also places the subject into an investigative
role.

		So I think as Gary is framing the question, and I think as Bill and
John are concerned about, and I think as Jerry used the de minimis, I
mean you know whether you do this or that, I mean I think from a
practical perspective it's not that important in terms of risk.  But the
way Garry's talking about it, and I understand there's a consistency
here.  There's a lack of alerting the IRB to changes in the protocol.

		Here there are two changes.  One was the use of participants also as
researchers or whatever, and the second one was changing the exclusion
criteria.  And here there's a repetitive not informing the IRB, not even
informing them now when it's been I don't know how long since the study
has been conducted and the investigator has been aware.  And for
consistency, you know, we all agree that changing a compound is scarier.
 But yet the consistency of the issue really is, as Gary has framed it,
does EPA want to communicate to the investigators or do we as a Board
want to communicate that it's within your purview and we'll decide when
it gets to us how dangerous it was, but is it in your purview not to
comply with the regulations in terms of informing your IRB when you make
a change.  And so I guess that's what we're grappling with, as I
understand Gary.

		Yes?

		DR. PARKIN:  I just wanted to explain a little bit on what Suzanne was
saying.

		You know, whenever there is a change in the research team, if you add
somebody onto the team or they go off the team, you have to report it.
This IRB didn't get the opportunity to decide whether this particular
activity that these subjects were going to do to other subjects would
then constitute them being part of the research team.  So that's another
reason why it should have been reported.

		MR. CARLEY:  A point of clarification.  In section 9.3 of the protocol
entitled Study Material Administration the first sentence reads as
follows: Study materials will be administered to each subject by
Carroll-Loye technicians.

		DR. CHADWICK:  And if it wasn't in the protocol, the IRB forms
certainly should have asked who was performing the procedures.

		CHAIR FISHER:  Okay.  So the question before us, it seems to me so far
framed, is the major violation here is consistent with the violation
that we found in the other study which is a failure to report to the IRB
on not just one, but two changes, and whether or not that rises to
substantial noncompliance is I think the issue.  That we're not arguing
that putting cream on or not putting cream on is a high risk.  And we're
not even arguing, because we're not sure what the subjects actually
expected.  Although the informed consent says a technician is going to
be putting it on.  Because we also know there's dual roles.

		So it seems to me the singular issue that we know is true is that
there's a lack of compliance and we do not want investigators thinking
it's up to them to judge what they tell, especially since there's e-mail
and you could just e-mail somebody.  I'm doing this and it's expedited
review.  It doesn't take forever.

		So, I'm shifting back and forth. But anyway, that's how I see where we
are right now.

		So is anybody in a different place than that right now or wants to
make a recommendation for where our consensus might lie?

		DR. PHILPOTT:  So that's what I'm asking, going to ask.  Are you
framing that in the sense of the question to the ethics reviewers now of
do we think given the discussion whether or not we have reached a
substantial compliance barrier?

		CHAIR FISHER:  Right. And also to look at consistency in our
judgments.

		Yes?

		DR. PHILPOTT:  I have been seesawing back and forth and back and
forth. I think we're all troubled by this.  And a lot of it is it's just
very hard to just separate this out from the previous discussion that we
had before the break.

		Framed that way and framed in the larger sense of the HSRB's role in
setting precedent, I am leaning towards saying no, don't use it.

		DR. MENIKOFF:  Okay.  I guess I haven't changed my mind on this.  I
mean, if the two things we're referring to are the change in who applies
it and the 24 hour rule, I think those are the two we're talking about,
right?

		On the 24 hour one my take on this, and maybe I'm just misinterpreting
it, is that there's either a miscommunication or whatever that it didn't
sound as if a change was taking place.  That the only thing that was
clear in the protocol was that they weren't applying it to --

		CHAIR FISHER:  Oh, Jerry, I don't think that's the one we're talking
about.  I think we realize, we agree with you.

		It's really lack of telling the IRB two things.  The IRB wasn't told
about the exclusion.

		DR. MENIKOFF:  The 24 hour?

		CHAIR FISHER:  Yes.

		DR. MENIKOFF:  But that's what I'm saying there wasn't anything to be
told.  I thought there was notion that that wasn't changed.  That in
fact the investigator's understanding was what the rule was was that the
only people they were excluding were people who before they enrolled in
the study had applied the compound within 24 hours.  So that -- I could
see a legitimate argument here that he didn't understand that there was
anything he was changing that he was supposed to tell the IRB about.
And given that take, which sounds pretty reasonable to me, I find it
hard to blame him for that.  That that isn't a real noncompliance issue.
It's a lack of communication or just a different viewpoint on two people
in terms of whether the study was changed on that point.

		It sounds perfectly reasonable that what we're talking about is the
only exclusion was applying the stuff during 24 hours before you
enrolled in the study. So I guess on that ground I don't think that was
an issue that he should faulted for.  At least there's a plausible
interpretation that there was nothing for him to report on that because
he didn't make a change.

		So then we're left with one change in terms of my viewpoint.  I think
that's a relatively minor thing.  And in terms of consistency if we're
saying there's substantial noncompliance every time sometime happens in
the protocol effectuating the study that differs from what was laid out
in the protocol, I suspect if we went back and reviewed every other
study we did before, we would be concluding none of the data from any of
those studies could be used.

		I draw a huge line between those sorts of things, which I again if
we're back to just a technician who applies the cream or whatever,
that's minor versus again changing the actual test compound, which is
the reason this Committee exists and we would spend the most time over
the past year and a half, or whatever it is, is huge.

		So I do think the Committee has been making a consistent line between
these two things.  And I acknowledged you could fault him for, again,
not giving every change to an IRB.  But unless you're going to
individualize this and say it's a particular investigator who has a
history of doing X or Z, but as a specific matter if we're talking just
about the changes that were made in this study, I don't think we'd be
consistent to say that the particular change of having a fellow
participant apply the cream is such a huge deviation that that would
cause us to not allow the data to be used.  That we would be
inconsistent in applying a stricter standard than we have applied to
other protocols we reviewed.

		CHAIR FISHER:  Richard and then Steve and then Sean.

		But I also want to make a suggestion in terms of wording.  Because we
do need to move on.  And it seems like we're all kind of torn.  Probably
some people probably think what are they talking about?  Why are they
spending so much time on this?  I understand that, too.  So I don't bore
you to death.

		So it seems to me perhaps what we might say in the report is is that
there were, you know, violations of specific requirements but the Board
could not reach consensus regarding whether they went to the level of
substantial noncompliance, and leave it at that.  Because I think we
could talk about this all day and keep seesawing.

		So, you know, if that's where we can go, I think sometimes that's
where we have to go.  But let's try to -- rather than keep talking about
that, see whether we're comfortable with that language with articulating
exactly what we saw as wrong.

		I think Jerry -- If we do choose to go this way, that we could not
reach consensus on whether or not it was substantial noncompliance, I
think Jerry's framing of why we're being consistent is a good one.
Because I think it is important that we're comfortable with consistency
in our judgment.

		So I'll ask Rich and Steve and whoever else it was. Oh, Sean.  For
feedback.

		DR. SHARP:  What's swaying me is the way in which you presented the
problem.  And I think this is helpful. To focus not on the changes that
were made, but on the failure to report the changes to the IRB,
following up on Gary's lead there.

		And for me I think the failure to report those series of deviations,
not one, not two, there's actually multiple deviations here.  That that
was an error of judgment on Dr. Carroll's part.  But if you were to look
closely at a lot of different protocol, you're going to see other errors
of judgment being made.

		And so, again, just focusing narrowly on that failure to disclose the
change to the IRB for me doesn't rise to that level where I would want
to say that he's substantially not in compliance here.

		CHAIR FISHER:  Steve?

		DR. BRIMIJOIN:  Well, I just want to come down heavily on Jerry
Menikoff's side of the seesaw.  Yes.  And I mean I would like to argue
that we should try to see consensus around some version of that idea
rather than abdicating.

		And I don't feel that we are at risk of sending a mixed message, an
inconsistent one.  We've already told the investigator in the strongest
possible terms how we feel about substituting one substance for another,
however similar they might seem in his judgment. And here the issue is
whether the investigator even recognized these things as being
deviations that needed to be reported rather than deliberating willfully
withholding information from an IRB.

		CHAIR FISHER:  Okay.  So now if we're framing it as Steve and Jerry
have, is that what we're comfortable with in terms of the reasons why it
was not substantial noncompliance?

		DR. PHILPOTT:  I guess I'm going to be writing a minority report then.
 Because I'm still going to come down on the other side.  And part of it
is getting back to the exclusion criteria.  We have a response from Dr.
Carroll to Mr. Carley's review in which his interpretation is more the
interpretation that we have been running with, not with how you think
you could look at the protocol if you looked at the strict wording.

		And so it's fine splitting hairs, or fine splitting of hairs I should
more accurately say.  I guess I'm troubled by the historical pattern
here. And I'm very leery of setting a precedent where we're going to say
a certain level of doing this is okay.

		CHAIR FISHER:  Okay.  So I think we do -- we have a precedent about
this before when there's been a somewhat lack of consensus.  We have
said a majority thought this, however some thought that.  Okay.  And we
that's how we will write it.  We will write it up in that manner.  And
using both I think Garry's and Jerry's kind of frame of reference, which
is very good.

		And we also have time.  Maybe we'll also be convinced about something
by the time we get to our teleconference.  Because that has happened
also where we've just withdrawn our disagreement.

		So that's where we are.  And we will go on to the next.  Good.  Okay.

		MR. CARLEY:  WPC-001.

		CHAIR FISHER:  Right.  Kevin and John are going to speak so quickly.

		MR. CARLEY:  We're waiting to get the right presentation on the wall.
There it is. That's the one.

		We going to skip some of this.  Please go to slide 3.

		This protocol was submitted in the July, the day after the consent
forms were signed for these by the untreated subjects for this last one.

		It proposes a field study in the mosquitoes repellent efficacy of
three materials, all of them contained picaridin as the sole active
ingredient.  Two of them are registered, one's a 7 percent pump spray,
one's a 15 percent pump spray. And there's also an unregistered lotion
that's the subject of a pending application that is 15 percent
picaridin, but it's combined with a sunscreen.

		And this is an interesting case because the registrant has several
picaridin products.  And we told them that we needed data on their
picaridin products.  They came up with a proposal that said we'll test
the 7 and 15 percent pump sprays, and we want to extrapolate from that
data to our other products that have comparable concentrations and
similar formulations of ingredients; they're all alcohol-based spray
solutions or alcohol-based moist toilette wipe-on sort of things and we
agreed to that scheme.

		So the two registered materials are surrogates, in a sense, for
several others.  I've forgotten exactly how many, eight or so I think.
Yes, there's at least six.  So that's the context in which this study is
being proposed.

		The lotion product, it's the only lotion.  It's the only one combined
with a sunscreen.  So we said no extrapolation for that one.  We want
you to test that one directly.

		The protocol is closely similar to the ones that we have just been
discussing.  And we think it's rip for HSRB review.  And it needs to
come to the HSRB, and Kevin is now going to pick up with his science
review.

		MR. SWEENEY:  Slide 8.

		Okay.  The objectives are essentially the same as the studies we just
discussed.  I think John just articulated why the data are being asked
for.

		So go to the next slide.

		In terms of toxicities, materials they're pretty benign.  I think the
MOEs are quite high, 7 to 15 percent sprays and got a sunscreen
combination product as well.

		Next slide.

		The study design is quite similar to what we've discussed all day.
Ten subjects per treatment.

		Dosimetry phase, and it'll be shared with the next protocol as well.
Aspiration training, et cetera.  And the study is not blind because
we've got two different types of formulations.

		Okay.  Sample size, the same thing.  Same criteria at this time. And
I'll talk a little bit more about it relates to what we just discussed
today when we get to the end here.

		Okay.  Next slide.

		Okay.  In terms of efficacy trials, it's exactly -- it's pretty much
the same thing.  I mean, you have untreated subjects monitoring mosquito
pressure, they attended by various technicians that are aspirating
mosquitoes before they can probe or bite.  And everybody, both treated
and untreated subjects, are exposed one minute every 15 minutes.

		Again, we're going to determine a CPT value.

		The next slide.

		Field sites.  We don't know if they're the same yet, but we know that
they're either going to be in the central valley of California in
Southern California.  It depends on seasonality.  Probably West Nile
Virus activity as well.

		Lively mosquito populations, again Aedes vexans, Aedes melanimon,
Aedes taeniorhynchus, Culex tarsils and Culex pipens.  And it could be
there could be other mosquito species in the habitat, and we've
mentioned some others today.

		Next slide.

		End points are going to be exactly the same as what we discussed all
day long.  We're going to have a CPT value, a mean CPT value for each
site reported, probably a pooled one as well as far the value itself.
And then also a Kaplan-Meier analysis to look at the survivorship.

		Next slide.

		The deficiency we've noted is that the lotion product, that is the
sunscreen 15 percent picaridin product wasn't adequately categorized in
the protocol, although we have full categorized in the application for
registrations pending with the agency at this time.

		Next slide.

		Okay.  In terms of the scientific standards.  Like here's the
appropriate place, of course, to make a few comments.  In light of what
we discussed today, I mean this protocol is written and it's very
similar to what we had reviewed previously last January.  And, of
course, we had a study that was reviewed today based on that protocol.
So I think some additional comments that will probably be appropriate
for us to make would be related to randomization, pooling of data, et
cetera, how we're going to handle to this data. It's pretty much what
we've talked about all day long.  And what's most appropriate in terms
of the experimental design, how many days you could test should all be
on the same day, et cetera.  And those are things I think we'll carry
into our discussion with reference to this.

		So I think that's pretty much it.

		MR. CARLEY:  And you want to do clarifying questions, if any?

		CHAIR FISHER:  Yes.  Is there any clarifying questions in terms of the
science?

		Okay.

		DR. CHAMBERS:  I have one.  The alcohol-based formulations that's the
same in the pump spray and the toilette that they're planning to use?
Is that correct, the same?

		MR. SWEENEY:  Correct.

		DR. JOHNSON:  Yes. You said ten subjects.  Are they going to be the
same ten subjects on all three repellents, or it'll be ten new subjects
for each repellent?

		MR. CARLEY:  I'll say a few words in a moment about the subject
selection, the pool they come from.

		DR. JOHNSON:  Okay.  All right.

		MR. CARLEY:  I think I'll address that.

		The ethics assessment is going to be the whirlwind tour.  And for
those of you who are new to this exercise, I hope you can keep up.  If
you have a problem, just ask.

		I'm going to skip this one.

		Subject selection.  Subjects will be recruited from -- this is a
quotation from the protocol "subjects in previous Carroll-Loye repellent
efficacy tests have agreed and requested to be in our volunteer
database."

		Dr. Carroll has told us in the past about how many people are in that
database.  My memory is it's like  60 or 70, something like that.  Yes.
That's about the size of it.

		And depending on your availability at a particular time when he can do
this study, it may be the same ones that we were just talking about, it
may be different ones at the different sites.  It's hard to predict.
They will come from this small pool.

		Past studies have involved typically some overlap between sites.  Some
of the same subjects being done at both sites.

		And as Kevin pointed out, this study is really more like SCI-001 than
WPC because it has the three materials.  So there's the potential for a
more complex design, but it's not addressed.  This is what is says about
the subject selection.

		Again, it has experienced subjects serving as untreated controls.  So
far as we can tell, no eligible subjects would come from populations
that would be vulnerable to coercion or undue influence to participate.

		The usual risks from repellent studies are present here.  There are
risks from the repellents themselves.  Risks from bites, potential bites
at least. And risks from arthropod-borne disease.  There are some other
risks associated with the mandatory pregnancy testing. And the protocol
is designed to minimize them effectively, but they're not addressed.
They're not discussed.  This is something I realized in reviewing this
protocol. It's also been true for the previous protocols from
Carroll-Loye, I just didn't notice it before.  But there it is.

		There are many actions taken to minimize risk.  Note that the protocol
calls for applying the repellent by skilled technicians. And this one
calls for post-test analysis of aspirated mosquitoes for pathogens and
promises to report any positive findings back to the subjects so that
they can be particularly alert to any symptoms of possible infection.

		The probability of harm is correct. Characterized as extremely small.
We agree with that assessment.

		There are no direct benefits to the subjects.  And the primary direct
beneficiary would be the sponsor.  If the materials are proven effective
and remain on or enter the market, in the case of the new one, indirect
beneficiaries might include repellent users who like these better than
other repellents.

		There are not a lot of obvious opportunities.  There aren't any
obvious opportunities to further reduce risk while maintaining the
scientific design. The residual risks are very low and almost certainly
offset by expected social benefits.

		The ethics review, as for the two earlier studies, has been provided
by an independent investigational review board incorporated of Florida.
They reviewed and approved these protocols and consent materials in
mid-July.  They're independent of the sponsors, independent of the
investigators registered with OHRP.

		I'm sorry, Dr. Parkin, I didn't include their number, but at your
suggestion I will in the future.

		They are not currently accredited by the AAHRPP.

		They have told us in an e-mail communication that their procedures
haven't changed since they'd sent them to us before.  These procedures,
as you will recall, have been covered by a claim of confidentiality.

		No new information about the IRB qualifications, training,
certification, et cetera has been provided with this protocol either.

		Back one.

		The protocol describes two distinct processes for the pre-identified
untreated controls and for the plain old treated subjects.  There are
separate consent forms, as was the case for WPC-001.  The consent form,
like the protocol, says nothing about any risks of embarrassment or
other psychological risks like to the pregnancy testing.

		The respect for subjects is okay.  We saw nothing to indicate that
their privacy or confidentiality would be violated.

		Medical care, if needed, would be provided at no cost.

		The applicable standards here are in 40 26 K and L.  There is still a
glitch in it.  One of the data collection forms which is missing. There
is no form attached to the protocol for recording the primary efficacy
data here.

		And approved product labels and the proposed label for the pending
product should be attached and used in the dosimetry phase as part of
the effort to get a typical consumer dose.  We ought to let people read
the label.  It's available to typical consumers, make sense of it and
use that as a guide to how to apply it, how much to apply it.

		The conclusions are that everything is okay except for those two
relatively minor points.  And that if further revised consistent with
those points, it will meet the applicable requirements.

		The charge questions are the familiar ones.  Is the proposed research
described in protocol SPC-001 from Carroll-Loye Biological Research if
it revised as suggested in EPA's review, does the research appear likely
to generate scientifically reliable data useful for assessing the
efficacy of the test substances for repelling mosquitoes.  And does the
research appear to meet the applicable requirements of 40 CFR Part 26
subparts K and L.

		CHAIR FISHER:  Thank you.

		Jan?  Oh, I'm sorry.  I should have asked --

		DR. PHILPOTT:  That's fine. I just have, and I may be thinking of a
completely different IRB 8( hour into a very long day.

		One of the independent IRBs, not the independent IRB, but one of the
commercial IRBs that we have reviewed in the past there was concern that
we have not had the information to adequately review their competence,
essentially. If I recall there was an IRB that hadn't submitted
information about their membership and background and things like that.

		CHAIR FISHER:  Is this a question about whether or not this is the
IRB?

		DR. PHILPOTT:  Well, and if this is the IRB because we don't see that
information, do we have it now?  Or was that EIRB?

		MR. CARLEY:  No. It was this IRB with respect to which you raised the
question in your comments on the WPC protocol.  In the ethics comments
about that protocol you said something like we don't -- we'd like to
know more about the qualifications and the accreditation status of IIRB.
 And we haven't gotten any more information about those two points.

		I'm not certain at this point.  I, too, am suffering a certain amount
of smear in my brain.

		 I think the lists of members and their degrees and their role on the
Board and some of those things have been shared with you.  The question
that was raised in the earlier comment had specifically to do with their
training and the Board's accreditation.

		We have not gone back to the Board and asked them to please send us a
list of all the training that all of their members have had.  That would
be pretty extraordinary behavior.  We'd want to do it across the board.
We haven't got there yet.

		CHAIR FISHER:  Jan?

		DR. CHAMBERS:  I don't really think --

		CHAIR FISHER:  Comments?  Okay. Jan?

		DR. CHAMBERS:  One more time.  I really don't think there's very much
for me to comment on this since it is so similar to the protocols we've
seen before.

		I presume that all of the extended discussion earlier today will go
into EPA's comments to trim up that protocol.

		The only deficiency you all noticed was the information about the
formulation of the lotion product.  And I assume that that will be
fixed.  So that doesn't concern me at all.

		So I really have no concerns at all about this, except in the data
interpretation.  And this is kind of a new wrinkle in that three
products will be tested, and I do understand that.  But two of them will
be used to extrapolate to two others.

		And the 7 percent pump spray will be used to extrapolate to the 10
percent pump spray. That's conservative.  I think that's fine.  But it
will also be used to extrapolate to the 5.75 percent towelette, the same
sort of thing with the higher dose pump spray.

		And I'm not real comfortable with the interpretation that that's valid
if the towelette would not administer the same amount of the insect
repellent.  However, the dosimetry might show that you would apply more
using a towelette than you would with a pump spray.  So if the dosimetry
shows that the towelette formulation administers about the same amount
as the pump spray, then I am perfectly comfortable with the data being
extrapolated. However, if the average person would apply less with the
towelette, then I think those response considerations, just like the
people talked about earlier with the DEET and everything would not allow
you to extrapolate to the lower one.

		But that's using the data for the extrapolation a little bit later.
As far as the way the protocol is laid out, I have no issues with that.

		CHAIR FISHER:  Thank you.

		Kannan?

		DR. KRISHNAN:  This is very similar to the SCI-001 I think, pretty
much.

		I have nothing to add except to say that I think I look forward to
some of the comments and discussions about the design and results, what
it statistically shows.  Because it very much relates to those issues
that we alluded to in January.

		CHAIR FISHER:  Suzanne?

		DR. FITZPATRICK:  I don't have anything additional to add.  I'm just
wondering if EPA has the ability to request that before this lab starts
to do another study they all get trained.  I don't know if that can be
one of your recommendations or not.

		MR. CARLEY:  We could certainly recommend that.

		CHAIR FISHER:  Science and ethics?

		DR. FITZPATRICK:  Compliance with human subject regulations

		CHAIR FISHER:  Didn't we ask for that before?

		MR. CARLEY:  Yes.  And as Dr. Carroll pointed out to your earlier
today, after that recommendation he took the training that you
recommended where he did not find anything that directly addressed this
question of --

		CHAIR FISHER:  Or remembered, anyway.

		MR. CARLEY:  Yes.

		CHAIR FISHER:  Okay.  Dallas?

		DR. JOHNSON:  Yes.  Looking at page 14 of the protocol there's a
listing of subjects and subjects one through ten are assigned a lotion,
11 through 12 are assigned the 7 percent pump and 21 through 30 the 15
percent pump.  And then there's two subjects, I guess, are untreated.
So I take that to mean that there's going to be 32 completely different
individuals involved in this study.

		And I currently serve as a consultant to the Army Research Office
Human Research and Engineering Directorate in which I review protocols.
And I've reviewed, I don't know, 30 protocols a year over the last four
years.  And in the process of doing that I've review them from a
statistical point of view and an experimental design point of view. And
in the process of doing that I've tried to increase the level of
sophistication and the level of statistical expertise among all the
researchers that I consult with, or work with, or provide advice to.
And this would not be acceptable.  If I were reviewing this for them, I
would not accept this protocol.

		I would want a listing of what subjects were going to be given what
product on which days.  I would like to know exactly how the process is
going to go on. And if you do that, then you should avoid the kinds of
things that you saw in the other protocols that we just currently
reviewed.

		And so I think -- if I'm going to serve on this Board for a long time,
at least I think I've been appointed for a three year term until I get
kicked off.  But I think in the process of doing that we have to
increase the level of sophistication that goes into these protocols with
respect to the experimental design.

		CHAIR FISHER:  So let me ask you question.  I'm sorry. I just wanted
to ask a procedural question.  Because I think what you're saying is
that in some sense without this detail it may be premature for us to
make a judgment as to the extent to which this could be carried out and
a way that could be analyzed.

		In addition, I don't see our role as designing this study.

		So if we thought it was premature and wanted to see it again in terms
of a design, are the elements that we talked about for these other
protocols, is that sufficient information to know what needs to be in
there?

		DR. JOHNSON:  I've not seen the previous protocol, so I don't know
whether the level --

		CHAIR FISHER:  No. I mean what we talked about today.

		DR. JOHNSON:  I'm not sure I understand the question. I'm sorry.

		CHAIR FISHER:  Okay.  Sue, did you want to --

		DR. FISH:  Yes.  And I think this is what you're getting at.  And so
I'm directing my question to Dr. Johnson and Dr. Kim.  But from what I
heard this morning from our consultants and the tremendous variability
of field study situations, the tremendous number of factors, et cetera,
if we're thinking about improving the quality of the science, wouldn't a
crossover design deal with some of that variability in a --

		DR. JOHNSON:  Right.  And I --

		DR. FISH:  So is that what you're asking, Celia?  Did we learn this
morning things that would help improve the science?  Is that what your
question was?

		CHAIR FISHER:  I'm thinking that one option we have is to say it's
premature for us to look at this because we really don't have any idea
what they're doing with the subjects, we don't know if it's a cross over
or not.  And I guess my question is -- at the same time I don't think
we're here for you to design this particular study.  And so the question
is is there any other resources other than what we were speaking -- what
we were speaking about today and the issues raised about pooling and
about cross over, and about Latin square design, if anybody read the
transcript would that be sufficiently informative as to the kind of
things we expect to see in additional to what we were told by the
consultants?  Right?  That's what I was asking.

		DR. JOHNSON:  Yes.  My point is that I don't care whether it's a cross
over design.  I mean, I would be glad to approve one that's a cross over
design.

		I don't care whether each subject is only evaluated once or you have a
parallel line study or a parallel treatment study.

		And I'm happy with either one of those, but it needs to be stated in
the protocol.

		CHAIR FISHER:  But we're in a -- not even going there.  I mean, are we
at a state where we're saying it's premature for us to see this because
there is no -- to be consistent if we approved it, we don't know what
we're approving.

		DR. JOHNSON:  If we approve, we could be in the same problem a year
from now.

		CHAIR FISHER:  The same problem.  I mean, if that's what you're
saying, it seems to me the conclusion is this is premature.  Something
has to come back with a much more sophisticated explanation of subjects,
design, how they're randomized, whether it's cross, whether it not
crossed.

		Jan?