VOICE: Let me ask a very narrow clarifying question here.  The two
untreated subjects in the mosquito field study who are used to verify
biting pressure, are they or are they not employees of Carroll-Loye?

		DR. CARROLL: They're not employees.  They are people who have worked
with me many times, that have participated in many studies, two or three
a year.

		VOICE: But they don't hit the exclusion criterion of people who are
dependent on you for employment or academically; is that correct?

		DR. CARROLL: No, they have other careers.  They just like doing this
kind of work on weekends.  A few weekends a year.  They are not in any
way legally or practically employees.

		VOICE: And in terms of the information in the protocols about
recruitment and informing and consenting, they are part of the same pool
as everybody else, right?  They just happen to be people that you have
known for awhile, but they are from the university community, subject to
the same exclusion factors, they're getting the same briefing?

		DR. CARROLL: Yeah, they are not treated in any way different at all.

		VOICE: Okay, that was our understanding, but I wanted to make sure it
was clear.

		DR. FISHER: Yes, Sean.

		DR. PHILPOTT: So one question that I've been mulling over in my head
for the past couple of minutes gets back to what Janice originally
talked about when she was in Florida.

		And you said in response to that that there are times when you bring
your students with you, subjects.  But that raises a number of issues as
well  in terms of voluntariness of withdrawal, particularly if you have
flown them to Florida with you.

		Why are they coming with you to Florida?  Just solely for
participation in this study?  And how is that reflected in the consent
documents and in their compensation?

		DR. CARROLL: You've asked - their compensation is at the same hourly
rate.  They don't pay any costs for transportation.  It does not say in
the current documents that if they acquire transportation that would be
regarded as unusually expensive to successfully complete their
withdrawal purpose that that would be covered.  And in fact it's just
implicit at this point.  It is not specifically addressed.

		DR. FISHER: So I think the recommendation would be if it's not already
that for those who are being transported that the informed consent quite
clearly include information that says you can withdraw without any
penalty, which means we're taking you back and you still got the same
hotel room.

		DR. CARROLL: Well, we're flying you back.

		DR. FISHER: Right, we're flying you back and you still have the same
hotel room.  Some times when you - there are times when the fact that
there will be no penalty for withdrawal needs to be more clearly
explained depending upon the context in which the subject is in.

		And I think what Sean is implying is that you might want to enhance or
we might recommend that you enhance the informed consent for those
subjects so they don't think their travel back is dependent on their
participating.

		DR. CARROLL: Dr. Fisher, another clarifying question about this, our
understanding is that withdrawal from the field of study phase amounts
fundamentally to declining to pull your sleeve up at the next time act.
But whether you are a 30-minute drive away from home in a bus in
California or a half a day flight across the country in Florida, you
still have to get home.

		I don't think Florida makes a very significant difference here in the
whole question of withdrawal.  You could make the protocol regardless of
what the place is more explicit that on the day of field testing here is
how you will get from the collection point to the test site and back
again, or something like that.  And this would not be affected.  We will
get you home if you withdraw.

		But I repeat, it doesn't seem to me that the freedom to withdraw is
affected very much by whether you are on foot in the boonies in the
central valley or on foot in the Florida Keys.  You still need to get
home, and you still have the same circumstance to withdraw from if you
choose to do so in the middle of the field study.

		VOICE: I agree with Mr. Carroll.  And I think the only real difference
is that subjects who go to Florida to participate in the study have
themselves an ethical obligation to complete it.

		DR. FISHER: I'm going to ignore that comment and go right on to
something else.  No, it's the same issue, it's the Florida issue.

		I actually didn't think about this before, but in searching the
document I didn't see that the Florida part of the study is explained in
the consent form.  That's separate, and there might be a transportation
issue and a time issue.

		How is it that you might discuss or describe to the California
participants their opportunity to travel to the other study site?  Or
did you intend to use mostly Florida people?   Because it's not in the
consent form at all.

		DR. CARROLL: In the past we've used mainly Florida people, and one or
two experienced could come along.  I think Dr. Philpott's question was
excellent, and yours as it extends it.  The reason it gave me pause
initially is because we've never really had anyone who didn't want to go
to Florida.  Usually that's not the opportunity.

		But we're mainly dealing with people who want to participate.  We get
calls throughout the year.  Is there another test coming up soon?  You
think you might go to Florida again?  We often - you know it's fun to go
to the Florida Keys.  It's more economical and more practical to do the
work in California.

		So I have not formalized that as much as I would have had I had more
experience.  With the current study, since we will be relying on more
subjects, although we've been proposing and exploring ways to be most
efficient, to minimize the number of subjects, we would need to
transport more to Florida, several people.

		And again, we are principally dealing with attitudes of people who
just really would like to go along, because you can go to the Florida
Keys in the winter.

		But it would entail describing the logistics of the situation very
clearly.  And I do think there would be concern of a person who might
wish to withdraw because they are uncomfortable with what they are
experiencing in the test would be, I might say, unintentionally feel
coerced by an obligation since they've had the luxury of being flown
across the country to Florida for free.  And I wouldn't them to feel
like they are in that position.  So I think that merits additional
clarification.

		In contrast to what Dr. Lebowitz has experienced, these are not tests
where you just end up seeing how few bites you can manage to get.  We
have very very few mosquito approaches.  With the modern generation,
these alternatives are much better repellents.  The subjects are just
waiting for hours to get their first approach.

		So even in the Florida Keys where it seems like it might be a mosquito
jungle, it's not often likely to be in a situation where the person who
is in love with their tropical vacation and suddenly feeling they really
need to get out of there immediately but they don't feel they can ask.

		I don't think that will happen, but I would like to make it explicit
to subjects that they do have the ability to withdraw at any time, even
under the Florida vacation scenario.

		So I think more words should be added, I will add more words for any
test that is going to go to Florida.

		VOICE: That issue by the way came up in looking at how one protects
deployed forces in theaters, and it's part of an Academy of Science
committee I served on.  And the armed forces had a phenomenal amount of
data as did the contractors to the U.S. government that sort of
reflected even within the FIFRA reflected a different scenario as you
described which is why I realized I had blocked on what I had read on
pages five and six, it conflicts with different levels of types of
knowledge.

		And so it wasn't - although my own experience has been terrible, and
I'll never go back to Florida, that didn't have anything to do with it.
That must have been a subjective kind of rationale.

		But in fact there if you say from your experience that they have to
wait hours to be approached by a mosquito, you probably have knowledge
about those specific locales that the armed forces never studied.

		DR. CARROLL: That the armed forces never studied?

		VOICE: Or didn't report on because they might have to kill us.

		DR. CARROLL: Well, I'm not consulting for the armed forces pesticide
management board.  That's a management board on mosquito repellants.
And in fact I'm doing my best to transfer the kinds of ethical insights
we've had to the practices that I use there.

		DR. FISHER: Lois?

		DR. LEHMAN-McKEEMAN: I'll preface my question by saying that I know
very little about the biology or the husbandry of ticks.  But in reading
the protocol, just a question of clarification.

		The tick protocol indicates that the ticks used in the study which are
laboratory ticks are reared on quarantined rodents.

		DR. CARROLL: Yes.

		DR. LEHMAN-McKEEMAN: Now I didn't know precisely what that meant.  But
as a person who is in fact highly allergic to rodents I was wondering
whether one of your criteria for exclusion in that study might need to
be individuals who are in fact sensitive to rodents?

		DR. CARROLL: From a biological standpoint I cannot imagine why that
would be necessary.  One thing that the ticks do after they take a blood
meal from a hamster that is kept in quarantined in the sense of
protected from disease contamination of the rodents, the ticks ingest
the blood meal, and then they really reform their body very substantial
away from the rodents, because they undergo a tremendous metamorphosis
from one stage to the next.

		So they're barely the same arthropod, let alone having the true taint
of a rodent still on or near them.

		It's a very interesting point, principle to bring out.  But as a
biologist I can't imagine a real world concern from that.  But I will
let it bounce around and think about it.

		DR. FISHER: Jerry.

		DR. MENIKOFF: I have a question about the medical monitoring that you
have in place.  It sounds like these anaphylactic (phonetic) type
reactions that might occur here are extremely unlikely.  Is that
accurate?

		DR. CARROLL: Yeah, I've never seen one myself, nor do I know anyone
personally in the field or anyone that I know personally who has seen
one or knows anyone who has had one.

		DR. MENIKOFF: But at the same time you've also made the decision that
you are going to notify the hospitals about the fact that you are
conducting a study and give them some information in advance I'm sure as
to why you made that decision?

		DR. CARROLL: Just A, because of the potential inherent inefficiencies
of the emergency rooms.  And the possibility that giving them
foreknowledge might smooth things should we need to utilize their
services.

		And because we can't control everything in this kind of interaction.
I realize that is true of life itself, but we've got individual subject
variations, individual mosquito variation, the interaction of subjects
and mosquitoes, the interactions of these repellents, all mixed in
together.

		So I think it's a variety of low risks being mixed together, but we
can't control all the epiphenomena.

		DR. MENIKOFF: In light of that would it be overly burdensome to
actually identify a physician who could serve as an emergency contact
and who you could brief in advance so that there could be some person
who is much more familiar with the study itself?  I mean is that
something that is possible?

		DR. CARROLL: That would be very possible, and very straightforward.
Such people already exist in my community.

		DR. FISHER: Any other questions?

		Okay, thank you very much, Dr. Carroll.  And also thank you for all
the efforts you've put in, and certainly the consideration and respect
for our comments.

		We were impressed.

		So I guess we should do the - should we do the studies separately from
our perspective, or together?  Separately?

		Okay, okay, so Lois would you like to begin to speak to 003?

		DR. LEHMAN-McKEEMAN: Certainly.  I will be very, very brief.

		I would also echo the sentiment regarding the fact that these revised
protocols clearly reflect what was careful and conscientious
consideration of all the discussions several months ago.

		So to the question, it is my conclusion that this particular study
will generate scientifically reliable data.

		The study now has a clear rationale, and again, relative to some of
the earlier questions, these are new formulations for which this kind of
an evaluation is required.

		And again, in light of the questions and discussions we had, these are
- this is a far more complete protocol with emphasis again on limiting
the weaknesses that were described previously, and I'll just highlight
several of them, including the fact that the formulations themselves are
now going to be characterized including their stability.

		Each subject serves as his own control, and the study increased from
six to 10, and with these data now there is a description of the
analysis of the data yielding the complete protection time as well as
potentially a relative protection value.

		So it seems to me that the study as it is designed and now presented
to us will generate the kinds of data that will be useful for evaluating
the efficacy of IR3535 against ticks.

		There are two comments that I want to make of minor substance with
respect to potential improvement to these studies.  One has to do with -
and I think this was mentioned in the EPA review, but not highlighted in
your comments.  There is a suggestion in the protocol that because of
the aerosol in the pump has the same concentration of ingredient, albeit
different excipients, might be potentially tested in the same subjects.

		My suggestion would be that that should not be the case; that the
lotion should be tested separate from the pump, which should be tested
separate from the aerosol, which would mean then the utilization of 30
subjects and not potentially 20.

		And the other comment I had, and in part for me it was a little
difficult to follow exactly.  But I think one fo the strengths of the
study is going to be the fact that there will be some better dosimetry
data here, so it's not just a function of whether this thing works, yes
or not.  But because of the dosimetry leg there will be some indication
of the amount of product that has been used, which can go to assessing
retrospectively that we have not caused any safety issues.

		What wasn't clear to me was that that was going to be done in a way
that was going to generate really accurate data.

		As I understood the gauze bracelets, the lotion made sense to me.  You
basically just weight the bottle.  But the aerosol and the pump appear
to be done by measuring the weights of these gauze bracelets being put
on the arm.  And if that's being done outside, then I immediately have
the question of, well, these are somewhat volatile with respect to their
formulations.  So what is done to basically minimize the change in
weight that is going to take place?  Are they being weighed immediately?
 Are they being put away somewhere?  That kind of information just
wasn't there for me.  And I think the spirit is there to do it
correctly, and perhaps the information you have a plan.  But I think
that that would be the one place where that could be improved with
respect to detail just to make certain that that was in fact going to be
an accurate and valid assessment.

		But those are really my only two comments with respect to any negative
or weaknesses.  Otherwise I think this is going to represent quality
data.

		DR. FISHER: Thank you.  Richard?

		Okay, and David?

		DR. BELLINGER: I concur with Lois.  I was very impressed with the
improvements in the quality of the protocol.

		My only comment is sort of a more general one, first of all, I liked
the addition of the dosimetry piece.  I think that will be very helpful.

		But in some ways I think it got things a little backwards.  I would be
more interested in knowing what the effective dose is and then
instructing people to apply that amount rather than finding out what
amount people applied, and then find out if that works.

		I mean it's a different question.  But perhaps it can be answered in
another study.  But otherwise I think it's a very strong study as it's
written presently.

		DR. FISHER: Okay.  So I think we'll do the science comments.

		DR. KRISHNAN:  Just for the record I wanted to repeat the comment on
the dose.

		DR. FISHER: Okay, the dosimetry or the dose.

		DR. KRISHNAN: I think so that the studies on dosimetry and efficacy
are done without compromising safety, it would be useful to indicate the
known NOIL (phonetic) or safe level.  In this case there is a 300
millogram per kilo identified as an animal NOIL for example.  So that
they can ensure that the dosimeters do not contain more than the code
approximate safe levels.  One could always take the animal NOIL and
divide by 100 or so as a margin of safety, something like that.

		So I will be interested to see that lowest level that could be used in
the dosimeters for doing these studies.  That's basically my concerns.
Don't compromise anything, but I know because of the smaller negligible
risk associated with this.

		DR. FISHER: I think we'll go to the ethics, then we'll come back to a
summary of both.

		Dr. Philpott?

		DR. PHILPOTT: So I'm going to focus of course on just ticks right now,
and the charge question for the ethics relate specifically to whether
this study as submitted now complies with the requirements of the
subparts K and L.

		And I'm going to start with subpart L because that specifically
addresses the question of exclusion of children, pregnant women, and now
with the revision, nursing women, and it's very clear from our exclusion
criteria that the requirements of subpart L are met.

		Subpart K relates to submission of documentation from the IRB to
demonstrate appropriate  scientific and ethical review.  The issue of
the confidentiality of procedures aside, I - we've received the minutes,
and I see no evidence from them that we are not in compliance of subpart
A at this point either.

		Now it was very hard for me, however, since the HSRB is not supposed
to be an IRB, but it's hard for us to take off our hats.  I'd like to
start by commending Dr. Carroll for this revision.  I think he took all
of our comments at the last meeting to heart, and he was actually very
gracious about it.  And I wish people who submitted stuff to my IRB
would be as kind.

		I just have a couple of minor suggestions.  I believe that he has
addressed all of the concerns that we raised at the previous meeting
with respect to the concerns about coercion and voluntary informed
consent, particularly came up with a novel approach for dealing with the
confidentiality issue as it relates to women and the over-the-counter
test for pregnancy to meet compliance with subpart L.

		I did notice two minor things that should be considered, and that is
on the informed consent document for AMD-003 under the benefit it
specifically lists compensation for your participation as a benefit, and
that should not be there.  I was surprised that the IRB let that go
through.

		I also noted under the section for consent and signature, the last
page of the informed consent document, it authorizes the release and
disclosure of medical information.  I don't quite see why the release
and disclosure of medical information for this particular study is
required.

		DR. FISHER: Let me just ask, is this for - this would probably be
beforehand?  I assume is this required for safety information?

		(Off mike response)

		VOICE: Just following up on that point, maybe some of the eligibility
information they're collecting might fit under something in terms of
that.

		Bottom line, I like what everybody else said, both Dr. Carroll and EPA
did a great job inasfar as the earlier comments.  I agree with Dr.
Philpott's conclusions that basically this needs to be applicable
statutory standards

		One very minor comment I'll make, in general in risks I think it's a
good thing to give as much available information as there is.  And in
particular, the current consent language is relatively vague about the
knowledge we already have about the possible side effects of the base or
the active ingredient.  It says you may experience blah blah.

		To the extent in fact we know there is a very low likelihood of
experiencing that, I think it's beneficial to actually say that instead
of just using the vague words such as may.  Give greater details, and in
fact that would be more encouraging to subjects if you tell them one
person in 100 has skin reaction to this or something to that effect.

		Other than that, generally very good.

		DR. FISHER: Richard.

		DR. SHARP: Just two points.  The first is that the concern that I had
initially put out there about the fact that this may be a well designed
study  but we also need to raise that bigger question about whether it's
also going to answer an important question that we don't have an answer
to yet.  The discussion seems to clearly indicate that in fact there is
reason to conduct this study from the point of view of assessing the
efficacy of the product.

		So I want to make it very clear that I'm withdrawing that, and make it
clear that I'm convinced on that point.

		Second has to do with the suggestion that we've already touched upon.
I think it would strengthen this protocol from the point of view of
ethics to identify a physician who is clearly designated as responsible
for assisting in the very unlikely event that there is a serious adverse
event; somebody who is accountable in some way, and familiar with the
protocol.

		So again if that isn't particular burdensome, I think that that is a
strong addition here.

		DR. FISHER: Okay, good.  So I'm going to go back over the science.

		So in terms of the strengths it's careful and conscientious.  It has
new formulations for which the data - it's going to develop new
formulations for which the data is required.  It's a more complete
protocol.

		This study will generate scientifically reliable data.  There is a
clear rationale.  The formulation is now better characterized with
stability.  The increase in N is good, with subjects as their own
control.  And analysis of the data is now provided, which will also
provide information on quick and relative protection.

		It could be improved.  The lotion should be tested on subjects
separate from the - separate subjects, which means you may need 30
subjects, not 20 subjects.

		Dosimetry data is valuable in and of itself.  There was a question
about with using the gauze bracelets then outside, what the volatility
is in terms of measuring the weight.  So it might be important to give
additional information on that.

		Also it would be useful to indicate the Noel (phonetic) and Loel
(phonetic) information that is currently available, as one is talking
about dosimeters, to ensure that they are actually at a safe level.

		And I think the suggestion for future research is whether or not
measuring what the effective dose is, and then kind of informing the
application.

		Any other points, or did I get something  just totally confused?

		VOICE: The only thing you confused was the two that should not be
combined are the aerosol and the pump.

		DR. FISHER: Great.

		Oh.  Got it.  Okay.

		So any other comments?  Now go to the ethics, the study met
requirements of subpart L in terms of exclusion of women and children,
and went beyond with the nursing women.

		Subpart K it appears as if it meant those criteria based on the
materials that we received.  There appears to be sufficient benefit
based on finding out the efficacy of the product formulation.

		In terms of improving the study, benefits needs to be taken out of the
informed consent - I mean, I'm sorry, compensation needs to be taken out
of the informed consent as a benefit.

		The release of medical information statement needs to be deleted.

		Risk information in the informed consent might be made more specific
since there's information that's there, rather than may be, that there
is a low probability, there is a likelihood some people get this,
whatever is appropriate.

		And in addition to the hospital that it would be helpful to identify a
specific physician in the area in case of the unusual event that there
is an adverse reaction that there is a physician who is aware.

		Any other comments on the ethics?

		VOICE: Just a point of correction.  L now requires that nursing women
be excluded, so it didn't go beyond.

		DR. FISHER: Thank you.  Okay.

		VOICE: Let me just add for clarification. We put out a proposal, I've
forgotten exactly when, it was sometime just before your last meeting
that we were going to do this refinement of the rule, to add nursing
women to the prohibitions.

		And we said this would become effective if there were no comments on
it, that we received no comments on it.  So it magically became
effective on August 22nd.

		So now the - all of the various provisions, the prohibition sections
of the rule, the ones that prohibit EPA testing, the ones that prohibit
third party testing, and the ones that prohibit EPA consideration, all
three of those passages in the rule now refer to children defined as
under 18; pregnant women; or nursing women.  In all three places.

		DR. FISHER: Okay, yes?

		VOICE: Can I ask a question?  What was the statement on medical
information that you wanted to move from the section, where it say
because of the need to release information?

		VOICE: So on the AMD-003 consent form last page, which is I think page
seven - I don't know the page in the document, right above the signature
line where it says consent, it says, release of medical information.
What's interesting is that is not in AMD-004.

		DR. FISHER: But anyhow, there is no medical information that is
needed.  It was just kind of plugged in there as something that was on
more clinical ones, so he's not collecting any medical information.

		(Off-mike comments)

		DR. FISHER: Do we have a consensus?  Any other comments on 003?

		Okay, we'll move to 004, and that's Jan I believe you have the brief.

		DR. CHAMBERS: I'd like to add my comments to some of the others that
have been said, and commend Dr. Carroll for his careful revisions and
being very responsive to comments we made a few months ago.

		What I did in my critique last time was go through the scientific
questions that we as a board have, and I'm going to run through those
same things again quickly.

		This time a scientific question was stated, that is, to test the
efficacy of this IR3535 for repelling mosquitoes.  The existing data
were not adequate to answer the question for these new formulations.

		Because existing data were not adequate to answer the question of
efficacy, new studies involving human studies are necessary.

		The potential benefits of the study were clear, that an effective
repellent would be available; it would have either greater efficacy
and/or fewer drawbacks than what was currently approved.

		It's likely the benefits would be realized, that is, the efficacy of
the repellent, because there is a long positive history of this compound
from its European uses as a repellent.

		The risks have been more extensively described as have the strategies
to minimize risk.  And the most likely relevant risk would be disease
transmitted by the mosquitoes, and that's been dealt with to minimize
the risk.

		He also indicates that the inert ingredients in the formulation lack
toxicity at exposure levels anticipated, and that was one of the
questions we had earlier.

		With respect to study design criteria, the purpose of the study was
clearly defined.  There were specific objectives and hypotheses, the
hypothesis being that IR3535 is an effective repellent.

		The studies as described can test this hypothesis.

		Sample size is now a definite 10 individuals; it was a little fuzzier
before; and two negative controls, and no positive controls.

		The number of subjects would be repeated in two locations.  There is a
plan allocating individuals to treatments.  And the findings from the
study can probably be generalized beyond the study sample.

		With respect to participation criteria, there are more extensive
justification for selection of the target population.

		The participants were representative of the population of concern, but
however, as was pointed out earlier, that wouldn't include everybody,
but there's really no way around that.

		The inclusion-exclusion criteria are appropriate.  Sample is not a
vulnerable group.  With respect to measurement criteria, the
measurements were expected to be accurate and reliable.  The
measurements were appropriate to the question being asked, and quality
assurances were in place.

		Statistical analysis criteria, data should be able to be analyzed
statistically, and my spin on it is the statistical method is
appropriate.

		Laboratory and field conditions.  No laboratory experiments here.
Field conditions were representative of the intended use, and the
protocol now includes a stop rule plan and medical management plan.

		So in conclusion the revised protocol contains considerably greater
detail than the original and it answers all the scientific questions
that were posed by the HSRB in its initial review.

		The PI has been extremely responsive to the original review comments,
and the revised protocol should generate scientifically valid results of
efficacy in repelling mosquitoes.

		And I'd just like to add with one editorial comment.  I rode up here
on the plane yesterday with somebody from Mississippi who is studying
the incidence of West Nile Virus in our state, and we've just had the
worst year that we've ever had.  I think we've had 147 cases with six
deaths this year.  And so I will certainly be enthusiastic about the
develop a product that would be more effective, and more likely to be
used by people, because we really need it.

		DR. FISHER: Thank you.

		Steve?

		(CD Change)

		STEVE: Following Janice's lead, I went through the exact same list of
points and I came up with almost identical language. And I too was very
impressed by the improved quality of this protocol, and the great
thought that went into it.

		DR. FISHER: Suzanne?

		DR. FITZPATRICK: I'll third that.  Dr. Carroll did a good job.

		The only two things that I would have liked to have seen would be a
copy of the California Department of Pesticide Regulation experimental
subject bill of rights.  It's probably more of an ethical thing.

		And also one of my pet peeves - this is an ethical thing - the
expiration date should be on the consent form.  Even though they are
following continuing review, the consent form is out of date without
that.

		DR. FISHER: Thank you.

		Any other comments on the science?

		Okay, let's move to the ethics.  I can't read the -

		DR. PHILPOTT:  It's me again.  I'm busy today.

	ETHICS

		So once again, great job.  Thank you for being so responsive.  And I
can - I can conclude that once again with the addition of the minutes
from the IRB meeting, and the exclusion criteria now expanded to include
nursing women, that the AMD-004 does appear to meet the applicable
requirements of both subparts K and L.

		Just a couple of comments in addition to what Suzanne has already
brought up regarding ethics comments that I agree with.

		I'm a little concerned, as you might have been aware from my questions
of Dr. Carroll, regarding the idea of recruiting subjects in California
and then flying them out to Florida.  That could raise questions of
undue influence, both for recruitment purposes as well as for
voluntariness of withdraw, and I echo Sue Fish's comments earlier, her
questions about the two negative controls that serve to determine biting
pressure, and that there needs to be a lot more explicit discussion of
how they're recruited, and also the consent procedures involved in
bringing those individuals into the study.

		DR. FISHER: Thank you, Sean.

		Jerry - or somebody.  Jerry.

		DR. MENIKOFF: Yes, I agree with Dr. Philpott's comments.  One thing
I'll just note for the record.  The risk section is actually very well
done here.  In addition to noting you may get West Nile virus, and even
though they correctly note - I'm assuming it's correct - that your
likelihood of getting it is so low, they go on to point out what might
happen to you from West Nile virus, including pointing out
disorientation and possible coma and paralysis, which is just a good
example of just letting a person know that this stuff could happen to
you.  So I just wanted to note that.

		But I think it meets the appropriate statutory standards.

		DR. FISHER: Thank you.

		Richard?

		DR. SHARP: Apart from the comment that we made earlier about medical
monitoring, I have no other additions.

		DR. FISHER: Great.  Okay.  So I'm going to read what I think we said.

		For the science, I didn't get everything Jan said, because she was
reading so quickly.  Fortunately she'll be writing this.  But based on
our criteria, the question was stated, that the existing data is not
adequate to answer the question.  The benefits are clear in terms of
finding out something about the efficacy of the formulation.  The
benefits have great potential to be realized.  Risks and strategies to
minimize the risk are much better described and designed.  The purpose
is clearly defined.  There are specific hypotheses and they can be
tested.  The sample size is better.  There are no positive controls.
There are of course two different locations.  There are plans for
treatment.

		The generalizability is as good as one is going to get in these
situations.

		There is a better justification of subject selection.

		Measurements are appropriate, adequate and reliable.  The data can be
analyzed statistically, and the field conditions are representative of
the intended use, and therefore, there is the conclusion that data
generated will be helpful in producing scientifically reliable data,
useful for assessing the efficacy of the test substance for repelling
mosquitoes.

		Any other comments?  Yes.

		VOICE: There is one observation that I wanted to make, which I think
we need to clarify before you with Dr. Carroll, and that is whether this
protocol calls for testing these materials in both California and
Florida, or whether it is set up to describe a test which could be
conducted in either California or Florida.

		I'm not certain of the answer to that, but from the way Dr. Chambers
summarized it, my sense is that she thinks it's both-and.  I read it and
I thought I read either-or.

		So let's get that cleared up before we get agreement.

		(Extended off-mike comment)

		VOICE: Habitat not meaning state, meaning something on a much smaller
scale.

		DR. FISHER: Okay.  With respect to the ethics, the study meets
criteria of subpart K and L.  The rests as shown were very informative,
and the informed consent.  It would be good to have a copy of California
bill of rights given to the subject; is that what you want?  Okay, so
given to subjects.

		There should be expiration dates on the consent form, and if Florida
is used, then as we discussed, the logistics need to be explained so
that the freedom to withdraw is clear in the consent, and I think as
John Carley is pointing out, this may be needed both for somebody - it
may be needed even if they are not going to Florida, if they are taken
into the wild somewhere or something like that.

		Also, the two untreated subjects, it must be clear that they are
treated with the same inclusion -exclusion criteria as others in terms
of vulnerability and risk and that the IRB has reviewed them as well.

		And the medical model, monitoring should be similar whether you're in
California or Florida; there should be some arrangement with a local
physician in case of an adverse event.

		Any other comments?  So we have consensus on 004?

		Congratulations.  This is our first revised approved protocol - well,
not approved, but recommended for approval protocols.  Recommended or
whatever, positive.  So I think that's great.

		Okay, what I'd like to - it'd be great to - I think we should take a
break and then go even if it's a little over 5:00 just finish up on
going about the guidance for people submitting protocols.

		Oh, I'm sorry.  But I think we'll combine that, right?  Because the
review format - is the review format different from the -

		VOICE: The framework that is attached to the draft PR notice is the
same framework that used for the assessment of these protocols.

		DR. FISHER: Right, but I thought we'd handle it altogether.

		VOICE: It's a bundle.

		DR. FISHER: Right.

		So 15 minutes?  Ten minutes?  What do you want?  Ten.

		(CD Change)

		VOICE: I think there are some points that you do need.  I will
characterize my presentation in one word: brief.

		I think there are some points that you do need.  I will characterize
my presentation in one word, brief.  So give me a break.

		First a correction.  The date is not October 19th; I didn't think we'd
get this far today.  But you continue to amaze me.

		What is a PR notice?  It stands for pesticide regulation notice.  They
are designated by the year in which they are released, a hyphen and then
a sequential number.

		It's a longstanding series.  Informal nonregulatory guidance
documents, they are advisory in nature.  OPP uses them to communicate
with the regulated community and other stakeholders.

		The audience intended for this particular one is anyone who either
plans to conduct research involving intentional exposure of human
subjects intended to be submitted to us under the pesticide laws, or
anyone who submits the results of completed research to us whether or
not it involves intentional exposure for consideration under the
pesticide laws.

		Our main concerns - well, the main points in the notice are the
schedule of meetings, and that of course would be something that needed
to be renewed periodically to tell people what their target dates are.
And then how and when to submit protocols; that's the principal focus;
how and when to submit the documentation of ethical conduct for
completed research.

		Our main concerns are that submitters be able to understand the
applicable requirements, and then be able to meet them on the first
pass.  The experiences that we've had over the last several months with
Scott Carroll's protocols, with the AETF protocols , with the
requirements for multiple submissions on the red study and so on, we
want to get past that transitional stage.  We want to put something out
that tells people what to do clearly enough so they can get it right or
nearly right first time out of the box.

		And then our basic questions, which kind of telegraph the charge: if
submitters comply with the guidance and its notice, will we have
everything that we need, and will you have everything that you need?
Will we both be able to find it easily?  Is this an appropriate way to
organize, index and summarize this stuff?

		In implementing 1125, this is the submission of protocols, the
protocol submitter has to write the protocol and pull together all the
supporting materials as required by 1125.  That's a much larger and more
complicated job than it used to be for these people simple to knock out
a protocol.

		They have to get IRB approval.  They have to get all that additional
documentation from the IRB.  They may have to obtain approval from state
authorities; it varies by state.  They have to compile an index.  The
index that we expect them to use is attachment eight to the PR notice.

		It's the same document that we used as our completeness check for 1125
submissions.

		Then they have to send the whole bundle to us far enough in advance of
the HSRB meeting that we can review it, make the necessary decisions,
get it queued up for your consideration, and make it available to you
and to the docket.

		Then when we get it we have to assess the  - doublecheck the
completeness of the package and notify the submitter of any
deficiencies, and then we complete the framework, attachment B, for the
protocol.

		Now we're not going to do the framework until we're satisfied that we
have the complete package.  But once we've crossed the completeness
hurdle then we'll do the framework, then the assigned ethics and science
reviewers will do an integrated narrative review based on a single joint
execution of the framework.

		If it's acceptable we'll send the review out to the submitter and
schedule the protocol for your review.  If it's significantly deficient
we'll notify the submitter for correction, but it will fall off out of
the queue for HSRB review.

		The framework as I mentioned this morning is heavily adapted from the
original work that Emanuel did.  What are we doing it?  We want to make
sure that all the critical questions are addressed.  The framework as we
have proposed it here contains some points that were not within the
lists that you all provided us after the June meeting.  I'll point out
which ones those are.  These are things we still think are important,
and there may be others yet that either you or we think of that we want
to add to the framework.

		We want to organize information from the protocol that is relevant to
our acceptance judgment.  Our intention is that the framework, or the
unshaded portions of the framework, are going to be filled up with
quotations from the protocol, from the submitted package; mock
judgments.

		We don't want to answer questions yes or not.  We want to say, here's
what it says in the protocol about that, and then put in parentheses
that this is on page 46 or whatever, so that there is a link between the
big pile of stuff.  And you saw that  the Carroll protocols as amended
end up being about an inch thick.  Well, it's hard to master all that
information.

		So the framework is kind of the intermediate point, it's the set of
pointers to the real deal.  And then the final purpose is to provide the
supporting documentation for the narrative review, which summarizes the
judgments and conclusions, and makes a decision without the
acceptability in terms of the applicable standards.

		There are the items two through eight on this list are the same ones
you're accustomed to seeing on the other adaptations of the Emanuel
framework.  There is an inelegance.  I probably should have called the
identification block A, and then I could have left the rest of them
numbered one through seven instead of changing the numbers.

		But it's the same topics you've seen before.

		The parenthetical numbers here are the numbers in the list of science
criteria from your - it was from the draft final report from the June
meeting.  There don't happen yet on the slide to any ones from the
ethics committee, but I'll explain those when we get to them.

		So for example Item C there that's in the framework are all the
prerequisite studies in hand, that was not on the list of science
criteria.  You talked about it, but it didn't make its way into that
list.  We wanted it in here so that we could be sure that it had been
addressed.

		And the last point on this slide, how would the data be used by EPA,
was also not on your list, but it's addressing that question, how would
this fit into the weight of evidence.  What sort of poll in our
understanding would it plug?

		Next one.  This is the first of multiple ones on study design.  Let's
see, B, is there adequate statistical power to definitively test the
hypothesis?  This question was raised explicitly in the NAS
recommendation 5-1, but it wasn't on the list of science criteria.
Obviously it belongs there.

		The "how will subjects be exposed" is just the description.  So many
subjects exposed this way, that way; that needs to be in there
somewhere.

		The rationale for the choice of test material and formulation is as
important as the rationale for the choice at those levels and the
staging. So we wanted to be sure that one got covered.

		Next one, let's see, we added in K; are there adequate and appropriate
controls.  All of the others of these, obviously you can see that we
shuffled the order quite a bit.  But the questions are there.  We
thought that this sequence was consistent with our experience of
extracting tidbits from studies, and would be a little easier to fill
out by the sequence that you all suggest.

		Then when we go to subject selection, next slide please, the one area,
1111A3, the ethics subcommittee, used very different types of citations
in your last draft report, so they weren't numbered one, two, three,
four, five.  And these are references that were in the stuff the Skip
Nelson presented at the June meeting.

		Subject selection in general is covered under 1111A3.  The very
important question how and from what population will subjects be
recruited, but we want to know that, so we plugged that in.

		On risks and benefits, we separated, as you saw in the assessments
that I presented of the Carroll protocols, we separated the presentation
of qualitative risks from the probability of the occurrence of each of
those risks.  And I think that is a very helpful way to break down what
we know and don't know about risks.

		And the question about weather post-exposure monitoring is - would
continue long enough to be able to see potential adverse effects is one
again that was part of your discussion but it didn't turn up in the list
of criteria so we added that in.

		Continuing on the next slide, none of these were specifically listed
in the ethics subcommittee, but the bottom line, are the risks
reasonable, we broke down these five predecessor questions as a good way
to work our way up to being able to address the question, are the risks
reasonable?

		Bear in mind, however, that in the framework, what we would put in
there in this section, 5K, would be what the protocol says about the
reasonableness of the risks.   It's in our narrative review that we say,
and here's our judgments about that.

		Independent ethics review is implicit in the references that were made
to 1111, which is the IRB's criteria for decision.  It was explicit in
the cited NAS recommendations.  Who reviewed it?  Are they independent?
Are they registered?  And so on.

		Then on informed consent, the D and E were added.  Obviously relevant
to protocols that we've looked at last time and this time, and they
needed to be made explicit.

		On the next slide, we added all of these.  These are particularly
relevant, I think, to agricultural worker exposure studies where there
are much more likely to be language differences, and if you will power
differences, between - I don't mean statistical power either - power
discrepancies between the investigators and the subjects, that have to
be compensated for, and we would expect to see them addressed in
protocols.

		Then on respect for subjects, this was mentioned by the ethics
subcommittee, these are the same questions we have been asking.

		That's what we've got in the framework for the protocols.  All but
three of the numbered science criteria from your previous report are
covered.  The three that are omitted, one was an oversight; it's the one
about Q/A measures.  The next version of this will plug that in.  It was
just a mistake.

		The other two that were omitted were the two that specifically
questioned the concordance between lab and field conditions, and those
only apply in a relatively narrow range of studies, so we decided to
drop them out of the generic framework.

		In cases such as some of the efficacy, repellant efficacy situations
where that is important, obviously, it becomes part of the science
review.  But in terms of being a general characteristic for this overall
framework, it didn't seem appropriate to include it in all cases, so we
skipped those.

		1303 is a little bit different situation.  You saw what happened when
the size of the ROAT study more than doubled when we went back to them
and asked them to comply with 1303.  This is a temporary phenomenon.
Most studies like that are going to have to come in for protocol review,
and most of those documentation requirements will be addressed in
responding to 1125.  There won't be much left.

		Next slide, please.  1303 requires submission of documentation not
previously submitted to EPA.  So if something has been through the
protocol cycle, there won't be a lot more left to do here.  But the
study submitter, in a case like this, which spanned the implementation
date of the rule, or in a case where it's like an observational study
where it doesn't require prior protocol review, when they finally submit
it, they'll have to put all this stuff together.  They will collate it
and index it, again, indexing it according to the checklist that we
provided in appendix C that says these are the requirements of 1303, and
send it in.

		Then we check the submission for completeness.  When it's complete, we
review the science.  Here we're talking about separate science and
ethics reviews.

		Then if the decision is that we think we want to rely on this study in
our science assessment, then and only then will we do the ethics review.
 If it's not going to pass scientific muster, we don't need to do an
ethics review.

		We send the reviews that we conduct back to the submitter, and if it's
required, we schedule it for review by you.  I won't remind you, unless
you want me to, of the exceptions, which cases don't have to come to
your attention.

		The ones that do are intentional dosing studies, conducted since the
new rule, or conducted prior to the new rule but which measure toxic
endpoints.  Those are the ones that are required to come to you before
we rely on them in our actions.

		There are the charge questions, but before I stop Bill wants to say
something.

		DR. BRIMIJOIN:  Actually, two very short points.  The document that we
prepared and asked the board to comment on is a draft document.  Our
plan is to revise it in light of the comments that we received from you.

		One of the things I am confident we will do is add additional material
relating to submission of protocols for which parts of the submission
are claimed to be confidential business information.  So this PR notice
will likely have additional paragraphs of text dealing with how
submitters should handle CBI claims.  It may be nothing more than to
refer to existing documentation.  But we wanted to alert you that we
will be making that revision, and that tomorrow's discussion will be
helpful to us in thinking about what we want to put into it.

		Once we have revised it, our plan will be to make it available to the
public generally so that they can comment on it, and that comment may
lead us to make further revisions.

		And finally our experience as we continue to deal with protocols and
completed studies and so forth may lead us to make further revisions.

		MR. CARLEY: Let me add one other point.  I was told earlier today by
somebody who was here in the audience that we should expect to receive
within the next few days a couple of new study submissions, subject to
1303.  They were initiated before the rule, submitted now, and I had
sent this guy this draft a few weeks ago.  He said they responded to it.
 So we'll have some other tests of how it works with real life stuff,
which may also influence some changes that we make.

		DR. FISHER: Bill, I just wanted to underscore again and get a
clarification.  The board may not be in a position to give you advice
tomorrow about how we view CBI.  We're going to be talking about it for
the first time.  I think it's something we're going to be specific and
very careful about because of issues that we've discussed before.

		So I'm a little taken back that this will go out to the public.  You
are assuming that you will have sufficient information from us tomorrow
to move ahead with a portion related to CBI.  I don't necessarily think
the board has yet committed to be able to make recommendations to you
about that.

		BILL: I understand, Dr. Fisher.  And I'm always the optimist, first of
all, about how useful the board's advice will be.  And even the
discussion itself I think will be informative for us.

		And I expect that at the very least we can include in this PR notice a
description of how we currently handle CBI claims, and documentation and
formatting and that sort of stuff, which will be very useful to remind a
group of people, Dr. Carroll for example, who has not been accustomed to
dealing with EPA protocol.  This is a new audience, and we will be
looking at it, and who would probably benefit from that very - that at
the very least.

		And if we go beyond that and elaborate on something, that's good news.
 But it is - both John and I have said, these notices are not binding,
nor are they necessarily the final word ever spoken.  We expect to
revise and improve upon the guidance.  So if the board comes back and
gives us advice sometimes, three, six, nine months from now on CBI
issues, we can revise the guidance to reflect that.

		MR. CARLEY: let me just add one more thing about that.  We feel
considerable urgency to get something out there that has some kind of
official status that says, dear world, here is how to put the package
together.

		If we don't get that out there, we have no control over the form that
the package assumes, and believe me, bringing order out of these piles
of things is not quick or easy.

		DR. FISHER: It reminds me of some of these bills in Congress, that all
of a sudden all these other things are amended to it.

		And so I guess I'm very much for what we saw here, and you've asked us
to provide you comments with.  The fact that there has to be a tag on
about CBI on this document, I don't see us not making any kind of
specific recommendation on CBI tied to whether this document can or
cannot go out.

		So I'm just a little concerned about the fact that you can make them
two documents, or you could make it an appendix, I don't really care.
But I don't think CBI should hold up this, number one; number two, I
wouldn't want anything to go out - and that's up to you - but anything
that would imply - this what you have done here is so really I think
such a tribute both to you as well as to the board in terms of taking
how you've observed us and the criteria, taking what's best from it,
taking what we've stated as our criteria, and along with your
responsibilities, integrating them into a document that can really
provide very useful information to registrants, not only in terms of how
you are going to respond, but what the board is expecting.

		I'm concerned that if attached to this there's something to do with
CBI, it's going to misinform the public that what you are putting in
there is something that the board may have some expectations to show.
Clearly I also understand you want to get in perhaps the information you
are going to be presenting to us tomorrow, which is detailing what CBI -
how CBI might be defined, what the EPA process is, if you are going to
try to evaluate something as EPA.  Those are all facts.

		But to assume that there is a specific type of process that will be
amenable to the way that the HSRB sees their responsibility, I just hope
that that - you're very careful in not communicating that if in fact
there is not a decision that's reached about that.

		MR. CARLEY: The distinction is clear, and clearly understood by us,
between saying something about how the board is going to handle CBI,
which we have no intention of doing in this PR notice, and telling
potential submitters if you want to register a claim of confidentiality
for any of the material within the scope of this submission, here's how
to label it.  That's the sort of thing that we're talking about.

		We can't tell people that you can't send us anything until we've
resolved how the HSRB is going to handle it.  We also don't want to not
tell them how  to identify exactly what it is that they're claiming to
be confidential.  And I hope that is helpful.  The scope of this notice,
the purpose of this notice, is to tell people how to label it, how to
package it, when they send it to us, and how to tell if they've got it
all, so that we can all get a better package the first time out.

		It's not to say what we're going to do with it; it's not to say what
you are going to do with it.

		DR. FISHER: I think we're clear except for the way this is written.
The way that this is written is how not only they're presenting it to
you, but what would be helpful in presenting it to us.  The HSRB is
constantly mentioned in this document, which I think is wonderful.

		All I'm saying is that if the CBI is within this same document then it
may misinform registrants that there has already been a decision about
how that information is going to be presented to the HSRB.

		So I just want to make that distinction that there is not this
misimpression that what was integrated in terms of our criteria in terms
of this document, that anything - that we've expressed any kind of point
of view, or there has been some resolution about how CBI is going to be
handled with respect to the board.

		And that's a discussion we will have tomorrow, but I don't want us to
be forced into - or for you to have an unrealistic expectation that we
might come up a specific way of handling it.

		Sue and then Mike.  CBI?  Are we finished with that?

		(Off-mike comment)

		Yes.

		DR. LEBOWITZ: If CBI is not part of 261125 or 261303, then if we deal
with just the part that has to do with those parts, then I think that's
what they want to send out quickly, then the CBI thing is a separate
issue.

		And I think as you said, very clearly, we have to consider that
separately, because we don't want it to interfere or hold up the other
discussions.

		But as long as we're talking predominantly about what should be
submitted as far as 261125 and 1303 then I think we can clearly be able
to discuss that, and make some recommendations as to what might go out
for public comment.

		VOICE: I mean we're going to - the point of this of course is to
discuss these issues, and I think we need to talk tomorrow about the CBI
issues and all that.

		But what I'm hearing Dr. Fisher say, which I initially would kind of
agree with is that it would be - it seems that this is a very coherent
document that could go out with its own 2006 dash number, and subsequent
CBI document could go out.  I don't think we need to decide that today,
because we haven't heard enough about - but that's the flag you're
raising.

		DR. FISHER: Maybe you want to put it out simultaneously, that's fine.
But it shouldn't be under the same - I don't think it should be under
the same umbrella.  It infers that the same kind of collaboration and
discussion on the part of the board is also part of that CBI assessment.

		VOICE: Would it be possible to put it in a PR notice that says, if you
want to make CBI claims about any of the material that you are
submitting, Dr. Lebowitz, under the requirement of say 1125, here's how
to do it, but if you do it, until the question of how the HSRB will deal
with CBI is resolved, we won't be able to schedule this for review.

		DR. FISHER: I think that may happen, but that's for the discussion
tomorrow.

		All right.  So - yes, Susan.

		Let me just on how we should do this, I'm trying to figure out.
Should we just go page by page, and if anybody has a comment on the
pages?  Is that how we should do it?  Or what do you think is the best
way to do it?

		What did you say?

		VOICE: I would suggest we look at appendix B, and realize that A and C
are relevant.  They have to respond to A and C specifically.

		Appendix B actually covers the format, which is what we're asked to
comment on, and lays it out appropriately to cover the points that were
raised in the presentation.

		MR. CARLEY:  To avoid having to refer to page numbers in the package,
we could also go back to the slides in the beginning with number 11,
which, it's not a perfect transcription, there are some slight changes
in words for brevity, but these are the points that are in the
framework.

		DR. FISHER: I think, Michael, there's actually two charges.  But we
can start with the one that you were just talking about, which is the
appendix, and what we have been familiar with with respect to how they
organize the information.

		And then I believe what we were going to talk about tomorrow, but I
think we're going to talk about today, is just the rest of the material
which I had a few comments on.

		VOICE: I was just suggesting that because it in fact does cover a lot
of the stuff that we created, and is easier to deal with in a way.  And
it represents a format.

		DR. FISHER: Jerry, do you want to take the lead on that?

		DR. MENIKOFF: Sure.  Actually I only have one semi major comment.

		I was noting if you go back to our ethics, HSR ethics rules, or
suggestions, from whichever meeting we addressed this, one of the
categories we had was on risk minimization.  And it struck me that much
of what we've actually been talking about today, and even in prior
meetings, has related to risk minimization.  And that currently doesn't
show up as a separate numbered heading under your framework.

		MR. CARLEY: That's 5(c), what steps are proposed to minimize risk.

		DR. MENIKOFF: It's a subset.  In other words it seems to me we're
spending huge amounts of time on risk minimization, and it is one of the
major headings under the regulations; it's one of the four major
headings under our ethics criteria.  And in fact look for example at
2(c), (d) and (e) for example, it struck me, the whole issue of do you
need to be exposing human subjects in the first place, it seems to me a
lot of the subheadings, like those three, 5(c) and a few others, could
all be put together under a major subheading, a numbered heading of risk
minimization that would go right before risk-benefit analysis.  It just
- at least from the ethics viewpoint, and from the regulations, this is
an important enough concept, and we seem to be spending so much time on
it, that it would not be getting enough emphasis unless we actually have
a heading which says, risk minimization, and that's a good place to put
together all the sub questions that relate to risk minimization.

		And in fact you can expand on some of these and say you know - because
the current question is a little vague, and you really want to push them
on that, you know, what things have you thought about in terms of moving
to reduce the risk, or something.

		Again, I haven't worked out all the subheadings.  But it just strikes
me, that's an important enough issue that we keep coming back to again
and again that it should be highlighted even in terms of the submitters
so they think about it, so they're going to know ahead of time that
we're going to be worrying a lot about this.

		That was the major thing on that.  Other than that, I think you did a
great job on this.  Why don't I end on that?

		DR. FISHER: Michael?

		DR. LEBOWITZ: I was I think a secondary reviewer.  An earlier part
that we are combining with this, if you want to talk about the framework
first, it's okay with me.

		VOICE: I just have maybe a question, Mr. Carley, or a suggestion.  And
that is, under framework five, with benefits, there are three questions
about subject remuneration.  And we talked a number of times in here
about remuneration not being a benefit.  I don't think it's a risk.

		But I wonder if it fits better under respect for subjects, number
eight.  Because we talked there, one of the questions is about
voluntariness and withdrawal from the protocol.

		It seems that the remuneration questions might fit better there, and
help emphasize to the submitters that subject remuneration is not to be
considered a benefit.

		VOICE: I had the same thought, only I thought it should go under four,
which is subject selection, how you pick subjects, and how you get them
to enroll.  So I think I agree 100 percent, I think those in the next
slide need to go to this slide.  So with the remuneration - slide 16.

		DR. FISHER: Oh, how will they be recruited, and who is vulnerable, and
what kind of remuneration, because that really speaks to the
vulnerability.

		I guess I don't really care, one way or the other.

		VOICE: Well, the only - if we included it even under risks and
benefits, it still may be - I think it's important to include that they
are not - but isn't that still kind of leading them to think about it as
a benefit, if it's under risk benefit?

		VOICE: Right, that's what Sue and I are saying, we need to get it out
of there.  We need to get it off the benefit list, and on to either
subject selection - number four is subject selection, number eight is
respect.

		VOICE: I would defer to Gary.  I don't think - I can see arguments for
either four or eight.  The big thing is to get it out of five.

		VOICE: Those of us who actually do human subjects research are
familiar with the requirements of our local IRBs, and they are usually
not structured anywhere remotely like this.

		What they normally do is, they consist of many many more discrete
sections with very, very specific questions that the IRB wants you to
answer.  So it isn't questions about, does your protocol have a stopping
rule or a medical management plan, but how are you going to monitor
patient safety, something very specific that they want you to have a
specific answer to.

		So I think then instead of using a manual framework, what's done here,
this is a reasonable starting point, don't get me wrong.  But the manual
framework was developed as a way to summarize all the different
guidelines that have been developed over the last 50 years.  It's a
philosophical document.  It's meant to capture the big normative
commitments and research.  It is not meant to serve as a guide for
preparing a protocol.

		I mean if you wanted to develop such a comparable thing here, I think
the starting point would really be to start with the IRBs, and see what
different institutions are using with regard to these questions.

		So for me, when I thought about it in those terms, I think there are
lots of things that aren't on this checklist right now that probably do
need to be on there.

		One that comes to mind has to do with who is going to be obtaining
informed consent?  How is that person being trained to answer questions
about the study?

		Again, all sorts of things like that really come to the surface for me
when you think about it in those different terms.

		VOICE: I may be getting confused, but I think there are two kinds of
documents that are going out here.  One is advice to submitters about
how to prepare protocols, what has to be there.  This is for EPA's use,
right?  This is what John and Fuentes (phonetic) and all are going to go
through, to summarize their conclusions, it's their initial review that
we will be guided by, or let's say, will stimulate our discussion here,
and it's quite a different thing.

		And of course if the submitters had this in front of them, then they
might structure their protocol a certain way.  But they are two entirely
independent things, and I don't think one is going to impact the other.

		VOICE: I don't think they are independent.  Under procedures,
regarding submission and review of the proposals for new research, point
two says, organization of submission.  This is directed to those who
will be submitting, and it says that a section of the protocol should
address all the topics identified in appendix B.

		So I think it is meant as an attempt to guide the submitters, so
additional light on it would be appropriate.

		DR. FISHER: I think Steve's point, if I understand it, is a little
different.  I think that where - one of the things we're doing is where
- first of all this follows what our guidance was and our criteria that
we established.

		I think Steve was making an argument that what an IRB requires we're
going to be reading from the IRB report, and what they submitted to the
IRB.  So your question - and this is really what we and EPA have found
are the questions that keep coming up even though we have the IRB
information.

		So this really is in addition to help them - to help registrants
clarify the kinds of questions that we have been asking.  So in that
sense I think we need to keep separate the kinds of questions that are
IRB, and those that have been keeping coming up in terms of our being
able to assess the benefits.  These are the questions that aren't always
asked, or at least explicit, in the IRB materials that we have and we
keep asking that.

		But by the way, we all agree with you about the amendment.  Sue and
then -

		VOICE: Just one small point, too. Does everyone know that Emanuel
himself thinks that this framework is flawed?  He actually has a follow
up paper in which he describes additional principles that he thinks that
are important supplements to -

		DR. FISHER: But I just would say on John's behalf, he's really - he
keeps saying he's still doing it from the Emanuel model, but this has
really moved in the direction that we have discussed with him.

		VOICE: I thought I made it pretty clear this morning that we have gone
a long way from referring to this as the Emanuel framework.  And I never
used the word, Emanuel, in any of my presentation materials, let the
record show.

		DR. FISHER: Right, right, yes.  And so I think for those of us who
have seen the transformation we are incredibly impressed, as we always
are with John.

		VOICE: Let me point something out.  This is a very good slide to
illustrate it.  Most of the questions that were in the scientific
criteria list from your report of the last meeting, like these, are
framed as yes-no questions.  And that's all very well when you are doing
the sort of assessment that Dr. Chambers just ran down when she was
doing her summary on EMD-004.

		But for purposes of - for the purpose that I described earlier where
we are trying to use this as a way of assembling and collecting the
information relative to our assessment, these questions worded in this
way are not very helpful.  And certainly as a template for how we want
the investigators to write their protocol, this is a lousy idea.

		We don't want them to say, 8(a), yes; 8(b), yes.  That would not be
useful information.

What we want is to frame this, how will information be managed, or how
in concrete detail will information be managed to ensure subject
privacy?

		There might be a subordinate question that says, if you are going to
use an over-the-counter pregnancy test, how are you going to handle the
results, and sharing them with the subjects, or calling names in the
room saying, the following six people are pregnant; please leave.

		How are you going to do this?  So there is a lot of room for
refinement.  My observation with respect to Dr. Sharp's comment is that,
yeah, these are more philosophical than some of the questions asked on
IRB applications, but at the same time these broader questions are not
often asked on IRB applications, and what my experience has been that
when I frame this broader question, then I rummage through what I've
got, and I may point to different places where different parts of the
answer are located.  But there is a requirement to do some assembly
above the level of just aggregation that is typical of an IRB
application.

		DR. FISHER: I'm a little unclear about where we're going right now.
It seems to me we were given this.  And then it seems as if you're
saying that the way these questions are phrased may not be helpful, that
you'd rather phrase them in the how-to.  So I'm just trying to get from
you, John, what you want from us?  Was this supposed to be a final copy?

		MR. CARLEY: First off, it's not final.     It's a discussion copy.

		DR. FISHER: Okay.  Because I agree with what you just said.

		MR. CARLEY: I'm kind of joining in taking pot shots at the draft here.
 Let the record show that Rich Fenske wrote these questions.

		(Laughter)

		VOICE: Let the record show that framework seven, all the questions are
not yes-no.  You just chose eight to make me look bad.

		DR. FISHER: Okay, okay.  What I want to do is, I was to have Sue,
Mike, Steve, and Sue talk as they haven't had any - even though we're
still on the same topic.  And I want to come around and try to focus.
So if this is about focus, let's talk about focus.

		So who's next?  Mike?  Sue, you don't want it?  Okay.

		VOICE: Under the framework, the instructions specifically say, respond
with a quotation or paraphrase from the submitted material is going to a
specific page reference, which is what Mr. Carley said.  So it's not
just a yes-no.

		Number two, it's already been stated and I want to emphasize, the
information that is submitted by the applicant includes all the IRB
material from whatever IRBs they had to go to, singly or multiply, and
have to respond also not only to these questions but to questions - but
the parts of appendix A and C from the law that specifically they have
to specifically apply.

		So I think the overall, I think this is a great effort.  I think we
may quibble with some of the categories and the order of the categories,
but I don't want to get into that.

		One of the areas that we never covered in our criteria that I would
like to see covered, the chair mentioned an area today, was, it'd be
nice if we know what in fact EPA - what questions EPA has and whether
it's a potential problem.  In the same way, every time you see a
proposal, a good proposal, in most of the reviews I do, you see a
section that talks about limitations.  It talks about potential problems
and how they resolve it.  And I would like to actually see that in the
submission as well as in EPA's review, the DER or WOE, whichever you
prefer, because it's critical.

		We know that you have these reservations.  We want to know as
discussed by some of the applicants in public commentary, we want to
know what they think their limitations are and how they intend to deal
with it or have dealt with it.  In the same way we had a lovely
discussion of how the insect repellant protocols were approved by
interchange, and the new thoughts about possible issues and problems.
So I think that has to be a part of it as well.

		The other part, you in the charge specifically ask about specific
kinds of studies, and the fact that for instance one of our criteria, or
part of our framework, had to do with field versus lab.  Well, I think
there needs to be some guidance about specific kinds of studies
somewhere in here, maybe ancillary to it.  So they're gone through the
whole thing.  And then there were specific aspects of the study like
they're doing both field and lab, and they should talk about those, that
aspect, or those aspects of the study.

		I don't know that we know all of those.  You may have a better feel
for the kinds of submissions you've had, and what different guidance for
various types of issues.

		I think that is sort of ancillary to the primary thing.  First you
want to have general guidance for all research.  And then potentially as
this will be a living document potentially, at some point you will want
to have specific guidance for different kinds of research, but you don't
want to hold up the process or the notion that they have to answer these
- give information on these general questions primarily.

		So I in general think that this would be a phenomenal help to you guys
as well as us, and help the applicants tremendously as well.

		DR. FISHER: Let me - we're going to have Steve, then Sue Fitzpatrick,
Gary, then Ken.  But I just want to list what I've heard so far.  And I
also think it's an extraordinary document.  I found it really easy to
read for the Carroll study.  And I really - so I think these
modifications are just an improvement.

		So but I thought it was really good.

		So so far I've heard the risk-benefit analysis should be separated
from the risk, is that what you said basically?  Risk minimization.

		Remuneration shouldn't be within the benefit.  I think it was
suggested it be in section four.

		John Carley had a suggestion that the questions be rephrased for a
how-will rather than something that is just simply a yes-no.

		Limitations of the study - and once again, that's not a negative,
because we are all used to writing limitations of studies, which is your
greatest opportunity to say I know, but this is why it has to be this
way.  So it's always a positive which we always, many of us do all the
time in our studies.

		And then guidance on specific types of studies.  And I guess guidance
here is really what guidance has already been expected by EPA.  For
example, once the insect repellants are out, or the guidelines, things
like that.  So I agree that would be helpful.

		So Steve, so let's keep listing things in the way we're going to help
them.

		VOICE: Maybe I should just subside, because I'm still somewhat
confused.  It seems to me that we're trying to get at sort of two things
almost at the same time.  One is the guidance to proponents of what
questions need to be addressed.  And I think we've got a great list of
them, but I do agree that they should be rewritten.

		Right now they're written in a way as if we were checking off answers.
 John was going through the protocol and sort of summarizing answers, at
least many of them but not all.

		So I think this should be looked at again in terms of telling the
proponents exactly what we want them to provide.  And certainly there
should be no yes-and-no questions; they should all in the form of, tell
us what you are doing on this point.

		If this - and what I'm unclear about is the extent to which this
framework for submission, organizing submissions, or at least guidance
for organizing submissions, also translates into how you are proposing
to present your scientific and ethical reviews to the board.  And they
may be similar, they might even be almost - they might even be
identical.  But I suspect they are - they could be different.

		So I think here is where I am.  I may be a little confused.  I think
perhaps an entirely separate although related framework, if you don't
intend to strictly follow this now, answering these questions or
assessing how the proponent has addressed these points, that would be
one good way to carry us through your view of the protocols.

		But if you don't intend to do that, I think you'd be free to do it in
another way.  But in any event your framework will be different from -
the precise wording and terminology that you use will obviously be
different from the registrants.

		MR. CARLEY: Shall I try to clear up some of that?

		I think that at some sort of level of an ideal we would like to be
able to use the same structure as a guide to submitters and as a tool in
our review and as a way of presenting things to you, and then in turn,
you could use it as a tool in your review.

		I would submit that at least in the course of our review, assuming
somebody sent us something that was an attempt to respond to this draft
as we expect to see in the next few days.  It will be interesting to see
how it worked.  I would think in preparing our reviews we would at the
very least write new topic summaries, in the shaded blocks at the top of
each section.  And then we would make our independent judgment about the
applicable standards, and whether they were satisfied, and what
discrepancies or deficiencies we found, and how much weight we gave to
them, and those sorts of things that you've seen in our previous
reviews.

		And then similarly, at the next stage, where we've done our review,
and we were going to present it to you, you would make different
summaries, different perhaps saying that some of the things that we
noted weren't important, or adding other things to the list or whatever.
 The need for some sort of convenient sort of annotated directory to a
big pile of stuff like this is going to apply to every step along this
review process.

		And the more complex the study the more important it is to have a
handy tool.  And if the same took will work for all the players, then
nobody has to convert it as we move from one stage to the next in the
process.

		The labor component, both from Jack Carroll's perspective and from
ours, in getting from where we were at the June meeting to where we were
with these in mid-September is huge.  And what we are trying to do here
is just make that whole thing not have to be done over and over again as
the framework shifts.

		DR. FISHER: This is a great start, what you did.

		Suzanne.

		DR. FITZPATRICK: So I'm a little confused.  You are proposing that the
sponsor or investigator fills out this form?  Or this is the form that
you are going to fill out once you get the materials?

		MR. CARLEY: We would like them to take the first crack at it, and then
we are going to do something similar, but with independent conclusions,
and perhaps different conclusions.

		DR. FITZPATRICK: I mean I think you're right in having them do it,
because I'm a little concerned that you've got very short timeframes
once you get this review.  And my suggestion is, why aren't you having
them submit this electronically?  Then you can just add your comments to
what they have already filled in.  If they fill out the form in
reference to that part that's in the protocols, then you can just add
your comments to it after that, and save a lot of time on your part.

		Because basically, and I don't know if you have 75 calendar days or
working days.

		MR. CARLEY: No, we were talking about calendar days.

		DR. FITZPATRICK:   Calendar days, so you have 25 days from when it
gets to the board, only 50 calendar days to do one of these things.
That's pretty short.

		MR. CARLEY: Well, we have noted that that's not a very long time.
What we've been getting, and what we would hope to get routinely, and we
need to add something to the PR notice about this as well, is the
specification of the form of submission.

		If we get PDFs generated from word processing files for example, we
can select and edit and diddle and plug in perfectly well.

		If we get scanned PDFs from handwritten IOB documents, as we did in a
lot of this stuff, that's a different matter.  But those are basically
read only documents anyway.  All of the formatted stuff that we got from
Carroll we got in the form of PDFs generated from word processing.  So
it was perfectly straightforward to select and copy or diddle, you know,
edit in whatever way we needed to, yet we still had a read-only PDF to
preserve the original submission.

		And that's probably the way we'll handle that as something simpler
than agreeing on another kind of protocol for submission, which could
take years.

		DR. FITZPATRICK: But your notice only asks for it in triplicate,
you're not asking for an electronic submission.

		MR. CARLEY: Yes.

		DR. FISHER: All right, and let's try to keep this to the
recommendations.  I think having too much of a how-to how-to.  So I
think your recommendation was really good.  The details of how to we can
leave it up to John unless there is a question of clarification that he
has.

		I think it's Gary and then Ken and then Lois.

		DR. CHADWICK:   To follow up on Suzie's suggestion, if you make this a
form that is filled out by PIs, will that require OMB clearance?

		MR. CARLEY: Yes, it would.

		DR. CHADWICK: Whereas if you do it yourself it wouldn't?

		MR. CARLEY: That's correct.

		DR. CHADWICK: Just checking.  Things have changed since I left the
government.

		A couple of concrete suggestions.  On slide 18, items D and E, I
suggest to you are not really informed consent, but might more readily
fit into what you call respect for subjects on eight or even four.  But
I would suggest you move those, because although they are tangential to
informed consent, they really don't fit in with the others you have
there.

		And in line with Jerry's comment on slide 20, which is the respect for
subjects slide, I think C is actually risk minimization, and that should
go there.  And that might serve as the basis for Congress to build a
separate side for risk minimization.

		The last question, I've got a major question, probably tackle this
tomorrow at about 11:25, but the last question I have concretewise on
this form is on slide 17 C, keep the IRB registered with OHRP.  Any IRB
can register with OHRP.  What is it that you are looking for there?  I
mean there's registration.  There's insurance with OHRP, and there is
also accreditation.

		Is there some level of quality or qualification that you are going
after?

		MR. CARLEY: That's the general idea.  We've worded that question
various ways in various generations of the framework.  And we don't want
to answer questions that require us to do extensive or time-consuming
research.  What we want to do is something that we can do a quick look
up on an OHRP website.  This is kind of the minimum question.  We look
to see if OHRP has ever heard of these folks, and then if they say that
they have also got an assurance of this scope, or they worked with these
institutions, I would pull that other information.

		DR. CHADWICK: I would suggest to you that registration with OHRP is no
indication of quality or anything other than maybe name recognition.

		MR. CARLEY: If you can suggest something else that would be a more
appropriate way of trying to determine whether this is a legitimate
outfit, a specific screening question, we would welcome it.

		DR. CHADWICK: I would suggest leaving it in I suppose in the meantime,
but you might expand it to, are you registered, do you have insurance,
are you accredited.

		DR. FISHER: Okay, Kannan?

		DR. KRISHNAN: Question and a couple of comments.  As others said the
framework nicely conveys the expectations fo our science and ethics
analysis.

		In terms of the study design, the slides 12 and 13, if I understand
correctly you are going to have a question on QAQC?

		MR. CARLEY: Yes?

		DR. KRISHNAN: Because that one is missing right now.

		MR. CARLEY: Yes, that's where it would go.

		DR. KRISHNAN: That should go.  And then in the same category as let's
say slide twelve when we talk about the dose, I would put in one or two
additional questions, the first one being, how will the dose be
measured?  Because oftentimes as we look at some of the dermal studies
and so on, that is always a question as to what was the amount delivered
and so forth.

		So just giving the concentration of the - or the exposure level as we
have in C - I mean G, 3G or slide twelve, where it says what is the
basis of the charge to the dose/exposure level?  I think that is not
alone sufficient, because often we are asking the question of how is the
dose being measured or quantitative.  They have to have some idea of
what was actually provided to the individuals.

		The other question still related to the dose, either can stay here or
in risk minimization, it would be, how does the dose compare to the
known NOILs (phonetic) or safe levels.  I think that is a critical one.

		If that comes about in the discussion of choice of dose that would be
nice, but it doesn't always come out as we look at some of the protocols
we have seen.  We have to raise a question clearly, so I wouldn't mind
asking the question separately.  How does that compare with the known
NOILs or the levels.  I think that's important, so that they get an idea
of the margin of safety.

		One other question that I have for you is in section five, the first
question.  It says qualitative risks, maybe slide 15.  I was more
looking for something related to irreversible serious effects.  So I
don't know if it's a qualitative risk, as used here, is routine
terminology that's used in ethics evaluation, or would it be better to
ask a question of the nature of the risk, I mean something in
parenthesis that relates to irreversible and serious, or that's not what
you had in mind in this question?

		MR. CARLEY: What I was trying to do with the wording here was simply
separate the nature of this from the probably of its occurrence.  And
then with that in mind, the question of whether the risk was something
reversible, or something of a serious consent would be attributes of the
nature of the risk it would belong in my expectation in 5A.

		We got substances here that have some remote probability to increase
serious risks, and I've been trying to make sure that those things don't
get mingled so it's clear.

		DR. FISHER: I think Lois has a comment, and then I want to ask a
general question and move towards a conclusion.

		But Lois?

		DR. LEHMAN-McKEEMAN: I have a couple of specific and then one general.

		In section three part - of appendix B, basically study design, the
last G, it asks what is the basis for the choice of dose level exposure.

		I think the thing that's missing from that particular section is that
this board has gone on record and advised against single dose level
studies.  So I think we should actively include after G something to the
tune of, if the study involves a single dose level what is the rationale
and justification for only using one dose level.

		That was the element that I thought might be missing.

		And I'll say that I'm kind of on the same page as Steve is in that -
and maybe one of the things that was done here is that in the text
you've provided, and I don't have the page number, but it's under
procedures regarding submission and review of proposals for new
research.  Point two describes the organization of the submission.  And
bullet one says, the protocol should address all of the topics
identified in appendix B.  That's very clear.

		What might be useful there is to add another active statement
somewhere in this document to indicate that EPA's review will in fact be
based on the completeness and comprehensiveness of the response to all
of the issues in Appendix B.

		That makes it very clear what you guys are going to do with the data.
Where I come out in being a little confused with ultimately how we used
this is, our priorities, we're not going to see these studies unless you
have decided that they do meet a minimum criteria of quality for us to
see, as I understand it.  If you decide that they're deficient we won't
see them.

		So we can use this as a starting point, but in reality I think we're
going to be more focused on, were there limitations that we see.  So
it's useful for us, but ultimately it's not going to be the definitive
criteria that we use.  Because we're not going to see this.  We're only
going to see this when it's passed your muster.

		DR. FISHER:  One of Richard's concerns was whether or not having that
kind of a protocol will be - will it unintentionally make the
registrants think that this is all they have to do.  In other words if
they answer every single question.  And I think it's a little similar -
I think Lois took it beyond that, and then Lois - the way I would frame
Lois' point is, will they think if they've answered all those questions
the HSRB is going to approve it.

		Now, we already know that that's not the - that's never necessarily
the case.  Because every study we see is something that you've brought
to us, that you have thought about in a positive way, and the  HSRB does
or does not agree with that in some way.

		So I guess the caution is, how do we frame this in such a way that
we're losing information, number one, which I think is Richard's
concern, and number two, that we're not misinforming those who are
submitting that in fact if they answer those questions and you submit it
to the HSRB that that means there's going to be a positive approval.

		John and then Mike.

		VOICE: Quick response on G - the registrants are accustomed to the
idea that we don't necessarily accept everything they send us.  And I
don't think any of them suspect that the HSRB approves all the protocols
that they submit.  So I don't think there is a real big risk there of
misinforming.

		In terms of the loss of information, we're going to have the complete
documents.  This is still a sort of annotated index of where to find the
stuff - but it will never substitute for the whole thing, and both we
and you will be reviewing the whole thing.

		DR. FISHER: Lois, did you - okay, Mike and then -

		DR. LEBOWITZ: Yes, I was going to answer your question, too.  It's
just like when we do a grant proposal, and then we do an IRB form.  And
this is not the IRB form, but this is the annotation that in this case
is for EPA, maybe us.  But certainly EPA to do the science and ethics
reviews - so we need to have them try to address these questions to both
EPA and possibly federal health EPA put it in a framework for us so that
we have a fairly good working document from which to go to because not
all of us are going to worry about - like I did find - basically the DOE
on hexavalent chromium - and so that helps us as well as helps them.

		DR. FISHER: Kannan.

		DR. KRISHNAN: I presume you will include  the title of this appendix
called framework or protocol assessment in the list of documentation
required, like in appendix A or appendix B for the new protocols, or the
review of human research, in the list of the documentation I presume you
will be adding this one, framework for -

		MR. CARLEY: I don't think we'd expected to, because appendices A and
C, there's nothing in there that isn't a direct quotation from the rule,
saying this is what the rule requires.  It's not saying here is the
table of contents for your entire submission.

		DR. FISHER: Let me just ask impressions.  I have around 12 comments
that were made, even though there was a lot of discussion but I think in
terms, I think it's around 12.

		It's not clear to me what is our - is this something we need to
discuss more tomorrow morning?  Is there a direction we want to have EPA
- are we saying EPA should go into?  I'm not - I didn't see this as that
critical of the document, and I may be getting that wrong.

		Is this the fine-tuning that the general thing was, for what was
presented here, was good, and acceptable with taking into account these
issues we raised to try to improve it.

		So that's where we are.  We're not saying, John, go back, rewrite the
whole thing.  We're saying, John, you did a great job, and since we
can't let anything go, this is what we think will improve it.

		So just then to summarize - yes, briefly.

		VOICE: I wouldn't quite go that far - not the document's a bad
document or anything like that.  But I have - concerns as well,
reservations about the fact that once this is made public, this may be
seen as the essential item that we'd go and start with applications.
And since you haven't really built up a lot of experience in doing these
types of things so far, we put that out there now, it's going to be seen
as a little early.

		VOICE: Gary.

		VOICE: And, again, I think that's - that argued against Susie's
suggestion - I think if we put this out, say this is what EPA is going
to use the index and the - to make it very clear that this is not
something necessarily that the investigator should fill in, whatever,
but it does give them the information that says this is what he did,
he's going to look for in and amongst your materials.  And I think that
- I think from that standpoint I'm fairly comfortable with EPA - you
know, they have been doing it.  They have been using various versions of
this, and I'm comfortable with them continuing.

		DR. FISHER: And I think where we're moving - so basically then a
solution is, one of the solutions is, at this point in time, at least I
can have the PI fill it in so that they - what they have to write but
that they need to provide all of that information, at least for this
time around, and we can - we would see how it works.

		And perhaps a clear statement about the fact that this is not all
that's required but this is helpful in terms of identifying some salient
information that will be helpful in moving the protocol along.  So I
think that might get at your concern.

		So basically our points are, separate section on risk minimization,
making sure there's - the remuneration is in section four, shifting some
og those questions to how rather than a yes/no, stating limitations of
the study, providing guidance when it exists, or a website that they can
go to.  And I think you might want to consider whether it's important to
look - to refer them if they wish to go to the HSRB sites because we
certainly have different criteria that we talked about, too, which might
be helpful but shouldn't be part of your document.

		We're now thinking there might be some risk having it electronically
filled out by the PI, but at least at this time we'll see how it works.

		Slide eighteen items G and E, respect for subjects.  I wrote that
down, but I think Gary said something.  Need to get - move to the
respect for subjects, what are you looking for with respect to OHRP
registration - that registration really is not a big deal, you might
want to ask whether or not they have an assurance by OHRP and whether or
not they're accredited and by whom are they accredited.

		Study design, I think - I mean Kannan said a lot of things that - but
I think that has something to do with concentration and dose that needs
to be in there.  Also I think he also pointed out that when information
on NOEL and LOEL are available and would help with the - making a better
justification for whatever dose is selected, that should be included.
Also that in the study design, the basis of the choice of the dose level
should be in there.

		I think Lois said something to the extent that if you're only going to
do a single dose level study, beware that he grades that better than -
whatever that is.  But basically they should, you know, need to look at
- we had a lot of criteria and comments about that, so I think - just
put that in better.  And that we just want to make sure that this will
be a test in some sense, and hopefully it works really well and is very
educative, and maybe we'll have protocols that we might recommend or -
sufficient because people don't have to go back to the drawing board,
that they understand where EPA and the board are coming from.  So is
that where we are?

		VOICE: If the registrants are necessarily turning in a complete
protocol and all the IRB materials and all the traditional materials, I
don't understand what the harm is - an informed approach from the
protocol.

		VOICE: Well, it's going to - a lot of time and frustration.

		VOICE: I think that was the whole point of the exercise, to save time
for the PI, save time for EPA, and they were - and if we don't do that,
we get nowhere.

		VOICE: These are the basic questions we keep asking.

		VOICE: Okay, so - yes, Susan.

		VOICE: Well, so if you don't require it they just keep guessing -

		VOICE: If we don't require them to provide this information, we can
inform them that these are the concerns that are going to be addressed
in EPA's review, and we can advise them to be sure that they've
addressed them all and to tell us where to find their -

		VOICE: That's exactly what I think we should do.

		DR. FISHER: Okay, yes, Suzanne?

		DR. FITZPATRICK: Are we going to make any comments in the PR notice
tomorrow or today?

		DR. FISHER: Well, I'm asking you.  I think we should end today, but we
can make - you mean the beginning part?

		DR. FITZPATRICK: Yes, the beginning part.

		DR. FISHER: Why don't we save time, it won't be a long time tomorrow,
unless there is one - does anybody -

		DR. FITZPATRICK: I only have a couple here.

		DR. FISHER: Because we also have to ask for public comment on this
tomorrow.  So we'll reserve maybe a half hour or an hour at the most,
and then we are going to do CBI.

		Then, I was talking to Paula, I don't think it's necessary that we do
the conflict of interest because it was an administrative meeting.

		VOICE: And you feel it's not needed at this time.

		DR. FISHER: I don't think so, unless anybody does, because we were
talking about the information he sent out to you.  It seemed pretty
clear.  And so -- remember he sent a form out to be filled out.  So I'm
not sure at this point --

		VOICE:  Right, this is for the board members' recollection.  Several
weeks ago, I sent out a note to everyone to update your financial
disclosure form.  I know all of you have done that and it addresses the
reason why it is being done.  So that really was part of the driver of
having this administrative meeting.  I think that issue helped address
Dr. Fisher's questions.

		Just to add on -- can I make a few more remarks?

		DR. FISHER:  Sure.

		VOICE:  Okay, Dr. Fisher mentioned we are going to have a public
comment period tomorrow morning.  We'll begin on the PR notice.  It was
in the Register this afternoon but we want to again provide the public
an opportunity to make any remarks.

		The CBI discussion will be earlier so we are going to probably end
earlier tomorrow.  So I think it is hard for us to gauge what exact time
but you might want to be thinking about possibly moving up your flights
if an earlier flight is available by a few hours in that respect.  So
plan accordingly for that.

		DR. FISHER:  Yes.  And we could guess about it tonight, I guess, in
terms of what time.  But in case anybody really wants to change their
flight, I think, you know, one would be very realistic that we would be
done because we are only going to do really the CBI.

		PARTICIPANT:  (Inaudible.)

		DR. FISHER:  Well, that's -- we can do that, sure.  Yes, why don't we
do that.  If we go over, we'll be a little hungry but -- okay.

		The other thing is take your name badges with you.  They don't have
enough of these so they are going to let us in with name badges.  There
is no shuttle tomorrow.  So we will all walk across with our baggage.
And be aware -- oh, also, it could take a long time getting through, you
know, because they have to check everything.

		Hotel check out is at noon.  So we might want to do that -- maybe take
a break at ten or something or something like that.  Or else we'll just
check out when we -- I'll check out in the morning but I know some
people sometimes want to go back.  But let's -- and allow plenty of time
to get through.

		Now the next thing is for those who are going to dinner, which is a
lot of us, do you want to meet in the hotel here?  Or in the lobby at
the other hotel?  Or are we even -- it is six o'clock.  We have a half
an hour.  It's right across.  We're eating at the Hyatt at six-thirty.

		Meet at the Hyatt?  Yes.  Okay, very good.  Thank you all.  We're
going to meet -- oh, I don't know.  Somebody make a decision.

		(Whereupon, the above-entitled meeting was concluded.)

	NEAL R. GROSS

	COURT REPORTERS AND TRANSCRIBERS

	1323 RHODE ISLAND AVE., N.W.

(202) 234-4433	WASHINGTON, D.C.  20005-3701	www.nealrgross.com

	 page \* arabic 1