1
DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
PEDIATRIC ADVISORY SUBCOMMITTEE OF THE
ANTI-INFECTIVE DRUGS ADVISORY COMMITTEE
Wednesday, February 4, 2004
8:00 a.m.
Advisors and Consultants Staff Conference Room
5630 Fishers Lane
Rockville, Maryland
2
PARTICIPANTS
P. Joan Chesney,
M.D., Chair
Thomas H. Perez,
MPH, Executive Secretary
SGE CONSULTANTS
(VOTING):
Mark Hudak, M.D.
David Danford, M.D.
Richard Gorman, M.D., FAAP
Robert Nelson, M.D., Ph.D.
Susan Fuchs, M.D.
Robert Fink, M.D.
Victor Santana, M.D.
Norman Fost, M.D., MPH
Judith O'Fallon, Ph.D.
Ralph D'Agostino, Ph.D.
Mark Fogel, M.D.
Tal Geva, M.D.
Craig Sable, M.D.
Vasken Dilsizian, M.D.
Marilyn Siegel, M.D.
Phillip Moore, M.D.
MEMBERS
(VOTING):
Mary Glode, M.D.
Steven Ebert, Pharm.D. (Consumer Representative)
FEDERAL EMPLOYEE
(VOTING):
Mario Stylianou, Ph.D.
INDUSTRY
REPRESENTATIVE:
Samuel Maldonado, M.D.
FDA:
Julie Beitz, M.D.
Sally Loewke, M.D.
Susan Cummins, M.D.
Diane Murphy, M.D.
3
C O N T E N T S
Call to Order,
P. Joan Chesney, M.D.
4
Recap of Day 1,
David Danford, M.D.
4
Discussion of
Questions to Committee
11
4
1
P R O C E E D I N G S
2
Call to Order
3
DR. CHESNEY: Welcome back,
everybody.
4 Dr. Loewke is going to give us an
overview of the
5 questions again but, first, the
folk at the FDA had
6 asked for one of us to do a recap
of what we
7 covered yesterday and Dr. David
Danford, our
8 resident cardiologist, has
offered, under duress,
9 to do that.
10
[Laughter]
11
So, why don't you go ahead?
12
Recap of Day 1
13
DR. DANFORD: Thank you, Dr.
Chesney. The
14 subcommittee had quite a full day
yesterday of
15 excellent, very informative
presentations on
16 pediatric cardiac imaging and the
agents currently
17 in use to enhance that
imaging.
18
FDA began by identifying four classes of
19 these injectables, including
gadolinium agents for
20 cardiac MRI, radiopharmaceuticals
for evaluation of
21 myocardial function and perfusion,
microsphere
22 contrast for echocardiographic
image enhancement,
23 and iodinated contrast for
angiography and CT.
24
With the exception of the iodinated
25 contrast, which is labeled for
angiographic use in
5
1 children as young as one year of
age, all pediatric
2 cardiac use of these agents is
currently off-label.
3 Desiring to obtain information
about these agents
4 that would allow labeling for
pediatric use, FDA
5 assembled speakers to address,
one, what pediatric
6 subpopulations receive these
agents; two, what
7 diagnostic purposes are being
served; three, how
8 the imaging data affects patient
management; and,
9 four, what additional labeling is
needed.
10
From this, it was hoped that we could
11 determine what, if any, pediatric
labeling
12 information could be extrapolated
from the adult
13 experience and what research
studies should be
14 designed to obtain the data
required for
15 responsible pediatric
labeling.
16
Dr. Geva introduced the concept that there
17 are huge numbers of patients
living with congenital
18 heart disease in the United States
that are
19 surviving longer, and frequently
they have residual
20 anatomic and functional
cardiovascular impairments
21 and may have a lifelong need for
medical
22 surveillance that includes cardiac
imaging.
23
We repeatedly heard from multiple
24 presenters that unenhanced
standard, regular old
25 echocardiography was the imaging
modality of first
6
1 choice for most of these
patients. It accounts
for
2 more procedures than MRI, cath, CT
and nuclear
3 studies combined. Its shortcomings are
poor
4 diagnostic quality in certain
subgroups of
5 patients, like older and bigger
patients, those
6 with chest wall deformities or
prior cardiac
7 surgeries, those with pulmonary
disease and those
8 in whom the primary focus of
diagnostic interest is
9 outside the heart, for example,
aortic arch,
10 pulmonary artery branches,
systemic or pulmonary
11 veins. Unenhanced echo is also suboptimal when
the
12 diagnostic question is one of
coronary perfusion.
13
So, when standard echo fails to provide
14 the diagnostic information
required for management
15 of heart disease one of the other
imaging
16 modalities is selected. MRI is one of
those
17 modalities, and we heard from Dr.
Fogel that
18 gadolinium contrast is injected in
the large
19 majority of pediatric cardiac MRI
examinations.
20 MRI often provides images superior
to echo for
21 aortic arch and its branches,
pulmonary arteries
22 and veins and the systemic veins,
and it can also
23 provide information on myocardial
perfusion and
24 tissue
characterization.
25
The anatomic MRI
data is suitable for
7
1 processing into 3D reconstructions
that are
2 aesthetically impressive and
highly clinically
3 relevant for the guidance of
surgeons and
4 interventional cardiologists as
they plan
5 treatment. MRIs applications are limited
by
6 artifact when objects made of
certain metals are in
7 the field of
interest.
8
There was support in our discussions for
9 investigations to define the
appropriate pediatric
10 gadolinium dose, its safety in
children with heart
11 disease and the diagnostic
accuracy in pediatric
12 cardiac
applications.
13
Like MRI, cardiac CT is also superior to
14 standard echo for imaging of
extracardiac large
15 vessel abnormalities like aortic
aneurysm, double
16 aortic arch and other vascular
rings, pulmonary
17 artery sling, pulmonary branch
stenosis, aortic
18 coarctation and pulmonary systemic
venous
19 anomalies.
20
Nonionic iodinated contrast is used in
21 essentially all pediatric cardiac
CT exams. It
has
22 a long record of safe use in
children and is
23 approved for angiography in
patients as young as
24 one year old. The subcommittee heard
concern,
25 however, about radiation exposure
from CT imaging
8
1 and struggled with the issue of
separating the
2 risks of the contrast agent from
the risks of X-ray
3 exposure.
4
Like CT, cardiac catheterization with
5 angiography utilizes nonionic
iodinated contrast
6 material and X-rays. It has broad
diagnostic
7 applicability in a wide range of
conditions,
8 including both intracardiac and
extracardiac
9 anomalies, and is increasingly
performed as a means
10 to treat the condition by means of
balloon
11 valvuloplasty or angioplasty,
stent placement, the
12 creation of holes where they are
physiologically
13 advantageous and the closing of
holes where they
14 are not.
15
The diagnostic information obtained with
16 angiocardiography is, therefore,
often with
17 immediate application to
therapeutic intervention.
18 Even in the shrinking minority of
such procedures
19 now done for purely diagnostic
purposes the
20 anatomic details provided
angiographically often
21 guide surgical
treatment.
22
One speaker suggested that there were few,
23 if any, pediatric labeling issues
remaining about
24 the use of iodinated contrast
material in the
25 cardiac cath lab, but another
suggested that we
9
1 actually lack information about
the true maximum
2 safe dose and in some complex
cases in the cath lab
3 we enforce an artificial maximum,
resulting in
4 deferred angiography and return to
the cath lab for
5 second procedures that might not
be in the
6 patient's interest if it were
established that
7 greater volumes of contrast could
safely be
8 administered in a single
sitting.
9
We heard that nuclear cardiac imaging
10 differs from the modalities we
have discussed so
11 far, and its focus is not on
anatomy but on
12 function, blood flow and
myocardial perfusion.
Not
13 surprisingly, its applications in
the
14 cardiomyopathic processes and
abnormalities of
15 pulmonary blood flow and coronary
arterial
16 perfusion were emphasized. The use of
radioactive
17 pharmaceuticals to obtain this
information is
18 associated with radiation exposure
to the patient.
19
While there was support for studies to
20 determine the pediatric safety and
appropriate
21 pediatric dosing, concerns were
raised that NIH
22 guidelines for radiation exposure
in pediatric
23 research subjects may be an
impediment.
24
Contrast echocardiography employs
25 encapsulated air or other gas
bubbles to enhance
10
1 endocardial edge detection by
harmonic ultrasound
2 imaging. This adds information on
myocardial
3 function and perfusion to the
cardiac anatomic and
4 Doppler blood flow diagnostic
information that is
5 generally available on standard
echo.
6
The potential for pediatric application or
7 contrast echocardiography is
currently largely
8 unrealized as most pediatric
centers do not provide
9 routine contrast echo
services.
Nevertheless,
10 there was interest in obtaining
pediatric safety
11 and efficacy data for these
contrast agents as some
12 experts would estimate that as
many as five percent
13 of all patients having pediatric
echocardiography
14 would benefit from the clinical
information about
15 myocardial perfusion and
ventricular function that
16 contrast
provides.
17
Finally, representatives of a number of
18 national professional
organizations, including the
19 American Academy of Pediatrics,
the American
20 Society of Echocardiography,
American Society of
21 Nuclear Cardiology, Society of
Nuclear Medicine and
22 a representative of one
pharmaceutical company all
23 spoke in strong support of FDA's
initiatives to
24 promote responsible pediatric use
of these agents
25 through labeling.
11
1
DR. CHESNEY: Thank you very
much. That
2 was excellent. We should have asked you for
copies
3 last night.
4
DR. DANFORD: I wasn't ready
last night.
5
DR. CHESNEY: Thank you. I did have one
6 announcement to make. Dr. Hari Sachs had asked
me
7 to tell you that on March 29-30
the FDA and NIH are
8 jointly sponsoring a neonatal
workshop, in
9 Baltimore, which will cover pain,
pulmonary,
10 neurologic and cardiac issues, and
there is more
11 information available on the web
site for anybody
12 who is interested--and
ethics.
13
Dr. Loewke, would you like to get us
14 started on the job at
hand?
15
Discussion of Questions to the Committee
16
DR. LOEWKE: Good
morning. I just
wanted
17 to clarify a couple of points and
maybe run through
18 an example that might help the
discussion for
19 later, so bear with me here. Let me find my
20 slides.
21 [Slide]
22
I wanted to talk a little bit about
23 extrapolation. The agency has commented that
when
24 there is potential to use adult
efficacy data and
25 extrapolate that to the pediatric
population--I
12
1 just wanted to clarify that we
would fully intend
2 to do PK parameters, PK studies
and safety studies
3 in the pediatric population. So, the question
that
4 is posed to the panel today is
whether or not there
5 is any case in which we can
extrapolate efficacy
6 data to children so we wouldn't
have to do large
7 efficacy trials in the pediatric
population.
8
[Slide]
9
I don't want to beat a horse to death but
10 I wanted to just throw these back
up so we can see
11 what really is approved in the
pediatric
12 population, and reiterate that
everything that
13 really was talked about yesterday,
most of it is
14 being used off-label in the
pediatric population.
15
What I really wanted to focus our
16 discussion on is what products are
currently being
17 used in a large enough population
that additional
18 drug labeling would make a
considerable health
19 benefit and make efficacy trials
feasible.
20
I just wanted to walk through an example.
21 I hope it might help. Dr. Fogel talked
about
22 gadolinium yesterday and he had
identified that MR
23 angiography is performed in
patients with
24 congenital heart disease to look
at vascular
25 anatomy. So, I am thinking that obviously there
is
13
1 benefit in this particular area to
study the
2 gadolinium product. The question is that first
we
3 need to identify which patient
populations.
I
4 assume you are looking at things
such as anomalous
5 vessels, aneurysms, coarctations,
etc. that you
6 pointed out. So, what are the
relevant
7 populations? We just need to identify
what
8 specific groups of patients we
want to look at
9 anatomy for.
10
Within that population, are all the
11 abnormalities considered
equal? I don't mean
from
12 a clinical standpoint but I mean
from an imaging
13 standpoint. Could you do a general
angiography
14 exam with gadolinium and see all
of these different
15 types of abnormalities, or would
you have to change
16 your procedure or modify your
procedure for any
17 particular one? If that is the case, we would
tend
18 to probably exclude that. We want to try to get
a
19 homogeneous group of patients in
which all those
20 types of anomalies or
abnormalities of vasculature
21 you want to look at would be
captured in a standard
22 MRI angiography. I don't know if it is possible;
I
23 am just throwing it out
there.
24
Then, we would need to identify whether
25 just knowing vascular
abnormality--do you find that
14
1 clinically useful? Do we have to prove that
that
2 is clinically useful? If we have to prove
that,
3 how would we go about proving that
as part of the
4 clinical
trial?
5
Then, how do we validate the findings on
6 the MR angiography? I was thinking last
night
7 maybe many of these patients go on
to
8 interventional angiography. Maybe we could use
the
9 findings of that procedure to
confirm the
10 abnormality seen on MR. Maybe many of
these
11 patients go on to surgery and we
could use surgical
12 findings to confirm the
abnormalities picked up by
13 MR.
14
That is just sort of an example of how we
15 are trying to work through these
and the types of
16 information we are trying to get
so we can try to
17 figure out where to
go.
18
DR. CHESNEY: Just before you
sit down,
19 could I ask the committee and our
consultants
20 whether you have questions for Dr.
Loewke as to
21 exactly what they are looking
for? Yes, Dr.
22 D'Agostino and then Dr.
Fogel.
23
DR. D'AGOSTINO: If you break
down every
24 possibility we could go on
forever. Are
you
25 looking for some sort of general
type of indication
15
1 so that then there is sort of a
guideline or
2 response to these questions that
sort of gives some
3 input on how one would go about
putting the trial
4 together? I am just concerned that
the
5 specifications, you know, can get
very, very
6 detailed. When you were saying can you lump
these
7 together, there were some people
on this side of
8 the table shaking their heads, no,
you can't.
So,
9 does that mean that for each
possible condition
10 there is another trial, or are you
just looking for
11 some sort of generalities in terms
of how you could
12 give guidance to industry and the
FDA and some
13 sense from the advisory
committee?
14
DR. LOEWKE: We are trying to
capture what
15 information and what populations
are large enough
16 that we can pursue efficacy trials
that would give
17 benefit to the pediatric
population. If we
can't
18 lump patients, then we have a
problem.
19
DR. D'AGOSTINO:
Right.
20
DR. LOEWKE: But I needed to
hear from the
21 panel what they think we can or
cannot do, given
22 their
experience.
23
DR. D'AGOSTINO: I went
through this with
24 the FDA in terms of pain models
and we ended up, in
25 terms of analgesics, laying out a
tremendous number
16
1 of pain models, and
what-have-you. In the end
we
2 just said we can't fill page upon
page upon page
3 but there are some general
principles, and I am
4 gathering that that is where you
are heading, that
5 there are specifics but there are
still general
6 principles that would lead from
one condition to
7 another so that we could give you
decent input to
8 putting trials
together.
9
DR. LOEWKE: From the talks
yesterday,
10 generally a role that I was seeing
is that we are
11 largely doing these studies to do
anatomy. CT
does
12 that; MR does that. There are reasons to
do
13 perfusion studies in kids. So, knowing those
14 global areas, now I just want to
get a little more
15 to what specific populations shall
we be looking at
16 because why are you doing these
studies? Then,
how
17 we should at least design the
endpoints that would
18 have clinical value to the
community? Then we
can
19 go from
there.
20
DR. D'AGOSTINO: We do a lot
these--the
21 Framingham study, and we find
oftentimes that you
22 find calcium or something like
that and you get all
23 upset about it. To produce a better image of
that
24 that we don't know what to do with, or
anything
25 like that, isn't very
helpful. So, when you say is
17
1 it clinically useful, then does
that mean that we
2 have to be able to identify in the
protocol that it
3 actually has a clinically
meaningful condition that
4 is tied into it? Or, is it just an enhancement
of
5 the image that we may not know
anything about?
6
DR. LOEWKE: Well, that is
what we are
7 trying to get
at.
8
DR. D'AGOSTINO:
Right.
9
DR. LOEWKE: We don't just
want
10 enhancement. If it doesn't mean anything and
isn't
11 useful to the practicing
community, then that is
12 not the
endpoint--
13
DR. D'AGOSTINO: So, we need
a standard
14 beyond just the
image.
15
DR. LOEWKE:
Right.
16
DR. D'AGOSTINO: Thank
you.
17
DR. CHESNEY: I have Dr.
Fogel, Dr. Geva,
18 Dr. Fink and Dr.
Fost.
19
DR. FOGEL: I wanted to step
back for just
20 a minute. Yesterday we got a lot of
speakers
21 together and we heard all sorts of
wonderful talks
22 about how we use contrast agents
and how we might
23 eventually design efficacy and
safety trials in
24 children to prove that that,
indeed, is efficacious
25 and safe in children and adds
clinical benefit and
18
1 value to their medical
care.
2 I
guess I want to step back for one
3 second. I guess this was bothering me last
night
4 and this morning, that is, a
number of people
5 brought up the notion that a
number of these agents
6 are off-patent. We could sit here all morning
and
7 talk about what wonderful trials
we would design
8 and how we would do it but, from a
practical
9 standpoint, how will the FDA
approach, once we do
10 give recommendations--how will the
FDA approach
11 getting the trials done? I mean, is there
some
12 sort of carrot that you guys think
you are going to
13 stick in front of the
pharmaceutical industry, as
14 you did with the pediatric
exclusivity rule, that
15 would be able to accomplish
this? Or, is
this
16 really more an academic
discussion?
17
DR. CUMMINS: This is not
just an academic
18 discussion. I want to reassure all of you of
that.
19 I spent most of my time yesterday
talking about the
20 on-patent process. There is an off-patent
process
21 as well. That off-patent process is done
in
22 collaboration with the National
Institutes of
23 Health. It is specified in the
Best
24 Pharmaceuticals for Children
Act.
25 Annually--actually it has been a
couple of times a
19
1 year, the NIH lists in the Federal
Register drugs
2 that are high priority for study
and the FDA
3 develops a written request for
those high priority
4 drugs and issues them to
industry. If
industry
5 does not want to conduct the
studies, then those
6 off-patent written requests are
referred to the NIH
7 and the NIH then translates them
into request for
8 proposals and they are awarded for
study.
9
We have been doing this now for about 18
10 months. We have a process in place. A couple of
11 contracts have actually been
awarded. There is
a
12 coordinating center that is
coordinating all these
13 studies and there is definitely a
mechanism for
14 translating the recommendations
that we get from
15 you all into studies for
off-patent products.
16
DR. FOGEL: That is
great. I must
have
17 missed that yesterday. Thank you.
18
DR. CUMMINS: Well, I don't
think I
19 explained it enough so rest
assured.
20
DR. CHESNEY: Could we ask
you--we were
21 discussing this in the van this
morning--does the
22 NIH have money to do these
studies, or do they go
23 in a list and maybe the top one is
funded and the
24 other hundred
aren't?
25
DR. CUMMINS: Without being
responsible
20
1 for spelling out the NIH process
in detail, yes,
2 they have funding to do these
studies.
These
3 studies are not funded through the
NIH Foundation;
4 they are funded through the NIH
budget.
5
DR. D. MURPHY: They have
some funding,
6 yes. You know, Congress suggested that they
have
7 200 million dollars for this and
then appropriated
8 none. So, the issue is that the institutes are
now
9 each having to find this money,
and they have.
10 But, you are right, there clearly
are limitations
11 and you will have to march through
the priority
12 list.
13
DR. CHESNEY: Thank you, Dr.
Murphy. Dr.
14 Geva, Dr. Fink, Dr. Fost and Dr.
Nelson.
15
DR. GEVA: I wanted to ask a
question.
16 What are the advantages or what is
the incentive
17 to, let's say, get gadolinium for
pediatric
18 cardiology applications approved
by the FDA?
19
DR. CUMMINS: The approval
would allow for
20 labeling of a product in the
pediatric population
21 so it would give us data on
efficacy, on dosing and
22 on safety that we could then put
into the label.
23 Currently, as you all
acknowledged, we don't have
24 that information in the
label. The products
are
25 all being used off-label.
21
1
DR. GEVA: Perhaps if I may,
to just
2 answer some of the questions that
were asked
3 earlier about the patient
populations and specific
4
diagnoses--to answer your
specific question, I
5 would think that what you are
looking at is
6 essentially the entire population
of patients with
7 congenital heart disease as far as
designing these
8 studies. I don't think that it makes a lot
of
9 sense, at least early in the
process, to break it
10 down to very specific
diagnoses.
11
I can tell you that of the patients who
12 come for an MRI examination, as
Dr. Fogel mentioned
13 yesterday and that is the
experience in our center
14 as well, the majority get
gadolinium MRI studies.
15 So, to start breaking it down into
specific
16 diagnoses you would probably be
doing yourself a
17 disservice. Now, there are a number of ways
by
18 which you can address the issue of
efficacy and
19 that would be a fascinating
academic discussion.
20
DR. CHESNEY: Thank you. Before we get
21 down to that issue, I think Dr.
Fink had a question
22 and Dr. Nelson had a
question.
23
DR. FINK: I guess mine
actually coincides
24 with what Dr. Geva was
saying. I don't
really
25 think that you can measure
efficacy for these
22
1 agents and what we really need is
safety and PK/PD
2 data for their usage in children
because what I
3 heard yesterday is that there are
differences in
4 technology, and which agent is
most effective may
5 depend on how many tesla your MRI
scanner has; the
6 experience of the operator;
whether the
7 cardiologist prefers MRI or CT
after they have done
8 the echo. And, the effectiveness we are
really
9 looking at may depend on the
thoracic surgeon or
10 the skill of the interventional
cardiologist and
11 these are really agents for
helping to just do the
12 image. So, I think efficacy for these
agents
13 really is the imaging and what we
primarily want in
14 pediatrics is safety and PK/PD
data.
15
DR. LOEWKE: We need to give the
user
16 information about the performance
of these agents,
17 and we look at the image and we
compare it to a
18 standard of truth to show them how
it performs to
19 what may be currently used. It gives them a
sense
20 of how this performs; do they want
to use this in
21 place of something else. So, there is value and
it
22 is very important to look at the
efficacy of these
23 products.
24
DR. FINK: I didn't hear a
whole lot of
25 discussion yesterday about
different agents that
23
1 are used or what we are comparing
it to. It
seemed
2 like for MR it was pretty much
gadolinium and that
3 there wasn't a lot of variation in
agents.
4
DR. LOEWKE: I am not sure I
understand
5 your
question.
6
DR. FINK: For efficacy are
you looking at
7 the various efficacies of the
different gadolinium
8 agents or variation between, let's
say MR versus
9 CT?
10
DR. LOEWKE: No, you are
looking at the
11 particular MR agent and you are
comparing it to
12 what--depending on what we define
as a standard of
13 truth, whether it be a comparator
agent that is
14 already approved for the
indication or whether it
15 is a standard of truth such as
conventional
16 angiography that is currently a
gold standard for
17 use in the cardiac population
today. So, it
gives
18 the user a sense of where this
falls into their
19 arsenal, and how to use it, and
how to rely on the
20 information that they get from
it.
21
DR. FINK: But it would seem
that that is
22 primarily machine driven. A 3 tesla coil is
better
23 than a 1.5 tesla coil, or a 16
detector CT is
24 better than a 4 detector CT. It would seem like
25 the technology available has a far
greater impact
24
1 than potentially these
agents.
2
DR. LOEWKE: I think we heard
yesterday
3 that it is a combination of both
the agent, the
4 drug and the user too. It is a combination. We
5 try to put factors in place to
accommodate for some
6 of those issues when we design a
trial.
7
DR. CHESNEY: Dr.
Nelson?
8
DR. NELSON: I guess I have a
question and
9 a comment. I just want to make sure I know
which
10 are on-patent and off-patent so as
we are
11 discussing the issue I have a
sense of the public
12 health impact for the feasibility
of doing the
13 trials. I guess since Bristol-Myers Squibb
likely
14 is the one who put in those two, I
am inferring
15 from the fact that they presented
on nuclear
16 imaging that, in fact, the nuclear
imaging products
17 are on-patent. I am assuming most of
the
18 gadolinium products, unless there
is some fancy one
19 in the wings, are off-patent. The nonionic
20 contrast is probably off-patent
but the fancy
21 echocardiography bubbles are
likely on-patent
22 because that is new. Have I gotten that right? I
23 am just trying to understand which
are on- and
24 off-patent as we are discussing
these different
25 modalities.
25
1
DR. CUMMINS: Whether or not
a drug is on
2 patent is actually more
complicated than one might
3 imagine, and I would encourage you
to put aside the
4 patent status of any product and
focus on the
5 product. We really need your scientific
advice.
6 Then we can think about how that
fits into the
7 whole on-patent/off-patent
process.
8
DR. NELSON: So be it. Let me then
9 continue. I am still unclear about the issue
of
10 extrapolation and trying to
separate out in terms
11 of properties of the agent and the
resolution of
12 the imaging versus application to
the population.
13 Part of this, in my mind, then
translates to how
14 you would try to design a
trial. For example,
when
15 I listened to the echocardiography
presentation and
16 looked at the slides, it sounds
like that one of
17 the issues is the ability to
differentiate a
18 tissue-liquid interface and the
relationship
19 between the resonance of the
bubbles and the
20 harmonics of the machine in
relationship to the
21 harmonics of the tissue and the
harmonics of the
22 liquid--so, a very complex
interaction. If
you
23 said that what you need to see a
good image is a
24 resolution better than--I think
you mentioned 1 mm
25 or 2 mm, 1-2 mm, the question then
is under what
26
1 circumstances can you demonstrate
that you have a
2 product that gives you that 1-2 mm
resolution
3 assuming all other factors remain
constant as far
4 as tissue harmonics and liquid
harmonics.
5
So, if I was looking at a protocol and
6 asking do you need to do that in a
neonate to
7 answer that question, you know,
can you demonstrate
8 a 1 mm resolution, my question
would then be are
9 all other factors equal apart from
the properties
10 of the agent itself? That would be the
question
11 and then you would have to tell me
what are the
12 harmonics of the adult tissue of
the heart. I
13 would then say, well okay, if it
is the same use
14 adults; if it is not use
kids. So, that is
the
15 kind of technical question I would
ask in
16 evaluating a
protocol.
17
If then you said, okay, we have an agent
18 that has demonstrated 1-2 mm
resolution, do we then
19 take it to a pediatric population
and try and show
20 that we can find clinically useful
information?
21 That then goes to the next step
and I think it goes
22 to trying to sort out what is the
nature of the
23 kinds of questions that we need to
ask.
24
I must confess, you know, I understand an
25 image. If anybody in the audience is in art
27
1 history or art appreciation, I
mean imaging is--but
2 it is unclear to me--if you took
the gadolinium MRI
3 scans, if you see a double arch
you are going to
4 see a double arch and I am not
sure you need to
5 know 1 mm resolution to see a
double arch.
So,
6 some of the questions are going to
vary depending
7 upon the modality. It sounds to me, from what
I
8 saw, I confess it looked like most
of the complex
9 questions are in the nuclear and
the echo where
10 there are still a lot of
unanswered questions,
11 whereas in the CT and the MRI it
was more a
12 question of extracardiac use of it
for imaging of
13 vessels that you can't see in the
other modalities,
14 putting function
aside.
15
So, I think, you know, as we go through
16 these--I mean, all the questions
break down each
17 particular imaging modality so it
is not only
18 population but it is what do we
really need to see
19 via CT, via MRI versus imaging and
the like. So,
I
20 think separating out those
questions is important
21 and that is why when I think about
PK and safety
22 data I also consider the basic
properties of the
23 agent, independent of whether or
not you are using
24 it to find clinically useful
information.
25
I don't know if that helps.
You know, can
28
1 you extrapolate? If all you need to do is see a
1
2 mm vessel, find a 1 mm vessel in
an adult
3 basically, if that is all you need
to see. You
4 don't use kids until you have to
use kids.
5
DR. CHESNEY: Lots of hands
and lots of
6 lists here but, Dr. Siegel, do you
have a specific
7 response to his
comment?
8
DR. SIEGEL: To three of the
comments.
9 First on the patient population
for each
10 examination, I think the patient
population is
11 really more than complex heart
disease. There
are
12 several things that have been
brought up here.
13 One, the extracardiac or the
vascular lesions; two,
14 valvular lesions; three, simple
septal lesions;
15 and, four, complex heart
disease. So, if we
are
16 looking at that, and that does
bring up the point
17 of, as you said, if we see a
vascular lesions how
18 sophisticated do we need to
get? We have seen
it
19 and that is the end of the
imaging. So, looking
at
20 the patient population we need to
sort of deal with
21 those areas, where each of these
exams fits in and
22 do we need more to confirm it or
do we stop at a
23 certain
point.
24
I think the other confusion in my
25 mind--there are two things. There is endpoint and
29
1 gold standard. I think maybe we are
overlapping
2 them. The endpoint would be a clinical
outcome.
3 If we were doing antibiotics, you
know, does the
4 patient get better? An endpoint here is a
little
5 bit more difficult to define. But if you look at
6 it clinically, there are I think
at least two
7 endpoints. If somebody has a widened
mediastinum,
8 whether it is on a CT or MR to
look at the arch,
9 and we find something and we can
say what is the
10 clinical usefulness? The clinical usefulness
there
11 terminates further imaging
studies. We are
not
12 going to have a correlate on
that. So, in
some
13 cases the clinical usefulness is
that it terminates
14 additional imaging studies or
diagnostic workup.
15 In other instances it is going to
lead to further
16 evaluation or treatment. So, if we do a study
and
17 you see a septal lesion, it is
perhaps going to
18 lead to echo or
catheterization.
19
So, to me, the two clinical endpoints, at
20 least in a simplistic world, would
be termination
21 of additional studies and end of
the workup or if
22 we need further workup. That is a clinical
23 outcome.
24
Gold standard then is if we wanted to
25 confirm a lesion that needed
further workup, how do
30
1 we do it? Again, it is going to depend on
the
2 modality. If I am doing CT, you know,
probably
3 echo is going to have to be my god
standard if I
4 wanted to do a study. If this is an
incidental
5 pickup, it probably would go to
echo but somebody
6 might say do an MR. I mean, that is going to be
a
7 little tougher. If you design a study you
could
8 probably get very specific on what
you wanted to do
9 clinically after you find a lesion
and it is up to
10 us perhaps to suggest or up to a
clinician to
11 decide what they want. But I think we are
dealing
12 with, you know, gold standard and
endpoint here,
13 and gold standard might vary for
each study.
14
DR. CHESNEY: Thank you. I have Dr.
15 Dilsizian, Dr. Gorman, Dr. Geva
and Dr. Fogel.
16
DR. DILSIZIAN: I guess I
wanted to
17 respond to Dr. Loewke's
request. There are
two
18 questions you asked. One is extrapolation
from
19 adults to kids. I think yesterday we all
said
20 adults and kids are
different. But, at the
same
21 time, I would like to emphasize
that a lot of the
22 things we use, let's say, in
nuclear medicine
23 perfusion imaging and
function--the concept of flow
24 and function can be extrapolated
from adults to
25 kids but what we need to do then
is that at the end
31
1 it would be wise to test these in
adults because
2 the dosimetry is much more
favorable. Once
you
3 have shown your efficacy and the
accuracy in
4 adults, now you can, in essence,
apply this in kids
5 but with the caveat that it has to
be retested
6 because their vessels may be
small; the organs are
7 smaller; the radiation exposure is
now different.
8 But I think that it is perfectly
safe or wise, at
9 least in my mind, to have it
approved in adults at
10 first and then accept it in kids
but then repeat it
11 in kids to see whether a
difference exists or not.
12
The reason I say that is because, for
13 example in nuclear, as you know,
perfusion and
14 function has been approved by the
FDA. It is
one
15 of the few indications that has
been done. But
we
16 now are extrapolating use in kids
but we haven't
17 really tested in kids. So, I think it would
be
18 wise, again, for echo bubbles or
DTPA to do the
19 same thing. I think we have to first show
efficacy
20 in adults and then apply it in
kids. I know
they
21 are different but, given the
safety issues, I think
22 it is always wiser to test it in
adults first.
23
DR. CHESNEY: Can I ask you
how do you
24 define
efficacy?
25
DR. DILSIZIAN: There are two
approaches.
32
1 For perfusion imaging one would
say, in adults for
2 example, I would like to detect
coronary artery
3 lesions so I can angioplasty that
lesion or send
4 the patient to surgery. Therefore, we use
5 traditionally coronary angiography
as the gold
6 standard and say can I
non-invasively predict a
7 perfusion defect which will then
guide cath and
8 angioplasty or
surgery?
9
We have learned, however, since then that
10 there could be perfusion defects
that are not
11 necessarily anatomical. There could be
12 vasoconstriction or other
physiological parameters
13 of hypertrophic cardiomyopathy
where we have no
14 coronaries but the demand is
different.
So,
15 physiological information is not
necessarily
16 equivalent to anatomical
information.
17
So, the next question is how do I judge
18 those patients? I hope I made the case that
in
19 those patients you look at
outcome--syncope, sudden
20 cardiac arrest--to see whether
identifying those
21 patients and treating them or not
treating them
22 changes the outcome of that
patient's symptoms.
23 So, those are the two
endpoints. One is
an
24 anatomical correlate as a gold
standard and the
25 other one would be
outcomes--syncope, sudden
33
1 cardiac arrest or some other
adverse events.
2
DR. CHESNEY: I think Dr.
Siegel mentioned
3 yesterday that accuracy is
efficacy here, efficacy
4 of diagnosis. Next, Dr. Gorman and then Dr.
Geva
5 and Dr.
Fogel.
6
DR. GORMAN: The question of
gold standard
7 is one that we didn't discuss much
yesterday but
8 the clinical definition I think
has already started
9 to be expressed and expounded
here, which is that
10 the clinical definition of a gold
standard is if
11 you stop intervening at that time
and your clinical
12 predictions come true, then you
made a clinical
13 diagnosis that was
appropriate. If you
continued
14 to intervene after you do a
procedure of any of
15 these sorts and the next procedure
confirms your
16 diagnosis, then it was again an
efficacious
17 procedure. So, you then begin to have a
moving
18 gold standard target which is that
for each of
19 these many lesions that we could
discuss there is a
20 series of modalities that would
help diagnose them.
21
Clinically, there is a pediatric
22 population that is enriched for
cardiac lesions and
23 everyone undergoes cardiac imaging
and I would
24 suggest them as a potential first
place to start
25 study design. Every single one of those undergoes
34
1 a cardiac imaging procedure I
think in the United
2 States for whether they have
clinical findings or
3 not. They also have potential
benefit.
4
DR. CHESNEY: Dr. Geva, Dr.
Fogel and Dr.
5 Sable.
6
DR. GEVA: To go back to the
efficacy
7 issue, I would like to expand on
Dr. Siegel's
8 comment and that is that there are
at least two
9 ways of defining efficacy in the
context of this
10 discussion. One is diagnostic accuracy and
it
11 depends on the specific trial and
the specific
12 lesion or group of lesions that
are being
13 investigated. One can choose an appropriate
"gold
14 standard" and that may be
something that has been
15 around for decades, such as
angiography which is
16 commonly accepted as the best that
is currently
17 available; surgical observations;
a compilation of
18 all available imaging tests--there
are several ways
19 of going about putting together a
reference
20 standard. Not all of these are true gold
standards
21 but they have been around long
enough and that is
22 what is being used most commonly
so if a new agent
23 or a new technique is being
proposed it is a common
24 thing to test it against
those.
25
Then, a different approach to efficacy is
35
1 to look at an outcome, clinical
outcome with the
2 use of a new diagnostic
technique. To give
a
3 specific example, currently all
patients, let's
4 say, who are candidates for a
certain surgical
5 procedure, let's say the Fontan
operation,
6 routinely undergo cardiac
catheterization and one
7 can design a study whereby instead
of routine
8 cardiac catheterization selected
patients undergo
9 non-invasive preoperative testing
and that is an
10 arm in a clinical trial. Patients are
randomized
11 to standard invasive testing
versus non-invasive
12 testing. Then one can look at set
clinical
13 outcomes--freedom from
intervention, length of stay
14 and so on and so
forth.
15
So, studies like that can certainly be
16 designed. Although you don't directly test
the
17 diagnostic accuracy of, let's say,
gadolinium MRI,
18 you are testing whether the use of
gadolinium MRI
19 can be used in order to achieve
equivalent clinical
20 outcome but with less cost, less
risk for the
21 patients, less radiation and so
on.
22
DR. CHESNEY: Dr. Fogel, Dr.
Sable and Dr.
23 D'Agostino.
24
DR. FOGEL: Yes, I have a
number of
25 comments. First going to the efficacy issue, I
36
1 just wanted to say that I strongly
support the
2 notion that efficacy is a very
important part of
3 this entire discussion. It goes towards the
whole
4 notion of, because we have seen a
potpourri of
5 diagnostic imaging modalities,
obviously, if you
6 have efficacy on the various
imaging modalities in
7 a given patient population or a
given category of a
8 patient population you can then
compare the various
9 diagnostic imaging modalities and
say, well,
10 imaging modality X is more
efficacious than imaging
11 modality Y in this particular
instance and that
12 would actually improve patient
management and
13 patient care in the sense that you
would then have
14 some real data to say, well, if
this patient comes
15 along with a certain likelihood
the best clinical
16 pathway for one to follow would be
to get imaging
17 modality X and then Y and then go
on to
18 intervention Z because we have
shown that X is more
19 efficacious than Y in this patient
population.
20
So, I think that that would be very
21 useful. It would improve patient safety
because
22 you wouldn't have to do sedation
for an
23 echocardiogram and then do
sedation for an MRI; you
24 could just do it once and then
move on to the next
25 diagnostic imaging modality or
therapy. So, I
37
1 think that would be very important
to do and I
2 voice strong support for
efficacy.
3
In terms of efficacy being a clinical
4 outcome, which I have heard a
number of speakers
5 talk about, we all have to
recognize that imaging
6 in an of itself, to use the
clinical trial
7 terminology, is really a
surrogate, and it is a
8 surrogate for something that is
really true, which
9 would be holding the heart in your
hand and being
10 able to see the whole heart, being
able to
11 miniaturize yourself down to a
teeny little person
12 and see that little coronary
artery and walk
13 through it. But apart from that, it really is
a
14 surrogate.
15
As such, with clinical outcome there is so
16 much that--let me step back for
one second.
The
17 imaging itself is just one
component of a
18 multi-faceted thing that is going
to happen to the
19 patient. There are all sorts of other
imaging
20 modalities that might occur, as
well as
21 interventions and postoperative
care.
22
So, although I guess you could design
23 trials that would have imaging
modalities and look
24 at the clinical outcome, I would
imagine you would
25 need a lot of patients and it
would be very noisy
38
1 because there are so many other
factors that go
2 into a patient's clinical outcome
other than the
3 diagnostic imaging modality. I think it would
be
4 very, very difficult in terms of
being able to show
5 efficacy in that particular
way. Now, if you
want
6 to do it against a gold standard,
that would be
7 surgical observation,
unfortunately, sometimes
8 pathologic observation. That is totally
different.
9 But clinical outcome sounds like
it would be pretty
10 noisy data.
11
Finally, the last thing I wanted to
12 mention is the extrapolation issue
of Dr. Nelson.
13 I have to say that I don't really
think you can
14 extrapolate from adults to kids,
as we all
15 mentioned yesterday. I don't think that if
you
16 have a 3 mm or 4 mm aorta in a
child you can then
17 say, well, can I see a 3 mm
coronary artery in an
18 adult? Well, if I can see a 3 mm coronary
artery
19 in an adult, then I can certainly
see a 3 mm aorta
20 in a child. That doesn't really work. There are a
21 lot of technical issues that go on
in there--tissue
22 attenuation, the size of the
patient, how big a
23 field of view you need to see the
various
24 structures--a lot of technical
things go into the
25 fact that I don't think you can
really do a good
39
1 extrapolation from adults into
children and I would
2 be very wary of doing
that.
3
DR. CHESNEY: Dr. Sable and
Dr.
4 D'Agostino, and then I would be
very interested in
5 polling all our experts to see if
they agree with
6 you. Let's do that right now, if you don't
mind.
7 Would you all agree that you can't
extrapolate from
8 adult data to children? I think that was one
of
9 the big
issues.
10
DR. MOORE: I would not
agree. I
would
11 say, just to focus on what I think
the issue here
12 of this subcommittee, whether
additional labeling
13 is required for some of these
agents and labeling
14 specific for pediatrics to make
sure that these
15 agents are safe and effective, I
would argue a
16 little bit along Dr. Nelson's
lines that gadolinium
17 and certainly iodinated contrast
have a lot of data
18 that is available both in adults
and children in
19 terms of their safety and efficacy
in other areas
20 in the body and in other
modalities which can be
21 translated over to cardiac
imaging. I would
argue
22 that the focus really needs to be
on some of the
23 newer agents and perhaps some of
the
24 radiopharmaceuticals and some of
the echo contrast
25 agents in terms of the specific
issues with safety
40
1 and
efficacy.
2
Just
to speak to that point, you know the
3 gold standard in many institutions
nowadays for
4 some of these cardiac lesions is
no longer
5 angiography; it is already
considered gadolinium
6 MRI or iodinated contrast CT. So, to then go
back
7 and say we are going to evaluate
efficacy in these
8 agents that are already clinically
being used in
9 many areas of the country as the
gold standard in
10 these applications doesn't make a
whole lot of
11 sense to me, and I think we can
extrapolate from a
12 lot of the data that is already
out there for some
13 of these very experienced
agents.
14
DR. SIEGEL: Well, I am going
to go the
15 opposite
way.
16
DR. CHESNEY: Dr.
Siegel?
17
DR. SIEGEL: I don't think we
can
18 extrapolate because of the various
varying factors
19 in children, which would be the
smaller size; the
20 faster heart rate; the inability
to hold their
21 breath; the motion. I think that is going to
make
22 it harder to see or more difficult
to see these
23 smaller
lesions.
24
As far as just following up on another
25 comment, I do agree that safety
issues have been
41
1 proven in the iodinated contrast
media, but I am
2 not sure about the efficacy
because that has really
3 not been shown in children. I think we still
have
4 to prove
that.
5
DR. DILSIZIAN: I actually go
somewhere in
6 between.
7
[Laughter]
8
And the answer is, as I said before, yes,
9 you can extrapolate but do test
again in the kids.
10 The reason I disagree with the
comments is that
11 everything we have talked about,
whether it is
12 gadolinium, micro bubbles or
perfusion, we tested
13 in adults first and then we are
testing it in kids.
14 The knowledge base came from
adults. We
15 extrapolate to the kids but we
haven't really
16 checked the efficacy in the kids,
which has to be
17 tested. Yes, there is extrapolation but test
again
18 in the kids.
19
DR. SABLE: I think, as
everyone seems to
20 be agreeing, it is not a simple
answer. First
of
21 all, we can't come up with a
blanket answer for our
22 different modalities. Just to use echo as
an
23 example, I think if you divide
patients by weight
24 or size above a certain age and
weight there is
25 probably reasonable utility to
extrapolating for a
42
1 given patient population. For example, a
14-year
2 old who had Kawasaki disease with
a structurally
3 normal heart would be a very
reasonable population
4 to study, very much based on
extrapolating from
5 adult data, although I think it
should be done in
6 children also. Conversely, a 3-year old who had
a
7 transposition repair in whom we
want to try to
8 assess regional wall motion I
think has a lot more
9 unanswered
questions.
10
Just to kind of cover one other thing
11 about gold standards versus other
ways to design
12 tests, I think a lot of us feel
that MRI or
13 contrast-enhanced CT may be a gold
standard for
14 some things, but the reality is
that in most adult
15 studies that I would pattern my
pediatric studies
16 after they are not using gold
standards because it
17 is much more difficult to design
tests using a very
18 subjective standard which is
widely accepted as
19 having a physician or a group of
physicians look at
20 different segments of the heart
and saying I can
21 see it well; a little bit; not at
all, and asking
22 the question does this modality
improve my ability
23 to see what I am trying to
see. Most tests
are
24 much more easily designed but
clearly not as
25 elegant as having a gold standard
such as MRI or CT
43
1 or the ultimate gold standard
which would be
2 surgical or pathology which we
rarely have.
3
DR. CHESNEY: Dr. Geva, can
we extrapolate
4 from adults to
children?
5
DR. GEVA: I agree with Craig
that this is
6 complex. There is no blanket answer. I would say
7 with regard to the gadolinium MRI
that it is age
8 related and you can extrapolate a
little bit to the
9 adolescent and adult with
congenital heart disease
10 perhaps. But when it comes to young children
with
11 small body size the answer is
no.
12
DR. CHESNEY: Dr. Loewke,
does that help
13 with your question about whether
we can extrapolate
14 adult to pediatric
data?
15
DR. LOEWKE: Yes, it
does. Thank
you.
16
DR. CHESNEY: Yes, Dr.
Fogel?
17
DR. FOGEL: Listening to all
my colleagues
18 talk, you know, I do agree that
for children who
19 are in the adolescent age group
that are getting
20 close to adulthood you could
potentially
21 extrapolate from adults to
children. But I
guess,
22 again using the terminology of
surrogate, when you
23 are talking about this you are
really talking about
24 using adult studies as surrogates
for looking at
25 childhood efficacy in these
patients. You know,
44
1 using surrogates has all sorts of
issues and
2 problems. I mean, the Fleming and Demetz
article
3 basically states that a whole lot,
and I would
4 still be very, very wary about
doing that.
5
But using gadolinium-enhanced MRI or CT as
6 a gold standard, if you do it
already why do more
7 clinical trials? I think what we are missing
in
8 the literature is rigorous,
large-scale trials that
9 look at this. We have numerous reports with
small
10 numbers of patients that add up to
a certain
11 number--maybe add up to a mildly
large number of
12 patients but we don't have
large-scale, rigorous
13 clinical trials that look at
it. Then, there
is
14 anecdotal evidence but I think if
we are going to
15 serve our patients properly we
need to have the
16 data to then show
them.
17 DR.
CHESNEY: Dr. D'Agostino, did you
have
18 a comment?
19
DR. D'AGOSTINO: I wanted to
comment on
20 the trial design. I am not sure, given what I
have
21 heard and what I know about these
procedures, that
22 clinical outcomes are necessarily
a useful way,
23 just to endorse what Mark was
saying, because there
24 are so many other things that go
along with the
25 actual decisions in terms of what
medical practice
45
1 is going to do beyond the
imaging.
2
The other comment is that I would have
3 thought, again from what I know
and what I have
4 read, that a simple trial that you
can do here is
5 basically to have the individual
go through this
6 procedure with and without the
imaging agent, or
7 different levels of the imaging
agent, and then ask
8 the question does the higher level
of the imaging
9 agent somehow or other add more
information to
10 improve the clinical decision on
that individual.
11 It is a simple trial and the point
is how do you
12 decide on the clinical
information. You know,
the
13 sort of subjective way of having a
panel do it, and
14 so forth, blinded or unblinded, is
a matter for
15 discussion but I don't think we
want to run to the
16 notion of clinical outcomes, and I
do think that
17 the trial design doesn't have to
be very
18 complicated and we should try to
avoid that.
But
19 the outcome being clinically
meaningful is a real
20 trick, be it a gold standard or
something else.
21
DR. CHESNEY: Dr. Sable, and
then I think
22 we will go on to question number
two.
23
DR. SABLE: I want to add one
more comment
24 about extrapolation. I think that it is
25 important--and I am kind of
biased--to
46
1 differentiate what I do from what
all of my
2 colleagues do. All of my colleagues are
already
3 using contrast in some percentage
of the studies
4 and that is probably the rule
throughout the
5 country. Conversely, there are almost no
pediatric
6 echocardiographers using contrast
and the idea of
7 us using contrast, although I am
obviously an
8 advocate for it, is a much bigger
leap. For us
to
9 even think about using it in our
clinical practice
10 needs an incredible amount of push
and support.
11 So, even if you could extrapolate,
if I have a
12 17-year old who comes into my lab
who has the exact
13 same criteria as an adult and I
want to do a
14 contrast study, it is going to be
a much bigger
15 issue for me to do it. But we do have
patients
16 that we would like to do in our
lab. So, the
17 practicality of the issue is that
even if you could
18 extrapolate, the pediatric cardiac
community needs
19 additional enhancement to
undertake contrast.
20
I will just kind of end by using the
21 example from Dr. Gardiner's talk
yesterday. A
22 company that makes Definity and a
nuclear medicine
23 agent was very adamant that we
think about using
24 his agent for a population of
maybe 4,000 studies a
25 year but didn't even mention using
one of his other
47
1 agent for a population that has a
million studies a
2 year. So, I think that just kind of brings
home
3 the point that there is just a
huge gap between
4 using contrast echo in the
practical setting and
5 using the other
agents.
6
DR. CHESNEY: Dr. Siegel and
then Dr.
7 Santana.
8
DR. SIEGEL: Just one comment
about the
9 research possibilities, I think
designing these
10 trials in children is going to be
difficult because
11 you can't really use different
concentration doses
12 of drugs. It would be very difficult to get
it
13 through an IRB and you certainly
can't do it in the
14 same patients. You would have a very mixed
patient
15 population.
16
One of the issues we haven't addressed is,
17 you know, do we need to get down
to the level of
18 doing animal research and really
getting back to
19 basics? It is the only way I think we will be
able
20 to look at different doses versus
enhancement and
21 different flow rates, if that is
important to you,
22 versus enhancement, and I don't
think we will be
23 able to do that on a pediatric
population.
Adults,
24 yes, probably but not in
children.
25
DR. CHESNEY: Thank you. Dr. Santana and
48
1 then we will see if we can
start--
2
DR. D'AGOSTINO: Can I make a
comment?
3
DR. CHESNEY:
Yes.
4
DR. D'AGOSTINO: When I was
talking about
5 the trial I was saying a simple
trial but I didn't
6 say it would be simple to
do.
7 [Laughter]
8
It is a different matter altogether in
9 terms of can you operate it. But the design of
10 running to a clinical outcome and
so forth I think
11 is a much harder to thing to do
and probably has
12 tremendously difficult
interpretation problems.
13
DR. SIEGEL: I think we are
proving this
14 whole thing is going to be
difficult to do.
15
DR. CHESNEY: Dr. Santana
first and then
16 Dr. Loewke.
17
DR. SANTANA: Having
experienced sitting
18 through pediatric oncology
committee meetings at
19 two separate meetings where we
discussed the issue
20 of extrapolation of adult oncology
data to
21 pediatrics, I have learned two
lessons that I think
22 may be relevant to this
discussion. The first
is
23 that although I think in general
we agree that it
24 is not wise to extrapolate adult
data directly into
25 pediatrics because there may be
different disease
49
1 processes; there may be different
issues of
2 tolerance; and ultimately there
are differences in
3 functionality, PK, organ maturity,
when forced to
4 think about this issue, the
pediatric oncology
5 committee did come up with a few
examples in which
6 we were able to fulfill the
criteria that the
7 disease process was similar enough
that it was not
8 ethical to do efficacy trials in
children, and we
9 should put our resources in doing
the type of PK
10 safety studies that are more
relevant.
11
So, the challenge I think for my
12 colleagues--although we all like
to say that in
13 general terms we should not
extrapolate, the
14 challenge is to come up with
examples in which you
15 can extrapolate and that will save
us time, effort
16 and safety for our patients so
that then we can do
17 those studies more wisely and
capture that data
18 quickly and get more information
out to consumers
19 and
practitioners.
20
So, that was just a word of wisdom by
21 extrapolation. We all like to say, no, let's
not
22 extrapolate; they are
different. But
force
23 yourself to think that there may
be scenarios in
24 which you will be able to
extrapolate and those are
25 the ones that I think we need to
bring forward to
50
1 resolve some of these
issues.
2
DR. CHESNEY: Dr.
Loewke?
3
DR. LOEWKE: I just wanted to
make a
4 comment that seeing more doesn't
necessarily mean a
5 benefit. These drugs are not without risk. So,
6 obviously, the utility of the
information you are
7 getting is very important and that
is, again, a
8 risk-benefit
assessment.
9
DR. CHESNEY: Dr. Glode and
Dr. Fink, and
10 then I think we need to push on to
begin question
11 two.
12
DR. GLODE: I just wanted to
clarify a
13 question and I think reemphasize
the comment that
14 Dr. Siegel just made. It seemed to me, or at
least
15 I wanted to confirm that for some
of these agents
16 not only dose but infusion rate
are issues to be
17 potentially
studied.
18 The
comment I wanted to make is just a
19 comment very similar to what Dr.
Siegel just
20 commented on in terms of if your
goal was to find
21 the lowest effective dose--again,
a presumption
22 that a lower dose translates to a
safer dose--I
23 don't know how you are going to do
that in
24 children. In animals, yes, and hope that
that
25 translates or something. But it does seem very
51
1 problematic to say here is our
standard dose X and
2 we are randomizing people to half
X, and the
3 endpoint is that we couldn't read
your study and it
4 gave us no valuable
information. So, now we
need
5 to sedate your child again and do
another study.
6 So, the study design is pretty
problematic in
7 trying to get to the lowest dose
that gives you an
8 interpretable
image.
9
DR. CHESNEY: Dr.
Fink?
10
DR. FINK: It strikes me that
we are
11 spending all this time talking
about these agents.
12 It is wonderful. It would also be interesting
to
13 see if equal time was spent
looking at the
14 equipment. How much of the equipment we
are
15 talking about is actually licensed
for use in
16 neonates?