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
Advisors and Consultants Staff Conference Room
5630 Fishers Lane
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.
Mary Glode, M.D.
Steven Ebert, Pharm.D. (Consumer Representative)
FEDERAL EMPLOYEE (VOTING):
Mario Stylianou, Ph.D.
Samuel Maldonado, M.D.
Julie Beitz, M.D.
Sally Loewke, M.D.
Susan Cummins, M.D.
Diane Murphy, M.D.
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
Questions to Committee
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.
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
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
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.
The anatomic MRI
data is suitable for
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
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
1 and struggled with the issue of separating the
2 risks of the contrast agent from the risks of X-ray
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
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
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.
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
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
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.
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
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
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
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
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
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
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
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
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?
DR. CUMMINS: Without being
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
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.
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
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
24 DR. FINK: I didn't hear a whole lot of
25 discussion yesterday about
different agents that
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
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
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
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
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
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.
I don't know if that helps.
You know, can
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
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
24 Gold standard then is if we wanted to
25 confirm a lesion that needed
further workup, how do
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
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?
DR. DILSIZIAN: There are two
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
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
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.
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.
Then, a different approach to efficacy is
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.
24 DR. FOGEL: Yes, I have a number of
25 comments. First going to the efficacy issue, I
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
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
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
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
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
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
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
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
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
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,
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
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
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
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.
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
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.
DR. CHESNEY: Thank you. Dr. Santana and
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.
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
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
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
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
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? There are huge improvements in
17 resolution at least with MR and CT that could be
18 done with better design of the equipment or
19 attachments that optimize it for the infant where
20 you get the collectors and the collimators much
21 closer to the patient.
22 My guess is that there would potentially
23 be more to gain by equipment redesign and algorithm
24 specifically designed for the neonate than by the
25 dyes, and you might be able to cut
dosages far more
1 dramatically by getting manufacturers of the
2 equipment interested in looking at the problem.
3 Just out of curiosity, are any of these
4 devices actually licensed for use in premature
5 infants or neonates? Because it seems like they
6 come on the market for adults and they get used in
7 kids because that is what is available.
8 DR. LOEWKE: I don't think that CDRH is
9 here--they were here yesterday--to answer that
11 DR. CHESNEY: Dr. Maldonado?
12 DR. MALDONADO: Just about that, actually
13 I approached Dr. Feigel, who is the Center Director
14 of Devices, recently because I was curious about
15 how we will go to approve a device for children.
16 He told me that the Center for Devices doesn't
17 approve those devices for particular populations.
18 You are right, Dr. Fink, they are approved for a
19 participant image in this case but there is no
20 reference to where these devices could be used.
21 DR. CHESNEY: Approved for human use and
22 neonates are human. So. I keep putting off
23 question two but let's have two more, Dr. Fogel and
24 Dr. Danford.
DR. FOGEL: Yes, I just
wanted to respond
1 to the question about dosing. At least for MRI for
2 example, as I mentioned yesterday, gadolinium is an
3 adjunct to the rest of the study and not a study in
4 and of itself for the vast majority of the studies,
5 not all but for the vast majority of the studies.
6 So, if you have an MRI scan that has half a dose of
7 gadolinium versus a full dose of gadolinium versus
8 a dose and a half of gadolinium, you wouldn't
9 necessarily get uninterpretable information from
10 the entire study because you would have done the
11 non-contrast part as well and maybe gotten the
12 information but you certainly would be able to make
13 a diagnosis. Now, would it change the clinical
14 outcome? Would the surgeon not like it as much as
15 if we had done the 3D and had them take a look at
16 the 3D? Probably not but you certainly would get
17 that information.
18 If you address it along the same lines as
19 you would in a blood pressure clinical trial, it is
20 the same thing versus getting a placebo. I mean,
21 you know, you have to accept that when you enter
22 into a clinical trial there are some people who
23 will benefit and some people who won't benefit.
24 DR. CHESNEY: Dr. Danford?
DR. DANFORD: I am going to
1 just a minute with Dr. Loewke's remark that we
2 really need to prove that better imaging translates
3 into better outcomes. In an ideal world, of
4 course, we would prove that but, as a practitioner
5 in pediatric cardiology, I think that the better
6 you see this stuff the better job your surgeon and
7 your interventional cardiologist is going to be
8 able to do for the patient. We haven't yet reached
9 the plateau where we have such high quality imaging
10 that we absolutely know stuff. It is still shades
11 of grey and degrees of confidence and we are still
12 surprised sometimes by what our surgeons find that
13 we were not expecting.
14 And, I think the proliferation of all of
15 these imaging modalities that we have heard about
16 speaks to that. You wonder why are we developing
17 all of these things. Don't we already have either
18 an accurate diagnosis or not? I think it is more a
19 shades of grade phenomenon and the better imaging
20 we get, I think the better outcomes we are going to
21 have. I have no data to support that but I think
22 that is true.
23 DR. CHESNEY: Thank you, Dr. Danford. I
24 know Dr. Siegel has to leave a little bit early
25 this morning--oh, that is
different than my
1 question two. My question two says please discuss
2 each of the following questions for cardiac CT. I
3 must have the wrong set of questions. Sorry.
4 DR. SANTANA: Dr. Chesney, may I make a
6 DR. CHESNEY: Dr. Santana?
7 DR. SANTANA: As I have heard all the
8 discussions yesterday and today, I am still a
9 little bit like Skip was yesterday, disoriented,
10 because we are talking in certain scenarios about
11 anatomy, in certain scenarios about perfusion, in
12 other scenarios about the tools, the machines, the
13 operators, in other scenarios about the agents.
14 So, one thing that would be very helpful to me, as
15 we go through each of the modalities, is if the
16 panel of experts, one or many, could specifically
17 tell us what is the question that is most
18 clinically relevant to them. If they were given
19 one choice to do a study with this modality and
20 this patient population, what is the burning
21 question that they want answered. Rather than, you
22 know, trying to design fifty trials, it may be
23 better if they would help us or the FDA by saying
24 this is the question that is most relevant right
25 now. Let's put our money into it; let's put
1 effort into it; let's move forward.
2 DR. CHESNEY: Thank you. That was maybe
3 your idea yesterday. Somebody raised that as a
4 potential way of addressing this.
5 DR. D'AGOSTINO: That is what I raised
6 yesterday but was 24 hours too early I guess.
7 DR. CHESNEY: Well, you phrased it
8 differently in the van. It came out very clearly,
9 what is the burning issue for each one of our
10 experts. The FDA has put a lot of thought into
11 these questions so we want to be sure to address
12 them as well, but maybe each of you could start by
13 saying in the best of all possible worlds, this is
14 the question that I would like addressed and then I
15 will address (a) through (f). Dr. Siegel, you are
17 DR. SIEGEL: Okay, we will start with
18 cardiac CT. I think there were sort of three basic
19 elements discussed yesterday and it is really
20 safety, dose and efficacy. If I look at that for
21 CT, the safety has been proven. My issue is dosing
22 and actually other elements of technique.
23 I don't know the dose that will work best
24 for CT. We use doses that are based on information
25 dating back to the '60s and '70s
and that is the
1 standard dose we use now. My feeling is that for
2 CT we can get away with a lower dose. I have used
3 it but we have no large series on that. So, my
4 question is what is the minimum dose that we can
5 use that will provide an effective or diagnostic
7 The other issue for CT is what is the flow
8 rate that will also provide an effective and
9 diagnostic image? So, those are the issues I need,
10 the more technical factors to optimize a study for
12 DR. CHESNEY: That is very valuable.
13 Maybe we could go (a) through (f) now and you can
14 just give us one-word answers and then we will move
16 DR. SIEGEL: Okay, imaging agents further
17 study? No, I think it is a mature population and
18 the safety of these agents has been proven.
19 What population should be studied? I
20 think we addressed that before. We could divide it
21 into four populations, the vascular lesions,
22 valvular lesions, septal lesions and complex heart
24 I will step back for a second and say if
25 we look at the vascular lesions
such as the aortic
1 lesions, the arch lesions and some of the pulmonary
2 slings we may be able to extrapolate on that.
3 There are series both in the MR literature,
4 primarily in the MR literature and some in the CT
5 literature and certainly in the adult literature
6 that CT is efficacious for the diagnosis. Those
7 are large structures; it is going to be valuable.
8 But I think the other three categories,
9 valvular lesions, septal lesions and complex heart
10 disease are patient populations that need to be
11 studied. You can further say patient population by
12 age, and I think the age we really need to look at
13 is the younger patients. For CT, those are
14 patients who are six years of age and younger, the
15 ones who are more likely not to cooperate or hold
16 their breath and are smaller in size.
17 Moving on, what disease states should be
18 studied? To me, that is the same as sort of the
19 patient population unless you have another
21 What endpoints? Again, endpoints, to me,
22 are going to be different from gold standard, and
23 that would be clinical outcome either leading to
24 further studies to validate the finding on CT or
25 termination of imaging
studies. We could, of
1 course, talk about research but I think that will
2 come a little bit later.
3 How should a trial be designed? If I
4 think the burning concern is dose and flow rates,
5 as I mentioned, it is going to have to be animal
6 studies. We cannot do that on children. It just
7 will not be approved. I can't imagine any IRB
8 approving that. So, that would have to be an
9 animal study with varying doses. I have the
10 numbers but I don't think we have to say the exact
11 numbers. Varying flow rates and then looking at
12 enhancement, standardizing the study by automated
13 means and looking at various structures in the
14 heart and even outside the heart. That I think is
15 the type of trial that I would be designing.
16 By designing that type of trial you would
17 also be able to look at whether there is diagnostic
18 information, whether we can see these structures.
19 Hopefully, at that point we would be able to
20 translate some of this use in children. Perhaps
21 these studies could also be done in adults; they
22 are being done and we might want to look at that
23 information when those trials are completed to see
24 if we can extrapolate that information and where
25 our starting point would be.
1 How should the standard for comparison be
2 defined? Is there a gold standard? I think if we
3 were to do those studies the gold standard would be
4 cardiac cath. I think that has been the gold
5 standard for a while. That is probably what I
6 would suggest for the animal studies.
7 I think if we do a pediatric population it
8 is going to be more different because of the
9 radiation issue and we would not really be able to
10 say let's do a cardiac catheterization on
11 everybody; the risk is going to be too great. You
12 would have to redefine your gold standard and then
13 I might say let's go for echocardiography,
14 hopefully with some contrast agent by that time, to
15 minimize radiation risk. That is always going to
16 be the concern when we design any study for CT.
17 DR. CHESNEY: Thank you. Comments? Dr.
18 Nelson and Dr. D'Agostino and then maybe Dr. Loewke
19 could tell us if we have answered everything for
20 question number two or three.
21 DR. NELSON: I agree with your
22 observations about the risk and how it would be
23 hard to design a trial like this, but let me see if
24 I can ask you a question that might give a little
25 bit of an opening. Would there be a population
1 that might be going to surgery anyway where the
2 surgeon would say if you don't see this as well as
3 you would because you have done half a dose of
4 contrast I can check it operatively and it won't
5 put the patient in any different risk relative to
6 having been exposed to the risk of a lower quality
7 study because you have done a lower dose of the CT?
8 If it is possible that the gold standard would
9 still be done, in whatever instance this might be,
10 and the person doing it would not have lost
11 information that they wouldn't be able to verify
12 at that time that you might be able to make an
13 argument for putting the child at that risk. You
14 might, but it is a reach.
15 DR. SIEGEL: Right now you couldn't vary
16 the dosage. I think if I go and start saying
17 instead of using 2 mL let's do our studies with 1
18 mL I am experimenting without approval.
19 DR. NELSON: I am assuming you would
20 design a protocol that way. I am just thinking
21 that the point at which, from a risk perspective,
22 an IRB might say it is justified is if the gold
23 standard would still be done, and at the time that
24 that gold standard would be done, such as surgery,
25 the operator would not have lost
1 they couldn't otherwise verify, and there might be
2 a chance that they would let you take the risk of a
3 lower quality study.
4 DR. SIEGEL: In some places it might, but
5 you are absolutely right, you might say that I want
6 to do, you know, 1 mL/kg based on the adult
7 work--it has to be based on something, and that
8 would be a possibility. Then the patient--to be
9 part of the study the clinician would either have
10 to agree to do a cardiac cath because he is going
11 to do it anyhow or the patient is going to surgery.
12 I mean, I have that type of study now, a rather
13 limited study, so I think that is doable. But,
14 again, it is going to be a little more difficult to
15 get through a number of IRBs.
16 Just as a quick comment, a few years ago I
17 tried to get a similar study through by saying I
18 would like to do patients with reduced
19 milliamperage or current. We were using 200 and I
20 said let me drop it to 150, 100 and then 50, and I
21 couldn't get it approved because they were
22 concerned it wouldn't be a diagnostic study and I
23 would be repeating it. So, by dropping the
24 contrast, I think there may be the same concern
25 about that. I think we can design a study. It is
1 going to be a little bit more difficult to do given
2 the radiation. That is why I suggested the animal
3 model. But I agree with you, there would be some
4 possibility to do that.
5 DR. CHESNEY: Dr. D'Agostino?
6 DR. D'AGOSTINO: I have three comments.
7 The answer to part (a) where you said nothing needs
8 further study, I thought that was the whole purpose
9 of the question, to sort of identify which agents
10 do need further study.
11 The second and third questions I have is
12 that if we had the design that I was calling simple
13 before and one was the echo and the other was the
14 imaging agent, that gives you the two measurements
15 on the individual to make those comparisons and try
16 to get the clinical benefit, and so forth, so it
17 fits in very much I think with what I was
18 suggesting earlier.
19 The third question in terms of the dose,
20 couldn't one do some animal studies, maybe some
21 sort of Phase II type of studies getting some idea
22 of the dose, and then move on to the Phase III
23 study where you have the dose fixed and also the
24 injection rate, and so forth? I mean, a little
25 mixture of the animal studies to
1 information and move to something like a
2 dose-ranging study with a small number of subjects
3 to give you an idea. The study for the efficacy is
4 the fixed dose, fixed infusion echo versus the CT.
5 DR. SIEGEL: Going backwards, I think I
6 agree with you on the last point. I think I
7 mentioned that we start with an animal study with
8 the varying doses and then translate it to
9 pediatric patients using echo as the comparison of
10 the standard.
11 The contrast agents that are being used
12 for this have been studied in detail. There is a
13 lot of information out there. They are approved.
14 Their safety is known. I don't think we are going
15 to see new contrast agents. It is not the contrast
16 agents; it is really the dose and flow rate that we
17 are dealing with. These are safe. They work. We
18 don't need to develop new ones. What was your
19 second question?
20 DR. D'AGOSTINO: What I was calling a
21 simple design before, that you need two
22 measurements and you could do an echo on an
23 individual and then the imaging agent at a fixed
DR. SIEGEL: I agree. You start with the
1 CT and then we do the echo to confirm it.
2 DR. CHESNEY: Dr. Stylianou, you had a
4 DR. STYLIANOU: I have a comment also. As
5 far as the animal studies are concerned, even if
6 you do the animal studies you still have to test in
7 humans eventually. And, my guess is that a
8 clinical trial is probably unrealistic because of
9 the toxicity involved. One possibility would be a
10 case-control type of study. You could have two
11 groups and match them by some characteristic like
12 age, body mass index or some kind of
13 characteristic, and you can have a study doing it
14 that way.
15 DR. CHESNEY: A prospective study?
16 DR. STYLIANOU: A prospective study.
17 DR. D'AGOSTINO: What are you matching?
18 DR. STYLIANOU: At this time I am not sure
19 how to match but at least it would be a way--
20 DR. D'AGOSTINO: But what is it? People
21 with two different procedures?
22 DR. O'FALLON: Stratifying.
23 DR. STYLIANOU: Right.
24 DR. SIEGEL: But I don't see how this gets
25 us to dose or flow rate issues.
1 DR. STYLIANOU: You test it. You said the
2 doses are already safe but is it tested?
3 DR. SIEGEL: The current dose is tested
4 but we don't know how low we can go on the dose--
5 DR. STYLIANOU: Right.
6 DR. SIEGEL: --and get a diagnostic image.
7 DR. STYLIANOU: So, basically you have to
8 test a lower dose to see if it is effective.
9 DR. SIEGEL: Correct, and again it can be
10 different in a pediatric population because if you
11 get a non-diagnostic study you have irradiated a
12 patient for no reason and then you have to either
13 repeat that study or do another study. That is the
14 dilemma we are in with CT because of the ionizing
16 DR. CHESNEY: Dr. Sable?
17 DR. SABLE: I think we need to be a little
18 bit careful when we are designing studies. If we
19 are going to use echo as a gold standard, which is
20 safe, simple, low cost and portable, then why do we
21 need to do another study that may be more risky? I
22 think CT has a lot of wonderful potential for many
23 things that are much better than echo--
24 DR. D'AGOSTINO: Couldn't you ask do you
25 get more information out of the CT
than the echo?
1 DR. SABLE: Well, if we are asking that,
2 then we shouldn't be using echo as a gold standard.
3 DR. D'AGOSTINO: It is not a gold
4 standard, it is a comparison.
5 DR. SABLE: I think when we design our
6 studies we just need to be careful--
7 DR. D'AGOSTINO: But you can use a gold
8 standard if you have a gold standard or you can use
9 a comparison. The question is do you get some
10 information from the CT.
11 DR. SIEGEL: Right. I mean, we are not
12 saying that CT becomes the first imaging study.
13 Echo is still the first imaging study. But let's
14 say the echo is equivocal, then we are going on to
15 CT, and I am basing this on our adult population,
16 as I said, with congenital heart disease which is
17 1,200 patients and we have done a number--at least
18 300. We are doing them because of equivocal study
19 or sometimes there is a murmur and it is the first
20 diagnostic study we are doing. So, the question
21 is, you know, is it efficacious and can we use it
22 if there is an indication for it because of an
23 equivocal echo or because it is an incidental
24 pickup. If it is an incidental pickup, do we need
25 to go further? But I don't think this is a
1 first-line imaging study.
2 DR. SABLE: Sure, and I certainly agree
3 with all that. This is not a question that CT
4 doesn't add a lot to equivocal echoes; the question
5 is when we are designing studies, if we are putting
6 echo as part of your study design to validate CT,
7 then I think an IRB could look at that and say,
8 well, why are you even doing the study? I think
9 that is a different question than whether or not CT
10 adds to equivocal echoes. I think we need to be
11 careful about using circular logic.
12 DR. SIEGEL: Yes, I am agreeing with you.
13 I think if we do the echo and it is diagnostic we
14 don't go further. But we would have to identify
15 the population that would have an equivocal echo,
16 or perhaps postoperative if it is Mustard or
17 Senning procedure and there is a question of a leak
18 and you need a better definition. That is a large
19 population and perhaps the postoperative patients
20 might be another population. But we are not here
21 to really design the study in detail right now.
22 DR. CHESNEY: If I could ask FDA about a
23 procedural issue here, if we are going to have to
24 discuss (e), trial design, on each one of these we
25 are going to be here for several
days. I am
1 wondering if we can't just omit (e) and--
2 DR. NELSON: And the ethics disappear--
3 DR. CHESNEY: And I am not making the
4 ethics disappear; just to get through each one of
5 the questions for everything but (e), and then we
6 address issues of trial design. Can I get a show
7 of hands from the pediatric committee? Does that
8 sound like a reasonable approach?
9 DR. O'FALLON: I think we could talk about
10 design in about three minutes and get that off the
11 board. All right? May I do that?
12 DR. CHESNEY: Wait just a minute, I have
13 to absorb that.
15 DR. SANTANA: Joan, I agree with that. I
16 think if we frame the question that Dr. D'Agostino
17 and I have been trying to push, which is tell us
18 what is the question that is more relevant in your
19 disease and what you want to do, then we could have
20 a brief discussion about how that trial should be
21 designed rather than discussing every single
22 permutation of every possible trial to be done. I
23 think if we look at it that way we should be able
24 to help the discussion.
DR. CHESNEY: All right. So, before we
1 address any of these questions we will just address
2 the most important thing for you and how you would
3 like to set up the study, and then we will come
4 back to these questions. Is that what I am
5 hearing? That is not what Dr. O'Fallon is
6 suggesting, Dr. Santana. You are suggesting that
7 we ask each person to tell us the most burning
8 question and how they would design the trial.
9 DR. SANTANA: Right, like Dr. Siegel did.
10 She did that I think very appropriately. She told
11 us what her issues were if she wanted to answer
12 this question. She wanted to look at dose. She
13 wanted to look at infusion rate. She wanted to
14 look at animal models and then she was thinking how
15 she would take that into a clinical trial,
16 comparing it to another modality. If we have that
17 kind of discussion, we may be able to get some
18 comments like Skip was making about whether it was
19 ethical or whether there would be issues that would
20 have to be approached in a different way.
21 DR. CHESNEY: I just have a feeling that
22 we are going to be going on and on if we get into
23 that. All right, Dr. O'Fallon, if you can solve it
24 in three minutes we are wide open.
DR. O'FALLON: I have been
1 quietly, letting you guys have your say, but I
2 think that we can cut through on the issue of
3 design. I think that there is a basic strategy
4 that applies to all of them. Not all of them will
5 use every piece but there is a basic procedure that
6 has to be used to go through this and we don't need
7 to deal with it for every single modality.
8 I think that basically you have to define
9 your study goals. Are you looking at movement?
10 Are you looking at anatomy or are you looking at
11 what? Disease identification, whatever? But you
12 decide the goal. Then you have to rank in your
13 particular disease the contrast agents that are of
14 most importance to you. Then you have to define
15 what initial dose levels you want to study based on
16 adult levels and/or animal models, but, you know,
17 you have to decide what you want to do. Then you
18 do your pharmacokinetics and dose levels and
19 flow--in this case flow levels, but that would have
20 to be well defined before you went into the
21 children. But then when you had realistic levels
22 you would go ahead and perform the PK and dose
23 level which could include flow level studies.
24 Now you have to define your age groups.
25 Are you going to do it in
adolescents? Are you
1 interested in neonates? What are we dealing with?
2 But you have to define that and you would have to
3 do them I think in each age group in order to
4 characterize the adverse events. You know,
5 everybody is making the assumption that they know
6 what they are, but they have to be defined to at
7 least get some preliminary data on adverse events
8 in each of these age groups that you choose to use
9 it for.
10 Of course, you have to define your success
11 endpoint which would be in terms of image quality
12 or diagnostic utility. That you would have to
13 design for each one of your things. That is what
14 you would be talking about up here.
15 I mean, there is a basic strategy for
16 doing the design in these studies and, like Dr.
17 D'Agostino was saying, it is pretty much a simple
18 deal because they really do have PK and dose level
19 information in order to provide the kind of
20 information that will be needed for labeling.
21 DR. CHESNEY: Dr. Beitz?
22 DR. BEITZ: I would say that what Dr.
23 Siegel responded with was really excellent and is
24 the kind of thing we are trying to get from the
25 panel. So, if we could go through the different
1 modalities in turn and just get some brief answers
2 and then let the panelists and other members have a
3 discussion for maybe five, ten minutes afterwards
4 and then go on to the next, that would be I think
6 DR. CHESNEY: Thank you. So, we will
7 proceed to cardiac MRI. Dr. Maldonado?
8 DR. MALDONADO: I just have a quick
9 question for Dr. Siegel. I think that you seem to
10 be comfortable with the safety of these contrasts,
11 as I heard, but I still don't understand why you
12 want to go down in the doses if you feel that the
13 safety is not a problem. The reason I ask this is
14 because when we are trying to go to small molecules
15 in my field, go down in the doses, we are trying to
16 optimize safety without losing much in efficacy.
17 Since you seem to be comfortable with the safety,
18 are you trying to optimize the efficacy with going
19 down with the doses?
20 DR. SIEGEL: Well, i think as we discussed
21 yesterday, we think that less is better so it would
22 be nice to be able to use less. The safety is
23 proven. The other thing in CT is if we can lower
24 the dose and give less volume we may be able to
25 inject it faster and get better
1 if we can increase the flow rate, then we can
2 increase our enhancement so we will get better
3 images. They will be better diagnostically; I am
4 not sure, you know, that they will be better images
5 from our quality standpoint. So, lowering the
6 volume makes it easier to get the total amount of
7 contrast in somebody who is small.
8 DR. CHESNEY: Thank you. Dr. Fogel, if
9 you would first tell us what is the most burning
10 issue for you if you had a wish-list, and then
11 address (a) through (f) and very briefly (e)?
12 DR. FOGEL: Sure. Well, in my mind, I
13 have to say there are two most burning issues. One
14 is anatomy and being able to get efficacy data and
15 safety data on anatomy with relation to dose. The
16 second burning issue, real quickly, would be
17 perfusion and viability, which I think is very
18 under-utilized in congenital heart disease in our
19 patient populations and I think gadolinium-enhanced
20 MRI could add greatly to that. So, those are in
21 general the two burning categories which I would
22 like to see addressed.
23 What imaging agents need further study?
24 Well, in MRI it is fairly easy. The vast, vast,
25 vast majority is gadolinium and
nobody is using the
1 manganese or the superoxide iron particles,
2 although there are some studies being done but I
3 don't know if they are being done in cardiac very
4 much. So, for me gadolinium would be the only
6 What patient population should be studied?
7 Again addressing the anatomy and perfusion, for
8 anatomy I think you could probably lump all the
9 extracardiac vasculature into one patient
10 population. The key would be the size of the
11 patient whether they be neonates, infants,
12 toddlers, children, and then adolescents. There
13 was a good case made that you could probably
14 extrapolate adolescents from adult data so I am not
15 as strongly married to that as I am to neonates,
16 infants, toddlers and children. So, I think those
17 would be the patient populations.
18 In terms of the types of disease processes
19 and the patient population, it would be those
20 patients who have extracardiac anomalies like
21 coarctation, postoperative tetralogy, postoperative
22 transposition. Those would be the patient
23 populations--the postoperative Fontan patients.
24 Those would be the patient populations that I would
1 In terms of perfusion and viability, again
2 I would say that we would have to address both the
3 size issue--neonates, infants, toddlers, children,
4 and I would put in as a patient population the
5 people who are at most risk for myocardial
6 perfusion defects and scarring of the myocardium.
7 Those, for example, are patients after a Ross
8 procedure where they get coronary manipulation;
9 patients after transposition of the great arteries;
10 after arterial switch procedures who also get
11 coronary manipulation; and those patients, although
12 rare, who have native coronary artery anomalies,
13 like anomalous left coronary, and come to medical
14 attention. All those patients would have the
15 opportunity to benefit from myocardial perfusion.
16 What endpoints should be used? As Skip
17 was alluding to, I think the gold standard would
18 probably be surgery, and for perfusion I think
19 nuclear medicine would probably be the gold
20 standard that I would use for the perfusion defects
21 because that is the most widely accepted, although
22 it still has issues with radiation and things of
23 that nature. But this is a wish-list; this isn't
24 how we would actually do it in practice.
In terms of dosing, presently for
1 extracardiac anomalies, for example, we usually use
2 a double dose of gadolinium so I would advocate
3 maybe just four categories; double dose, one and a
4 half, one and then half a dose of gadolinium, just
5 thinking off the top of my head how one would do
6 that and randomize people to those four dosing
8 I would just like to point out that with
9 MRI gadolinium is an adjunct and we will get other
10 information from the study which will help the
11 surgeon. I would also have a gold standard which
12 would be surgical observation. You know, in any
13 trial in the high risk procedures that we do,
14 unfortunately, sometimes we will have pathologic
15 observations but in either case we will have direct
16 human observation which would be the gold standard.
17 I also want to point out that when we are
18 looking at these dosages we know what the upper
19 dose is and we have gotten a lot of safety data
20 from anecdotal evidence from various studies,
21 numerous studies in the literature on upper dose of
22 gadolinium. It is the lower dose and the risk of
23 not getting a diagnostic gadolinium study rather
24 than giving too much and causing toxicity. So, I
25 think that is an important point
for us to
2 Then, how should the standard for
3 comparison be defined? Is there a gold standard?
4 In answering the other questions, you have to
5 necessarily answer that. So.
6 DR. CHESNEY: Thank you very much. I am
7 hoping that when we get through we can come back to
8 issues of study design. Dr. Nelson?
9 DR. NELSON: Mark, for perfusion issues
10 now what tests are being done? I mean, would you
11 do a nuclear scan? DR. FOGEL: Normally what
12 we will be doing will be nuclear scans and/or
13 cardiac catheterization to see if there was any
14 coronary artery stenosis or some microcirculation
15 perfusion abnormality. So, these would have been
16 done clinically anyway and the question would be
17 whether or not MRI--because of its greater tissue
18 characterization, no ionizing radiation, being
19 non-invasive--would have a benefit so that in the
20 future you would be able to obviate the need for
21 cath and/or nuclear studies to a great degree and
22 just be able to use MRI instead.
23 DR. CHESNEY: Go ahead.
24 DR. NELSON: Just as a follow-up, I think
25 there can be some general
principles outlined in
1 terms of trial design that if, in fact, the gold
2 standard would be performed anyway--I mean, I think
3 that is an important one, then you want to avoid a
4 repeat procedure. So if, in fact, the gold
5 standard would be done anyway and the risk of a
6 repeat procedure is not there because you would
7 then proceed to that gold standard without
8 repeating your MRI, I mean, I think that is the
9 general principle. So, I think you can outline
10 some general principles of a trial design that
11 would allow you to generalize across all of these
12 possible scenarios.
13 DR. CHESNEY: Dr. Ebert had his hand up,
14 then Dr. Fost and Dr. Santana.
15 DR. EBERT: Just a follow-up question, Dr.
16 Fogel, I think earlier in your comments you
17 mentioned that you could also design this is a way
18 where you would not use contrast in an MRI. That
19 could also serve as a control in some of these
21 DR. FOGEL: Yes, well, what we basically
22 do is we basically do the non-contrast studies
23 first, if nothing else, as a localizer to how we
24 are going to do the contrast studies. So, the
25 contrast is more of an adjunct to
it rather than
1 standing on its own merit, although there are some
2 times when it does stand on its own merit but as a
3 general rule we do the non-contrast enhanced first,
4 get some information that way and add more
5 information by doing the gadolinium.
6 DR. CHESNEY: Dr. Geva, you have some
7 expertise in this area. I wondered if you wanted
8 to comment. Then I have Dr. Fost, Dr. Santana and
9 Dr. D'Agostino.
10 DR. GEVA: I just wanted to comment about
11 the endpoint and reference standard for a potential
12 study design. I would have some concern about
13 relying on surgical observations alone. Number
14 one, it does have its own limitations. Although it
15 appears on the face of it as if the surgeon opens
16 the chest and sees everything, that is far from
17 being the case. I would propose for consideration
18 as a blanket reference standard for studies on
19 diagnostic accuracy you might want to look at
20 something like summation of all available
21 diagnostic information on a patient. Some of these
22 patients will have clinically indicated cardiac
23 catheterization with extra angiography. Actually,
24 some will also have CT. Some will have surgical
25 observation. Some will have autopsy findings.
1 That information can be combined together.
2 DR. FOGEL: I just want to say that I
3 understand that surgery is not a be-all and end-all
4 in and of itself, but any gold standard has a
5 false-positive, false-negative and sensitivity and
6 specificity rate. And, I think that for most gross
7 anatomical manipulations that the surgeon is going
8 to do for a diagnosis or for an extracardiac
9 structure that they are going to be sewing
10 together, they are going to be deeply involved in
11 manipulating the tissue itself, and the success or
12 failure of the surgery depends upon how well they
13 manipulate the tissue we are trying to image
14 non-invasively and that is the best gold standard
15 that we have. I don't pretend to say that that is
16 the be-all and end-all by any means, but at the
17 moment I think it is the best we have. Comparing
18 it to echo and angiography, I don't think that they
19 are gold standards in the sense that for the things
20 we are talking about, that patients have to go
21 surgery for, it is ultimately going to be up to the
22 surgeon to be able to manipulate the tissue in such
23 a way to have a good clinical outcome for the
24 patient, and that seems like to would be the gold
25 standard we want to shoot
for. Again, surgeons can
1 be wrong, heaven forbid, and it certainly is not
2 100 percent of a gold standard.
3 DR. CHESNEY: Thank you. Dr. Fost?
4 DR. FOST: A couple of questions, Dr.
5 Fogel. So, you are proposing doing children who
6 are already scheduled for a cath to look for
7 perfusion problems, and you are suggesting doing an
8 MRI before you go to cath?
9 DR. FOGEL: Well, this would be patients
10 who you would be considering who might have some
11 coronary artery issues and some coronary artery
12 problems. I mean, there would be clinical
13 justification in all patients who have coronary
14 artery manipulation that you would want to see
15 whether or not coronary artery manipulations that
16 were preformed by the surgeon, for example after a
17 Ross procedure or after an arterial switch
18 procedure, whether or not that put any of the
19 myocardium at risk. We do have some individuals
20 after those surgeries who then get coronary
21 ischemia. We see this on the EKG and other things.
22 Or, decreased myocardial performance that might
23 suggest that there may be some coronary perfusion
24 issues that we would need to address. Now, the
25 knee-jerk reaction and the first
thing you would go
1 for would be a nuclear medicine study, and other
2 individuals would go for cardiac cath. Therefore,
3 as people are saying, you would have done those
4 things anyway. These would be patients who are at
5 risk who you would have done those things anyway
6 for, and now you would add on the MRI as an
7 additional test.
8 DR. FOST: So, this would be a
9 non-therapeutic MRI for this child.
10 DR. FOGEL: Correct.
11 DR. FOST: And that meets minimal risk
13 DR. FOGEL: I would believe so, yes.
14 DR. FOST: Would they need separate
15 sedation for that?
16 DR. FOGEL: Well, depending on the age
17 group, they could potentially need extra sedation.
18 That is correct.
19 DR. FOST: And are there data on that
20 question in adults? That is, does MRI predict or
21 correlate with cath data for perfusion problems?
22 DR. FOGEL: There is a number of papers
23 that have been done in adults, looking at ischemic
24 heart disease and comparing it against PET, that
25 have shown that MRI was very good
in that sense, in
1 actually advocating the use of MRI for that patient
2 population. Can you then say that the coronary
3 artery disease that we see in kids--can you then
4 extrapolate that from ischemic heart disease to
5 congenital heart disease coronary artery issues is
6 another question. I don't think you can but if you
7 have information in adults saying that it could
8 potentially be useful, then I think that would be a
9 good basis for you to then go ahead and move along
10 into kids.
11 DR. FOST: Might it be different in
12 infants than adults?
13 DR. FOGEL: Well, most of the time the
14 microcirculation and the actual obstruction that
15 you might find in the major coronary arteries are
16 atherosclerotic in nature, as opposed to patients
17 who have undergone cardiac-pulmonary bypass and
18 actually taking the coronary arteries and moving
19 them, and flipping them, and putting them in all
20 sorts of other geometric ways you might not
21 necessarily think that it may be as efficacious in
22 kids as it might be in adults. Plus, with kids you
23 have smaller children and you need a greater
24 resolution to tell differences in myocardial
25 perfusion. In children you might need a 1 mL or
1 sub milliliter pixel size to be able to tell issues
2 of hypoperfusion whereas in an adult it may be 1.5
3 mL, 2 mL limit of resolution with which you might
4 be able to tell perfusion defects. So, you may not
5 necessarily think that you could do it in adults
6 and not doing it in kids.
7 DR. FOST: Thank you.
8 DR. CHESNEY: Dr. Santana, D'Agostino and
9 Nelson, and we will let you go first and then we
10 will go on to the next question.
11 DR. LOEWKE: What I am hearing is you are
12 looking at probably two types of clinical trials,
13 one to get an anatomic delineation type of a claim,
14 and one for a functional perfusion type of claim.
15 I know you said this was a wish-list but I have to
16 go back to your perfusion gold standard, just to
17 throw it out there. Nuclear medicine is not
18 approved. The radiopharmaceuticals are not
19 approved for perfusion in kids. So, do you have
20 any other suggestions?
21 DR. FOGEL: Yes, but it is actually, in
22 fact, in clinical practice used all the time in
23 children. I don't know the numbers specifically
24 but the numbers were shown yesterday. It was a
25 considerable number of patients in
1 population in whom it is used. I guess outside the
2 regulatory arena it is considered the gold
3 standard. Cardiac catheterization doesn't
4 necessarily address the microcirculatory issues
5 that would be addressed with perfusion defects that
6 are shown by MRI as well as by nuclear studies.
7 So, I think if you were just going to use
8 cardiac cath alone it would be a suboptimal trial
9 and less accepted by the general community of
10 physicians than if you use the
11 radiopharmaceuticals. I know that that might
12 present a regulatory issue from your standpoint but
13 I think you might have--and I don't know if that is
14 a total brick wall that can't be broken down or if
15 it is something that can be finessed and
16 side-stepped, but I think it would be better for
17 general acceptance among the entire medical
18 community if something like radionuclide
19 pharmaceuticals were used. And, I am not a big fan
20 of radiopharmaceuticals but it is a gold standard.
21 So, that is what I would use.
22 DR. CHESNEY: That is why we are meeting.
23 Dr. Santana, Dr. D'Agostino, Dr. Nelson, and then
24 we are going on to the next question. We have just
25 had another question added so we
need to get
2 DR. SANTANA: Can you clarify for me--I
3 should have asked this yesterday but it didn't come
4 up until today when I realized what you were
5 talking about in terms of your potential trial
6 designs--how many times within a given MRI can you
7 administer gadolinium or, because it has such a
8 half-life time, is it that you can only do it once
9 and you are over with it?
10 DR. FOGEL: Well, we can give it a couple
11 of times as long as the dose during that entire
12 session does not exceed the maximum dose which is
13 40 cc or a double dose up to 40 cc, depending on
14 the kilo body weight. We do that a number of times
15 for the perfusion abnormalities so, for example, we
16 will inject half a dose of gadolinium, get three or
17 four slices, and then wait a few minutes, inject
18 another half dose, get three or four at different
19 orientations and then do that a couple of times;
20 then wait five minutes and then do the viability
21 portion. So, you get basically two for the price
22 of one.
23 DR. SANTANA: So, you could do a study in
24 which there was an intra-patient escalation of
25 dosing once you defined what the
target lesion was
1 that you were after. So, to address some of your
2 issues of dosing of gadolinium the patient could
3 have an escalation--I was thinking about anatomy
4 actually, not perfusion. Once you identified what
5 the target lesion was that you were looking at with
6 X dose, you could administer that patient a
7 different dose and see if you improved your
8 efficacy of defining that target lesion within the
9 same patient. So, the incremental risk would be
10 the risk of giving another dose certainly, and the
11 incremental risk of more time under the machine.
12 DR. FOGEL: Right, you could do that with
13 half a dose and one and a half doses, which would
14 actually add up to two doses. You can't do it with
15 the double dose because that is the maximum you can
16 give. And, you couldn't do it with one dose
17 because you couldn't give one dose and then do
18 another dose because they are the same dose. But
19 you could potentially do that with half a dose and
20 one and a half dose so you could simplify the trial
21 to a certain extent that way. That is a very good
23 DR. CHESNEY: Dr. D'Agostino?
24 DR. D'AGOSTINO: Fortunately, Victor just
25 asked half of my question. The other half is to
1 the FDA. If you did a design that had no contrast
2 versus contrast at some fixed level, would that be
3 an acceptable design if you could show clinical
4 benefit, gold standard and so forth with none
5 versus some and get more information standard some?
6 DR. LOEWKE: You would have to be able to
7 identify that the added information had clinical
9 DR. D'AGOSTINO: Exactly, you would have
10 to show that you do get clinical benefit but, you
11 know, could you do the MRI without any gad in it
12 and then do it at a particular level and show that
13 that particular level does, in fact, add
14 information? Because you automatically do it at no
15 level, right?
16 DR. LOEWKE: I mean, we have approached
17 things before in that fashion. That was before we
18 have moved forward with clinical utility. So, it
19 would be very important that the added information
20 really had value that you could clearly identify.
21 DR. D'AGOSTINO: Right, but it is not an
22 unacceptable design?
23 DR. LOEWKE: It is something that would
24 need further discussion.
DR. D'AGOSTINO: Yes, thank
1 DR. CHESNEY: Dr. Nelson?
2 DR. NELSON: I have just two comments to
3 follow-up on some of Norm's questions. There is
4 precedent both for local protocols as well as for
5 NIH-funded studies for limited procedural sedation
6 to be considered a minor increase for
7 non-therapeutic procedures. There is also
8 precedent for trying to minimize the risk of
9 sedation by combining the MRI being performed when
10 there is an anesthetic being provided for other
11 reasons, either operatively or that real fancy
12 picture you showed us yesterday, Phil, of the UCSF
13 slide in and out between MRI and catheterization
14 which, sounds to me like the perfect venue for this
15 kind of MRI/catheterization because you are just
16 sliding the patient back and forth a few feet, it
17 would seem.
18 DR. CHESNEY: We have been asked to
19 include Dr. Moore in all of these modalities. So,
20 that is going to be an additional question and I
21 would like, unless there is some strong feeling, to
22 move on to the cardiac ultrasound, hoping to take a
23 break at the end of that and then we can address
24 the nuclear imaging and angiography. But Dr.
25 Siegel looks insistent.
1 DR. SIEGEL: One quick comment as we go
2 through the rest of it, I just thought about one
3 other way to do research and to maybe complicate it
4 more, we forgot about simulation models. With all
5 the computer designs out there now, we would be
6 able to look at certain facets at least in CT and
7 maybe in MR using computer models. That is just a
8 thought. It just dawned at me that if I am looking
9 at dose and I am measuring density I could probably
10 do this with a computer phantom, setting up the
11 appropriate computer example. So, it is just
12 another thing to put on the table if anybody thinks
13 that is appropriate as we discuss other modalities.
14 DR. CHESNEY: Thank you. I am glad you
15 were insistent. Dr. Sable, are you ready?
16 DR. SABLE: Sure.
17 DR. CHESNEY: Please tell us what is your
18 most burning issue in the best of all possible
19 worlds, and then if you could address (a) through
20 (f), please.
21 DR. SABLE: Well, I think to me the most
22 burning issue is to try to incorporate contrast
23 echo into evaluating left ventricular function and
24 wall motion in complex patients in whom we can't
25 get good pictures with routine
echo. I think that
1 is probably the most important thing and would be a
2 starting point as a basis to do other things with
3 contrast echo.
4 I think in terms of what agents need to be
5 studied in pediatrics, there is the most experience
6 in adults with Optison and Definity so I would
7 clearly focus on those two drugs, both looking at
8 the necessary dosing and safety in anything that we
10 In terms of which populations should be
11 studied, I think there are a couple of groups that
12 I would divide them into. If you think about
13 patients with poor windows, they can be patients
14 like after cancer where you just need functional
15 studies, or patients with complex heart disease
16 that have unusually shaped ventricles or single
17 ventricles, right ventricles acting as systemic
18 ventricles such as in Mustard or stenting repairs.
19 I think another group of patients would be those
20 who would need stress echo evaluation, including
21 patients with Kawasaki disease, heart transplant
22 and patients who have undergone operations that
23 involve the left coronary artery or the arterial
24 switch procedure. I think later on we could move
25 towards doing perfusion studies,
but I think the
1 first step would be to look at left ventricular
2 opacification both at rest and exercise.
3 In terms of using endpoints, I think that
4 the ideal is using a gold standard and in this case
5 probably MRI or nuclear medicine could be a gold
6 standard, but I think the more practical approach
7 to using an endpoint, and it is probably easier
8 with echo than other modalities because we can vary
9 without increasing risk sedation or time, we can
10 get pre- and post-injection images to see if there
11 is an improvement using the standard American
12 Society of Echo wall motion score. We have 22
13 segments for every patient so the power of the
14 study could be achieved relatively easily with not
15 a huge number of patients.
16 In terms of trial design, I would start
17 with a group of patients such as those with poor
18 windows that I had mentioned, and pick a drug like
19 Definity or Optison and use incremental dosing
20 based on weight to get a sense of do we get
21 improved images; how long does that image last for;
22 and comparing it to the pre- and postop and pre-
23 and post-injection state.
24 A second, probably softer endpoint would
25 be does adding contrast obviate
the need to do more
1 invasive studies? We could do a randomized,
2 controlled study, although the ethics of that may
3 be challenged based on adult literature and we may
4 need to consider using historical controls.
5 That probably gets to trial design. I
6 think I would start with using an older population
7 and then gradually work my way down to smaller
8 patients. I think I will stop there and answer
10 DR. CHESNEY: Dr. Loewke?
11 DR. LOEWKE: I was wondering, you had
12 mentioned stress testing, are you talking about
13 exercise only? Pharm stress only? If you do
14 exercise, how low can you go age-wise and actually
15 get patients to cooperate? I will throw a monkey
16 wrench in here as well. I believe--and there is
17 somebody here I believe from Cardiorenal--that the
18 pharm stress agents aren't approved in kids.
19 DR. SABLE: Certainly, that is true and
20 there is maybe one more paper on stress echo in
21 children that is on contrast echo in children.
22 That being said, a large number of us do dobutamine
23 stress echo. It is a little bit cumbersome, as one
24 can imagine, to have somebody run and then throw
25 them onto the bed to image
them. You can do a
1 little better with some of the odometers where you
2 are lying flat. Tal can probably speak to this.
3 They probably do more than we do in their lab. But
4 it is much easier to do dobutamine stress echoes
5 and that would probably be the way we go. If you
6 look at Dr. Kimball's study, I think they did 19
7 dobutamines and 2 ergometer stress echoes in their
8 study. Clearly, we could be having the same panel
9 meeting about dobutamine stress echo and come up
10 with all the same issues that I just mentioned for
11 contrast echoes. We are a little bit further along
12 in that realm.
13 In terms of age, we have done them down to
14 a year, a year and a half. Then you get into the
15 whole issue of sedation and that clearly needs to
16 be a part of any equation with echo if you are
17 doing very small children. With older children,
18 probably beyond four or five, it is not as much of
19 an issue.
20 DR. CHESNEY: I have Dr. Ebert, Dr.
21 Gorman, Dr. Moore and Dr. Geva.
22 DR. EBERT: I have a question for Dr.
23 Loewke. As we go through some of these
24 specifically, does the agency feel pretty
25 comfortable about measures of
safety, either short
1 term or long term, that you are going to
2 incorporate into these, with MRI or with any of the
3 other modalities?
4 DR. LOEWKE: Obviously, we would welcome
5 any information that you can provide on how you
6 feel safety should be incorporated into trial
8 DR. SABLE: I think with any type of
9 stress echo or contrast echo we would need to
10 monitor vital signs and pulse oximetry very
11 frequently, probably similar to some of the
12 conscious sedation protocols, for a set period of
13 time after the study is done, probably at least an
14 hour. Obviously, we would be watching for more
15 severe adverse events and reporting those.
16 DR. CHESNEY: Drs. Gorman, Moore, Geva and
18 DR. GORMAN: I was hoping not to have to
19 ask this question because I was hoping it would
20 come out, but what has been the barrier that has
21 prevented these contrast agents from being used in
22 echocardiography? Clearly, it is not fear of using
23 things off-label because pediatricians do that all
24 the time. Clearly, it is not that it hasn't been
25 used in adults. So, what has been the barrier that
1 has prevented this modality from leaping, as all
2 the other technologies have leapt, to pediatrics?
3 DR. SABLE: There are two answers to that.
4 The first one is that every patient that comes to
5 one of my colleague's labs is probably the only
6 patient they are dealing with for at least a few
7 minutes, and they are all going to have an IV and
8 they are all going to be prepared to get contrast.
9 So, it is kind of the mind set.
10 Whereas, in a busy echocardiography
11 laboratory--we do about 50 studies a day in our
12 laboratory and we usually have three or four rooms
13 going at once--we have very limited nursing. We
14 have maybe one nurse that is there to cover a
15 sedated echo which we still use oral sedation for.
16 So, putting an IV in, in the midst of a very busy
17 echo lab is much different than for some of the
18 other modalities.
19 The economics of echocardiography is that
20 in many cases we are supporting other programs. We
21 have a huge volume, a huge money-maker and it is
22 hard for me to convince my administrators who are
23 looking at the practicality of doing this that
24 instead of doing seven echoes using one sonographer
25 I want to do one echo using one
1 doctor and at least one or two nurses. So, I think
2 that is a huge barrier. It is inappropriate but it
3 is the reality.
4 The second barrier is what I alluded to
5 earlier, that is, the drug companies which are
6 making these agents--I have talked to them at
7 several meetings--don't seem to have much interest
8 and they seem to be scared of getting into
9 pediatrics. Clearly, the talk we heard yesterday
10 from Bristol-Myers was much more focused on the
11 nuclear agent even though the discussion included
13 DR. GORMAN: I can understand the economic
14 argument inside a hospital, but not much
15 echocardiography actually goes on in hospitals.
16 So, why isn't some entrepreneurial private practice
17 group that does echoes doing this? I mean, if
18 there is really a need out there for this--if there
19 is really a diagnostic utility to this that
20 clinicians will use, then generally what happens is
21 people use it and either show it works or doesn't
22 work and reimbursement follows after that.
23 DR. SABLE: Yes, I think that even though
24 a large proportion of pediatric echo is done in
25 community hospitals or in smaller
1 echo is going to start in tertiary care large echo
2 labs. So, I think it would primarily be hospital
3 based early on. It has been something that I have
4 been trying to push in my institution and I think
5 it is somewhat resources and just a different way
6 of thinking. A lot of the people who refer
7 patients--a lot of my colleagues who refer patients
8 for echoes are used to getting an answer in five or
9 seven minutes so it is kind of changing the mind
10 set. Hopefully, Dr. Kimball's paper will circulate
11 through the pediatric cardiology community and the
12 American Society of Echo that you heard yesterday
13 will change the mind set. I think in general, for
14 lack of a better term, it may be ignorance. Very
15 few of us even think about it.
16 DR. GORMAN: One more, is there something
17 uniquely different about these agents? Are these
18 really something that has traveled the border of
19 drugs and devices? Are these bubbles really
20 bubbles or are they particles that don't break
22 DR. SABLE: I think they break down. I
23 think another issue is that the way they interact
24 with the echo machine--before I prepared for this
25 talk I read a couple of contrast
echo books and the
1 principles behind them, and the way you use them is
2 complex and intimidating and it is really a whole
3 new science to learn. So, I think it is more that
4 than actually concern about safety or particles
5 breaking down. I mean, the potential, as I
6 presented yesterday, is so great and if it could be
7 done in a routine echo setting--I have talked to a
8 number of adult echocardiographers who do this on a
9 daily basis and there is a huge learning curve to
10 get started and a lot of us aren't willing to take
11 this learning curve. Clearly, I am here as a
12 representative of an academic echo lab that feels
13 the learning curve is certainly worth it.
14 DR. CHESNEY: Drs. Moore, Geva, Nelson and
15 then I think we will take a ten-minute break.
16 DR. MOORE: Well, I will just follow-up on
17 that. Dr. Gorman played devil's advocate for me so
18 I appreciate that. But our experience, interacting
19 quite a bit with our own echo lab which has had an
20 interest in contrast echo for years and interacts
21 very closely with the adult echo lab because we are
22 not a free-standing children's hospital, has really
23 found a relatively limited utility in the smaller
24 patients with regards to the current echo contrast
25 agents. I wouldn't say that is to say there
1 applications and there may not be huge future
2 applications for it.
3 I would say in our own experience the
4 limitation has primarily been added value in terms
5 of the younger patients. We even started using
6 some of the Optison type contrast in the cath lab
7 looking at different shunts in very specific
8 indications and found over time that it really
9 wasn't giving us a lot of added value. Because of
10 that, we limited its use.