1

 

                DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

                      FOOD AND DRUG ADMINISTRATION

 

                CENTER FOR DRUG EVALUATION AND RESEARCH

 

 

 

                 PEDIATRIC ADVISORY SUBCOMMITTEE OF THE

 

                ANTI-INFECTIVE DRUGS ADVISORY COMMITTEE

 

 

 

 

 

                      Wednesday, February 4, 2004

 

                               8:00 a.m.

 

 

 

             Advisors and Consultants Staff Conference Room

                           5630 Fishers Lane

                          Rockville, Maryland

 

                                                                 2

                              PARTICIPANTS

 

      P. Joan Chesney, M.D., Chair

      Thomas H. Perez, MPH, Executive Secretary

 

      SGE CONSULTANTS (VOTING):

 

         Mark Hudak, M.D.

         David Danford, M.D.

         Richard Gorman, M.D., FAAP

         Robert Nelson, M.D., Ph.D.

         Susan Fuchs, M.D.

         Robert Fink, M.D.

         Victor Santana, M.D.

         Norman Fost, M.D., MPH

         Judith O'Fallon, Ph.D.

         Ralph D'Agostino, Ph.D.

         Mark Fogel, M.D.

         Tal Geva, M.D.

         Craig Sable, M.D.

         Vasken Dilsizian, M.D.

         Marilyn Siegel, M.D.

         Phillip Moore, M.D.

 

      MEMBERS (VOTING):

 

         Mary Glode, M.D.

         Steven Ebert, Pharm.D. (Consumer Representative)

 

      FEDERAL EMPLOYEE (VOTING):

 

         Mario Stylianou, Ph.D.

 

      INDUSTRY REPRESENTATIVE:

 

         Samuel Maldonado, M.D.

 

      FDA:

 

         Julie Beitz, M.D.

         Sally Loewke, M.D.

         Susan Cummins, M.D.

         Diane Murphy, M.D.

 

                                                                 3

 

                            C O N T E N T S

 

      Call to Order, P. Joan Chesney, M.D.                       4

 

      Recap of Day 1, David Danford, M.D.                        4

 

      Discussion of Questions to Committee                      11

 

                                                                 4

 

  1                      P R O C E E D I N G S

 

  2                          Call to Order

 

  3             DR. CHESNEY:  Welcome back, everybody.

 

  4   Dr. Loewke is going to give us an overview of the

 

  5   questions again but, first, the folk at the FDA had

 

  6   asked for one of us to do a recap of what we

 

  7   covered yesterday and Dr. David Danford, our

 

  8   resident cardiologist, has offered, under duress,

 

  9   to do that.

 

 10             [Laughter]

 

 11             So, why don't you go ahead?

 

 12                          Recap of Day 1

 

 13             DR. DANFORD:  Thank you, Dr. Chesney.  The

 

 14   subcommittee had quite a full day yesterday of

 

 15   excellent, very informative presentations on

 

 16   pediatric cardiac imaging and the agents currently

 

 17   in use to enhance that imaging.

 

 18             FDA began by identifying four classes of

 

 19   these injectables, including gadolinium agents for

 

 20   cardiac MRI, radiopharmaceuticals for evaluation of

 

 21   myocardial function and perfusion, microsphere

 

 22   contrast for echocardiographic image enhancement,

 

 23   and iodinated contrast for angiography and CT.

 

 24             With the exception of the iodinated

 

 25   contrast, which is labeled for angiographic use in

 

                                                                 5

 

  1   children as young as one year of age, all pediatric

 

  2   cardiac use of these agents is currently off-label.

 

  3   Desiring to obtain information about these agents

 

  4   that would allow labeling for pediatric use, FDA

 

  5   assembled speakers to address, one, what pediatric

 

  6   subpopulations receive these agents; two, what

 

  7   diagnostic purposes are being served; three, how

 

  8   the imaging data affects patient management; and,

 

  9   four, what additional labeling is needed.

 

 10             From this, it was hoped that we could

 

 11   determine what, if any, pediatric labeling

 

 12   information could be extrapolated from the adult

 

 13   experience and what research studies should be

 

 14   designed to obtain the data required for

 

 15   responsible pediatric labeling.

 

 16             Dr. Geva introduced the concept that there

 

 17   are huge numbers of patients living with congenital

 

 18   heart disease in the United States that are

 

 19   surviving longer, and frequently they have residual

 

 20   anatomic and functional cardiovascular impairments

 

 21   and may have a lifelong need for medical

 

 22   surveillance that includes cardiac imaging.

 

 23             We repeatedly heard from multiple

 

 24   presenters that unenhanced standard, regular old

 

 25   echocardiography was the imaging modality of first

 

                                                                 6

 

  1   choice for most of these patients.  It accounts for

 

  2   more procedures than MRI, cath, CT and nuclear

 

  3   studies combined.  Its shortcomings are poor

 

  4   diagnostic quality in certain subgroups of

 

  5   patients, like older and bigger patients, those

 

  6   with chest wall deformities or prior cardiac

 

  7   surgeries, those with pulmonary disease and those

 

  8   in whom the primary focus of diagnostic interest is

 

  9   outside the heart, for example, aortic arch,

 

 10   pulmonary artery branches, systemic or pulmonary

 

 11   veins.  Unenhanced echo is also suboptimal when the

 

 12   diagnostic question is one of coronary perfusion.

 

 13             So, when standard echo fails to provide

 

 14   the diagnostic information required for management

 

 15   of heart disease one of the other imaging

 

 16   modalities is selected.  MRI is one of those

 

 17   modalities, and we heard from Dr. Fogel that

 

 18   gadolinium contrast is injected in the large

 

 19   majority of pediatric cardiac MRI examinations.

 

 20   MRI often provides images superior to echo for

 

 21   aortic arch and its branches, pulmonary arteries

 

 22   and veins and the systemic veins, and it can also

 

 23   provide information on myocardial perfusion and

 

 24   tissue characterization.

 

 25             The anatomic MRI data is suitable for

 

                                                                 7

 

  1   processing into 3D reconstructions that are

 

  2   aesthetically impressive and highly clinically

 

  3   relevant for the guidance of surgeons and

 

  4   interventional cardiologists as they plan

 

  5   treatment.  MRIs applications are limited by

 

  6   artifact when objects made of certain metals are in

 

  7   the field of interest.

 

  8             There was support in our discussions for

 

  9   investigations to define the appropriate pediatric

 

 10   gadolinium dose, its safety in children with heart

 

 11   disease and the diagnostic accuracy in pediatric

 

 12   cardiac applications.

 

 13             Like MRI, cardiac CT is also superior to

 

 14   standard echo for imaging of extracardiac large

 

 15   vessel abnormalities like aortic aneurysm, double

 

 16   aortic arch and other vascular rings, pulmonary

 

 17   artery sling, pulmonary branch stenosis, aortic

 

 18   coarctation and pulmonary systemic venous

 

 19   anomalies.

 

 20             Nonionic iodinated contrast is used in

 

 21   essentially all pediatric cardiac CT exams.  It has

 

 22   a long record of safe use in children and is

 

 23   approved for angiography in patients as young as

 

 24   one year old.  The subcommittee heard concern,

 

 25   however, about radiation exposure from CT imaging

 

                                                                 8

 

  1   and struggled with the issue of separating the

 

  2   risks of the contrast agent from the risks of X-ray

 

  3   exposure.

 

  4             Like CT, cardiac catheterization with

 

  5   angiography utilizes nonionic iodinated contrast

 

  6   material and X-rays.  It has broad diagnostic

 

  7   applicability in a wide range of conditions,

 

  8   including both intracardiac and extracardiac

 

  9   anomalies, and is increasingly performed as a means

 

 10   to treat the condition by means of balloon

 

 11   valvuloplasty or angioplasty, stent placement, the

 

 12   creation of holes where they are physiologically

 

 13   advantageous and the closing of holes where they

 

 14   are not.

 

 15             The diagnostic information obtained with

 

 16   angiocardiography is, therefore, often with

 

 17   immediate application to therapeutic intervention.

 

 18   Even in the shrinking minority of such procedures

 

 19   now done for purely diagnostic purposes the

 

 20   anatomic details provided angiographically often

 

 21   guide surgical treatment.

 

 22             One speaker suggested that there were few,

 

 23   if any, pediatric labeling issues remaining about

 

 24   the use of iodinated contrast material in the

 

 25   cardiac cath lab, but another suggested that we

 

                                                                 9

 

  1   actually lack information about the true maximum

 

  2   safe dose and in some complex cases in the cath lab

 

  3   we enforce an artificial maximum, resulting in

 

  4   deferred angiography and return to the cath lab for

 

  5   second procedures that might not be in the

 

  6   patient's interest if it were established that

 

  7   greater volumes of contrast could safely be

 

  8   administered in a single sitting.

 

  9             We heard that nuclear cardiac imaging

 

 10   differs from the modalities we have discussed so

 

 11   far, and its focus is not on anatomy but on

 

 12   function, blood flow and myocardial perfusion.  Not

 

 13   surprisingly, its applications in the

 

 14   cardiomyopathic processes and abnormalities of

 

 15   pulmonary blood flow and coronary arterial

 

 16   perfusion were emphasized.  The use of radioactive

 

 17   pharmaceuticals to obtain this information is

 

 18   associated with radiation exposure to the patient.

 

 19             While there was support for studies to

 

 20   determine the pediatric safety and appropriate

 

 21   pediatric dosing, concerns were raised that NIH

 

 22   guidelines for radiation exposure in pediatric

 

 23   research subjects may be an impediment.

 

 24             Contrast echocardiography employs

 

 25   encapsulated air or other gas bubbles to enhance

 

                                                                10

 

  1   endocardial edge detection by harmonic ultrasound

 

  2   imaging.  This adds information on myocardial

 

  3   function and perfusion to the cardiac anatomic and

 

  4   Doppler blood flow diagnostic information that is

 

  5   generally available on standard echo.

 

  6             The potential for pediatric application or

 

  7   contrast echocardiography is currently largely

 

  8   unrealized as most pediatric centers do not provide

 

  9   routine contrast echo services.  Nevertheless,

 

 10   there was interest in obtaining pediatric safety

 

 11   and efficacy data for these contrast agents as some

 

 12   experts would estimate that as many as five percent

 

 13   of all patients having pediatric echocardiography

 

 14   would benefit from the clinical information about

 

 15   myocardial perfusion and ventricular function that

 

 16   contrast provides.

 

 17             Finally, representatives of a number of

 

 18   national professional organizations, including the

 

 19   American Academy of Pediatrics, the American

 

 20   Society of Echocardiography, American Society of

 

 21   Nuclear Cardiology, Society of Nuclear Medicine and

 

 22   a representative of one pharmaceutical company all

 

 23   spoke in strong support of FDA's initiatives to

 

 24   promote responsible pediatric use of these agents

 

 25   through labeling.

 

                                                                11

 

  1             DR. CHESNEY:  Thank you very much.  That

 

  2   was excellent.  We should have asked you for copies

 

  3   last night.

 

  4             DR. DANFORD:  I wasn't ready last night.

 

  5             DR. CHESNEY:  Thank you.  I did have one

 

  6   announcement to make.  Dr. Hari Sachs had asked me

 

  7   to tell you that on March 29-30 the FDA and NIH are

 

  8   jointly sponsoring a neonatal workshop, in

 

  9   Baltimore, which will cover pain, pulmonary,

 

 10   neurologic and cardiac issues, and there is more

 

 11   information available on the web site for anybody

 

 12   who is interested--and ethics.

 

 13             Dr. Loewke, would you like to get us

 

 14   started on the job at hand?

 

 15             Discussion of Questions to the Committee

 

 16             DR. LOEWKE:  Good morning.  I just wanted

 

 17   to clarify a couple of points and maybe run through

 

 18   an example that might help the discussion for

 

 19   later, so bear with me here.  Let me find my

 

 20   slides.

 

 21             [Slide]

 

 22             I wanted to talk a little bit about

 

 23   extrapolation.  The agency has commented that when

 

 24   there is potential to use adult efficacy data and

 

 25   extrapolate that to the pediatric population--I

 

                                                                12

 

  1   just wanted to clarify that we would fully intend

 

  2   to do PK parameters, PK studies and safety studies

 

  3   in the pediatric population.  So, the question that

 

  4   is posed to the panel today is whether or not there

 

  5   is any case in which we can extrapolate efficacy

 

  6   data to children so we wouldn't have to do large

 

  7   efficacy trials in the pediatric population.

 

  8             [Slide]

 

  9             I don't want to beat a horse to death but

 

 10   I wanted to just throw these back up so we can see

 

 11   what really is approved in the pediatric

 

 12   population, and reiterate that everything that

 

 13   really was talked about yesterday, most of it is

 

 14   being used off-label in the pediatric population.

 

 15             What I really wanted to focus our

 

 16   discussion on is what products are currently being

 

 17   used in a large enough population that additional

 

 18   drug labeling would make a considerable health

 

 19   benefit and make efficacy trials feasible.

 

 20             I just wanted to walk through an example.

 

 21   I hope it might help.  Dr. Fogel talked about

 

 22   gadolinium yesterday and he had identified that MR

 

 23   angiography is performed in patients with

 

 24   congenital heart disease to look at vascular

 

 25   anatomy.  So, I am thinking that obviously there is

 

                                                                13

 

  1   benefit in this particular area to study the

 

  2   gadolinium product.  The question is that first we

 

  3   need to identify which patient populations.  I

 

  4   assume you are looking at things such as anomalous

 

  5   vessels, aneurysms, coarctations, etc. that you

 

  6   pointed out.  So, what are the relevant

 

  7   populations?  We just need to identify what

 

  8   specific groups of patients we want to look at

 

  9   anatomy for.

 

 10             Within that population, are all the

 

 11   abnormalities considered equal?  I don't mean from

 

 12   a clinical standpoint but I mean from an imaging

 

 13   standpoint.  Could you do a general angiography

 

 14   exam with gadolinium and see all of these different

 

 15   types of abnormalities, or would you have to change

 

 16   your procedure or modify your procedure for any

 

 17   particular one?  If that is the case, we would tend

 

 18   to probably exclude that.  We want to try to get a

 

 19   homogeneous group of patients in which all those

 

 20   types of anomalies or abnormalities of vasculature

 

 21   you want to look at would be captured in a standard

 

 22   MRI angiography.  I don't know if it is possible; I

 

 23   am just throwing it out there.

 

 24             Then, we would need to identify whether

 

 25   just knowing vascular abnormality--do you find that

 

                                                                14

 

  1   clinically useful?  Do we have to prove that that

 

  2   is clinically useful?  If we have to prove that,

 

  3   how would we go about proving that as part of the

 

  4   clinical trial?

 

  5             Then, how do we validate the findings on

 

  6   the MR angiography?  I was thinking last night

 

  7   maybe many of these patients go on to

 

  8   interventional angiography.  Maybe we could use the

 

  9   findings of that procedure to confirm the

 

 10   abnormality seen on MR.  Maybe many of these

 

 11   patients go on to surgery and we could use surgical

 

 12   findings to confirm the abnormalities picked up by

 

 13   MR.

 

 14             That is just sort of an example of how we

 

 15   are trying to work through these and the types of

 

 16   information we are trying to get so we can try to

 

 17   figure out where to go.

 

 18             DR. CHESNEY:  Just before you sit down,

 

 19   could I ask the committee and our consultants

 

 20   whether you have questions for Dr. Loewke as to

 

 21   exactly what they are looking for?  Yes, Dr.

 

 22   D'Agostino and then Dr. Fogel.

 

 23             DR. D'AGOSTINO:  If you break down every

 

 24   possibility we could go on forever.  Are you

 

 25   looking for some sort of general type of indication

 

                                                                15

 

  1   so that then there is sort of a guideline or

 

  2   response to these questions that sort of gives some

 

  3   input on how one would go about putting the trial

 

  4   together?  I am just concerned that the

 

  5   specifications, you know, can get very, very

 

  6   detailed.  When you were saying can you lump these

 

  7   together, there were some people on this side of

 

  8   the table shaking their heads, no, you can't.  So,

 

  9   does that mean that for each possible condition

 

 10   there is another trial, or are you just looking for

 

 11   some sort of generalities in terms of how you could

 

 12   give guidance to industry and the FDA and some

 

 13   sense from the advisory committee?

 

 14             DR. LOEWKE:  We are trying to capture what

 

 15   information and what populations are large enough

 

 16   that we can pursue efficacy trials that would give

 

 17   benefit to the pediatric population.  If we can't

 

 18   lump patients, then we have a problem.

 

 19             DR. D'AGOSTINO:  Right.

 

 20             DR. LOEWKE:  But I needed to hear from the

 

 21   panel what they think we can or cannot do, given

 

 22   their experience.

 

 23             DR. D'AGOSTINO:  I went through this with

 

 24   the FDA in terms of pain models and we ended up, in

 

 25   terms of analgesics, laying out a tremendous number

 

                                                                16

 

  1   of pain models, and what-have-you.  In the end we

 

  2   just said we can't fill page upon page upon page

 

  3   but there are some general principles, and I am

 

  4   gathering that that is where you are heading, that

 

  5   there are specifics but there are still general

 

  6   principles that would lead from one condition to

 

  7   another so that we could give you decent input to

 

  8   putting trials together.

 

  9             DR. LOEWKE:  From the talks yesterday,

 

 10   generally a role that I was seeing is that we are

 

 11   largely doing these studies to do anatomy.  CT does

 

 12   that; MR does that.  There are reasons to do

 

 13   perfusion studies in kids.  So, knowing those

 

 14   global areas, now I just want to get a little more

 

 15   to what specific populations shall we be looking at

 

 16   because why are you doing these studies?  Then, how

 

 17   we should at least design the endpoints that would

 

 18   have clinical value to the community?  Then we can

 

 19   go from there.

 

 20             DR. D'AGOSTINO:  We do a lot these--the

 

 21   Framingham study, and we find oftentimes that you

 

 22   find calcium or something like that and you get all

 

 23   upset about it.  To produce a better image of that

 

 24   that  we don't know what to do with, or anything

 

 25   like that, isn't very helpful.  So, when you say is

 

                                                                17

 

  1   it clinically useful, then does that mean that we

 

  2   have to be able to identify in the protocol that it

 

  3   actually has a clinically meaningful condition that

 

  4   is tied into it?  Or, is it just an enhancement of

 

  5   the image that we may not know anything about?

 

  6             DR. LOEWKE:  Well, that is what we are

 

  7   trying to get at.

 

  8             DR. D'AGOSTINO:  Right.

 

  9             DR. LOEWKE:  We don't just want

 

 10   enhancement.  If it doesn't mean anything and isn't

 

 11   useful to the practicing community, then that is

 

 12   not the endpoint--

 

 13             DR. D'AGOSTINO:  So, we need a standard

 

 14   beyond just the image.

 

 15             DR. LOEWKE:  Right.

 

 16             DR. D'AGOSTINO:  Thank you.

 

 17             DR. CHESNEY:  I have Dr. Fogel, Dr. Geva,

 

 18   Dr. Fink and Dr. Fost.

 

 19             DR. FOGEL:  I wanted to step back for just

 

 20   a minute.  Yesterday we got a lot of speakers

 

 21   together and we heard all sorts of wonderful talks

 

 22   about how we use contrast agents and how we might

 

 23   eventually design efficacy and safety trials in

 

 24   children to prove that that, indeed, is efficacious

 

 25   and safe in children and adds clinical benefit and

 

                                                                18

 

  1   value to their medical care.

 

  2             I guess I want to step back for one

 

  3   second.  I guess this was bothering me last night

 

  4   and this morning, that is, a number of people

 

  5   brought up the notion that a number of these agents

 

  6   are off-patent.  We could sit here all morning and

 

  7   talk about what wonderful trials we would design

 

  8   and how we would do it but, from a practical

 

  9   standpoint, how will the FDA approach, once we do

 

 10   give recommendations--how will the FDA approach

 

 11   getting the trials done?  I mean, is there some

 

 12   sort of carrot that you guys think you are going to

 

 13   stick in front of the pharmaceutical industry, as

 

 14   you did with the pediatric exclusivity rule, that

 

 15   would be able to accomplish this?  Or, is this

 

 16   really more an academic discussion?

 

 17             DR. CUMMINS:  This is not just an academic

 

 18   discussion.  I want to reassure all of you of that.

 

 19   I spent most of my time yesterday talking about the

 

 20   on-patent process.  There is an off-patent process

 

 21   as well.  That off-patent process is done in

 

 22   collaboration with the National Institutes of

 

 23   Health.  It is specified in the Best

 

 24   Pharmaceuticals for Children Act.

 

 25   Annually--actually it has been a couple of times a

 

                                                                19

 

  1   year, the NIH lists in the Federal Register drugs

 

  2   that are high priority for study and the FDA

 

  3   develops a written request for those high priority

 

  4   drugs and issues them to industry.  If industry

 

  5   does not want to conduct the studies, then those

 

  6   off-patent written requests are referred to the NIH

 

  7   and the NIH then translates them into request for

 

  8   proposals and they are awarded for study.

 

  9             We have been doing this now for about 18

 

 10   months.  We have a process in place.  A couple of

 

 11   contracts have actually been awarded.  There is a

 

 12   coordinating center that is coordinating all these

 

 13   studies and there is definitely a mechanism for

 

 14   translating the recommendations that we get from

 

 15   you all into studies for off-patent products.

 

 16             DR. FOGEL:  That is great.  I must have

 

 17   missed that yesterday.  Thank you.

 

 18             DR. CUMMINS:  Well, I don't think I

 

 19   explained it enough so rest assured.

 

 20             DR. CHESNEY:  Could we ask you--we were

 

 21   discussing this in the van this morning--does the

 

 22   NIH have money to do these studies, or do they go

 

 23   in a list and maybe the top one is funded and the

 

 24   other hundred aren't?

 

 25             DR. CUMMINS:  Without being responsible

 

                                                                20

 

  1   for spelling out the NIH process in detail, yes,

 

  2   they have funding to do these studies.  These

 

  3   studies are not funded through the NIH Foundation;

 

  4   they are funded through the NIH budget.

 

  5             DR. D. MURPHY:  They have some funding,

 

  6   yes.  You know, Congress suggested that they have

 

  7   200 million dollars for this and then appropriated

 

  8   none.  So, the issue is that the institutes are now

 

  9   each having to find this money, and they have.

 

 10   But, you are right, there clearly are limitations

 

 11   and you will have to march through the priority

 

 12   list.

 

 13             DR. CHESNEY:  Thank you, Dr. Murphy.  Dr.

 

 14   Geva, Dr. Fink, Dr. Fost and Dr. Nelson.

 

 15             DR. GEVA:  I wanted to ask a question.

 

 16   What are the advantages or what is the incentive

 

 17   to, let's say, get gadolinium for pediatric

 

 18   cardiology applications approved by the FDA?

 

 19             DR. CUMMINS:  The approval would allow for

 

 20   labeling of a product in the pediatric population

 

 21   so it would give us data on efficacy, on dosing and

 

 22   on safety that we could then put into the label.

 

 23   Currently, as you all acknowledged, we don't have

 

 24   that information in the label.  The products are

 

 25   all being used off-label.

 

                                                                21

 

  1             DR. GEVA:  Perhaps if I may, to just

 

  2   answer some of the questions that were asked

 

  3   earlier about the patient populations and specific

 

  4   diagnoses--to answer your specific question, I

 

  5   would think that what you are looking at is

 

  6   essentially the entire population of patients with

 

  7   congenital heart disease as far as designing these

 

  8   studies.  I don't think that it makes a lot of

 

  9   sense, at least early in the process, to break it

 

 10   down to very specific diagnoses.

 

 11             I can tell you that of the patients who

 

 12   come for an MRI examination, as Dr. Fogel mentioned

 

 13   yesterday and that is the experience in our center

 

 14   as well, the majority get gadolinium MRI studies.

 

 15   So, to start breaking it down into specific

 

 16   diagnoses you would probably be doing yourself a

 

 17   disservice.  Now, there are a number of ways by

 

 18   which you can address the issue of efficacy and

 

 19   that would be a fascinating academic discussion.

 

 20             DR. CHESNEY:  Thank you.  Before we get

 

 21   down to that issue, I think Dr. Fink had a question

 

 22   and Dr. Nelson had a question.

 

 23             DR. FINK:  I guess mine actually coincides

 

 24   with what Dr. Geva was saying.  I don't really

 

 25   think that you can measure efficacy for these

 

                                                                22

 

  1   agents and what we really need is safety and PK/PD

 

  2   data for their usage in children because what I

 

  3   heard yesterday is that there are differences in

 

  4   technology, and which agent is most effective may

 

  5   depend on how many tesla your MRI scanner has; the

 

  6   experience of the operator; whether the

 

  7   cardiologist prefers MRI or CT after they have done

 

  8   the echo.  And, the effectiveness we are really

 

  9   looking at may depend on the thoracic surgeon or

 

 10   the skill of the interventional cardiologist and

 

 11   these are really agents for helping to just do the

 

 12   image.  So, I think efficacy for these agents

 

 13   really is the imaging and what we primarily want in

 

 14   pediatrics is safety and PK/PD data.

 

 15             DR. LOEWKE:  We need to give the user

 

 16   information about the performance of these agents,

 

 17   and we look at the image and we compare it to a

 

 18   standard of truth to show them how it performs to

 

 19   what may be currently used.  It gives them a sense

 

 20   of how this performs; do they want to use this in

 

 21   place of something else.  So, there is value and it

 

 22   is very important to look at the efficacy of these

 

 23   products.

 

 24             DR. FINK:  I didn't hear a whole lot of

 

 25   discussion yesterday about different agents that

 

                                                                23

 

  1   are used or what we are comparing it to.  It seemed

 

  2   like for MR it was pretty much gadolinium and that

 

  3   there wasn't a lot of variation in agents.

 

  4             DR. LOEWKE:  I am not sure I understand

 

  5   your question.

 

  6             DR. FINK:  For efficacy are you looking at

 

  7   the various efficacies of the different gadolinium

 

  8   agents or variation between, let's say MR versus

 

  9   CT?

 

 10             DR. LOEWKE:  No, you are looking at the

 

 11   particular MR agent and you are comparing it to

 

 12   what--depending on what we define as a standard of

 

 13   truth, whether it be a comparator agent that is

 

 14   already approved for the indication or whether it

 

 15   is a standard of truth such as conventional

 

 16   angiography that is currently a gold standard for

 

 17   use in the cardiac population today.  So, it gives

 

 18   the user a sense of where this falls into their

 

 19   arsenal, and how to use it, and how to rely on the

 

 20   information that they get from it.

 

 21             DR. FINK:  But it would seem that that is

 

 22   primarily machine driven.  A 3 tesla coil is better

 

 23   than a 1.5 tesla coil, or a 16 detector CT is

 

 24   better than a 4 detector CT.  It would seem like

 

 25   the technology available has a far greater impact

 

                                                                24

 

  1   than potentially these agents.

 

  2             DR. LOEWKE:  I think we heard yesterday

 

  3   that it is a combination of both the agent, the

 

  4   drug and the user too.  It is a combination.  We

 

  5   try to put factors in place to accommodate for some

 

  6   of those issues when we design a trial.

 

  7             DR. CHESNEY:  Dr. Nelson?

 

  8             DR. NELSON:  I guess I have a question and

 

  9   a comment.  I just want to make sure I know which

 

 10   are on-patent and off-patent so as we are

 

 11   discussing the issue I have a sense of the public

 

 12   health impact for the feasibility of doing the

 

 13   trials.  I guess since Bristol-Myers Squibb likely

 

 14   is the one who put in those two, I am inferring

 

 15   from the fact that they presented on nuclear

 

 16   imaging that, in fact, the nuclear imaging products

 

 17   are on-patent.  I am assuming most of the

 

 18   gadolinium products, unless there is some fancy one

 

 19   in the wings, are off-patent.  The nonionic

 

 20   contrast is probably off-patent but the fancy

 

 21   echocardiography bubbles are likely on-patent

 

 22   because that is new.  Have I gotten that right?  I

 

 23   am just trying to understand which are on- and

 

 24   off-patent as we are discussing these different

 

 25   modalities.

 

                                                                25

 

  1             DR. CUMMINS:  Whether or not a drug is on

 

  2   patent is actually more complicated than one might

 

  3   imagine, and I would encourage you to put aside the

 

  4   patent status of any product and focus on the

 

  5   product.  We really need your scientific advice.

 

  6   Then we can think about how that fits into the

 

  7   whole on-patent/off-patent process.

 

  8             DR. NELSON:  So be it.  Let me then

 

  9   continue.  I am still unclear about the issue of

 

 10   extrapolation and trying to separate out in terms

 

 11   of properties of the agent and the resolution of

 

 12   the imaging versus application to the population.

 

 13   Part of this, in my mind, then translates to how

 

 14   you would try to design a trial.  For example, when

 

 15   I listened to the echocardiography presentation and

 

 16   looked at the slides, it sounds like that one of

 

 17   the issues is the ability to differentiate a

 

 18   tissue-liquid interface and the relationship

 

 19   between the resonance of the bubbles and the

 

 20   harmonics of the machine in relationship to the

 

 21   harmonics of the tissue and the harmonics of the

 

 22   liquid--so, a very complex interaction.  If you

 

 23   said that what you need to see a good image is a

 

 24   resolution better than--I think you mentioned 1 mm

 

 25   or 2 mm, 1-2 mm, the question then is under what

 

                                                                26

 

  1   circumstances can you demonstrate that you have a

 

  2   product that gives you that 1-2 mm resolution

 

  3   assuming all other factors remain constant as far

 

  4   as tissue harmonics and liquid harmonics.

 

  5             So, if I was looking at a protocol and

 

  6   asking do you need to do that in a neonate to

 

  7   answer that question, you know, can you demonstrate

 

  8   a 1 mm resolution, my question would then be are

 

  9   all other factors equal apart from the properties

 

 10   of the agent itself?  That would be the question

 

 11   and then you would have to tell me what are the

 

 12   harmonics of the adult tissue of the heart.  I

 

 13   would then say, well okay, if it is the same use

 

 14   adults; if it is not use kids.  So, that is the

 

 15   kind of technical question I would ask in

 

 16   evaluating a protocol.

 

 17             If then you said, okay, we have an agent

 

 18   that has demonstrated 1-2 mm resolution, do we then

 

 19   take it to a pediatric population and try and show

 

 20   that we can find clinically useful information?

 

 21   That then goes to the next step and I think it goes

 

 22   to trying to sort out what is the nature of the

 

 23   kinds of questions that we need to ask.

 

 24             I must confess, you know, I understand an

 

 25   image.  If anybody in the audience is in art

 

                                                                27

 

  1   history or art appreciation, I mean imaging is--but

 

  2   it is unclear to me--if you took the gadolinium MRI

 

  3   scans, if you see a double arch you are going to

 

  4   see a double arch and I am not sure you need to

 

  5   know 1 mm resolution to see a double arch.  So,

 

  6   some of the questions are going to vary depending

 

  7   upon the modality.  It sounds to me, from what I

 

  8   saw, I confess it looked like most of the complex

 

  9   questions are in the nuclear and the echo where

 

 10   there are still a lot of unanswered questions,

 

 11   whereas in the CT and the MRI it was more a

 

 12   question of extracardiac use of it for imaging of

 

 13   vessels that you can't see in the other modalities,

 

 14   putting function aside.

 

 15             So, I think, you know, as we go through

 

 16   these--I mean, all the questions break down each

 

 17   particular imaging modality so it is not only

 

 18   population but it is what do we really need to see

 

 19   via CT, via MRI versus imaging and the like.  So, I

 

 20   think separating out those questions is important

 

 21   and that is why when I think about PK and safety

 

 22   data I also consider the basic properties of the

 

 23   agent, independent of whether or not you are using

 

 24   it to find clinically useful information.

 

 25             I don't know if that helps.  You know, can

 

                                                                28

 

  1   you extrapolate?  If all you need to do is see a 1

 

  2   mm vessel, find a 1 mm vessel in an adult

 

  3   basically, if that is all you need to see.  You

 

  4   don't use kids until you have to use kids.

 

  5             DR. CHESNEY:  Lots of hands and lots of

 

  6   lists here but, Dr. Siegel, do you have a specific

 

  7   response to his comment?

 

  8             DR. SIEGEL:  To three of the comments.

 

  9   First on the patient population for each

 

 10   examination, I think the patient population is

 

 11   really more than complex heart disease.  There are

 

 12   several things that have been brought up here.

 

 13   One, the extracardiac or the vascular lesions; two,

 

 14   valvular lesions; three, simple septal lesions;

 

 15   and, four, complex heart disease.  So, if we are

 

 16   looking at that, and that does bring up the point

 

 17   of, as you said, if we see a vascular lesions how

 

 18   sophisticated do we need to get?  We have seen it

 

 19   and that is the end of the imaging.  So, looking at

 

 20   the patient population we need to sort of deal with

 

 21   those areas, where each of these exams fits in and

 

 22   do we need more to confirm it or do we stop at a

 

 23   certain point.

 

 24             I think the other confusion in my

 

 25   mind--there are two things.  There is endpoint and

 

                                                                29

 

  1   gold standard.  I think maybe we are overlapping

 

  2   them.  The endpoint would be a clinical outcome.

 

  3   If we were doing antibiotics, you know, does the

 

  4   patient get better?  An endpoint here is a little

 

  5   bit more difficult to define.  But if you look at

 

  6   it clinically, there are I think at least two

 

  7   endpoints.  If somebody has a widened mediastinum,

 

  8   whether it is on a CT or MR to look at the arch,

 

  9   and we find something and we can say what is the

 

 10   clinical usefulness?  The clinical usefulness there

 

 11   terminates further imaging studies.  We are not

 

 12   going to have a correlate on that.  So, in some

 

 13   cases the clinical usefulness is that it terminates

 

 14   additional imaging studies or diagnostic workup.

 

 15   In other instances it is going to lead to further

 

 16   evaluation or treatment.  So, if we do a study and

 

 17   you see a septal lesion, it is perhaps going to

 

 18   lead to echo or catheterization.

 

 19             So, to me, the two clinical endpoints, at

 

 20   least in a simplistic world, would be termination

 

 21   of additional studies and end of the workup or if

 

 22   we need further workup.  That is a clinical

 

 23   outcome.

 

 24             Gold standard then is if we wanted to

 

 25   confirm a lesion that needed further workup, how do

 

                                                                30

 

  1   we do it?  Again, it is going to depend on the

 

  2   modality.  If I am doing CT, you know, probably

 

  3   echo is going to have to be my god standard if I

 

  4   wanted to do a study.  If this is an incidental

 

  5   pickup, it probably would go to echo but somebody

 

  6   might say do an MR.  I mean, that is going to be a

 

  7   little tougher.  If you design a study you could

 

  8   probably get very specific on what you wanted to do

 

  9   clinically after you find a lesion and it is up to

 

 10   us perhaps to suggest or up to a clinician to

 

 11   decide what they want.  But I think we are dealing

 

 12   with, you know, gold standard and endpoint here,

 

 13   and gold standard might vary for each study.

 

 14             DR. CHESNEY:  Thank you.  I have Dr.

 

 15   Dilsizian, Dr. Gorman, Dr. Geva and Dr. Fogel.

 

 16             DR. DILSIZIAN:  I guess I wanted to

 

 17   respond to Dr. Loewke's request.  There are two

 

 18   questions you asked.  One is extrapolation from

 

 19   adults to kids.  I think yesterday we all said

 

 20   adults and kids are different.  But, at the same

 

 21   time, I would like to emphasize that a lot of the

 

 22   things we use, let's say, in nuclear medicine

 

 23   perfusion imaging and function--the concept of flow

 

 24   and function can be extrapolated from adults to

 

 25   kids but what we need to do then is that at the end

 

                                                                31

 

  1   it would be wise to test these in adults because

 

  2   the dosimetry is much more favorable.  Once you

 

  3   have shown your efficacy and the accuracy in

 

  4   adults, now you can, in essence, apply this in kids

 

  5   but with the caveat that it has to be retested

 

  6   because their vessels may be small; the organs are

 

  7   smaller; the radiation exposure is now different.

 

  8   But I think that it is perfectly safe or wise, at

 

  9   least in my mind, to have it approved in adults at

 

 10   first and then accept it in kids but then repeat it

 

 11   in kids to see whether a difference exists or not.

 

 12             The reason I say that is because, for

 

 13   example in nuclear, as you know, perfusion and

 

 14   function has been approved by the FDA.  It is one

 

 15   of the few indications that has been done.  But we

 

 16   now are extrapolating use in kids but we haven't

 

 17   really tested in kids.  So, I think it would be

 

 18   wise, again, for echo bubbles or DTPA to do the

 

 19   same thing.  I think we have to first show efficacy

 

 20   in adults and then apply it in kids.  I know they

 

 21   are different but, given the safety issues, I think

 

 22   it is always wiser to test it in adults first.

 

 23             DR. CHESNEY:  Can I ask you how do you

 

 24   define efficacy?

 

 25             DR. DILSIZIAN:  There are two approaches. 

 

                                                                32

 

  1   For perfusion imaging one would say, in adults for

 

  2   example, I would like to detect coronary artery

 

  3   lesions so I can angioplasty that lesion or send

 

  4   the patient to surgery.  Therefore, we use

 

  5   traditionally coronary angiography as the gold

 

  6   standard and say can I non-invasively predict a

 

  7   perfusion defect which will then guide cath and

 

  8   angioplasty or surgery?

 

  9             We have learned, however, since then that

 

 10   there could be perfusion defects that are not

 

 11   necessarily anatomical.  There could be

 

 12   vasoconstriction or other physiological parameters

 

 13   of hypertrophic cardiomyopathy where we have no

 

 14   coronaries but the demand is different.  So,

 

 15   physiological information is not necessarily

 

 16   equivalent to anatomical information.

 

 17             So, the next question is how do I judge

 

 18   those patients?  I hope I made the case that in

 

 19   those patients you look at outcome--syncope, sudden

 

 20   cardiac arrest--to see whether identifying those

 

 21   patients and treating them or not treating them

 

 22   changes the outcome of that patient's symptoms.

 

 23   So, those are the two endpoints.  One is an

 

 24   anatomical correlate as a gold standard and the

 

 25   other one would be outcomes--syncope, sudden

 

                                                                33

 

  1   cardiac arrest or some other adverse events.

 

  2             DR. CHESNEY:  I think Dr. Siegel mentioned

 

  3   yesterday that accuracy is efficacy here, efficacy

 

  4   of diagnosis.  Next, Dr. Gorman and then Dr. Geva

 

  5   and Dr. Fogel.

 

  6             DR. GORMAN:  The question of gold standard

 

  7   is one that we didn't discuss much yesterday but

 

  8   the clinical definition I think has already started

 

  9   to be expressed and expounded here, which is that

 

 10   the clinical definition of a gold standard is if

 

 11   you stop intervening at that time and your clinical

 

 12   predictions come true, then you made a clinical

 

 13   diagnosis that was appropriate.  If you continued

 

 14   to intervene after you do a procedure of any of

 

 15   these sorts and the next procedure confirms your

 

 16   diagnosis, then it was again an efficacious

 

 17   procedure.  So, you then begin to have a moving

 

 18   gold standard target which is that for each of

 

 19   these many lesions that we could discuss there is a

 

 20   series of modalities that would help diagnose them.

 

 21             Clinically, there is a pediatric

 

 22   population that is enriched for cardiac lesions and

 

 23   everyone undergoes cardiac imaging and I would

 

 24   suggest them as a potential first place to start

 

 25   study design.  Every single one of those undergoes

 

                                                                34

 

  1   a cardiac imaging procedure I think in the United

 

  2   States for whether they have clinical findings or

 

  3   not.  They also have potential benefit.

 

  4             DR. CHESNEY:  Dr. Geva, Dr. Fogel and Dr.

 

  5   Sable.

 

  6             DR. GEVA:  To go back to the efficacy

 

  7   issue, I would like to expand on Dr. Siegel's

 

  8   comment and that is that there are at least two

 

  9   ways of defining efficacy in the context of this

 

 10   discussion.  One is diagnostic accuracy and it

 

 11   depends on the specific trial and the specific

 

 12   lesion or group of lesions that are being

 

 13   investigated.  One can choose an appropriate "gold

 

 14   standard" and that may be something that has been

 

 15   around for decades, such as angiography which is

 

 16   commonly accepted as the best that is currently

 

 17   available; surgical observations; a compilation of

 

 18   all available imaging tests--there are several ways

 

 19   of going about putting together a reference

 

 20   standard.  Not all of these are true gold standards

 

 21   but they have been around long enough and that is

 

 22   what is being used most commonly so if a new agent

 

 23   or a new technique is being proposed it is a common

 

 24   thing to test it against those.

 

 25             Then, a different approach to efficacy is

 

                                                                35

 

  1   to look at an outcome, clinical outcome with the

 

  2   use of a new diagnostic technique.  To give a

 

  3   specific example, currently all patients, let's

 

  4   say, who are candidates for a certain surgical

 

  5   procedure, let's say the Fontan operation,

 

  6   routinely undergo cardiac catheterization and one

 

  7   can design a study whereby instead of routine

 

  8   cardiac catheterization selected patients undergo

 

  9   non-invasive preoperative testing and that is an

 

 10   arm in a clinical trial.  Patients are randomized

 

 11   to standard invasive testing versus non-invasive

 

 12   testing.  Then one can look at set clinical

 

 13   outcomes--freedom from intervention, length of stay

 

 14   and so on and so forth.

 

 15             So, studies like that can certainly be

 

 16   designed.  Although you don't directly test the

 

 17   diagnostic accuracy of, let's say, gadolinium MRI,

 

 18   you are testing whether the use of gadolinium MRI

 

 19   can be used in order to achieve equivalent clinical

 

 20   outcome but with less cost, less risk for the

 

 21   patients, less radiation and so on.

 

 22             DR. CHESNEY:  Dr. Fogel, Dr. Sable and Dr.

 

 23   D'Agostino.

 

 24             DR. FOGEL:  Yes, I have a number of

 

 25   comments.  First going to the efficacy issue, I

 

                                                                36

 

  1   just wanted to say that I strongly support the

 

  2   notion that efficacy is a very important part of

 

  3   this entire discussion.  It goes towards the whole

 

  4   notion of, because we have seen a potpourri of

 

  5   diagnostic imaging modalities, obviously, if you

 

  6   have efficacy on the various imaging modalities in

 

  7   a given patient population or a given category of a

 

  8   patient population you can then compare the various

 

  9   diagnostic imaging modalities and say, well,

 

 10   imaging modality X is more efficacious than imaging

 

 11   modality Y in this particular instance and that

 

 12   would actually improve patient management and

 

 13   patient care in the sense that you would then have

 

 14   some real data to say, well, if this patient comes

 

 15   along with a certain likelihood the best clinical

 

 16   pathway for one to follow would be to get imaging

 

 17   modality X and then Y and then go on to

 

 18   intervention Z because we have shown that X is more

 

 19   efficacious than Y in this patient population.

 

 20             So, I think that that would be very

 

 21   useful.  It would improve patient safety because

 

 22   you wouldn't have to do sedation for an

 

 23   echocardiogram and then do sedation for an MRI; you

 

 24   could just do it once and then move on to the next

 

 25   diagnostic imaging modality or therapy.  So, I

 

                                                                37

 

  1   think that would be very important to do and I

 

  2   voice strong support for efficacy.

 

  3             In terms of efficacy being a clinical

 

  4   outcome, which I have heard a number of speakers

 

  5   talk about, we all have to recognize that imaging

 

  6   in an of itself, to use the clinical trial

 

  7   terminology, is really a surrogate, and it is a

 

  8   surrogate for something that is really true, which

 

  9   would be holding the heart in your hand and being

 

 10   able to see the whole heart, being able to

 

 11   miniaturize yourself down to a teeny little person

 

 12   and see that little coronary artery and walk

 

 13   through it.  But apart from that, it really is a

 

 14   surrogate.

 

 15             As such, with clinical outcome there is so

 

 16   much that--let me step back for one second.  The

 

 17   imaging itself is just one component of a

 

 18   multi-faceted thing that is going to happen to the

 

 19   patient.  There are all sorts of other imaging

 

 20   modalities that might occur, as well as

 

 21   interventions and postoperative care.

 

 22             So, although I guess you could design

 

 23   trials that would have imaging modalities and look

 

 24   at the clinical outcome, I would imagine you would

 

 25   need a lot of patients and it would be very noisy

 

                                                                38

 

  1   because there are so many other factors that go

 

  2   into a patient's clinical outcome other than the

 

  3   diagnostic imaging modality.  I think it would be

 

  4   very, very difficult in terms of being able to show

 

  5   efficacy in that particular way.  Now, if you want

 

  6   to do it against a gold standard, that would be

 

  7   surgical observation, unfortunately, sometimes

 

  8   pathologic observation.  That is totally different.

 

  9   But clinical outcome sounds like it would be pretty

 

 10   noisy data.

 

 11             Finally, the last thing I wanted to

 

 12   mention is the extrapolation issue of Dr. Nelson.

 

 13   I have to say that I don't really think you can

 

 14   extrapolate from adults to kids, as we all

 

 15   mentioned yesterday.  I don't think that if you

 

 16   have a 3 mm or 4 mm aorta in a child you can then

 

 17   say, well, can I see a 3 mm coronary artery in an

 

 18   adult?  Well, if I can see a 3 mm coronary artery

 

 19   in an adult, then I can certainly see a 3 mm aorta

 

 20   in a child.  That doesn't really work.  There are a

 

 21   lot of technical issues that go on in there--tissue

 

 22   attenuation, the size of the patient, how big a

 

 23   field of view you need to see the various

 

 24   structures--a lot of technical things go into the

 

 25   fact that I don't think you can really do a good

 

                                                                39

 

  1   extrapolation from adults into children and I would

 

  2   be very wary of doing that.

 

  3             DR. CHESNEY:  Dr. Sable and Dr.

 

  4   D'Agostino, and then I would be very interested in

 

  5   polling all our experts to see if they agree with

 

  6   you.  Let's do that right now, if you don't mind.

 

  7   Would you all agree that you can't extrapolate from

 

  8   adult data to children?  I think that was one of

 

  9   the big issues.

 

 10             DR. MOORE:  I would not agree.  I would

 

 11   say, just to focus on what I think the issue here

 

 12   of this subcommittee, whether additional labeling

 

 13   is required for some of these agents and labeling

 

 14   specific for pediatrics to make sure that these

 

 15   agents are safe and effective, I would argue a

 

 16   little bit along Dr. Nelson's lines that gadolinium

 

 17   and certainly iodinated contrast have a lot of data

 

 18   that is available both in adults and children in

 

 19   terms of their safety and efficacy in other areas

 

 20   in the body and in other modalities which can be

 

 21   translated over to cardiac imaging.  I would argue

 

 22   that the focus really needs to be on some of the

 

 23   newer agents and perhaps some of the

 

 24   radiopharmaceuticals and some of the echo contrast

 

 25   agents in terms of the specific issues with safety

 

                                                                40

 

  1   and efficacy.

 

  2             Just to speak to that point, you know the

 

  3   gold standard in many institutions nowadays for

 

  4   some of these cardiac lesions is no longer

 

  5   angiography; it is already considered gadolinium

 

  6   MRI or iodinated contrast CT.  So, to then go back

 

  7   and say we are going to evaluate efficacy in these

 

  8   agents that are already clinically being used in

 

  9   many areas of the country as the gold standard in

 

 10   these applications doesn't make a whole lot of

 

 11   sense to me, and I think we can extrapolate from a

 

 12   lot of the data that is already out there for some

 

 13   of these very experienced agents.

 

 14             DR. SIEGEL:  Well, I am going to go the

 

 15   opposite way.

 

 16             DR. CHESNEY:  Dr. Siegel?

 

 17             DR. SIEGEL:  I don't think we can

 

 18   extrapolate because of the various varying factors

 

 19   in children, which would be the smaller size; the

 

 20   faster heart rate; the inability to hold their

 

 21   breath; the motion.  I think that is going to make

 

 22   it harder to see or more difficult to see these

 

 23   smaller lesions.

 

 24             As far as just following up on another

 

 25   comment, I do agree that safety issues have been

 

                                                                41

 

  1   proven in the iodinated contrast media, but I am

 

  2   not sure about the efficacy because that has really

 

  3   not been shown in children.  I think we still have

 

  4   to prove that.

 

  5             DR. DILSIZIAN:  I actually go somewhere in

 

  6   between.

 

  7             [Laughter]

 

  8             And the answer is, as I said before, yes,

 

  9   you can extrapolate but do test again in the kids.

 

 10   The reason I disagree with the comments is that

 

 11   everything we have talked about, whether it is

 

 12   gadolinium, micro bubbles or perfusion, we tested

 

 13   in adults first and then we are testing it in kids.

 

 14   The knowledge base came from adults.  We

 

 15   extrapolate to the kids but we haven't really

 

 16   checked the efficacy in the kids, which has to be

 

 17   tested.  Yes, there is extrapolation but test again

 

 18   in the kids.

 

 19             DR. SABLE:  I think, as everyone seems to

 

 20   be agreeing, it is not a simple answer.  First of

 

 21   all, we can't come up with a blanket answer for our

 

 22   different modalities.  Just to use echo as an

 

 23   example, I think if you divide patients by weight

 

 24   or size above a certain age and weight there is

 

 25   probably reasonable utility to extrapolating for a

 

                                                                42

 

  1   given patient population.  For example, a 14-year

 

  2   old who had Kawasaki disease with a structurally

 

  3   normal heart would be a very reasonable population

 

  4   to study, very much based on extrapolating from

 

  5   adult data, although I think it should be done in

 

  6   children also.  Conversely, a 3-year old who had a

 

  7   transposition repair in whom we want to try to

 

  8   assess regional wall motion I think has a lot more

 

  9   unanswered questions.

 

 10             Just to kind of cover one other thing

 

 11   about gold standards versus other ways to design

 

 12   tests, I think a lot of us feel that MRI or

 

 13   contrast-enhanced CT may be a gold standard for

 

 14   some things, but the reality is that in most adult

 

 15   studies that I would pattern my pediatric studies

 

 16   after they are not using gold standards because it

 

 17   is much more difficult to design tests using a very

 

 18   subjective standard which is widely accepted as

 

 19   having a physician or a group of physicians look at

 

 20   different segments of the heart and saying I can

 

 21   see it well; a little bit; not at all, and asking

 

 22   the question does this modality improve my ability

 

 23   to see what I am trying to see.  Most tests are

 

 24   much more easily designed but clearly not as

 

 25   elegant as having a gold standard such as MRI or CT

 

                                                                43

 

  1   or the ultimate gold standard which would be

 

  2   surgical or pathology which we rarely have.

 

  3             DR. CHESNEY:  Dr. Geva, can we extrapolate

 

  4   from adults to children?

 

  5             DR. GEVA:  I agree with Craig that this is

 

  6   complex.  There is no blanket answer.  I would say

 

  7   with regard to the gadolinium MRI that it is age

 

  8   related and you can extrapolate a little bit to the

 

  9   adolescent and adult with congenital heart disease

 

 10   perhaps.  But when it comes to young children with

 

 11   small body size the answer is no.

 

 12             DR. CHESNEY:  Dr. Loewke, does that help

 

 13   with your question about whether we can extrapolate

 

 14   adult to pediatric data?

 

 15             DR. LOEWKE:  Yes, it does.  Thank you.

 

 16             DR. CHESNEY:  Yes, Dr. Fogel?

 

 17             DR. FOGEL:  Listening to all my colleagues

 

 18   talk, you know, I do agree that for children who

 

 19   are in the adolescent age group that are getting

 

 20   close to adulthood you could potentially

 

 21   extrapolate from adults to children.  But I guess,

 

 22   again using the terminology of surrogate, when you

 

 23   are talking about this you are really talking about

 

 24   using adult studies as surrogates for looking at

 

 25   childhood efficacy in these patients.  You know,

 

                                                                44

 

  1   using surrogates has all sorts of issues and

 

  2   problems.  I mean, the Fleming and Demetz article

 

  3   basically states that a whole lot, and I would

 

  4   still be very, very wary about doing that.

 

  5             But using gadolinium-enhanced MRI or CT as

 

  6   a gold standard, if you do it already why do more

 

  7   clinical trials?  I think what we are missing in

 

  8   the literature is rigorous, large-scale trials that

 

  9   look at this.  We have numerous reports with small

 

 10   numbers of patients that add up to a certain

 

 11   number--maybe add up to a mildly large number of

 

 12   patients but we don't have large-scale, rigorous

 

 13   clinical trials that look at it.  Then, there is

 

 14   anecdotal evidence but I think if we are going to

 

 15   serve our patients properly we need to have the

 

 16   data to then show them.

 

 17             DR. CHESNEY:  Dr. D'Agostino, did you have

 

 18   a comment?

 

 19             DR. D'AGOSTINO:  I wanted to comment on

 

 20   the trial design.  I am not sure, given what I have

 

 21   heard and what I know about these procedures, that

 

 22   clinical outcomes are necessarily a useful way,

 

 23   just to endorse what Mark was saying, because there

 

 24   are so many other things that go along with the

 

 25   actual decisions in terms of what medical practice

 

                                                                45

 

  1   is going to do beyond the imaging.

 

  2             The other comment is that I would have

 

  3   thought, again from what I know and what I have

 

  4   read, that a simple trial that you can do here is

 

  5   basically to have the individual go through this

 

  6   procedure with and without the imaging agent, or

 

  7   different levels of the imaging agent, and then ask

 

  8   the question does the higher level of the imaging

 

  9   agent somehow or other add more information to

 

 10   improve the clinical decision on that individual.

 

 11   It is a simple trial and the point is how do you

 

 12   decide on the clinical information.  You know, the

 

 13   sort of subjective way of having a panel do it, and

 

 14   so forth, blinded or unblinded, is a matter for

 

 15   discussion but I don't think we want to run to the

 

 16   notion of clinical outcomes, and I do think that

 

 17   the trial design doesn't have to be very

 

 18   complicated and we should try to avoid that.  But

 

 19   the outcome being clinically meaningful is a real

 

 20   trick, be it a gold standard or something else.

 

 21             DR. CHESNEY:  Dr. Sable, and then I think

 

 22   we will go on to question number two.

 

 23             DR. SABLE:  I want to add one more comment

 

 24   about extrapolation.  I think that it is

 

 25   important--and I am kind of biased--to

 

                                                                46

 

  1   differentiate what I do from what all of my

 

  2   colleagues do.  All of my colleagues are already

 

  3   using contrast in some percentage of the studies

 

  4   and that is probably the rule throughout the

 

  5   country.  Conversely, there are almost no pediatric

 

  6   echocardiographers using contrast and the idea of

 

  7   us using contrast, although I am obviously an

 

  8   advocate for it, is a much bigger leap.  For us to

 

  9   even think about using it in our clinical practice

 

 10   needs an incredible amount of push and support.

 

 11   So, even if you could extrapolate, if I have a

 

 12   17-year old who comes into my lab who has the exact

 

 13   same criteria as an adult and I want to do a

 

 14   contrast study, it is going to be a much bigger

 

 15   issue for me to do it.  But we do have patients

 

 16   that we would like to do in our lab.  So, the

 

 17   practicality of the issue is that even if you could

 

 18   extrapolate, the pediatric cardiac community needs

 

 19   additional enhancement to undertake contrast.

 

 20             I will just kind of end by using the

 

 21   example from Dr. Gardiner's talk yesterday.  A

 

 22   company that makes Definity and a nuclear medicine

 

 23   agent was very adamant that we think about using

 

 24   his agent for a population of maybe 4,000 studies a

 

 25   year but didn't even mention using one of his other

 

                                                                47

 

  1   agent for a population that has a million studies a

 

  2   year.  So, I think that just kind of brings home

 

  3   the point that there is just a huge gap between

 

  4   using contrast echo in the practical setting and

 

  5   using the other agents.

 

  6             DR. CHESNEY:  Dr. Siegel and then Dr.

 

  7   Santana.

 

  8             DR. SIEGEL:  Just one comment about the

 

  9   research possibilities, I think designing these

 

 10   trials in children is going to be difficult because

 

 11   you can't really use different concentration doses

 

 12   of drugs.  It would be very difficult to get it

 

 13   through an IRB and you certainly can't do it in the

 

 14   same patients.  You would have a very mixed patient

 

 15   population.

 

 16             One of the issues we haven't addressed is,

 

 17   you know, do we need to get down to the level of

 

 18   doing animal research and really getting back to

 

 19   basics?  It is the only way I think we will be able

 

 20   to look at different doses versus enhancement and

 

 21   different flow rates, if that is important to you,

 

 22   versus enhancement, and I don't think we will be

 

 23   able to do that on a pediatric population.  Adults,

 

 24   yes, probably but not in children.

 

 25             DR. CHESNEY:  Thank you.  Dr. Santana and

 

                                                                48

 

  1   then we will see if we can start--

 

  2             DR. D'AGOSTINO:  Can I make a comment?

 

  3             DR. CHESNEY:  Yes.

 

  4             DR. D'AGOSTINO:  When I was talking about

 

  5   the trial I was saying a simple trial but I didn't

 

  6   say it would be simple to do.

 

  7             [Laughter]

 

  8             It is a different matter altogether in

 

  9   terms of can you operate it.  But the design of

 

 10   running to a clinical outcome and so forth I think

 

 11   is a much harder to thing to do and probably has

 

 12   tremendously difficult interpretation problems.

 

 13             DR. SIEGEL:  I think we are proving this

 

 14   whole thing is going to be difficult to do.

 

 15             DR. CHESNEY:  Dr. Santana first and then

 

 16   Dr. Loewke.

 

 17             DR. SANTANA:  Having experienced sitting

 

 18   through pediatric oncology committee meetings at

 

 19   two separate meetings where we discussed the issue

 

 20   of extrapolation of adult oncology data to

 

 21   pediatrics, I have learned two lessons that I think

 

 22   may be relevant to this discussion.  The first is

 

 23   that although I think in general we agree that it

 

 24   is not wise to extrapolate adult data directly into

 

 25   pediatrics because there may be different disease

 

                                                                49

 

  1   processes; there may be different issues of

 

  2   tolerance; and ultimately there are differences in

 

  3   functionality, PK, organ maturity, when forced to

 

  4   think about this issue, the pediatric oncology

 

  5   committee did come up with a few examples in which

 

  6   we were able to fulfill the criteria that the

 

  7   disease process was similar enough that it was not

 

  8   ethical to do efficacy trials in children, and we

 

  9   should put our resources in doing the type of PK

 

 10   safety studies that are more relevant.

 

 11             So, the challenge I think for my

 

 12   colleagues--although we all like to say that in

 

 13   general terms we should not extrapolate, the

 

 14   challenge is to come up with examples in which you

 

 15   can extrapolate and that will save us time, effort

 

 16   and safety for our patients so that then we can do

 

 17   those studies more wisely and capture that data

 

 18   quickly and get more information out to consumers

 

 19   and practitioners.

 

 20             So, that was just a word of wisdom by

 

 21   extrapolation.  We all like to say, no, let's not

 

 22   extrapolate; they are different.  But force

 

 23   yourself to think that there may be scenarios in

 

 24   which you will be able to extrapolate and those are

 

 25   the ones that I think we need to bring forward to

 

                                                                50

 

  1   resolve some of these issues.

 

  2             DR. CHESNEY:  Dr. Loewke?

 

  3             DR. LOEWKE:  I just wanted to make a

 

  4   comment that seeing more doesn't necessarily mean a

 

  5   benefit.  These drugs are not without risk.  So,

 

  6   obviously, the utility of the information you are

 

  7   getting is very important and that is, again, a

 

  8   risk-benefit assessment.

 

  9             DR. CHESNEY:  Dr. Glode and Dr. Fink, and

 

 10   then I think we need to push on to begin question

 

 11   two.

 

 12             DR. GLODE:  I just wanted to clarify a

 

 13   question and I think reemphasize the comment that

 

 14   Dr. Siegel just made.  It seemed to me, or at least

 

 15   I wanted to confirm that for some of these agents

 

 16   not only dose but infusion rate are issues to be

 

 17   potentially studied.

 

 18             The comment I wanted to make is just a

 

 19   comment very similar to what Dr. Siegel just

 

 20   commented on in terms of if your goal was to find

 

 21   the lowest effective dose--again, a presumption

 

 22   that a lower dose translates to a safer dose--I

 

 23   don't know how you are going to do that in

 

 24   children.  In animals, yes, and hope that that

 

 25   translates or something.  But it does seem very

 

                                                                51

 

  1   problematic to say here is our standard dose X and

 

  2   we are randomizing people to half X, and the

 

  3   endpoint is that we couldn't read your study and it

 

  4   gave us no valuable information.  So, now we need

 

  5   to sedate your child again and do another study.

 

  6   So, the study design is pretty problematic in

 

  7   trying to get to the lowest dose that gives you an

 

  8   interpretable image.

 

  9             DR. CHESNEY:  Dr. Fink?

 

 10             DR. FINK:  It strikes me that we are

 

 11   spending all this time talking about these agents.

 

 12   It is wonderful.  It would also be interesting to

 

 13   see if equal time was spent looking at the

 

 14   equipment.  How much of the equipment we are

 

 15   talking about is actually licensed for use in

 

 16   neonates?  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

 

                                                                52

 

  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

 

 10   question.

 

 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.

 

 25             DR. FOGEL:  Yes, I just wanted to respond

 

                                                                53

 

  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?

 

 25             DR. DANFORD:  I am going to quibble for

 

                                                                54

 

  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

 

                                                                55

 

  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

 

  5   comment?

 

  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 our

 

                                                                56

 

  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

 

 16   starting.

 

 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

 

                                                                57

 

  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

 

  6   image?

 

  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

 

 11   children.

 

 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

 

 15   on.

 

 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

 

 23   disease.

 

 24             I will step back for a second and say if

 

 25   we look at the vascular lesions such as the aortic

 

                                                                58

 

  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

 

 20   definition.

 

 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

 

                                                                59

 

  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.

 

                                                                60

 

  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

 

                                                                61

 

  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 information that

 

                                                                62

 

  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

 

                                                                63

 

  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 get some

 

                                                                64

 

  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

 

 24   dose.

 

 25             DR. SIEGEL:  I agree.  You start with the

 

                                                                65

 

  1   CT and then we do the echo to confirm it.

 

  2             DR. CHESNEY:  Dr. Stylianou, you had a

 

  3   comment?

 

  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.

 

                                                                66

 

  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

 

 15   radiation.

 

 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?

 

                                                                67

 

  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

 

                                                                68

 

  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

 

                                                                69

 

  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.

 

 14             [Laughter]

 

 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.

 

 25             DR. CHESNEY:  All right.  So, before we

 

                                                                70

 

  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.

 

 25             DR. O'FALLON:  I have been sitting here

 

                                                                71

 

  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

 

                                                                72

 

  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

 

                                                                73

 

  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

 

  5   plenty.

 

  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 enhancement because

 

                                                                74

 

  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

 

                                                                75

 

  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

 

  5   agent.

 

  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

 

 25   target.

 

                                                                76

 

  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.

 

 25             In terms of dosing, presently for

 

                                                                77

 

  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

 

  7   levels.

 

  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

 

                                                                78

 

  1   remember.

 

  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

 

                                                                79

 

  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

 

 20   studies.

 

 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

 

                                                                80

 

  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. 

 

                                                                81

 

  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

 

                                                                82

 

  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

 

                                                                83

 

  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

 

 12   criteria.

 

 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

 

                                                                84

 

  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

 

                                                                85

 

  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 the childhood

 

                                                                86

 

  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

 

                                                                87

 

  1   moving.

 

  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

 

                                                                88

 

  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

 

 22   point.

 

 23             DR. CHESNEY:  Dr. D'Agostino?

 

 24             DR. D'AGOSTINO:  Fortunately, Victor just

 

 25   asked half of my question.  The other half is to

 

                                                                89

 

  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

 

  8   value.

 

  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.

 

 25             DR. D'AGOSTINO:  Yes, thank you.

 

                                                                90

 

  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.

 

                                                                91

 

  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

 

                                                                92

 

  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

 

  9   do.

 

 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

 

                                                                93

 

  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

 

                                                                94

 

  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

 

  9   questions.

 

 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

 

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  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

 

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  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

 

  7   design.

 

  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

 

 17   Nelson.

 

 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

 

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  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 sonographer, one

 

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  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

 

 12   both.

 

 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 clinics, contrast

 

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  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

 

 21   down?

 

 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

 

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  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 aren't

 

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  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.