FOOD AND DRUG ADMINISTRATION

	CENTER FOR DRUG EVALUATION AND RESEARCH

	MEDICAL IMAGING DRUGS ADVISORY COMMITTEE

	Monday,
	June 28, 1999

	The Ballrooms
	Gaithersburg Holiday Inn
	Two Montgomery Village Avenue
	Gaithersburg, Maryland

IN ATTENDANCE:

RUTH G. RAMSEY, M.D., Chairperson
Professor of Radiology
The University of Chicago, MC 2026
Department of Radiology
5841 South Maryland Avenue
Chicago, Illinois  60637-1470

LEANDER B. MADOO, Executive Secretary
Advisors and Consultants Staff (HFD-21)
Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane
Rockville, Maryland  20857

Committee Members

MARCO A. AMENDOLA, M.D.
Professor of Radiology
Department of Radiology (R-109)
University of Miami School of Medicine
1611 N.W. 12th Avenue
Building West Wing, Room 279
Miami, Florida  33136

PETER L. CHOYKE, M.D.
Senior Staff Radiologist
Diagnostic Radiologic Department
National Institutes of Health
9000 Rockville Pike
Building 10, Room 1C-660
Bethesda, Maryland  20892-1182

RICHARD J. HAMMES, R.Ph.
Director of Nuclear Pharmacy Services
Nuclear Medicine
Radiology Department, E3/382
University of Wisconsin Hospitals and Clinics
600 Highland Avenue
Madison, Wisconsin  53792-3252

IN ATTENDANCE:

Committee Members (Continued)

VICKI S. HERTZBERG, Ph.D.
Chair and Associate Professor
Department of Biostatistics
Rollins School of Public Health
Emory University
1518 Clifton Road, N.E.
Building GCR, Room 320
Atlanta, Georgia  30322

JONATHAN M. LINKS, Ph.D.
Professor of Environmental Health Sciences
The Johns Hopkins University
School of Hygiene and Public Health
615 North Wolfe Street, Room 2001
Baltimore, Maryland  21205-2179

ARNOLD W. MALCOLM, M.D.
Medical Director
Department of Radiation Oncology
St. Joseph Medical Center
Valley Radiotherapy Association
501 S. Buena Vista
Burbank, California  91505

LAURA L. BOLES PONTO, Ph.D.
Assistant Research Scientist
Department of Radiology
Division of Nuclear Medicine
University of Iowa Hospitals and Clinics
200 Hawkins Drive, Building JPP, Room 0911Z
Iowa City, Iowa  52242

MARK TULCHINSKY, M.D.
Assistant Professor of Radiology and Medicine
Department of Radiology
Penn State University Hospital
The Milton S. Hershey Medical Center
P.O. Box 850, 500 University Drive
Hershey, Pennsylvania  17033

IN ATTENDANCE:

Committee Members (Continued)

HARVEY A. ZIESSMAN, M.D.
Director, Division of Nuclear Medicine
Department of Radiology
Georgetown University Hospital
Gorman Building, Room 2005
3800 Reservoir Road, N.W.
Washington, D.C.  20007

Consultants

E. CAROLYN BEAMAN, M.H.S.
President
Sisters Breast Cancer Network
Lake Jackson, Texas
(Member, Oncologic Drugs Advisory Committee)

MARVIN KONSTAM, M.D.
Professor of Medicine
New England Medical Center
Boston, Massachusetts
(Member, Cardiovascular and Renal Drugs
 Advisory Committee)

Guest Experts

PETER HERSCOVITCH, M.D.
PET Department
CC NIH
Bethesda, Maryland

JAMES TATUM, M.D.
Special Assistant to the Director
Diagnostic Imaging Program
National Cancer Institute
Richmond, Virginia

	C O N T E N T S

	PAGE

Welcome and Introductory Remarks

	Ruth G. Ramsey, M.D.
	MIDAC Chair	8

	Patricia Love, M.D., M.B.A.
	Director, Division of Medical Imaging
	 and Radiopharmaceutical Drug Products
	CDER, FDA	10

Meeting Announcements and Conflict of Interest
Statement

	Leander B. Madoo
	Executive Secretary
	MIDAC, CDER, FDA	12

Open Public Hearing

	Jorge Barrio, M.D.
	Institute of Clinical PET	17

	Peter S. Conti, M.D., Ph.D.
	University of Southern California	19

Section 121 of the FDA Modernization Act (PET):
Overview of Proposed Regulatory Approach to
Three Drugs

	Jane Axelrad, Esq.
	Associate Director for Policy
	CDER, FDA	25

Committee Discussion and Questions	33

	C O N T E N T S

	PAGE

FDA Presentation on the Safety and Effectiveness
of Fludeoxyglucose F-18 Injection

Clinical Pharmacology/Pharmacology/Toxicology

	Adebayo A. Laniyonu, Ph.D.	46

Safety and Effectiveness in Oncology

	Florence Houn, M.D., M.P.H.
	Director, ODE III	53

Safety and Effectiveness in Cardiology

	Victor F.C. Raczkowski, M.D., M.S.
	Deputy Director, ODE III	99

Open Public Hearing

	R. Ed Coleman, M.D.
	Duke University	135

Committee Discussion and Questions	148

FDA Presentation on the Safety and Effectiveness
of Nitrogen N-13 Injection

Clinical Pharmacology/Pharmacology/Toxicology

	David G. Udo, Ph.D.	201

Safety and Effectiveness in Cardiology

	Florence Houn, M.D., M.P.H.	206

	C O N T E N T S

	PAGE

Open Public Hearing

	Jamshid Maddahi, M.D.
	University of California, Los Angeles	228

Committee Discussion	240

	P R O C E E D I N G S	(8:05 a.m.)
		DR. RAMSEY:  Good morning.  I'd like to introduce myself.  I'm Ruth Ramsey, and I will be the Chair of the committee here today.  I want to say what a pleasure it is to work with Leander Madoo, who is sitting on my left here, in organizing this and in making sure that all of our experts are here so that we can present our program today.
		I think the first order of business is to have everyone on the committee introduce themselves and tell what their role is here at this meeting.  So, I think we will start with Dr. Herscovitch, in the far corner, and we'll just work our way around the table.
		DR. MADOO:  Could you please speak into the mike.  I think we're going to have to double up on some of these mikes.  Sorry about that.
		DR. HERSCOVITCH:  Hi.  My name is Peter Herscovitch.  I am a physician and I am chief of the PET Imaging Section in the Clinical Center of the Intramural Research Program of the National Institutes of Health.  I am here as a consultant.
		DR. TATUM:  I'm Jim Tatum.  I am a physician.  I am from the National Cancer Institute Diagnostic Imaging Program.  And I am here as a consultant as well.
		MS. BEAMAN:  I'm Carolyn Beaman from Sisters Net Breast Cancer Network, a member of the ODAC Committee, and I am here as a consultant.
		DR. HERTZBERG:  I'm Vicki Hertzberg.  I chair the Department of Biostatistics at Emory University.  And I am a member of the committee.
		DR. TULCHINSKY:  Mark Tulchinsky, member of the committee, at Penn State University Hospital, one of the nuclear medicine and internal medicine physicians.
		DR. CHOYKE:  My name is Pete Choyke.  I am a radiologist at NIH, and I am a member of the committee.
		DR. MALCOLM:  My name is Dr. Arnold Malcolm, a radiation oncologist, medical director of the Radiation Oncology Department, Medical Center in Burbank, California, and a member of the MIDAC Committee.
		DR. MADOO:  Hi.  I'm Mr. Madoo.  I provide administrative coordination.  It's good to have you here.
		DR. PONTO:  I'm Laura Ponto.  I'm an associate research scientist at the University of Iowa in the PET Imaging Center, and I'm a member of MIDAC.
		DR. AMENDOLA:  I am Marco Amendola.  I am a physician, professor of radiology at the University of Miami in Florida, and a member of the committee.
		DR. ZIESSMAN:  I'm Harvey Ziessman.  I'm the director of nuclear medicine at Georgetown University.  I'm a member of the committee.
		DR. LINKS:  I'm Jonathan Links.  I'm a member of the committee.  I'm a professor at Johns Hopkins School of Public Health, and I'm also president-elect of the Society of Nuclear Medicine.  And from a conflict of interest perspective, I need to say that the views I'll be expressing are my own and do not necessarily represent either Hopkins or the Society of Nuclear Medicine.
		DR. LOVE:  Patricia Love, director, Division of Medical Imaging, Radiopharmaceutical Drug Products at CDER.
		DR. HOUN:  Florence Houn, office director for the Office of Drug Evaluation III.
		MS. AXELRAD:  Jane Axelrad, associate director for policy in the Center for Drug Evaluation and Research.
		DR. LANIYONU:  Adebayo Laniyonu.  I'm an oncology physician of medical imaging and radiopharmaceutical drug products.
		DR. RAMSEY:  Have we missed anyone here?
		DR. LOVE:  There will be a few other persons joining us shortly.
		DR. RAMSEY:  Okay, a few other people joining us shortly and we can introduce them when they arrive.
		I would now like to turn the podium over to Patricia Love.
		DR. LOVE:  Thank you, and good morning again.  Before we proceed, let me just make a couple of comments.  First, thank you, and welcome to everyone, our returning committee members, new committee members, guests, and consultants.
		Also, since we last met we have had a slight reorganization in terms of the Office of Drug Evaluation III, which is the CDER office in which the Division of Medical Imaging resides.  Dr. Florence Houn, to my right, is the new office director.  Dr. Botstein has retired since we last met.  Also, Dr. Victor Raczkowski, who will be joining us shortly, was the former deputy director within the division.  He is now the deputy director of the ODE.  So he will be here shortly and you will hear from him later on today.
		Today is going to be a very important meeting for us.  It is a step in a process to evaluate and develop new approval procedures for PET products, and that's part of the FDAMA initiatives and legislative responsibilities that we have.  Just after we go into the open public hearings, Jane Axelrad will give us an update on the types of procedures and other things that have been going on in the process of developing these approval procedures.
		Also, today is a little different because we do not have an identified sponsor for the product.  So the agency has been conducting the reviews to move us forward to determining whether or not we are going to be able to provide approval recommendations for certain types of products.  So your involvement in this process to us is incredibly important.
		Before we go into it today, there will be an open public hearing, and we'll pause shortly after these remarks for that part of the process, then we will move quickly through the agenda.  Different individuals will identify themselves as we are moving forward.  And if we need to stop at different places, please just ask and we can try to organize ourselves and make other logistics comments as we need to as we go through.
		Thank you.
		DR. RAMSEY:  Thank you, Dr. Love.
		According to my agenda, Leander Madoo will tell us about meeting announcements and conflict of interest statements.
		DR. MADOO:  Yes.  Hello, folks.  In terms of general meeting announcements, obviously, prior to the meeting, all participants at the table have received the rainbow version of our briefing documents; there are five volumes.  We also have at our disposal a more refined agenda.  You will note that appended to the agenda are four questions which will be considered relative to each of the three agents.  Two of the questions focus on FDG, one of the questions, number three, is the Ammonia N-13, and the water O-15 injection is question four.  You might want to be keeping these questions in the back of your mind as you hear the presentations.
		Speaking of the division presentations, they have been so kind to provide guest copies of the slides.  There is also a very convenient way you can jot notes down in the adjoining margin.
		I would like to note that we are very pleased to have one brand new member at this meeting today, and that is Dr. Tulchinsky from Penn State.  Thanks for joining the committee, sir.
		I also want to provide a little more perspective relative to our attendees.  We will be voting on these questions.  These votes are recommendational in nature.  We have two very distinguished people who are governmental-based who are actually functioning as guest experts, Dr. Herscovitch and Dr. Tatum.  These gentlemen will not be voting but will be able to contribute the breadth of their scientific knowledge throughout the course of the meeting and help the committee get acquainted with these difficult issues.  These two gentlemen are specialists in the area of PET.
		We also have at this meeting two consultants.  Dr. Marvin Konstam, who apparently has not yet arrived, his function is to provide sagacious counsel on the cardiovascular aspects, the cardiology aspects of these agents.  And we are also pleased to have from the Oncologic Drugs Advisory Committee Carolyn Beaman.  So both Carolyn Beaman and Marvin Konstam will be functioning as consultants, and they will be voting.
		So that kind of encompasses the general announcements.  One other point, we have decided to propagate the open public hearing throughout the meeting.  The rationale behind this is it gives some participants an opportunity to reflect on presentations and then comment.  So you will note that open public hearing, we will go through the formality of announcing it after I conclude my conflict of interest statement, but the open public hearing will be interdigitated throughout the meeting.  I believe the first open public hearings speaker formally will be a Ronald Coleman, M.D.
		Now on to the exciting conflict of interest statement.  The following announcement addresses the issue of conflict of interest with regard to this meeting and is made part of the record to preclude even the appearance of such at this meeting.
		Based on the submitted agenda for the meeting and all financial interests reported by the committee participants, it has been determined that all interests in firms regulated by the Center for Drug Evaluation and Research which have been reported by the participants present no potential for an appearance of a conflict of interest at this meeting, with the following exceptions.  In accordance with 18 U.S.C. 208(b)(3), full waivers have been granted to Dr. Vicki Hertzberg, Dr. Richard Hammes, Dr. Laura Ponto, and Dr. Jonathan Links.  A copy of these waivers statements may be obtained by submitting a written request to FDA's Freedom of Information Office, Room 12A-30 of the Parklawn Building.
		In addition, we would like to note that Dr. Ponto's son has been and will be employed as a summer student employee at the PET Imaging Center at the University of Iowa.  Although this interest does not constitute a financial interest in the particular matter within the meaning of 18 U.S.C. 208, it could create the appearance of a conflict.  However, it has been determined, notwithstanding this interest, that it is in the Agency's best interest to have Dr. Ponto participate in this meeting's ‑‑ thanks, Dr. Ponto ‑‑ discussions concerning the safety, effectiveness, and proposed procedures for obtaining marketing approval of the three positron emission tomographic drugs being addressed at this meeting.
		In the event that the discussions involve any other products or firms not already on the agenda for which an FDA participant has a financial interest, the participants are aware of the need to exclude themselves from such involvement and their exclusion will be noted for the record.  With respect to all other participants, we ask in the interest of fairness that they address any current or previous financial involvement with any firm whose products they may wish to comment upon.  Thank you.
		Now one other addendum relative to COI.  During the open public hearing, anyone who approaches the podium or microphone to make a statement, it is incumbent upon you to clarify any sponsorship you received to arrive at the meeting; i.e., some kind of fee that you are receiving or manner of conveyance.  I am sure Dr. Ramsey will insist upon that as well.
		Thanks for your attention.
		Dr. Ramsey?
		DR. RAMSEY:  Thank you, Mr. Madoo.
		One other committee member has arrived, Dr. Hammes.  Would you mind introducing yourself and telling your role on the committee.  You have to speak into the microphone so it ends up recorded.
		DR. HAMMES:  Richard Hammes, director of nuclear pharmacy services, University of Wisconsin.  I am the consumer's representative.
		DR. RAMSEY:  Thank you.
		Any other ones that I missed?  Okay.
		According to my agenda, we are now at the open public hearing portion of the program.
		Please identify yourself and tell your sponsorship, please.
		DR. BARRIO:  Yes, good morning.  I am Jorge Barrio.  I am the chair of the radiopharmaceutical committee put together under the initiative of the Institute of Clinical PET, with representation from the Society ‑‑
		DR. RAMSEY:  Excuse me.  It's almost impossible for us to hear you.  If you just sit at the table and use the ‑‑
		DR. MADOO:  The podium is fine.  Why don't you come to the podium.  The podium is probably more distinguished.
		DR. RAMSEY:  Would you mind starting over and introducing yourself again, please.  Thanks.
		DR. BARRIO:  Well, good morning.  I am Jorge Barrio, chair of the radiopharmaceutical committee formed under the initiative of the Institute of Clinical PET, and with representation from the Society of Nuclear Medicine, the ICP, and the American College of Nuclear Physicians.  As such, I'm coming representing this group.
		We have been working with FDA for about 18 months now to assist the agency in the formulation of the new radiopharmaceutical regulations mandated by FDAMA 1997.  These have been 18 months of very hard work for the agency and for us.  Today we meet here to review and discuss FDA findings of course on clinical indication for FDG, N-13 ammonia, and water.  I would like everyone to know, of course, that this represents a culmination of many months of intensive search and critical analysis of the scientific America literature.  On behalf of my colleagues in the room and also the PET community we represent, I would like to thank everyone in the agency for making all this possible.
		Today is a very exciting day for the nuclear medicine community because historic decisions are to be made for the long term future of PET and nuclear medicine.  I am sure the significance of this meeting has not been lost on anyone in this audience.  We are on the verge of seeing a new concept that we call molecular medicine introduced to every single patient in America, something that we wanted to do for a long time.  With FDG, N-13 ammonia, and O-15 water, we initiate a journey of transferring many years of research to a new clinical era of biological imaging.
		Again, I would like to thank the agency for this opportunity and for making all these discussions possible.  Thank you.
		DR. RAMSEY:  Thank you.
		Is there anyone else who would like to speak?  Yes, please come up to the podium.
		DR. MADOO:  I believe when the speakers were muddled that Dr. Conti announced that he had ICP ties.  Thank you.
		DR. CONTI:  That was Dr. Barrio.
		DR. MADOO:  Sorry, that was Jorge Barrio from UCLA.
		DR. CONTI:  My name is Peter Conti.  I am from USC, and the ICP also is sponsoring my trip out here.  I am also, just for the sake of disclosure, on the medical advisory board for a new company called Mobil PET.
		What I would like to do is, having gotten off the plane about an hour ago, I'm a little bit groggy from Los Angeles, but bear with me, is go through PET 101.  To many of you this will be a little bit boring.  But for those of you who have limited experience with this technology, hopefully in a few short moments I'll be able to explain it to you.
		This is a working definition that I use when I teach the residents at USC.  Positron emission tomography is an emerging clinical imaging modality which enables visualization and quantification of basic biochemical processes in vivo.  As Dr. Barrio alluded to a few moments ago, molecular medicine is entering a new phase and the diagnostic imaging tests that we have available to us are also going to be part and parcel of this new medicine.  Many of the tracers that we will be developing over the next few years will, in fact, be based on the advances in molecular medicine.
		Positron emission tomography is based in fact on the use of positron emitting isotopes.  In those lists you see in front of you here, fluorine-18 being the primary agent that we use for fludeoxyglucose, with 110 minute half-life; other isotopes, nitrogen-13 used for labeling ammonia, carbon-11 and oxygen-15 are other isotopes that are available.  These have, as you see, very short half-lives compared to many of the conventional isotopes that we use in nuclear medicine.
		These are some examples of compounds that have been placed into humans for imaging.  Of course, fluorine-18 FDG, we'll spend a fair amount of time discussing that over the next two days.  Oxygen-15 labeled water and N-13 ammonia also will be topics of discussion for today.  But others, many carbon-11 compounds have also been prepared and studied in humans.
		Again, I apologize, I'm going to try to give some very basic physics.  This is a schematic of a cyclotron which is used to produce the radio isotopes.  Essentially, we are accelerating charged particles within the cyclotron and bombarding target chambers that contain various substances of inert gases, liquids, or solids to produce radioactive material.  This material is swept out of the cyclotron and used in the processing of and synthesis of these radiopharmaceuticals.
		Here is an example.  You don't see very much here, but its a shielded cyclotron.  The unit is actually much smaller than this.  On the side here, however, are what we have the chemical processing units that are used to take the raw material from the target and synthesize this into various numbers of radiopharmaceuticals, including FDG.
		Once this material is prepared ‑‑ this is the cyclotron at USC, in the background you see it here ‑‑ this material is transferred over into a series of hot cells which is used to manipulate these vials of FDG and to prepare unit doses for patients.  All the traditional QC and other types of analytical tests that are done before release of these products are performed on-site.
		They are then used in a scanner.  This is a typical PET scanner.  Everything but the very fluorescent light that you see in the background comes with the camera.  But you have the ability to deliver these isotopes to the cameras on-site or off-site through delivery systems that are available throughout the communities now.  It looks very much like a CT camera.  The patient lies essentially on the table and receives an intravenous administration of these radiopharmaceuticals, there's a short uptake phase, for example, with FDG you're talking about a 30 to 40 minute uptake phase, and the patient is then scanned.  It could be for brain, cardiac, or whole-body imaging.
		The principle behind the positron decay is shown in this scheme, where you have proton-enriched nuclei which decay to form a neutron with the emission of a positive electron called a positron.  This will basically travel a very short distance through tissue until it encounters an electron in the local environment, at which point two 5-11 photons are emitted from the site of decay, and it is these photons that we will detect using coincident circuitry.  Here, for example, is another schematic showing these radiation detectors in the coincidence circuit with the decay event and the mass energy equivalent, resulting in two 5-11 photons.
		Shown on another scheme here then, this is a schematic of a brain within the ring of detectors around the patient in the scanner.  Each of these little stars represents a site of decay with the emission of these two photons which are then detected as a setting coincidence by a ring of crystals within the camera.
		Now, let me just show you one example of each of the three indications that we've used.
		Neurology and neurosurgery.  These are typical indications that are used now in the clinics with epilepsy, dementias, movement disorders, and vascular anomalies.  In addition to this and covered in cancer would be brain tumors in the area of neurosurgery and neurology.
		Here's a nice little summary slide from my colleagues at UCLA which show typical examples of neurological applications for PET.  With Alzheimer's disease, showing the typical normal cortical uptake in the frontal lobes, and you can see the decreased metabolism here, biparietal and bitemporal distribution.  A very classical pattern for Alzheimer's disease.  This differential between multi-infarct dementia and Alzheimer's disease is very critical.  And, of course, as the multi-infarct dementia would expect, these typical wedge-shaped lesions which can be cortical or subcortical in nature.  Of course, the patterns are obviously very different and can be used to discriminate in these patients.
		Some of the movement disorders.  Huntington's disease, showing decreased activity here in the basal ganglia.  Unlike cerebral palsy, for example, which shows decreased metabolism here in the thalami, you see decrease here in the caudate and putamen.  So this can be used, although not very commonly.
		In epilepsy, you have the inter-ictal picture where decreased metabolism is seen in the non-seizure state.  And you see this as a diminished glucose uptake in the cortex of the temporal lobe here compared to the contralateral side.
		And, of course, in tumors there is a wide spectrum of different presentations of tumors ‑‑ high, low, and intermediate grade, and various degrees of necrosis and liquefaction of many of these lesions.  So there's no typical pattern, if you will, for tumors.
		Now in the area of cardiology, coronary artery disease, cardiomyopathies, transparent evaluation, all the typical reasons why you would do a nuclear medicine scan, a stress test, if you will, for a patient with coronary artery disease and also for cardiac viability.  So we can see many of the things that you can see in other types of exams.  Here is an example of an apical infarct.  We'll spend a fair amount more time on this application, so I won't belabor this.
		And, finally, in oncology, in addition to diagnosis and grading, we're dealing with issues of staging or assessing response to therapy.  And we're looking at residual and recurrent disease in a wide spectrum of cancers.  Just one quick example of this, here's a case, multiple coronal views on the PET scan, the patient with advanced melanoma.  You can see very low background in most of the soft tissues and accentuation of uptake comparatively in multiple boney and soft tissue lesions in this patient.  These are very typical of the cancers that we can look at.
		I just want to show this one slide in terms of altered management because this is really the important factor in the introduction of PET in recent years.  These are some examples in the whole-body cancer area that show very significant management changes, colorectal cancer, lymphoma, and melanoma are listed here as examples.  So I think you are seeing significant alterations in how patients are managed.  Obviously, that not only affects cost, it affects quality of life for patients.
		So I hope in that very brief few minutes I was able to clarify some of the picture with PET.  If you didn't have this picture when you started out, hopefully it is a little clearer now.
		Thank you.
		DR. RAMSEY:  Thank you, Dr. Conti.  Very succinct, very nice presentation.
		We now move on to the next section of our program, and that is Section 121 of the FDA Modernization Act regarding PET scanning.  Jane Axelrad.
		MS. AXELRAD:  I'm Jane Axelrad.  I'm here today in my role as the chairman of the Center for Drug PET Steering Committee.  That committee is a cross-divisional working group that was created by the Center to implement Section 121 of the Food and Drug Administration Modernization Act.  I am going to be giving you a little bit of the legal and regulatory framework in which we're operating here for PET.
		Dr. Conti gave a very good description of PET technology and how it is used.  It has been in use for over 20 years.  There are at least a hundred different PET drugs we understand that are currently in various stages of development.  Of these PET drugs, only three have been approved by FDA.  Sodium fluoride F-18 injection is used for bone imaging.  Rubidium chloride, rubidium-82 injection is a myocardial perfusion agent that is useful in distinguishing normal from abnormal myocardium in patients with suspected myocardial infarction.  And fludeoxyglucose F-18 injection is used for the identification of regions of abnormal glucose metabolism associated with the foci of epileptic seizures.
		In the early 1990s, FDA began evaluating the development of PET technology which was moving out of the academic arena and into the mainstream of medical care.  At that time, FDA recognized the need to apply regulatory control mechanisms to this growing industry to ensure that PET drugs would be uniformly safe and effective as labeled in use in clinical care.  This part of the industry had previously been unregulated essentially by FDA.
		In 1995, FDA announced its regulatory approach in a series of documents and public workshops that indicated that after an 18-month implementation period, the PET industry would be expected to come into compliance with requirements for investigational new drug applications and new drug applications, and PET manufacturers would be expected to register as manufacturers and to adhere to current good manufacturing practice or, as we call them, CGMP regulations.
		However, in recognition that there exists certain features unique to the manufacture of PET products, most notably the fact that they are usually produced in very small amounts and have short half-lives that limit their geographic distribution, FDA published a proposed rule that would allow for waivers and exceptions to the CGMP requirements under certain circumstances.
		FDA was working with the PET industry to develop and provide guidance on NDA requirements in compliance with current good manufacturing practice requirements when the issue of regulation of PET drug products was raised in a legislative discussion of FDA reform.  The result of those discussions was Section 121 of the Food and Drug Modernization Act which took effect on November 21, 1997.
		Section 121 directed FDA to withdraw many of the documents that the agency had issued on the regulation of PET drug products and to develop alternative procedures for PET drugs within two years of passage of the Act.  Specifically, the Act directed FDA to establish appropriate procedures for the approval of PET drugs pursuant to Section 505 of the Federal Food, Drug, and Cosmetic Act, and appropriate current good manufacturing practice requirements for such drugs.
		In developing these procedures, the FDA was to take into account the special characteristics of PET drugs and the special techniques and processes required to produce them.  FDA is also required under the law to consult with patient advocacy groups, professional associations, manufacturers, and physicians and scientists licensed to make or use PET drugs.
		Under the Modernization Act, FDA was prohibited from requiring the submissions of new drug applications or abbreviated new drug applications for PET drugs that are not adulterated under the meaning of the Act for four years from the date of enactment of the Act, or for two years after the date on which the secretary establishes procedures and requirements required by the Act, whichever is longer.  We are, of course, still allowed under the statute to accept any applications that are submitted voluntarily.  FDA is in the process of developing the procedures required by the Modernization Act, and this meeting today is a very important step in that process.
		When FDA began implementing the Modernization Act, we first looked at the most commonly used PET drugs and thought about how best to bring them under regulatory control within the meaning of the Modernization Act.  We noted the existence of a large body of literature concerning F-18 fludeoxyglucose for a variety of indications, as well as literature on N-13 ammonia, and O-15 water.  It seemed to us that if a finding could be made that these drugs are safe and effective for some indications based on the literature, then this finding could form the basis for a new drug application.
		Shortly after the passage of the Modernization Act, the Institute for Clinical PET wrote to us about its plan to form a working group representing the PET community to work with FDA in developing the new regulatory requirements for PET radiopharmaceuticals.  FDA has held a series of working public meetings with the Institute for Clinical PET at which we discuss in a public forum our proposed regulatory approaches to PET that are under consideration at FDA.
		ICP endorsed the concept of concentrating on the most commonly used PET drugs and developing conclusions regarding their safety and efficacy based on the literature.  ICP provided articles and additional citations to the literature on the three PET drugs and indications that FDA decided to address first ‑‑ F-18 FDG for oncology and for myocardial hibernation, N-13 ammonia for myocardial perfusion, and O-15 water for cerebral blood flow.  FDA then conducted a review of the literature on these drugs for these indications.  We will present our preliminary conclusions to you today.
		After discussing these drugs at this meeting and hearing the Advisory Committee's views regarding their safety and efficacy, FDA will complete its review.  If the results of the reviews are that the drugs can be found to be safe and effective based on the literature, we intend to publish that finding in the Federal Register and invite applicants to submit applications that rely on the cited literature and findings for the safety and efficacy portions of the applications.
		I should tell you that this is not an unprecedented step.  The agency has done this before.  With regard to the use of oral contraceptive for emergency morning-after care, there were no companies that were willing to step forward and re-label their products for that.  So the agency did a review of the literature and determined that when labeled in a certain way that they could be used for that use.
		The agency presented its findings to an advisory committee and the committee agreed with the agency's conclusions.  The agency then published that finding and cited the literature in the Federal Register and invited the submission of applications.  A company did come forward and submit an application based on that and was approved based on the conclusions in the Federal Register and the citations to the literature.  So that is sort of the model that we're working on.  We would also publish proposed labeling for these products for the indications that we think it is safe and effective for in the Federal Register.
		As you can tell, these actions would greatly simplify the submission of applications for these drugs for these indications.  And this is why we are presenting our preliminary findings to you today and this is how your efforts today will fit into our implementation of Section 121.
		With regard to new PET drugs, after we address the more commonly used agents, we will be developing guidance for the PET community regarding the submission of applications for other products that might be based on the literature or that might be based on well-designed prospective studies.  You will see from our presentations today that we have identified certain characteristics of certain of the studies in the literature that made them more reliable indicators of safety and effectiveness and on which we based our reviews.  We hope that our analyses of the literature will provide a model on which the industry can base future applications where the literature is sufficient to draw conclusions on safety and efficacy.
		As you are probably aware, in May of this year we published a final rule on radiopharmaceuticals, implementing another section of the Modernization Act.  That rule described the types of indications for which FDA may approve diagnostic radiopharmaceuticals and the criteria FDA would use to evaluate the safety and effectiveness of a diagnostic radiopharmaceutical.  FDA expects that clarification by the regulation of the standards for evaluation of diagnostic radiopharmaceuticals will reduce the burden of developing and submitting an application for such a radiopharmaceutical, particularly for those that have well-established low risk safety profiles.
		FDA indicated that it will address how this rule will apply to PET drugs when it publishes its proposed procedures for PET drugs.  But we do hope that the principles established in the rules will provide a useful foundation for the development and approval of new PET products.  We will be developing additional guidance and procedures for these products in the future.
		You should also be aware that in a separate effort we are working on standardization of the chemistry, manufacturing, and controls portion of a PET application for the most commonly used PET drugs and on new current good manufacturing practice requirements.
		That's all that I have for my prepared remarks.  I would be happy to answer any questions that you might have.
		DR. RAMSEY:  Thank you, Ms. Axelrad.  We appreciate those comments.  Very nice presentation.  Thank you very much.
		Are there any questions from the panel members?  Is it appropriate to ask for audience questions as well?
		DR. MADOO:  Yes.  Sure.
		DR. RAMSEY:  Or from anyone in the audience.
		And here we are at the time for questions and comments from the committee members.  So I would like to ask if there are any questions or comments from the committee members.
		DR. LINKS:  Ruth, can we have a brief discussion on the categories of indications because that's going to frame the entire two days.  So could we hear from the FDA just very briefly the categories and a few comments about the character of the evidence they are looking for in each of those categories.
		DR. LOVE:  We're talking briefly amongst ourselves.
		Part of that is part of the presentation that each of us would be giving.  But, in general, the indication categories that are identified in the draft guidance for developing medical imaging drugs and biologics talks about four different categories ‑‑ structure, function, disease or pathology detection or assessment, and therapeutic or diagnostic patient management.  There are a lot of things to talk about there.  Are there some specifically focused questions or points that you want to hear?
		DR. LOVE:  What's the interplay between the rule which is final and the guidance which is draft?
		DR. LOVE:  Oh, okay.  The rule, yes, is final.  There are a number of places in the preamble to the rule where we indicate that there are certain things that would be clarified further in the guidance.  The guidance document was originally published in the fall of 1998.  And we've had two public meetings this year on the guidance document; one in January, where we met with representatives from CORAR, Council of Radiopharmaceuticals and Radionuclides, I may have gotten those two words reversed, and then on March 26th of this year we met again with CORAR and representatives of the newly formed MICAA, which is the Medical Imaging Contrast Agent Association, to talk about a number of different principles that are contained within the guidance document.
		It has certainly been identified to the agency by different persons that there are perhaps some unique issues for radiopharmaceuticals that may or may not always be relevant to contrast agents.  And the agency indicated in the last meeting in March that we do plan to clarify a number of different issues in the guidance document to talk about what things may be relevant more to one category of drugs and what things would be relevant to another category of drugs.
		The overall feeling from the agency as we developed the guidance document was that there are certain umbrella principles that would apply to all, meaning, the different indication categories, because a number of products, regardless of mechanism of action, are seeking the same types of indications, whether you have a product such as the one that we're talking about today with a short half-life that is looking at metabolic function, or whether you have a contrast agent that has some unique principles that allow it to be taken up in certain selective areas of the body.
		So, these indication categories that are identified in the rule are also found in the guidance document itself.  The draft, as you see from your package, talks about a number of ways that those indications can unfold for the different products.
		Some of the other questions that came up in the last two public meetings are, how do the indications themselves relate to one another; meaning, could you have a product that not only has a structural indication but also a functional indication, a disease-specific indication, and a patient management indication.  The rule indicates that all of these products are used for the diagnosis and treatment of disease or manifestations of disease in patients.
		From our perspective for the draft, all of the indications have a role to play in that process.  But for the actual indication of diagnostic or patient management, that role is specifically identified and the protocols there are specific statements within the studies that would allow you to identify what their hypothesis is and the study moves forward to actually show how that information affects the management of patients, and then the labeled indication of the package insert would carry that information.
		So, for example, many would use myocardial perfusion or cerebral perfusion assessments in patients with a wide variety of diseases.  But our current labels for approved products don't exactly state how that information is used.  It is a more global, functional kind of use.
		But if you wanted to say that that perfusion information would allow you to predict patient outcome, or would allow you to decide whether or not to perform a coronary artery bypass, and that information was to be in a label, then a study would be done to document that.  Perhaps it might involve clinical outcomes to show that you made the right decision and here's the outcome in the patient.  So that's how those indications might play out.
		DR. RAMSEY:  Yes.  Please introduce yourself and go ahead.
		DR. ZIESSMAN:  Harvey Ziessman.  I just need a clarification.  It was mentioned that this approach was taken before with the morning-after pill, that a literature search was made.  But then you said a sponsor was sought.  That is different now than what we're doing today; is that right?
		MS. AXELRAD:  No.  What we're doing today is trying to establish whether there is a foundation for making and publishing a finding of safety and efficacy.  And then we would be seeking sponsors; someone or many would need to come forward with an application.  But we're trying to simplify the applications so that essentially ‑‑ and one of the big obstacles is doing the clinical trials and developing the safety and efficacy part of the application, that's probably the largest chunk ‑‑ we would be essentially doing that by publishing the finding in the Federal Register.  So the safety and efficacy submission would essentially consist of a citation to the literature that is cited in the Federal Register, period.
	Then we're working on the other part with regard to chemistry.  And since we're also going to be publishing a proposed labeling, that would also be done essentially.  So we're really talking about basically a chemistry submission.
		DR. AMENDOLA:  Just to put this in some kind of ‑‑
		DR. RAMSEY:  Introduce yourself, please.  Thank you.
		DR. AMENDOLA:  I'm Dr. Amendola, a member of the committee.  Just to have some kind of perspective, I would like to know how many PET scanners are there in the United States.  And are they all in academic centers or are any in non-academic centers?
		MS. AXELRAD:  Does anyone have that information?
		DR. TULCHINSKY:  I believe it is about 70 centers, and not all of them are in academic institutions.
		DR. LOVE:  There are several free-standing entities that are developing that may or may not be directly related to a university facility.  Also, some of the facilities have subcontracted out to different commercial entities to actually manufacture the product on site in an academic facility.
		DR. TULCHINSKY:  I have a question for Ms. Axelrad.  Mark Tulchinsky, member of the committee.  In reference to the process that those new or all the drugs already, pharmaceuticals in this case, will undergo, just a few questions of housekeeping.  What term are we going to be using to call those radiopharmaceuticals?  Is it unsponsored?  That discussion has been addressed previously  in the November 17, 1998 meeting, I believe.  Is there a term to be used here?
		MS. AXELRAD:  We're still working on developing the procedures.  The focus of this meeting is on the issue of the safety and efficacy of these three commonly used PET drugs.  But we will be having additional public meetings with the industry to talk about the procedures.  We had preliminary discussions in November, and then additional discussions of the procedures at a public meeting in February.
		We believe that they won't be unsponsored.  There will be some sort of application.  Now whether they will be applications submitted under 505(b) or 505(j), which are essentially generic drug applications, we haven't resolved that yet.  We're looking at the different mechanisms and the existing regulations to see which of those will work better in terms of adopting procedures to actually have people submit applications.
		DR. TULCHINSKY:  Thank you.
		Therefore, would the questions concerning who would hold DMF would also reside at that same timeframe?
		MS. AXELRAD:  Yes, that's one of the options that we're looking at is to have someone hold a DMF and other people reference it.  That is one way to do it.  There are a lot of different regulatory ways to do this and we're trying to look at that to find the simplest way that meets all the regulatory requirements so that it really would be not a large burden to bring an application, certainly for these three drugs.
		DR. TULCHINSKY:  Thank you.
		DR. RAMSEY:  Any other questions, comments?
		MS. BEAMAN:  Carolyn Beaman, consultant to the committee.  Has it been established as of yet what will be the association between safety and efficacy as also quality of life?  I'm looking at the symptoms that seem to have been passed over or stated in terms of not significant.  Not significant as compared to what?  What's not significant as for what?  As for what period of time?  What are we looking at here?
		MS. AXELRAD:  I think each of the three PET drugs we're going to discuss has a specific intended use or indication we're looking at.  The indications are pretty specific in terms of, let's say for FDG in oncology, being able to identify abnormal areas of glucose metabolism to assist in evaluating presence or absence of disease in a specific patient population.  Whether these drugs can be used for other kinds of indications, there's a lot of other literature that we were able to look at but we have not focused in on for this advisory committee in terms of an indication for quality of life, or indication for surgical management, or indication for therapeutic options.
		Many of these drugs can have multiple indications.  But I think the ones we're going to be asking in terms of is there effectiveness and safety for this specific one, each one has very specific ones.  I know the PET community is interested in having more indications and we have to work with them on bringing those indications out as well.
		MS. BEAMAN:  Thank you.
		DR. TULCHINSKY:  One more question.  Mark Tulchinsky, member of the committee.  Ms. Axelrad, just to clarify, as we're working on the safety and efficacy questions, the F-18 FDG already has an NDA.  And, therefore, are we working on a supplement?
		MS. AXELRAD:  I think that is a question that we have to address.  It could be a supplement.  We could have the applicant for the original application could bring in a supplement to add these indications.  But the issue is what happens to everybody else, because right now that is the only approved application.
		The question would be whether the others would come in as 505(b) applications or whether they would come in as generic 505(j) applications.  And there are different regulatory requirements associated with these.  If you are a 505(j), for example, you have to show that you're essentially the same as the reference listed drug.  Which means that they have to show a degree of similarity to the drug that is in that one approved application.  And it may be difficult given the different methods of production, different strengths, and things that are out there.  And so it may be that they wouldn't qualify to come in as a generic drug application, they would have to come in as a 505(b)(2) application.
		It's just very legalistic and sort of technically complex from a legal standpoint.  But the gist of it is that if you're not exactly the same within the meaning of our regulations as the reference listed drug, then you have to come in as a 505(b) application.  But certainly the applicant who holds the original application could bring in a supplement.
		DR. TULCHINSKY:  Thank you.
		The last question for Ms. Axelrad.  Mark Tulchinsky.  As we're working on these three tracers today, are we to use the language as in Class I and Class II radiopharmaceuticals, or are we not?
		DR. LOVE:  I think we're not trying to look at it from the perspective of is it a Class I or Class II, we're not using those terms at this point.  But, yes, we do understand some of the principles in terms of safety evaluations certainly are implied or included in the concept of the Group I product.  I think we use Group I as opposed to Class I.
		I think what we're really seeking is your assessment of the actual data and whether you feel that it is reasonably safe.  The Group I/Group II concept still is in a draft guidance document.  It is not yet ready for implementation.  But from the perspective of how would one look at the safety of the product and do we feel there is enough information based on what we either know about the drug and how it already functions because it is FDG and it is already approved, or based upon what we know about the mechanisms of actions of ammonia in general or water in general in the body, taking that body of known information and putting it all together.
		DR. RAMSEY:  Jonathan Links?
		DR. LINKS:  Jonathan Links.  Back to the indications, just a point of clarification.  If we think there are multiple indications, that is, multiple types of indications, I assume it is better to have a completely separate sentence for each type of indication for which we think there is valid data than to join them together.  So in the context of answering your questions that you phrased, for example, if we think your questions bring two or more indications together, we're free to separate them out?
		DR. LOVE:  Absolutely.  What we're seeking are your thoughts on that matter.  And whether it is one large indication or multiple indications is fine.  I think one of the things that came up in the public meetings is these indications and these categories can be worded in different ways.  And there may be a level of a general physiologic indication for a product and there may also be a very specific disease-specific indication or treatment indication perhaps for one aspect or one particular population of patients may benefit.  So there are many different ways to word the indications, and whatever comments you have we would be glad to review.
		Thank you.
		DR. RAMSEY:  Any other questions, comments?
		(No response.)
		DR. RAMSEY:  I want to thank the speakers this morning.  Each one I think did a very nice, concise job.  The questions are also very insightful, as usual.
		I think it calls for a break on the program.  But I think there is no need for a break, so we'll just forge ahead here.  I understand from Mr. Madoo that the next speakers, even though we're ahead of schedule, are available for presentation.  So I would like to ask them to come up and do their presentations.
		I'm not sure exactly how these will be, but Dr. Sancho and Dr. Laniyonu, I apologize if I pronounced those incorrectly, are listed as the next speakers under the heading of "FDA Presentation on the Safety and Effectiveness of Fludeoxyglucose F-18 Injections:  Clinical Pharmacology, Pharmacology, and Toxicology."  They will be our first two speakers.  Could you please tell us your name. and then are these on the handouts that we can follow along?
		DR. LOVE:  Right.  We were anticipating a break, so I think the speakers are getting prepared right now.  The first speaker actually is going to be Dr. Laniyonu, and he will cover the information and then he will move through the rest of the presentation.
		DR. TULCHINSKY:  Dr. Ramsey, can we in meantime ask the housekeeping here to raise the temperature a bit.  Myself and my left-hand side neighbor are a bit cold.
		DR. MADOO:  We'll address your biological needs.
		(Laughter.)
		DR. RAMSEY:  I can't help but say, does this mean we turn the air conditioning up or down?  This has been a constant battle in our house.  So you said it very well.
		DR. LANIYONU:  Good morning.  My name is Adebayo Laniyonu.  I am a pharmacology and toxicology reviewer in the Division of Medical Imaging and Radiopharmaceutical Drug Products.  The topic of my presentation today on the pharmacology, toxicology, and clinical pharmacology of 18-F FDG is actually a joint presentation with my colleague Dr. Alfredo R. Sancho, who will do the clinical pharmacology portion of the review.  He did the clinical pharmacology of the view, and I was responsible for the pharmacology and the toxicology section.
		Both Dr. Raczkowski and Dr. Houn will be going into greater details on the approach taken for the individual section of the review.  This is simply a brief summary of what we did in the pre-clinical pharmacology section.
		First of all, we reviewed peer-reviewed publications that were written in English and conducted research on-line.  Secondly, we looked at materials that were reviewed previously as part of the 18 FDG NDA review for epilepsy.  And just as has been recounted several times today, it bears that we remember that actually FDG has already been approved for an indication.  Finally, materials were solicited from the PET community.
		Today, my talk will focus on these topics.  The first one will be the characteristics of 18-F FDG, its uptake and trapping mechanism.  The second one will be the theoretical considerations governing the use of these products.  I will then go on to very brief myocardial and oncological considerations, because, again, Dr. Raczkowski and Dr. Houn will be talking in greater detail on these considerations.  I will provide some dosimetry information, information on metabolism and biodistribution, and, finally, I will end my talk on toxicology.
		18-F FDG is a glucose analog with a fluorine substitution at position 2.  It concentrates in cells that depend on glucose as primary energy source or, worse, depend on glucose increases during pathophysiological conditions.  It shares similar kinetics of transportation and phosphorylation with glucose.  But as I will be pointing out during the course of my talk, there are subtle differences in the way the body handles the two hexoses.
		18-F FDG is transported across membranes by phosphorylated glucose transporters.  To date, at least eight subtypes of these transporters have been identified with varying degree of tissue selectivity and specificity.  They also vary in the way they are sensitive to hormones like insulin; some are very much affected by insulin, whereas others are not.
		Once 18-F FDG is taken intracellulary, it is phosphorylated by the enzyme hexokinase into 18-F FDG.  But that is really where the similarity with glucose rather ends because, unlike glucose, it does not enter into further metabolic pathway.  For example, it cannot be converted into glycogen, neither (inaudible) cycle for the production of CO2 and water.  In most cells, therefore, because there is very little phosphatase activity, and because we find out we don't have further conversion of the phosphorylated FDG into other metabolic pathways, you end up with an intracellular concentration of FDG.  Therefore, the amount of phosphorylated FDG you have within the cell would then depend on the balance between the activity of the glucose transporter, hexokinase activity, and the activity of the phosphatase.
		To allow for glucose quantification, the kinetic differences between glucose and 18-FDG transport and phosphorylation are reflected in a ratio called the "lumped constant."  There are lots of mathematics involved with this and there are various modifications that should keep us in the literature actually on a daily basis.  And I actually believe that some of the authorities that are responsible for the derivation of these constants are actually in this audience.  For the purpose of my talk, I will not go into further details on how the lumped constants are calculated.  But it is really variable depending on whether you are dealing with a situation in which there is luck, or there is lots of phosphatase activities; virtually many things can affect the lumped constants calculation.  So, briefly, the original decrease or absent uptake reflects absence of glucose metabolism.
		For the myocardial considerations, in general, fatty acids are preferred source of energy.  But then you have contributive use of glucose increases during hypoxic conditions because of glucose requirement for less energy.  Therefore, there is increased uptake of glucose analogs such as 18-FDG.  And then you can use that increase in uptake as a reflection of areas where you have glucose metabolism still taking place.
		In general, there are actually two key considerations.  In a situation where you have perfusion-metabolic match; that is, when you use FDG monitoring with the perfusion measurements, there is a simultaneous reduction in both FDG uptake and flow.  And there are actually instances in which FDG measurements can be used independently of measuring flow.  Secondly, in that instance in which there is a simultaneous reduction in both FDG uptake and flow, this in the literature that we reviewed was generally interpreted as a poor prognosis that revascularization would be of any help.
		The second instance is where you have official metabolic mismatch, there is a enhanced FDG uptake and reduced blood flow.  And in the literature that is usually interpreted as revascularization will actually improve performance.
		Factors that may affect the uptake process include fasting, insulin level, and diabetes.  And there are really lots of papers that you come across in the literature arguing or providing different perspectives on how these various factors might affect what you are trying to measure.
		For oncological considerations, we are all aware that there is variability in how oncological tissues present themselves.  Be as it may, tumors have very high glycolytic activity which may be due, in part, to high hexokinase activity, increase in the level of glucose transporter expression, or a decrease in phosphatase activity.  Depending on the tissue or location, one or two of these might be actually involved in the process of the high glycolytic activity that you have in tumors.  The net result anyway that there is increase in 18-F FDG uptake in tumor cells.
		Dosimetry information, 1 mil vial contains about 6.8 to 35.7 millicurie.  As pointed out earlier during the day, the physical half-life is about 210 minutes and it decays true positron emission.  And, of course, you have patients being encouraged to increase fluid intake and reduce exposure to the bladder which is the critical organ.
		Metabolism and biodistribution.  It is metabolized through phosphorylated intermediates to 2-fluoro-2deoxy-D-mannose.  Both FDG and FDM are rapidly cleared from the blood and brain, but less rapidly from the heart.  And there is some school of thought I believe that perhaps you may have accumulation of the metabolites for at least 90 hours after the procedure might have ended.
		There are variable levels of both FDG and FDG-6 phosphorylated tumors.  FDG is basically excreted in urine.  And, again, when one realizes that there are other normal physiological conditions, there is virtually no excretion of glucose in the urine.  This is an important difference between the way the body handles glucose and the way the body handles FDG.
		2-chloro-2-deoxy-D-glucose, I actually put this one in there because of the previous NDA and because of the changes in manufacturing processes, this used to be a manufacturing impurity.  We believe that the body handles CDG similarly to the way it handles FDG and glucose.
		For the toxicological studies, there is really no significant FDG toxicity found in studies that we reviewed in both dogs and mice.  The apparent level dose, that is, the dose that you cause 50 percent detal, is in mice about 200 milligram per kg.  In studies done in 1960s and early 1970s that used 2-D of the glucose, another analog of glucose, to ascertain the completeness of phagotamine in humans, 2-DG at a dose of 50 milligram per kg, which is more than or about 50 times the multiple of the human dose, caused hypoglycemic effects that are similar to that produced by insulin.  We were not able to find sufficient information on the effect of FDG on metabolism in compromised myocardium.  There is some information but not in great detail.
		So we came to a preliminary summary for the moment that says pharmacology, toxicology, and clinical pharmacology assessment supports use of 18-F FDG for oncology and myocardial indications.
		Thank you very much.
		DR. RAMSEY:  Thank you very much.
		Our next ‑‑ is Dr. Sancho doing a presentation?
		DR. LANIYONU:  No.
		DR. RAMSEY:  Okay.  That was including those two presenters.
		The next portion is safety and effectiveness in oncology.  Dr. Florence Houn, who is the director of the Office of Drug Evaluation III.
		DR. HOUN:  Hi.  Welcome.  Besides being the office director for Office of Drug Evaluation III, I am also an instructor in oncology at the Johns Hopkins Oncology Center, and I tend the Breast/Ovarian Surveillance Service.  I trained in cancer prevention and control from the NCI.  I have been at FDA for six years, the last four and a half were spent being responsible for the implementation of the Mammography Quality Standards Act, which all 10,000 U.S. facilities that perform mammography are FDA certified, accredited, and inspected.  The results of FDA's efforts in mammography quality have just been published in Radiology in February of this year showing great improvements in mammography quality.
		I'm going to be talking today o F-18 FDG in PET's use in oncology and trying to discuss safety and effectiveness for an indication for this product.
		I wanted to acknowledge my teammates in helping me perform the review.  Dr. Sabhan, Ms. Jordan, Dr. Hussong, Dr. Kasliwal, Dr. Laniyonu, who you've heard from, and Dr. Sancho, who also worked on the previous presentation.  I also want to thank Dr. Raczkowski, Dr. Love, and Dr. Lumpkin for providing me with comments as well.
		My preliminary conclusion are that there is effectiveness for FDG PET use in identifying areas of abnormal glucose metabolism to evaluate malignancy in patients with abnormalities found either by other testing modalities or in patients with an existing diagnosis of cancer.
		This is kind of a long, wordy indication.  I am going to try to explain the various components of it.  As you can see, there is a functional component, as we talked about earlier, in terms of how indications for radiopharmaceuticals are being structured.  We have a functional indication.  We also have an indication that is for diagnostic use, and I am going to explain that, how it differentiates from screening use.
		In the literature, IV doses of 200 to 740 megabecquerels were used, an average dose of 376 megabecquerels in the studies, and people were fasting at least for four hours or more.
		My approach to literature review was based on two guidances FDA has published, a Clinical Effectiveness Guidance that was published in May of last year, as well as the draft Medical Imaging Guidance that we've talked briefly about this morning.  I am also going to be talking about how I chose the intended use for F-18 FDG oncology, talk about the use of pathology as a standard for the studies that were done, the search methodology I used, the selection criteria of articles, the review of findings, and the preliminary conclusions.
		Now the Guidance on Clinical Effectiveness describes when FDA may use published literature alone in finding effectiveness.  Now I know many of you who have been on the committee are aware that FDA typically reviews two or more adequate and well-controlled clinical trials by the sponsor of a drug to determine effectiveness and safety.  The two trials are usually used to avoid systematic bias, to allow for independent substantiation of results, to avoid the chance occurrence of efficacy, and to avoid center or site or investigator-specific factors.
		Well, the literature can be used to support effectiveness.  And some of the principles we're looking at were were there multiple studies that were published with adequate designs, consistent findings, is there details in the protocol presented, including statistical plans or analytic methods, and a full counting of the enrolled patients, were the endpoints objective, were they appropriate, were the conclusions consistent across studies for efficacy and that they robust enough that did not require post-hoc analysis, was the conduct of the studies properly done with documented operating procedures.  And the literature, as Ms. Axelrad has explained, has been used before for effectiveness for other products, including secretin to evaluate pancreatic function, bleomycin and talc to treat malignant plural effusions, doxycycline for malaria, and recently thalidomide for erythema nodosum leprosum.  These have all been literature-based approaches for effectiveness.
		In terms of trying to define adequate and well-controlled studies in the literature, the draft Medical Imaging Guidance provided some foundation for what are some key parts of studies that highlight adequacy and being well-controlled.  One was the selection of subjects, were these the target population for which the drug is intended to be used.  The target population would include people who are suspected of having the disease, so some of them are going to end up having the disease as well as some will not.
		The guidance document also mentions readers and were they reading independently, were they masked, how were they masked, were they masked to previous clinical findings or at least to the final diagnosis, were images presented in a randomized fashion, were images, if they were paired, were they presented together or separate.  So all these kinds of factors on reading we looked at when we were reviewing the literature.
		In terms of a standard of truth for oncology, this is usually pathology.  But we also know that standards aren't perfect; they are subject to errors and limits in technology.  The problems with pathology, well, there is sampling error, how are you going to get the pathological sample, are you going to sample all abnormalities?  There is classification error involved in reading a slide.  And for non-patients you say who are non-cancerous or do not have cancer, how long should they be followed ‑‑ a month, a year, three years ‑‑ to say that they are truly disease free?  So these are some issues that the standards of truth pose problems for in defining a test in oncology.
		We also look at endpoints.  What is a PET-positive test?  How is that defined?  What are the criteria?  The analysis plans, were they done per patient, per organ?  Were they stratified by staging or by size of tumor or patient demographics?  And finally, does the study include some information about safety, toxicity or radiation assessment?
		For F-18 FDG in oncology, the intended use, as described earlier, was to assist in evaluating malignancy in a diagnostic population.  Why this intended use was chosen was that, in looking at the preliminary listing of articles, it seemed that most of its use was in evaluating malignancy, whether patients had it or not.  It was not used as a pathopneumonic definition of cancer but was used in assisting people in making this diagnosis.  It was used in a diagnostic population as opposed to a screening population; diagnostic population being defined as a population with either a known disease, these people have had a previous diagnosis of cancer and they are looking to monitor for recurrence, or people do not have a diagnosis of cancer but have a sign or symptom or other test abnormality indicating a potential problem.  This differentiates a population that screening, which is a healthy asymptomatic population without the disease, and that is most commonly done in terms of breast cancer screening, prostate cancer screening.
		In looking at this intended use for evaluating malignancy in a diagnostic population, one example is how PET has been used with solitary pulmonary nodules.  Each year there are about 130,000 cases of SPN.  There is some radiographic findings for being benign, such as having central concentric or stippled calcifications, or there is two-year follow-up and there's no change in the radiographic images.  But this poses a problem because people either are diagnosed because they have a symptom or they present because they have had a screening chest x-ray and this is a finding and they need further diagnostic workup to determine should this be biopsied or not.
		In terms of where this fits the indication section, we were talking earlier about what are the different types of indications, and we are proposing that for FDG oncology the use would be as a functional physiologic or biochemical assessment indication.  And that's why the phrase "to identify areas of glucose metabolism" is put in the indications as a functional biochemical assessment.
		The standard of truth we wanted to validate this against was pathology.  And as Dr. Laniyonu has stated, there is a pharmacological basis for having this functional claim in that cancer cells differ from normal cells in their metabolism.  There is elevated levels of hexokinase, phosofructokinase, and pyruvate dehydrogenase, there are lower levels of glucose-6, phosotase, and there is increased glucose transporter proteins 1 and 3.
		In terms of discussing a standard for PET, we are going to be comparing PET results to pathology results.  All the studies that have been chosen in this review have made that comparison and that allows us to calculate sensitivity and specificity.  Now, in evaluating the perspective performance of a new diagnostic modality, if it is based on the initial classification of an abnormality by conventional standards, such as x-ray or chest x-ray or MRI, this process doesn't allow the new technology to assess cases that are not picked up by the conventional methods.  And, therefore, I'm not going to make any attempt to comment on superiority of methods.
		The search methodology used was that on-line literature published between January 1 of 1990 and July 1 of 1998 was searched.  The trials had to be clinical trials in humans, they had to be published in English.  We used several on-line databases, as listed on the slide.  We also got many suggestions from ICP and the PET community.  And we also used references from the articles we had gotten previously.  In all, there were about 150 articles that were generated from this search.
		In trying to select articles that could be looked at for safety and efficacy being adequate and well-controlled, we looked for articles that were prospectively done.  In addition, that the PET results were compared to pathology results and that there was a clinical performance hypothesis.  Eventually, if there is safety and efficacy found for PET in terms of an oncologic evaluation indication, it is hoped that other kinds of indications such as quality of life indication, therapeutic management indication, others can also be studied for this product.
		We also looked for a well-described study population.  Enough detail had to be published about the PET imaging, the dosing, the acquisition, the image analysis.  I was looking at more than 50 evaluable patients, and that was chosen just to provide some more level of confidence in the study's estimate of PET's performance.  We did look at studies that had fewer than 50 subjects but they are not included in the write-up.
		There are many investigators who use their datasets multiple times in publications, and we looked at the larger dataset when that occurred.
		In trying to define what is adequate and well-controlled, in trying to separate that from other studies, we generated two studies that we felt could meet that definition that had a prospective enrollment, had at least 50 evaluable patients, and that there was considerable detail in terms of interpretive criteria and other aspects of the trial.  Other supportive studies, we had 14, which are also listed and we will discuss them briefly as well.
		The two studies that we'll spend a little more time with are the studies by Carr, published in Blood in 1998, and the study by Lowe done in 1998.  The other 14 supportive studies are listed in alphabetical order you see here.  The next slide has an omission.  Under Moog, there should be Sazon, S-A-Z-O-N, who published a study in 1996 that is included in the review but the name was omitted in this slide.
		The Carr study came out of the United Medical and Dental Schools of Guize and St. Thomas' in London.  It was published in 1998.  The objective was to use FDG to try to differentiate benign versus malignant marrow lesions in routine staging done in lymphoma patients.  These were patients who were already identified as having lymphoma.  There were 50 consecutive patients who were getting staging with routine PET and bone marrow biopsy.  There were 38 non-Hodgkin's lymphoma patients as well as 12 Hodgkin's lymphoma patients included in the study.  There were no sex or demographic information presented.
		The design was a prospective study that compared pathology results to PET results as well as to thoracic and abdominal CT, unilateral iliac crest aspirate or trephine biopsy.  All patients had their PET scans performed within four weeks of their marrow.
		The image protocol has some details, including the visual interpretation was done by three independent nuclear medicine physicians.  Abnormal was defined when uptake was equal to or greater than the liver uptake provided that the liver uptake was greater than the background.  Patterns were also noted in the image protocol, whether lesions were focal or diffuse.  And there had to be two out of three concurrence for a final PET reading.  A kappa score on agreement was tracked.  And the pathologists, there was some detail about the pathology protocol, including how the histology criteria was determined, the slides being checked by two hematologists and one pathologist who were unaware of the PET reading.
		A dose of 350 megabecquerels IV was given at greater than 16 hours after fasting.
		The sensitivity and specificity is presented, with 13 out of 16 people who had marrow lesions being picked up by PET, and 26 out of 34 who did not have marrow lesions being picked up by PET using unilateral bone marrow as the gold standard.  There was some discussion in the articles about the concordant and discordant cases and the authors discussed at length how to modify the PET results by trying to resolve PET-positive biopsy-negative patients.  But this form of discrepancy resolution where you're just looking at discordant cases just resolving the new technology-positive patients is a biased form of discrepancy resolution, and so we really didn't look at those results that the authors presented.
		Strengths of the study included that they use three independent readers, the criteria for PET reading was given.  They tracked agreement.  They masked the pathologists, that was specifically stated.  Histology protocol and criteria were given.
		Some of the weaknesses include that only 50 patients were in this study.  The biopsies were performed unilaterally, but this was the standard operating procedure for the hospital.  And that they tried to resolve the discrepant cases only using the PET-positive bone marrow-negative cases.  We don't really know if the readers were masked, but, because it was a prospective design, I am assuming they were masked to the final pathology reading and I believe they knew the initial diagnosis of the patients.  I had also as a weakness, going back one slide, Russell, that they combined the Hodgkin's disease and non-Hodgkin's disease patients.  That is because that bone marrow involvement may not be the same for both types of patients.  Non-Hodgkin's disease patients tend to have more of a probability for bone marrow involvement than Hodgkin's disease patients.
		In another study that we reviewed at length was a study done by Val Lowe in 1998.  This was a multi-centered trial from the University of St. Louis Health Science Center, Creighton University, Good Samaritan, and St. Joseph Hospital in Phoenix, Arizona, the University of Iowa Hospitals and Clinics, Northern California PET Center in L.A., University of Tennessee in Knoxville, and Vanderbilt and Duke also participated in this study.
		The objective of the study was to define sensitivity and specificity for PET in patients with solitary pulmonary nodules seen on chest x-ray or CT scan.  Eighty-nine consecutive patients were enrolled from October 1993 to August 1994.  As I said before, it was a multi-centered trial.  There were 61 men, 28 women involved, with the mean age of 63 years.
		The inclusion criteria was lesions that were at least 0.7 sonometers in size but no larger than 4 sonometers.  This dealt with the limits of resolution of the PET scanner.  And they had to be considered indeterminant by independent reading of the CAT scan or chest x-ray.  This was a comparative study between PET and pathology and standard uptake values, which is a semi-quantitative measurement of the ratio of measured radioactivity concentration in an area of interest to the estimated total body radiopharmaceutical concentration.
		The image protocol involved three nuclear medicine physicians who interpreted studies that they were not involved in.  They were masked.  There were two readings per PET image on film copies.  Disagreement involved consensus reading.  And agreement between the readers was tracked, and kappa was found to be 0.95, which is excellent agreement.  Abnormality was defined as an uptake greater than mediastinal blood.  This was considered positive.
		Chest x-rays and CAT scans were read by non-site radiologists who were masked.  This was to ensure that the patients had, indeed, an indeterminant diagnosis.  The dose was 370 megabecquerels IV after at least four hours of fasting.
		The results of the study showed that of the 89 patients, 60 had malignant lesions, 29 had benign lesions.  Fifty of the sixty malignant lesions dealt with non-small cell carcinoma, but there were five cases of melanoma.  There was one Hodgkin's disease, one small cell, one carcinoid, one neural cancer, one colon metastasis.  There were 29 benign lesions, of which 7 were granuloma, 7 others were coccidiomycosis, 4 had cellular debris, 4 had non-specific inflammation, 3 had necrotizing granuloma, 1 fibrosis, 1 hemangioma, and 1 aspertgelosis and metaplasia.
		Visual sensitivity was 98 percent with confidence intervals 91 through 100 using the exact method.  And specificity was 69 percent with a confidence interval of 49 to 85 percent.
		Now the strengths of the studies included the inclusion criteria, which was very similar to the clinical presentation of SPN patients.  There was detailed patient information tables.  There was discussion on the pathology standard.  Images were read by two readers that were independent, they were masked to the CT and x-ray findings.  Interobserver differences in PET were tracked and analyzed.  Sensitivity and specificity could be derived.
		Other strengths include, the article describes how disputes were resolved.  There was information on chest x-ray and CT readings, that these were controlled.  Many studies involved readings of these types of x-rays at referring physician locations, and many studies did not describe how they were handled by the study investigators, what readings were utilized, new readings or the readings from the original referring physician.  This study re-read every film.  It was a multi-centered trial.  The patients were numerous, and there was detailed patient information.
		Weaknesses of the study include that there were twice as many malignant lesions as benign lesions.  Maybe that not fully testing the capability of the technology in terms of the spectrum of disease.  There was no information on the pathology reading protocol.  And that there were sampling variations; 29 cases used the trans-thoracic needle aspiration for biopsy versus 60 cases using the open-lung biopsy for sampling.
		The next slide shows a series of supportive studies that are included in the medical review, that draft review that you all were given a few weeks ago.  In all, the 14 supportive studies and the two studies that we just talked about, Carr and Lowe, encompassed a variety of cancers ‑‑ non-small cell carcinoma, colorectal, pancreatic, breast, thyroid, melanoma, Hodgkin's disease, non-Hodgkin's disease, and metastatic cancers to liver, lung, bone, and axillary nodes.
		There was a total of 1,311 patients, most fasted for at least four hours or more prior to their IV administration of FDG.  Doses ranged from 200 to 740, with an average of 376.  In two studies they used doses based on weight, Valk in 1995 used 5.3 megabecquerels per kilogram, and Vansteen Kiste used 6.5 megabecquerels per kilogram.  Only one study utilized a dose over 550 megabecquerels.
		I am going to just briefly go through the studies.  You have them summarized in the packet before you and the actual studies have been included in your handouts.
		Avril's 1996 study was from Munich, Germany.  The goal was to define benign versus malignant breast lesions using PET versus pathology standard.  We have a sensitivity of 83 percent, a specificity of 84 percent out of 41 cancers and 31 benign lesions.  This study excluded pregnant women, excluded women with prior surgery, radiation therapy, and chemotherapy.  This study was done by tumor analysis as opposed to per patient.  But the study did include a subset of 20 patient images who were looked at again for reproducibility of drawing circles around the area of interest and tracking that interobserver agreement.
		The next study was Bury, done in 1997, from Belgium, dealing with staging of non-small cell carcinoma of the lung.  It was a PET versus conventional staging methodology study.  The PET readings were done independently but they were not masked in that the readers knew about the CAT scan and bone scans.  Then results were compared to each other, and in pertinent cases, with histology proof.  Metastatic sensitivity was 100 percent, 39 out of 39, specificity was 94 percent, 66 out of 70.
		Delbeke's study in 1998 was done in Vanderbilt.  It was a study of benign versus malignant hepatic lesions that were at least a sonometer in size.  The sensitivity ended up 90 percent, with a specificity of 96 percent.
		Dietlein published a study in Germany in 1997 on thyroid metastases comparing PET versus I-131 whole-body imaging.  This study excluded patients with diabetes or papillary microcarcinoma.  And all the patients had glucose less than 100.
		A study by Friess in 1995 out of Switzerland and Germany looked at pancreatic cancer versus pancreatitis and use of PET in differentiating those two diagnosis versus CT readings.  We have a sensitivity of 94 percent, a specificity of 88 percent out of 42 patients with pancreatic cancer and 32 patients with pancreatitis.  This study used furosemide, and contained a detailed patient line listing.
		Gupta did a study in 1996 on solitary pulmonary nodules, looking at would PET predict being malignant or benign.  The study came out of West Virginia University Hospital.  There were two readers who were masked to the histology data but not to the CT and x-ray findings.  Sensitivity was 93 percent, and specificity was 88 percent.
		Holder's study in 1998 from North Carolina looked at the detection of metastatic melanoma.  There is an error in this slide in that under image protocol the phrase "not all patients had bilateral bone marrow biopsy" really belongs here under Moog.  The sensitivity for the study was 94 percent, and specificity, 83 percent, with 52 patients having metastatic melanoma and 48 having non-metastatic melanoma.
		Another study by Lowe in 1994 out of St. Louis, Missouri, was looking at benign versus malignant lung lesions.  A sensitivity of 97 percent in terms of 59 out of 61 carcinomas being defined by PET, and a specificity was 87 percent, 23 out of 27 benign lesions being identified by PET.
		The last study here, Moog, was done in 1998 in Germany on Hodgkin's disease and non-Hodgkin's disease patients and looking at bone marrow involvement.  Not all of them having had bilateral bone marrow biopsy for the standard; 70 had bilateral biopsies while 8 had unilateral biopsies.  There was a visual sensitivity of 64 percent, 7 out of 11 who had positive bone marrow biopsies were picked up by PET.  A specificity of 85 percent, 57 out of 67 who were negative on bone marrow biopsy being PET negative.
		Sazon published a study in 1996 on lung lesions and whether they were cancerous or benign.  The sensitivity being 100 percent, 82 out of 82, and a specificity being 52 percent, 13 out of 25 did not have cancer.  This was a study out of the VA in West L.A., California.
		Schiepers, from Belgium, published a study in 1995 on identifying metastatic colorectal cancer on PET versus conventional imaging.  In terms of finding liver metastases, the sensitivity was 94 percent, 32 out of 34 were identified.  Specificity was 46 out of 46 who did not have liver metastases were PET negative.  The clinical follow-up for this study was over 14 months, which is one of the longer follow-ups.
		Utech published a study in 1996 from Illinois on axillary node staging with breast cancer.  A sensitivity of 100 percent, 44 out of 44 patients who were axillary node positive were identified by PET, while 60 out of 80 who had no axillary node involvement were PET negative.
		Valk's 1995 study was on the staging of lung cancer and indeterminant lung lesions, from the Northern California PET Center.  Mediastinal sensitivity was 83 percent, 20 out of 24 patients who had nodes were identified by PET.  Specificity was 94 percent, 49 out of 53 patients who had no mediastinal nodes were identified as PET negative.
		And finally, Vansteenkiste published in 1998 a PET and CT nodal staging of lung cancer.  And the use of these two modalities together compared to CT alone gave a combined sensitivity of 87 percent versus 59 percent.  So that was 59 out of 68 people who had nodes in their mediastinum were identified by PET compared to 40 out of 68 by CT.  This study excluded people who were diabetic, who were on steroids, who had heart failure, who had bulky mediastinal involvement.
		In looking at the literature, there was an absence of statistical criteria for significance and power.  Usually when FDA looks at studies, there is a Type I error, Type II error, the power is set.  It is not to say that these studies did not have these parameters set, they may just not be published in the article.  Of course, there was less information on protocols for imaging handling and reading criteria than protocols that you would get as a submission.  There is also an absence of source data, the line listings, and detailed line listings were available only in a few studies.
		Obviously, I'm looking at a very biased group of papers because they were all published.  Publication bias can refer to a variety of things, including the fact that I'm only looking at English studies, looking at those available in the electronic media, those that were published.  I'm also looking at either surgical literature, oncology literature, radiology literature, and each type of journal has a specific type of editorial policy on what type of information they want in their articles.  So there may be less information on image handling or blinding, those kinds of issues that we tend to pay more attention to when a sponsor comes before the agency in medical imaging.
		Finally, it is just hard to deal with verification bias.  It is hard to obtain pathology on all lesions.  It is hard to follow-up on all negative results.
		Other weaknesses of the literature include no control for prior imaging interpretations.  People who were identified as abnormal by a CT or chest x-ray, whether they used oral contrast agents, IV contrast agents, whether the interpretations were done by the referring physician and carried over to the study physicians.  A lot of this was not discussed.
		There was use of furosemide in a couple studies, and serum glucose was only mentioned in a few studies as well.  We do know that furosemide can effect sodium chloride potassium symport in the thick ascending limb of the loop of Henley, it can inhibit glycolysis, it can cause glucose pertabrations.  We also know that high serum glucose may compete with FDG and its effect on the drug's safety and efficacy was not really studied in the presented literature.  And finally, there are variations in pathological sampling that we mentioned.
		Now the literature has been reviewed before by the VA in 1996 and by Blue Shield Association Technology Evaluation Center in 1997, and I think they are going to be publishing their re-evaluation of PET again.  In those reviews of literature, these organizations paid a lot of attention to improved health outcomes, the utility that PET would give in terms of an incremental value in treating or in planning for patients.  And the critique from these organizations was that the literature at that time, the studies were small in number in terms of the patients they enrolled, they were retrospective, they were uncontrolled, they didn't really deal with interobserver variation.
		Although I think these criticisms are valid, the VA and the Blue Cross/Blue Shield Association is dealing with a different standard in terms of looking at the criteria for PET imaging.  Under the Food, Drug, and Cosmetic Act, we are required to have substantial evidence through adequate and well-controlled trials that qualified experts can responsibly and fairly determine that a drug does what it purports to do under specific conditions of use.  This is a different type of criteria than ensuring increased incremental utility of a technology in patient management or therapy, which is the criteria that these other agencies were using.		
		In looking at the preliminary review conclusions, I do think that there is efficacy in identifying areas of abnormal glucose metabolism for evaluating malignancy in patients that have an abnormality found by another testing modality or with an existing diagnosis of cancer.  There was one retrospective screening study which I looked at but did not include in this review.  Although the product may appeal to some for promotion for screening, it really has not been thoroughly tested in a trial for screening.  So that's why the review conclusions focus in on a diagnostic indication.
		The findings are consistent.  There are diverse malignancies that we looked at where there is a generalized mechanism of increased glucose utilization.  But it is not a tool that has 100 percent sensitivity or 100 percent specificity in that we know there are cancers that are less likely to show up on PET scans because their metabolism is different.  There is low grade non-Hodgkin's lymphoma which tends to be PET negative, bronchial alveolar cancer, renal cell cancer, these are cancers that may not show up as well on PET scans as other modalities.  But sensitivity and specificity can be calculated from the studies that we reviewed because pathology was used.
		In terms of safety, a small amount of FDG in glucose is introduced into the patient.  Dr. Laniyonu talked about the known metabolism excretion of this agent.  It has a short physical half-life.  The dosimetry information and risk of radiation, especially in a diagnostic population, is acceptable.  But we really don't have a lot of information in terms of its performance in patients with hyperglycemia.
		So I am going to conclude with my statement again on effectiveness in terms of identifying abnormal areas of glucose metabolism in the diagnostic population, and in terms of the IV doses used for the studies, and that these studies were performed with at least four hours of fasting prior to injection.
		Thank you.
		DR. RAMSEY:  Thank you very much, Dr. Houn.
		We're close to a time for a break, but I think it is appropriate now to pause for questions.  We will have Dr. Raczkowski present after the break, if that's okay.  Why don't we pause now for questions on the first two speakers, and then we will move on from there.
		Could you please introduce yourself?
		DR. KONSTAM:  Hi.  I'm Marv Konstam from New England Medical Center Tufts University, and I'm from the Cardiovascular and Renal Advisory Panel, and I'm eminently qualified to ask questions on this subject because I'm totally unbiased by any knowledge about oncology.
		(Laughter.)
		DR. KONSTAM:  I guess listening to the presentation made me want to just bring up some general questions regarding the process and the nature of the data, and then a couple of specific questions.
		I guess it is inferred but needs to be stated that the situation we're dealing with here is very, very different from any that most of us have participated in before in the review process.  And there are some major ways in which the datasets are, I hesitate to use the word, inferior, but I guess I'll use it, compared to the typical NDA.  I think Dr. Houn has identified some or most of these in her reviews.
		So, for example, we don't really have benefits of protocols.  We don't know really whether there were prestated analytic and statistical methods and whether those were adhered to.  The validity and the integrity of the datasets are not what we're used to.  The FDA generally has the entire dataset and reviews it in detail to verify the validity and integrity of it; we don't have that here.  And as Dr. Houn pointed out, there is a significant publication bias that is there, that is potential.  We just don't have any real idea what the magnitude of that is.  And there are others I think, and you pointed a lot of them out.  That's my comment.
		I guess I'm looking for some kind of response and guidance from the FDA about this in the sense that I think if this were NDA that a sponsor were bringing to us, these data would not really typically meet the qualifications for efficacy.  And so, philosophically, as we go forward, how are we to deal with this?  Is there some kind of pressing need to seek approvability on something less than typical standards?  Just any kind of advice or comments on the part of the FDA that you can give.
		DR. HOUN:  I think what we're asking for is ‑‑ there is a big difference in terms of typically people are sitting here looking at a very detailed clinical trial or two clinical trial protocols with a lot of information.  And we don't have that with the literature.  But what we do have with PET is a long history of use for oncology, since the 1970s, and a concern that if there is so much published literature available on PET and its performance, is this enough for a determination by qualified experts, such as yourself, that the drug is doing what it is purporting to do.  In my case, asking does it identify areas of glucose metabolism abnormality that can assist in oncologic evaluation in a diagnostic population.
		DR. KONSTAM:  I'm sorry.  May I understand that, and I think at the end of the day we're going to wind up, I'm inclined, I'll say right now, to accept your recommendation.  But I guess I'm wondering why I'm so willing to do that.  Maybe if you could define a little bit more clearly what are the circumstances or rationale with which we would so seriously, and I think it is a serious, a significant, let's put that word, deviation from our typical standards of approvability.  Maybe we could define that a little bit more clearly which would be useful going forward in other circumstances.
		DR. HOUN:  I don't know if you want to comment on this.  In terms of looking at clinical effectiveness, the model has been looking at two trials or more.  And when can published literature be used to support effectiveness?  That's what we're trying to do now.  And when it can be used is when there are multiple things we talked about in terms of are there multiple studies done, are there multi-center studies done, are there consistent findings, do some of the studies have protocols that are detailed enough to satisfy how images are handled for bias or how pathology is handled for bias, or how the study is overall conducted.
		It is true not one study may have all these things.  Many of the studies are strong in one aspect or a few aspects, but not all of them.  But in trying to look at the literature as a whole, does it support the use.
		Now we're not performing a meta-analysis.  And that's why we're not giving an overall sensitivity, an overall specificity because these studies are probably too diverse, with too many different populations, they're dealing with different diseases.  Cancers are not all the same.  We're not formally doing a meta-analysis.  But in trying to do an overall judgement of performance, does the literature support its ability to identify abnormal areas of glucose metabolism.
		DR. KONSTAM:  Well, let me just follow up and maybe ask specifically, and maybe this really relates as well.  This question with regard to the indication I think is both a question of indication and process but also a question of what the proper indications should be.  And that is cancer.  You point out that cancer is not just one disease.  And so, in fact, you're dealing with very many diseases.  And so, from a practical viewpoint, I would have some concerns about an indication that just says "cancer," "oncology" without some very specific details about what are the circumstances where it's proven efficacious and where hasn't it been.
		The specific example that I guess I don't know what to do with with regard to the bone marrow lymphoma study, which you identify as one of the two studies that reached your cut point of the highest standards of studies that there was, nevertheless, there were only 16 cases of positive bone marrow lymphoma and 13 of 16 of them were positive.  The degree of reassurance that a clinician in the field can have that they can believe that finding is, I don't know, a couple of orders of magnitude less than they're usually expecting from the FDA.  And the practical question I might ask of anyone with some oncologic background is, would anybody take that finding and skip the bone marrow aspirate or biopsy in somebody with Hodgkin's disease on the basis of that 13 out of 16?
		So, I would welcome any comments about those things.
		DR. TULCHINSKY:  Dr. Ramsey, can I make a comment?
		DR. RAMSEY:  Yes.
		DR. TULCHINSKY:  Thank you.  Mark Tulchinsky, member of the committee.
		I would like to address this question as to why are we doing things different.  That's a very appropriate question.  The FDA has been directed by the Congress to do things different.  In 1997, in that respect, they were asked to look at some of the tests that had very low risk, and in this respect would be PET, and scale down the rigor of assessment according to risk.
		If you, for example, take someone studying the safety of a suspension cord and you have an individual working on the 50th floor, you would really want to know that that suspension cord is safe and efficacious.  If, on the other hand, suspension cord is used for someone working on the floor here in the audience, I would submit to you that the rigor you would employ in studying that suspension cord would be fairly different.
		Therefore, looking at the PET radiopharmaceuticals, and given the safety profile, the rigor has been somewhat reduced for assessment of safety and efficacy as well as labeling indication.  So that's one aspect of your question.
		Now there is another one, and that is, how do we know that the indication you're proposing here, and you took an example of the bone marrow biopsy, is really a clinically useful tool?  And here, I think an appropriate comment would be that the clinical indication will be tested, certainly in the health care industry, as has been the case with lung cancer, the pulmonary nodule, and the health industry and HCFA will assess those things.  And if they are useful, they will be used.  If they are not, no one is going to spend the money to use it.  We're paying for the health care.
		DR. HOUN:  I would just make a comment that FDAMA does not direct us to use any different standards in terms of a lower standard.  They asked us to look at new procedures, develop new procedures to approve PET.  This procedure, in terms of looking at literature, is actually not a new one.  It hasn't been regularly used but it has been used in the past.  And the most recent was with the emergency contraceptives as well as with thalidomide.
		The standards for what you look at in the literature are going to be different than what you look at when you have two fresh clinical trials with the entire protocol before you.  But we're asking whether the committee sees through the body of literature, through the 16 various studies, there is another lymphoma study, it's still a small study as well, but whether this type of replication throughout the literature provides substantial evidence.  Now, substantial evidence is a term used legalistically.  It is not beyond a reasonable doubt, which is a criminal criteria, it is not a preponderance of evidence, which got O.J. Simpson, this is substantial as defined by Black's Dictionary as "more than an iota but less than a preponderance."
		(Laughter.)
		DR. HOUN:  And that is what FDA works on, substantial evidence.
		DR. KONSTAM:  I believe that I've heard different instructions than that.  That, in fact, the instructions that I'm used to hearing is that we're going to declare efficacy with a really, really high degree of certainty; and that is, that the chances that the findings that are supporting the indication are in error are really minuscule, I hesitate to use the word infinitesimal, but based on the way I've heard it, pretty close.  And if you think about the standard of two randomized, well-controlled trials, each being less than 0.05, that I think satisfies that.
		So I'm not trying to be argumentative.  I struggling with this.  But I guess I am just seeking some more rationale, if you will, for deviating from what I perceive the standard to be.
		DR. LOVE:  Whether or not this is more rationale, I'm not sure.  But basically, as Dr. Houn has just mentioned, there is a Section 121 and 122 which I think need to be sorted out.  Section 122 is the radiopharmaceutical legislative initiative which asked us to consider a number of features about how radiopharmaceuticals are used.  That is where this issue of Group I/Group II, and looking at safety and how we are sorting that out comes in.  And that is part of that rule and the guidance.
		The PET initiative, Section 121, requests us to develop approval procedures.  And in that process, what we have been doing is looking at whether or not there are some products and some ways we can approach the fact that we don't have an identified sponsor that might normally conduct the kinds of trials that you're talking about and submit the data with the degree of rigor we're accustomed to seeing in an NDA.  So we were looking to see could we, for at least some of the commonly used products that have been out there on the market, find sufficient evidence in the literature that we could use.  And part of the approach to that was them looking at the Center's guidance for establishing clinical effectiveness.  It does have a section in there about how to use the published literature, and a number of the principles that Dr. Houn talked about are in there.  So we're looking there.
		Now sometimes you can look at the literature and find articles that are almost as comprehensive, if not as comprehensively stated, as some of the information that is in an NDA, and that's very helpful.  There are other times that it is not that comprehensive.  So what we are trying to do is see whether or not there is enough information for these three drugs amassed over a period of ten or more years that with this collective information can give us the equivalent weight of what you might find for a brand new drug just coming out on the market where you haven't had the amount of experience that you have right now.  So there you are tipping the scale on the side of asking for a great deal of information because you only have these two studies and not a lot of history and the product is going to come out immediately and be used in a certain way.
		Here we have ten or more years of a product being used with a different set of data in terms of rigor.  But we are still trying to look in all three presentations to see if we have at least two trials that are still providing a large amount of information along with the detailed supportive information as well.
		Someone is asking me to mention that these are also diagnostic products.  So from a standpoint there, for all the products, regardless of whether it is PET or not, we are looking at, from a safety perspective as well as an efficacy perspective, what is the influence of the fact that the products are only used once or infrequently in a patient's lifetime.  That affects safety aspects.
		From a diagnostic aspect, though, we do recognize exactly what you're talking about.  We make major decisions on the basis of these diagnostic products and it is important that the decisions that are made are correct because they do influence the patient's ultimate management; whether they go farther on a diagnostic cue or whether that work-up is stopped, and what kind of medications are you going to receive, what kind of surgical intervention are you going to receive.  So that does have some influence on the risk-benefit assessment, looking at what is the risk of that drug and then what are the consequences from the treating clinician's perspective.
		But I guess going back to your question of why are we doing this.  Part of it is, yes, we do have a congressional mandate to develop approval procedures.  There are a number of ways we could choose to develop those procedures.  One of the issues that we were to take into consideration is the fact of how the products are used as well as something called "non-profit status," which we're still sorting out what does that mean exactly.  But one practical thing is that we don't have an identified sponsor to move forward with the development of a traditional NDA.  And it is for that reason that we have looked at whether or not we could do the review on the basis of the information that was already out there as opposed to seeking the type of study that one might normally seek.
		DR. RAMSEY:  I think I'm actually going to use the Chair's prerogative to declare a break right now.  Because I think this is interesting conversation, there will be other questions.  So rather than prolong it at this minute, you might just hold all those thoughts.  Let's break right now and we'll rejoin here in exactly fifteen minutes, which will make it 10:30.
		(Recess.)
		DR. RAMSEY:  I think we're ready to go ahead again.  So if everyone will please be seated, we will continue with the question and answer session for at least a few more minutes before we go to Dr. Raczkowski and his presentation, following which we will again allow time for questions that come up.  And as you notice in the program, there is time, Mr. Madoo has set up a nice program, so there is time for some interchange here, which I think is excellent.  We all need to feel comfortable going forward with whatever it is we decide to do here.
		I think, Dr. Tulchinsky, you had a question?
		DR. TULCHINSKY:  I was hoping to continue with the discussion that we were having here, and that was centered around the question of why is it all different this particular time.  And I was just going to mention the next point, and that is, if the indication, as stated above, was said to be fairly broad, that was the speaker's comment, if one looks at the indication list for gallium scintigraphy, it is not that much different.  In gallium scintigraphy, in package insert it says "indicated for some tumors in detection of disease."  It doesn't say lymphomas, it doesn't say any other specific tumors, it says some tumors.  So the deviation there is not that big, really it's none, frankly.
		So I just wanted to point out that as well.  Thank you.
		DR. RAMSEY:  Thank you.
		Please, go ahead.
		DR. MALCOLM:  Arnold Malcolm.  Yes, I think the comments that have been made are very relevant.  This is I think a truly difficult situation and different in a sense that, as already been stated, these products have been out here for many, many years and have been used over and over and over in clinical experience, and we have the information to go from.  It is different than an NDA in which, as has been stated, you have to come through with significant other data.  So this is somewhat different.
		However, I think the decisions that we make in this regard are going to have to be done with some caution because I think this circumstance may come along again either with products that have been out there in the past or perhaps new products that companies are going to want to produce in the future.  And then what do we do when the information is not there?  It may be a product also under the same circumstances for diagnostic purposes and how do we hold them accountable, and that they don't come in and say, okay, well, you've done this for these other products, why are you going to have us pass through the same rigor as you were describing earlier.
		So I think we have to look at this very carefully as we move forward.  Also I think it is important, as was discussed earlier, being an oncologist, we rely on these studies, PET scans on a daily basis.  But they're not used in screening purposes, at least I refuse to have it used in that form for me, and it is used as an adjuvant to other studies.  So it has been helpful when we have these dilemmas.  So I think we have to take all those things into account.
		DR. RAMSEY:  Thank you for your comments.
		Dr. Ponto.
		DR. PONTO:  Laura Ponto, the University of Iowa.  In all of these drugs we have to deal with two issues.  One is safety, and one is efficacy.  The safety issue, because this is an approved pharmaceutical already, is essentially one that we don't need to deal with I would think today.  Because it has been approved, we are assuming it is safe.  So we're only dealing with the efficacy issue.
		As someone who has been involved with the Points to Consider document for a number of years, we're trying to deal with different types of indications.  And the efficacy issue is going to come in how we state the indication.  We have posed the possibility of having a functional or a biochemical-based indication.  And yet the indication we're looking at here is more of a disease-specific indication.  And the evidence that we were presented is a disease-specific, being oncology, and we're going to look at the disease-specific indication.  We really have not yet looked at the evidence that we have before us for a total biochemical indication for this particular pharmaceutical.
		So I think that we're going to have to deal with all of these kinds of issues.  I guess one question that I would pose to the FDA is, why did we not look at the biochemistry-based evidence in the briefing documents that we received?
		DR. HOUN:  I think the indication proposed was biochemically-based in the sense it is specifically to identify areas of abnormal glucose metabolism, which is a biochemical function, a process.  The clinical trials that were presented in the literature did not specifically do pre-clinical testing or in vivo or in vitro testing on that aspect.  In terms of the patients they were later to study, what was their specific metabolism or numbers of glucose transporter proteins in this biopsy specimen of this particular tumor, that was not done.
		What we did separately, what Dr. Sancho and Dr. Laniyonu did was to look separately at the pharmacological basis for increased metabolism in cancerous cells.  But this was published literature or literature that was not from the clinical trials that we looked at.  So it was a separate data source.
		But in terms of giving this a disease-specific indication, I'm thinking that by framing it in terms of identifying areas of abnormal glucose metabolism to help evaluate malignancy, it is not specifically saying this is cancer or no cancer.  And as Dr. Howard mentioned, this would not even carry us; you know, in substitute for a biopsy, use this test.  In fact, probably labeling would carry many things about a positive test does not necessarily mean cancer as well as a negative test doesn't mean an absence of cancer, you have to use other clinical judgment and other information.
		But I am thinking we're trying to frame it in a biochemical indication.  But perhaps we're not successful and would look forward to suggestions.  Or if you think it should be more disease-specific.  I think where we ran into a problem is that there were so many different types of cancers being looked at.  And I was thinking if you give an indication with disease specificity, such as to diagnose breast cancer, or to help diagnose liver metastases, that level of evidence probably is higher overall than a broader one.  But perhaps my thinking is reversed.  I would be happy to hear the comments from the committee on what you think would be more logical, useful for this product.
		DR. PONTO:  I just have one other question and it is a little bit off of this topic.  Are we not going to deal with any neurological issues, only oncology and cardiology with respect to FDG?
		DR. HOUN:  At this point, the hypotheses for indication are the very specific ones dealing with the use of FDG for myocardial viability, use of FDG for assisting in malignancy workups, as well as ammonia for myocardial perfusion, and O-15 water for cerebral perfusion.  That doesn't mean that other indications that are supported in the literature cannot be brought forward.  In fact, we are working with the PET community to, as soon as we have our drafts finalized in terms of how we approach the literature, that can be used as a model for the PET community to also bring forward other indications that could be supported by the literature.
		DR. LOVE:  Just one additional comment.  The reviews that are being presented today were based on literature that we received up to this point in time.  So there is other work and we're aware that there are other interests for FDG in neurology.
		DR. CHOYKE:  Pete Choyke.  I'd like to just comment on Dr. Ponto's comment, because I was thinking along similar lines.  Your evidence was very substantial in favor of detection and characterization of tumors.  But when I hear the word "functional" or "biochemical" evaluation, it implies to me some assessment of level of activity within the tumor that has some prognostic or clinical significance.  We're not really talking about that.  We're really going into sort of a binary mode saying it's either there or not there, it's either benign or malignant.
		I wonder whether the phraseology for what the indication is wouldn't be better if something like detection and characterization rather than functional.  There may be functional information.  We're heard for years about the functional utility of PET.  But the data isn't really about function so much as detection and characterization.
		DR. LANIYONU:  If I could just make a quick comment on the biochemical basis of the mechanism of action.  I believe the earliest publication about the use of the deoxyglucose analog was that in (inaudible).  Part of the clinical dilemma in my mind is the fact there is really no controversy about how the deoxyglucose analogs work.  We have in vitro evidence, evidence from in vitro cell lines, and so on.  I addressed all these issues in my pharmacology/toxicology review.  So, invariably, the clinicians are relying heavily on the preclinical data that has been generated for more than 40 years now on the clinical biochemistry, just from a pure biochemical perspective.
		So I really do not believe that, while Dr. Houn referred to a mostly clinical, it has a great underlying basis of a biochemical assumption, which actually, in most analysis anyway, have been found to hold.
		DR. HOUN:  And I would add that in terms of clinicians understanding what the difference this scan offers versus other testing modalities, it is primarily biochemical information in terms of tumor metabolism.  But it is not stating more aggressive or less aggressive; that is not being looked at.  It is metabolism of glucose which has not yet been translated into does this mean a more aggressive tumor or a less aggressive tumor or what.
		But I am think that in terms of what the clinicians use this, it is not going to help so much structurally identify, delineate, but more in terms of pinpointing abnormal areas of glucose metabolism and could this be a tumor or not.
		DR. TULCHINSKY:  Yes, I would like to support your findings.  You were just saying you look towards the committee members to say, well, am I going in the right direction or not.  And I think you are going very much in the right direction.  What we have seen happen today is you didn't just put it in one of four bins as far as indications are concerned, which we were offered in the Act, and that is one of the four indication structures that were outlined earlier today, but, instead, you have interleaved the two, the functional assessment and pathology detection.  I really think that is a very proper, appropriate way to approach this particular radiopharmaceutical.
		DR. ZIESSMAN:  Peter, I think you do have to look at clearly functional.  We're talking about studies that have compared it to anatomical imaging and we are looking at a functional abnormality.  It is not just a matter of a diagnostic category, but, clearly, this is functional information you can't get from anatomical imaging.
		DR. CHOYKE:  As I was listening to the data, I was struck by how many papers in the literature in radiology say using iodinated contrast media would have the same kind of sensitivity and specificity.  We don't refer to iodinated contrast media as functional in any way.  For instance, you can tell by the enhancement patterns of liver lesions to some degree whether they are malignant or benign.  And that's functional.  But nobody ever talks about it in those terms.
		You could plug in virtually any contrast agent into these studies and get these results.  So why we're distinguishing it as functional because of how it happens is semantics I guess, and I know it is highly unpopular in this room.  But I just raise it as an issue because I know that many people naive to this situation really expect more from a functional study.  They're saying this actually tells me something much more about the tumor than an anatomic study.  So far, this data really doesn't.  That's the only point.
		DR. HERSCOVITCH:  Peter Herscovitch.  I would just like to make a few comments on all the previous comments and maybe harmonize some of the discrepant things that have been said.  I think perhaps we have some, I think, very good answers.  Definitely, for some of the malignancies that have been very well put together by Dr. Houn and summarized, we have the answers but perhaps the question as formulated doesn't quite match all the answers.
		Definitely FDG is a metabolic tracer, and that was the impetus for using FDG in, initially, brain tumors, and subsequently tumors below the frenum magnum.  But the evidence that has been presented to answer the question does not specifically address, for example, are we measuring glucose metabolism with FDG against an independent other method for measuring glucose metabolism in the tumors.  Rather, it addresses more diagnostic criteria in terms of the truth is, for example, pathology.  So although the original motivation is based on biochemistry and function, although the mechanism of trapping and retention of the tracer is based on function, the evidence that is presented to answer the question is not functional evidence, more it is classical sensitivity and specificity versus another truth or gold standard.
		So I guess in many ways many of the concerns are correct but maybe not relevant to the ultimate question, which is whether it is good in diagnosing or evaluating malignancy.  The mechanism is almost certainly biochemical and related to glucose metabolism.  But the evidence presented to support the use is not an independent measure of glucose metabolism, but rather pathology.  I think some of the data are extremely well presented even if they aren't in the form of a classic NDA submission.
		So I think everybody is really right in terms of the concerns they have expressed.  We don't have the answers specifically to part of the question, but then I would submit that we don't necessarily need the answer to whether it measures abnormal glucose metabolism with the degree of evidence that we do for how well it matches against the truth of pathology.
		DR. RAMSEY:  Thank you.
		That said, I think we will move on to the next portion of the program, which is Dr. Raczkowski.  He is going to tell us about the safety and effectiveness in cardiology.  Dr. Raczkowski is deputy director of the Office of Drug Evaluation III.
		DR. RACZKOWSKI:  Dr. Ramsey, members of the advisory committee, and participants in the audience, I am going to be presenting my clinical review of the safety and effectiveness data that I found in literature in support of a cardiac indication for F-18 FDG.
		There were several members of the review team.  It included Dr. Sabhan, statistics; Ruby Jordan, the project manager; David Hussong, microbiology; Robbie Kasliwal, chemistry; you have heard from Dr. Laniyonu about pharmacology and toxicology; and Dr. Sancho, biopharmaceutics.
		The preliminary conclusion that I reached in my review of the literature was that there was sufficient evidence to support a claim for F-18 FDG to identify left ventricular myocardium with altered glucose metabolism and reversible loss of contractility when it is used together with myocardial perfusion imaging.  And I will note now just so that folks don't get confused, this is worded slightly differently than slide number 93, but the slide on number 93 is what is intended.  And what I have left off here is that the indication would indicate that the product would be approved for use in patients with coronary artery disease and left ventricular dysfunctions.  So it would just be an addendum to this, defining the patient population in whom it would be safe and effective.
		In terms of the safety of the drug, we have already heard about the previous NDA in which doses up to about 10.5 millicuries were studied.  In most of the literature that I reviewed, doses of up to 10 millicuries were evaluated.  I would take some slight exception to one comment that was made earlier, in that I do think we have an obligation to look at the safety whenever a drug is potentially introduced into a new patient population, about whether that new patient population has any unique safety concerns.  And so, specifically, what I was looking for in my review of literature was whether there were any specific concerns in cardiology patients with F-18 FDG.
		In my review, the only thing that I noted was not a direct result of F-18 FDG, per se, but rather it was in a sense a by-product of the way the drug is used.  Sometimes it is administered in cardiology after a glucose bolus, in other times it is administered under fasting conditions.  And in those situations, patients with impaired glucose homeostasis may have some additional safety concerns.
		The criteria that we used were very similar to the criteria that Dr. Houn used in her review for oncologic indications.  I won't go through and reiterate them all, I will just cite some of the additional things.  Particularly for the cardiac indications, there were references in the American College of Cardiology, and the American Heart Association Guidelines, and the United States Pharmacopeia Drug Information book that were also culled.  These are the number of references that we received.  In addition, we also receive a number of references from the PET community.
		I took a similar approach to Dr. Houn in terms of my review, although the way I say things might be somewhat different.  The framework for the literature review was in part based on many of the concepts that are delineated in the Draft Guidance for Industry on "Developing "Medical Imaging Drugs and Biologics."  This shows where you can find it on the Internet.
		In terms of several claims, when I did my review of the literature I made a quick assessment of whether I thought the evidence supported a claim of diagnostic or therapeutic patient management, which generally requires a very high standard of evidence and data to support and oftentimes requires randomized prospective clinical trials.  In my review of the literature, I didn't really find adequate evidence to support a diagnostic or therapeutic management claim, per se.
		So if you asked me where would I classify the claim that I've had proposed, I would say it is probably a mix, as Dr. Tulchinsky has indicated.  Sometimes these things don't fit necessarily into just one category.  I would say there are functional physiological or biochemical components to it, but I would also say that there are disease detection assessment components to it as well.  In fact, you might also argue that it is under "Other" because it provides prognostic information about the functional status of myocardium.
		So what I looked for was whether the information would be clinically useful, whether the information in the papers was valid, and whether the product was studied in a defined clinical setting.  And I won't go into these in detail because Dr. Houn has already addressed many of these.  But I will comment on them throughout my talk this morning.
		By way of introduction, what I would like to do is, for those of you who are not cardiologists, talk about myocardium.  Myocardium when it is dysfunctional sometimes that dysfunction is reversible and other times it is not reversible.  A classic case of nonreversible myocardial dysfunction is when there is a myocardial infarct and the heart is irreparably damaged.  However, in the cardiology literature there are two main categories of reversible myocardial dysfunction that are often described.  One is myocardial hibernation, and I'll talk about that a little bit, that will be the bulk of my talk, and that is basically reversible myocardial dysfunction in patients with coronary artery disease.  So what myocardial hibernation is is chronic reversible left ventricular dysfunction due to coronary artery disease.  In contrast, myocardial stunning is also myocardial dysfunction but it oftentimes results from an acute post-ischemic insult to the heart.
		And just for purposes of my presentation in terms of clarifying my terminology, I'll use the terms hibernation and viability interchangeably even though there may be shades of difference in the way that the terms may be actually used.  In my view, the data support a claim for myocardial hibernation because hibernation implies a reversible state of myocardial dysfunction, whereas viability doesn't address the functional state of the myocardium, per se.
		And similarly, I will use the terms radionuclide uptake, radionuclide localization, and radionuclide accumulation to mean the same thing.  Most people in terms of jargon use the term uptake, although as we have heard from Dr. Laniyonu, FDG trapping is not only a result of glucose uptake into the cell but it is also a consequence of a phosphorylation and limited dephosphorylation.  However, in the literature oftentimes people refer to uptake.  Whereas, for the purposes of my discussion, I'm just using those terms interchangeably.
		Just a brief summary.  As Dr. Laniyonu said, F-18 FDG is taken up into the myocytes by the glucose transporter after phosphorylation by hexokinase, it is not metabolized further.  And so phosphorylated F-18 FDG accumulates in the cell and generates a signal.
		Also as alluded to by Dr. Laniyonu, most of the literature that I reviewed referred to the use of FDG in combination with perfusion assessment.  There are two basic patterns that are referred to.  One is flow metabolism mismatch, which is defined as increased accumulation of FDG compared to myocardial perfusion.  And that in the literature is thought to be reflective of hibernating tissue.  So, in other word, it is a hot spot in terms of the FDG compared to a cold perfusion spot.  And then on the alternative is the flow-metabolism match, which is concordant reduction in both F-18 FDG and in perfusion.  So, in other words, there is a decrease or a cold spot for FDG as well as for perfusion.
		One of the main criteria that I used, and I think it is different from some of the other applications that will be discussed or some of the other products that will be discussed, is that in my literature review the performance of FDG was not being compared to another product, or to a gold standard, or to pathology, or something like that.  But, rather, the results were compared to the functional outcome of the particular myocardial segment after revascularization.
		So, in other words, prior to revascularization, segments that were dysfunctional or that were asynergic were identified and then, after coronary revascularization either by CABG or through angioplasty, those same segments were re-evaluated to see if their function came back.  Whether or not that function came back in my review was the ultimate arbiter of what truth was or the true state of that myocardial segment, whether it was actually hibernating or not.
		I have ten studies I've summarized in my review, and in this talk they are all basically of the identical core design, which I would like to emphasize because, once we've walked through this prototype, all ten studies basically fit the same prototype.  And so that things don't get tedious, I will try to emphasize different things during each of the studies.  But let me just walk through the prototype so that people have an understanding of what the clinical trial design was for each of the studies that I reviewed.
		Basically, the studies enrolled patients who were planning to go to coronary revascularization either with coronary artery bypass or with angioplasty.  And in those patients, those patients had some sort of evaluation at baseline or prior to revascularization of their myocardial dysfunction.  Whether it was echocardiography, whether it was radionuclide ventriculography, or whether it was contrast ventriculography, it was not really particularly deemed to be relevant because each of those methods are sufficiently reliable and valid as methods to assess ventricular segmental motion.  So at baseline, asynergic myocardial segments were identified.
		And then the degree of severity of the dysfunction was ranked.  And usually this was done in almost all the studies on an ordinal scale, where, for example, one might be normal motion, slightly worse than normal motion might be hypokinesis, slightly worse than that may be akinesis, and then actual dyskinesis where the segment is moving in the wrong direction would be worse than that, and some studies even extended the scale by various ways, such as including aneurysms or breaking hypokinesis into mildly hypokinetic or severely hypokinetic.  But the bottom line is that wall-motion was assessed the same way by the ordinal scales in virtually all the studies, with one perhaps or two exceptions.
		Prior to revascularizations, these patients then usually had an assessment of perfusion.  Now whether it was perfusion that was assessed by PET with ammonia, or PET with rubidium, or whether it was some other marker of perfusion, like Thallium, again, in my review was not deemed to be a significant variable.  These methods are sufficiently reliable and valid for evaluating perfusion.
		And then there was some sort of assessment with F-18 FDG in terms of predicting viability.  Subsequently those patients underwent coronary revascularization.  And then after revascularization, the true state of those myocardial segments was then assessed.  And usually that was by the same technology, either echocardiography or contrast or radionuclide ventriculography that was used to assess the state of that segment at baseline or prior to revascularization.
		And if you have looked through my review, you will see that I spent a fair amount of time talking about what happened to patients, and who was included, who was excluded, whether the segments were included or excluded because I feel that's an important way in which a study can be biased.  If only the most representative patients or most representatives segments are selected, then that can give different assessments of performance measures like sensitivity and specificity than they might get if all those patients were included.
		Performance measures like sensitivity, specificity, and negative and positive predictive value were calculated by the usual formulas.  Since the studies were small, I want to emphasize some caveats about the calculations and the performance measures that are reproduced in my review and on some of these slides.
		First of all, many of these studies had other principal objectives than what I was actually at them for.  If you looked at my review, sometimes the review doesn't look very much similar to what the actual paper was.  And so, in a sense, this could be viewed almost like a retrospective analysis of the literature.
		Also, performance measures like sensitivity, specificity, positive/negative predictive values were derived from relatively small number of patients.  So you will see in the confidence intervals that some of them are fairly wide because the number of segments or the number of patients that were included were relatively few.
		Furthermore, there was no standard definition of what a myocardial segment is.  It was at the discretion of the investigator.  Some studies divided the heart up into three or five segments, others divided it up into many, many more.  And so it was simply a question of how the investigator chose to conduct his or her study in terms of defining how many segments there were per any given left ventricle.  And so, particularly when some of those segments may not be mutually exclusive of one another, or if they are overlapping one another, then it becomes difficult to start combining performance measures like sensitivity and specificity across studies.
		And finally, as everyone knows, performance measures like positive and negative predictive value, and accuracy are highly dependent or highly influenced by the prevalence.
		So some of the things that I looked for were whether there was a sufficient detail of study design, population, doses used, endpoints, image acquisition, image interpretation, and statistical analyses.  And I tried to lay that out pretty carefully in the written review.  And I'll go through that fairly quickly in my talk.
		I was concerned about whether there was an adequate study design, whether the study was appropriately controlled.  And, again, rather than a gold standard, I was looking at a functional outcome of hibernation, whether, in reality, after revascularization that particular myocardial segment regained its function or not.  A blinded image evaluation, and sufficient accounting of patients and segments.  And also whether the study population was sufficiently similar to the population in which F-18 FDG is intended.  And so that is why I added that slight addition to slide number 3, or as we will see it on slide number 93, that in the indication it would be worded for use in patients with coronary artery disease and chronic left ventricular dysfunction.  Because the bulk of the studies that I looked at evaluated the drug in that patient population.
		This is just for bookkeeping purposes.  These are the ten principal studies that I found in the primary literature that supported this claim.  They are listed alphabetically.  And I'll go through each one of them and try to emphasize slightly different points in each one.
		The first study was a study by Baer.  And the objective was to assess the predictive value of myocardial viability diagnosed by dobutamine transesophageal echocardiography compared with F-18 FDG PET for left ventricular recovery.  In my review and in my talk, I won't really be talking about the results of dobutamine echocardiography because, although I think that is relevant and highly useful clinically, the issue on the table is really whether F-18 FDG, there is enough evidence and data to support its use for this purpose.
		One of the criteria that I used, as similar to Dr. Houn, was whether the studies were prospective.  And virtually all ten of these studies were prospective studies, and some enrolled consecutive patients, and virtually all enrolled patients with coronary artery disease and chronic LV dysfunction who were planning to go for some sort of coronary revascularization procedure.
		Perfusion, interestingly, was not assessed in this study.  FDG was given at a dose of 10 millicuries.  Quantitative image evaluation, the heart was broken up into 28 segments, and the definition of viability I've emphasized in each of my slides, and in this particular study viability was defined as F-18 FDG accumulation of more than 50 percent of the maximum.
		Patients in that study underwent either CABG or angioplasty.  And then wall motion was assessed by transesophageal echocardiography.  It had blinded image evaluations by two readers on a four-point ordinal scale.  So 42 patients were included in the analysis, 26 of whom had improved function.  If you look on that as a segmental basis where there's 28 segments per patient, that ends up to be 1176 segments that could possibly be evaluated.  And I'll talk about this in a second, but let just run through the numbers.
		What this paper did is, as is typical, it restricted the evaluation to those 405 segments that were akinetic or dyskinetic at baseline or had some sort of abnormal function at baseline.  In other words, normal segments were not included in the analysis; segments that had normal function at baseline were not included in the analysis.  However, then there is another cut which was made, and that is that not all segments were included in the analysis that were akinetic or dyskinetic at rest.  In fact, only 371 segments of the 405 that were deemed to be successfully revascularized were included in the analysis.  So there's two primary levels here in which segments are not being included in the analysis.  One is if they are normal at baseline, they are being excluded.  And second, if the revascularization was not felt to be successful, then they were excluded.  And of those 180 had improved function.
		And so the diagnostic performance of FDG in this situation was calculated both by segment and by patient.  And, again, I don't want to emphasize too much the particular numbers here, but the sensitivity was 93 percent, these are the 95 percent confidence intervals going from 88 to 96 percent, and for specificity, going from 59 to 72 percent.
		So what were some of the strengths of this study.  Consecutive patients, prospective, the wall-motion assessment was blinded.  And as I pointed out in my review, there were two levels of blinding that I felt were most important for these studies and which I tried to emphasize.  One is whether the wall-motion assessment, which is the outcome of interest, whether those readers were blinded to the results of FDG or not; and the other is the opposite of that, whether the interpreters of the FDG PET images were blinded to the result of wall-motion analysis.
		Now, I think it is particularly important that because the wall-motion analysis in virtually all cases was a visual one, a qualitative one, on ordinal scales where investigators were trying to make a determination about whether it was hypokinetic or akinetic or dyskinetic wall-motion, that that sort of assessment be blinded.  And there were multiple readers for wall-motion and they were blinded.
		However, I will comment that even in a quantitative image analysis, as is done for many of the PET studies, there are reasons to think about blinding them as well.  That's because even in a quantitative analysis, to the extent that there is an operator/reader interaction, or regions of interest are being drawn, or there's any sort of human interface, that's a potential for bias if the PET reader is aware of what the wall-motion analysis showed.  However, in my review, I felt that that was less likely to be source of significant bias, and I thought that the wall-motion assessment was the most critical type of assessment that should be blinded.
		Limitations.  Not one of the studies that I reviewed had more than 50 patients that was included in the analysis.  But this was one of the three largest.  However, I felt that because there was sufficient similarity of the ten studies in terms of the procedures that were done and the outcomes that, in aggregate, although you can't necessarily point to one or just two, in aggregate the data were supportive of the indication that I had indicated at the outset of this talk.
		The number of PET readers was not specified.  And interestingly, in this study wall-motion assessment was based only on systolic wall thickening and not on wall movement.
		I do want to emphasize at the outset one other thing that I didn't emphasize about this study that I thought was a real advantage, and that is that a by-patient analysis was performed.  Whenever we are talking about units such as segments of a myocardium we run into the risk of that not having clinical significance to the patient.  Ultimately, what is of concern is that the diagnostic modality or therapeutic modality somehow ultimately benefit the patient.  And so patients are ultimately the unit of interest for all of these.  And this was one of the few studies that really did a by-patient analysis.  Most of the studies were limited insofar as they only did by-segment analyses.
		Ideally, what you would like to see is a clear progression that regional or segmental wall-motion results in global ventricular improvement in motion or function, which results in improvement in patient symptoms or in patient survival.  But most of the studies just really stopped at the level of just doing a segmental analysis.  When I get to the secondary literature that I reviewed, that's where I feel that comes in.  Because I think those secondary literature articles give a measure of comfort that this regional wall-motion improvement that we're seeing in these ten principal studies is being potentially translated into some sort of patient benefit in terms of either exercise capacity, symptoms, or survival.
		I'll go through these fairly quickly.  They are all of a similar design.  I'll just try to emphasize points that I haven't emphasized before.
		Gerber.  The objective was very similar here, consecutive patients with coronary artery disease.  This, along with one other study, only looked at the anterior wall of the left ventricular or the distribution of left anterior descending artery.  And that was the only myocardial region of interest for purposes of this study.  In other words, patients were enrolled only if they had dysfunction of the anterior wall at baseline.  And then, after revascularization, some sort of recovery of that anterior wall dysfunction was looked for.
		Ammonia PET agent was also used to assess perfusion.  And, again, there was a comparison in this study to the performance with low-dose dobutamine, in this case it was two dimensional echocardiography transthoracic as opposed to transesophageal echocardiography as in the study by Baer.
		Major limitations.  Doses were not specified.  However, the FDG interpretation was quantitative.  It involved an operator-interactive image analysis.  It was limited to the anterior wall segments.  And viability was basically assessed on whether there was a match/mismatch pattern.  Revascularization was performed by CABG or angioplasty, and the success of the revascularization was assessed by fairly rigors means by angiography.  And wall-motion was assessed by 2-D echo on a 3-point ordinal scale.
		Thirty-nine patients were included in the analysis.  And accordingly, since only the anterior segment was evaluated, only 39 segments were evaluated.  So in this case, there is a concordance between the by-segment analysis and the by-patient analysis.  It is essentially the same thing.  There were only three studies that in effect did that; the one I just mentioned by Baer, this study by Gerber, and another study that also limited the evaluation to the anterior wall.  And so, as I indicated, the diagnostic performance was calculated by-segment, but I assume that to be identical to the by-patient analysis.
		Here are the performance measures.  Again, you can see the spread.  A sensitivity of 75 percent, well, a sensitivity of 53 percent is equally consistent with the data, as is a sensitivity of 90 percent.  So the small sample sizes ‑‑ or specificity, perhaps this is even better, of 67 percent, a specificity of 38 percent is equally consistent with the data.  And so what to make with these specific numbers is hard to determine.
		The strengths include, it was a consecutive study of prospective patients.  All 39 patients were included in the analysis.  I've indicated that the by-segment analysis was equal to the by-patient analysis.  Wall-motion assessments included evaluation of not only wall excursion, in other words, is it moving hypokinetic or dyskinetic, but also is it thickening.  That is a somewhat more specific way of assessing true regain of function, because there is a tethering effect within the heart and segments can appear to move even without thickening even if they haven't regained their function.  And so systolic wall thickening adds a certain level of specificity in this particular study to the assessments of wall-motion.
		Major limitation, that the doses were not specified in the paper, the number of readers were not specified, and it didn't indicate whether the readers of the echo or PET were blinded.  One other potential limitation of this is that performance measures such as sensitivity and specificity that are calculated for the anterior wall may not be the same for other regions of the ventricle, may not be the same for the lateral wall.  And so that's a potential limitation of this study.
		The next study is by Gropler.  The objective was to determine whether prediction of recovery of left ventricular mechanical function could be accomplished more effectively by PET with carbon-11 acetate, which is a marker for oxidative metabolism, than FDG.  This was a comparative study.  Again, it enrolled patients with coronary artery disease, left ventricular dysfunction.
		Doses were assessed with a carbon-11 acetate, not the usual perfusion agent that jumps to mind when people think about it.  The dose was not specified in the paper but was referred to in a reference.  Quantitative image evaluation, 8 segments, but in this case viability in terms of a threshold was defined if FDG glucose normalized to flow was more than 2 standard deviations above the mean in controls.  Revascularization was accomplished with CABG or angioplasty.  And wall motion was assessed by each of the different methods ‑‑ echo, contrast, and radionuclide ventriculography ‑‑ on 5-point ordinal scales by blinded readers.
		Thirty-four patients were evaluated.  If you go back to 8 segments per patient, that comes out to 272 possible segments.  Again, only the 141 that were dysfunctional at baseline were assessed.  Of those, 116 were included in the analysis, and 46 of which had improved function.
		And so these are the measures of diagnostic performance.  And if this isn't immediately evident to folks, when I'm referring to prevalence here, what I am referring to is the 46 hibernating segments that regained function out of the 116 that were included in the analysis.  And that's true for all of these tables that I've shown.
		Again, wall-motion analysis was performed by two, blinded readers.  Well, it is an advantage to have more than one blinded reader or to somehow show that the results are not idiosyncratic to a particular blinded reader, or at least to be able to assess whether there is some sort of inter-reader variability.  And so that's one common theme that I've emphasized, is whether the wall-motion analysis or the PET analysis was performed by one or multiple readers.
		This study used several different modalities.  It used echocardiography, contrast ventriculography, PET, radionuclide ventriculography.  And somehow there has to be measures taken in a study that show that the segment under one modality is the same segment that you're looking at another modality.  And this study was fairly detailed in terms of the way it laid that all out.  I would like to emphasize that was one of the highlights or one of the strengths of this study.
		This study also performed an ROC analysis, which in some ways you could view as being hypothesis-generating as opposed to hypothesis-confirming, because the goal is really to try to identify a threshold from the ROC curve that will give you optimal performance.  But, on the other hand, an ROC analysis allows you to look at all the data.  Instead of assessing just one arbitrary threshold of FDG uptake at above 50 percent or below 50 percent, this analysis allows looking at every single data point and essentially allows for a true exploration of the data in terms of different thresholds.  Moreover, it allows for a truer comparison of different diagnostic modalities.  The purpose of this study, which I'm not emphasizing, was really to compare the performance with C-11 acetate with FDG.  And ROC curves, oftentimes by showing all the data you can see whether the curves intersect or not, whether they cross one another, and so forth.  And so that's a useful way of comparing two diagnostic modalities.
		Some of the limitations.  Again, not the prototypical perfusion agent was used.  The number of readers wasn't specified.  Ideally, there should be more than one.  Blinding of the PET readers was not specified, although grace can be given for that because it was a quantitative analysis.  And as is true for many of these studies, global and left ventricular function and clinical outcomes were not assessed.  Again, many of the studies just stopped at seeing whether regional myocardial function had improved or not.
		The next study was by Knuutie, et al.  It was to assess the value of PET FDG in predicting cardiac wall motion recovery after revascularization.  It involved consecutive patients with previous MIs who had wall motion abnormalities at rest.  Perfusion in this case was assessed with SPECT either with  thallium or tecnesium-99.  So, again, this underscores that different perfusion agents were used in these studies.
		The dose of FDG was 7 plus or minus 1.5 millicuries, and segments were deemed to be viable if FDG uptake was above the lower limit of normal segments.  Each left ventricle was broken up into 8 segments.  Revascularization was accomplished by CABG or angioplasty.  Wall motion, one blinded reader by echo on a 4-point ordinal scale.
		There were 48 patients, times the 8 segments gives you 384 possible.  There were 106 abnormal at baseline, 90 of whom were successfully revascularized, 27 of whom recovered function.  So the prevalence of abnormal segments or hibernating segments in this particular study was 27 that recovered function out of the 90.  And diagnostic performance was calculated by segment.  Again, here is performance measures.
		One thing this study did is it also determined an optimized threshold for sensitivity and specificity with a discriminate analysis, without consideration of perfusion.  And these were the performance measures that were obtained, which are substantially different, as you can see on the previous.  Specificity was fairly low, whereas sensitivity was high.
		This was the largest study I think.  It had 48 patients.  Wall-motion analysis was performed blindly.  Again, alignment of different modalities.  Even within PET, if it is done at different times, if the studies are done at different times, some statement should be made about how the segments were aligned.  And, in fact, there was actually a formal statement in the paper about how reproducibility of wall-motion analysis was assessed by the same reader over time.
		Some of the limitations.  Again, some of the studies just indicated that the study was blinded, but it didn't say to what.  That is potentially a problem because the wall-motion analysis, were they blinded to the PET studies, were they blinded to the clinical history, were they blinded to anatomic orientation; it is unclear.  And so a further level of detail would be helpful.
		The number of readers was not specified.  The blinding of whether the PET images were blinded or not was not specified.  And, again, there was no overall improvement of assessment of how did the patient do, or at least how did the whole left ventricle do.
		The next study by Lucignani, et al.  To identify hibernating myocardium with tecnesium SPECT compared to PET.  Again, same story, coronary artery disease, left ventricular dysfunction.  Perfusion, again assessed with SPECT.  6.8 millicuries was done.  Now here, this was one of the few studies that actually did a visual analysis of PET; most of them had some sort of quantitative assessment.  And so this was fairly unique in that regard.  The degree of uptake was assessed on a 3-point ordinal scale.
		The success of revascularization was assessed by rigorous means, by coronary arteriography.  And wall motion was assessed, in this case, with EKG-gated planar perfusion scintigraphy or first-pass radionuclide angiography, depending on the circumstance.  But the number of readers was not specified, and the blinding of readers was not specified.  This basically boiled down to whether or not the wall could be seen with the planar perfusion scintigraphy, and, if it couldn't, then the wall motion was assessed with first-pass radionuclide angiography.
		There were 14 patients, a small study, 5 segments per patient, 54 of them were asynergic at baseline, 40 of which improved.  And so the prevalence of hibernating myocardial segments in this study would have been 40 over 54, as we'll see on the next slide.  And, in addition, two multiple logistic analyses were performed.  And so the prevalence was 74 percent.  Here again we can see some of the spread that is a result of the small sample sizes.  The specificity numbers of 52 percent and 96 percent are equally consistent with this dataset.
		Two multiple logistic analyses were performed that showed the highest probability of wall motion recovery was associated with both F-18 FDG uptake as well as absent perfusion.  So that is sort of the extreme what we call flow metabolism mismatch.  A second multiple logistic analysis was performed without perfusion that showed even without perfusion the probability of wall motion recovery was increased as FDG uptake increased.
		Strengths.  I put down the qualitative evaluation as a strength because there may be circumstances in which, although it is debatable, there may be circumstances in which qualitative evaluations may be performed instead of quantitative ones.  And it is useful to show that the results can be confirmed by the human eye and aren't just an artifact of some quantitative measurement of instrumentation.
		They had multiple readers using evaluation of FDG PET and the perfusion images.  And stress hypoperfusion was also evaluated.  This is one of the few studies that evaluated stress hypoperfusion.  Most only evaluated hypoperfusion at rest.  So this is sort of looking at hypoperfusion sort of at yet another level and sort of broadening the scale, which was interesting.
		Again, major limitations.  Small sample size.  They didn't specify if the readers of PET and SPECT were blinded to the results of the wall motion analysis.  The number of readers to the wall motion analysis was not specified, and it wasn't specified if the wall motion analysis was blinded.
		I apologize if this is getting somewhat tedious.  We have a few more studies and I'll try to go through them quickly.
		A study by Maes to evaluate the ability of tecnesium MIBI to assess viability compared to PET with FDG and ammonia.  10 millicuries given.  Viability was done by looking basically at flow metabolism ratio.  Revascularization was through CABG only.  Regional ejection fractions were calculated to assess improvements in regional ventricular function.  So this is the one study, if I remember correctly, that did not use visual scales of hypokineses, dyskinese, askinese, et cetera.  It actually used regional ventricular ejection fractions to assess whether the myocardial ventricular function was recovered or not.
		Twenty-three patients.  Relatively small sample size.  This is the other study that only looked at the anterior wall.  One other aspect of this study is that biopsies were done at CABG.  And so this is one of the few studies that actually had some sort of morphological correlates as well to estimates of viability.  So if you would like to refer to that as a standard of truth on a morphological sense, I suppose you could.  But again, this is a case where the by-segment analysis is going to be identical to the by-patient analysis because only one segment per patient is being evaluated, that is the anterior wall segment.
		So, again, you can see the numbers.  Wide spreads because of the small sample size.  And as I indicated, morphological correlates were evaluated, which basically showed there was more fibrosis or greater degrees of fibrosis with greater likelihood of nonviability, as predicted.
		Again, number of readers not specified.  It wasn't specified if they were read blindly.
		A study by Marwick, the goal of this was to assess the metabolic response of hibernating tissue as assessed by PET imaging again with a different perfusion agent, though, rubidium in combination with FDG.  Revascularization by CABG or angioplasty.  Two blinded readers, 6-point ordinal scale.  Only 16 patients.
		Here's the performance measures.  Again, wide variation.
		Strengths.  Blinded evaluation of 2-D echoes, PET scans, and rubidium scans.  More than one blinded readers.  Stress hypoperfusion was assessed and post-exercise FDG uptake was assessed.  So, again, this is looking at sort of a different end of the spectrum or pushing the spectrum of perfusion abnormalities a step further than most of the other studies did.  Interestingly, in this study perfusion and PET studies were performed after revascularization as well.
		Most of these points I've already covered.  Although this study did look at symptomatic improvement in patients.  It was one of the few that did.  However, the conclusion was simply that the patients had improved angina compared to before revascularization.  But from the perspective of understanding whether FDG somehow could have predicted that improvement, there was no specific analysis that was done.  In other words, that improvement in angina could have just been from the revascularization alone and may not at all be correlated with the degree of viability as predicted by FDG at baseline.
		Tamaki, there are two studies by him and his colleagues.  I don't see anything particularly unique here, except that this is one of the few studies that actually looked at patients with fasting.  Most of the other studies were done on top of glucose load.  There are advantages and disadvantages to doing that, but this is one of the few studies that did it.
		Revascularization was by CABG alone.  The quality of the revascularization was assessed by evaluation of improvements in perfusion with ammonia.  So a fairly rigorous criterion.  And wall motion analysis was assessed by radionuclide ventriculography by three blinded readers.  Only 22 patients, 110 possible segments, only 46 of which were included in the analysis, 23 of which regained function.  Here are the performance measures.
		Strengths.  Again, multiple blinded readers, rigorous assessment of revascularization, good discussion of alignment of segments before and after revascularization as obtained by different modalities, as well as by PET before and after revascularization.
		Limitations.  Small sample size, and very, very little information about the study subjects was provided in this paper.  And that is an important point because in terms of knowing to whom this study is generalizable, it would be nice to know the ratio of men and women, basic demographic aspects of the patients, the nature of the coronary artery disease, how severe the left ventricular dysfunction is, and all those other sorts of details to know whether this particular study is generalizable to larger populations.
		Another study by Tamaki and his co-workers.  Again, done under fasting conditions.  Again, viability assessed by a match/mismatch pattern.  Three blinded readers for the wall motion on a 5-point ordinal scale.  Forty-three patients, one of the larger studies in that regard.  So that would be 215 possible segments, of which 130 were included.  And here is the performance measures.
		Again, of the ten studies, this was the second largest.  Wall motion analyses were performed by multiple readers that were blinded.  Rigorous assessment of the success of coronary revascularization.  This is another case in which all it said was that the readers were blinded but it didn't say to what they were blinded, again, an important thing to include in the manuscript.
		And this final study is actually one of the original seminal papers in the field, it is by Tillisch and co-workers, published in the New England Journal of Medicine in 1986.  There were many, many aspects of this study that were well done.  It is a fairly small study.  I point to it because there is not particularly anything unique that I can emphasize now that I've been through the prior nine studies, but just that there were many aspects of this study that were well done even though it was a small sample size.  These were the performance characteristics that were measured.
		So strengths.  Wall motion assessed by multiple blinded readers, consecutive patients were enrolled, these were all prospective studies, success of revascularization was assessed, and the alignment of myocardial segments was described across modalities.
		Small sample size.  Didn't specific the number of readers of PET, didn't specify whether the PET readers were blinded.  Again, this is another case where very few patient characteristics were described, so it is hard to know what the patient population was to whom those results may be generalizable.
		Now I'm going to go fairly quickly through the secondary published literature.  I provided a summary of it in my review.  What I was looking for in the secondary published literature was really a few things, which are highlighted on the next few slides.
		I wanted to see whether there was any literature that supported the clinical usefulness of PET with F-18 FDG.  In other words, it is not enough just to show that the segment improved but that the heart didn't or that the patient didn't, but rather what is the evidence that it is clinically useful or that it leads to appropriate clinical decisionmaking, and to provide support that cardiac PET imaging, as I just said, influences clinical decisionmaking appropriately.  It is not enough just to influence clinical decisionmaking, but it has to be influenced appropriately.
		I also looked at the secondary published literature to see whether regional left ventricular function was associated with global left ventricular functional recovery.  And again, as I emphasized at the beginning, to see whether those pharmacodynamic endpoints are translated into clinical meaningful endpoints, such as improvement in symptoms, improvement in exercise tolerance, or prolongation of survival.
		Now when we get into this sort of level, we're talking about levels of claims that are slightly further down on the scale in terms of being able to appropriately influence decisionmaking or whether influencing clinical outcomes and diagnostic and therapeutic management.  And so the argument that I am trying to make here is, basically, I didn't feel that the evidence was sufficient from these papers to uphold that sort of a claim on that level.  However, it was sufficient in the aggregate when you looked at those studies to support a claim of detecting myocardial hibernating tissue.
		Safety, basically no additional safety concerns were raised by some additional information that we've received at the agency as well as in the original NDA.  I mentioned the issue of glucose load or fasting, which isn't an issue of FDG, per se, but it is an issue of perhaps how the drug is used.
		And so my preliminary conclusions, and this is analogous to slide number 3 except that it contains the descriptor of who the patients are, is that the literature supports the use of FDG in patients with coronary artery disease and left ventricular dysfunction, when used together with myocardial perfusion imaging, to identify left ventricular myocardium with altered glucose metabolism and reversible loss of contractility.  That's a long sentence.
		One thing I would like to emphasize is that all these studies, for the most part, they only looked at the case of successful coronary revascularization.  Most of the analyses were limited to that case and so that may actually limit the usefulness of PET imaging.
		In other words, on the one hand, being able to evaluate the performance of FDG in only those patients in whom revascularization was successfully completed eliminates the variable revascularization from the analysis and gives you a truer assessment of the performance of the drug without other competing, confounding influence.  However, if the patient is unlikely to have a successful revascularization, then that would influence whether or not a PET imaging scan with FDG would be obtained or not, because if it is unlikely to be successful, then regardless of how good the test is, viability would likely not recover spontaneously.  And so the likelihood of successful revascularization should be considered carefully by health care providers before imaging with FDG is performed.
		And in terms of safety for the use for cardiac evaluation, it generally appears to be safe.  However, patients with impaired glucose homeostasis may require special precautions if they undergo fasting and/or glucose loading prior to drug administration.
		Thank you.
		DR. RAMSEY:  Thank you very much, Dr. Raczkowski.
		I think we will actually hold questions for now.  I have had a request by Dr. R. Ed Coleman, from Duke University, to go ahead with his presentation at this time, and so I would like to ask him to come to the podium.  We will hold questions until after his presentation, and then we will have open public forum and time for questions.
		Also, I would like to alert the speakers for this afternoon that although the questions have been excellent and lively, I have no idea exactly how many there will be and it may very well be that your presentations will be slightly before the time stated.  So if you could just be prepared for that.
		DR. MADOO:  Dr. Coleman, if you would, identify if you were conveyed or sponsored by anyone.
		DR. COLEMAN:  My name is Ed Coleman, I'm from Duke University, and I am sponsored by the Institute for Clinical PET.
		I would like to compliment Dr. Sancho, Dr. Laniyonu, Dr. Houn, and Dr. Raczkowski for the presentations they have given us here today.  What I'm going to do is to focus on the uses of FDG, and particularly my experience with the use of FDG primarily in oncology.  I'll make a couple of statements about its use in cardiology.  Dr. Maddahi will be talking later on in the open session after the N-13 ammonia presentation.  And as you've heard, the FDG is generally used with a perfusion agent and in most institutions with N-13 ammonia.  And Dr. Maddahi will talk a little more about its clinical applications.
		Let me start off with a patient that was studied recently at Duke University.  This was a lady that presented to the gynecology service, had a routine chest x-ray, and has a right upper-lobe nodule.  And by chest x-ray, this is indeterminant; by looking at that, cannot determine whether that is benign or malignant.
		The next study that was done was a CT scan.  And, again, on the CT scan we see this abnormality in the right upper-lobe, no characteristic findings that suggest that it is benign or malignant.  And so, again, this is an indeterminant pulmonary nodule.  This is a single pulmonary nodule.  On the CT scan there were no other abnormalities that suggested malignancy.  The lymph nodes in the mediastinum were normal, the bones that were seen on the chest CT were normal.  So we were left with an indeterminant lesion in the right upper-lobe.
		The next procedure that was obtained in this patient was a radionuclide bone scan.  I think one could question why that was obtained at this time, but it was.  At this time, again, we had no diagnosed malignancy.  The clinicians were very concerned that this was going to be lung cancer.  The bone scan is, as you see it here, in the left iliac wing we have a focal area of abnormal accumulation.  I would like for you to look at the spine, look at the sternum.  No other abnormalities.
		So at the time of the bone scan we obtained a plain film of the pelvis to see if there was a diagnostic lesion that would suggest malignancy.  There was not.  The plain film was normal at the site of abnormality on the bone scan.  In a patient with a malignancy, that is very worrisome for metastatic disease; that is, an abnormal bone scan, normal plain film.  The bone scan is more sensitive for detecting metastatic disease than is the plain film.  But with this patient not having a malignancy, no abnormality, a little bit of a quandary as to what this would mean.
		The clinicians then ordered a whole-body FDG PET scan, which I'm showing two of the coronal sections here, two of the more anterial coronal sections.  And what we are seeing here is abnormalities, this is in the sternum, and mediastinal lymph nodes on these two sections.  We do see that left iliac wing abnormality on that coronal section.  And as we go a little further postoral, we're seeing the right upper-lobe nodule, demonstrating that it is malignant, other mediastinal lymph node abnormalities, and multiple vertebral body abnormalities.  In addition to the left iliac wing abnormality, there was a right iliac wing abnormality.
		So we're seeing multiple lesions here that had not been detected on the other studies.  More detailed views of the chest show this right upper-lobe nodule, mediastinal lymph nodes that were all less than one centimeter on the CT scan, multiple vertebral body abnormalities, and if we look at this what we call a sagittal, or more side, view, it gives you more detail as to where the abnormalities are, in the sternum multiple vertebral bodies and in the mediastinum.  So this is the type of information that we are able to obtain from the PET scan.
		We have heard today that we're looking at fluorodeoxyglucose.  It is a biochemical marker.  The use of this really dates back to the findings of the biochemist Warburg, who in 1931 reported that tumor cells metabolize glucose avidly.  Then Dr. Sokoloff at the NIH worked on the 2-deoxy D-glucose to show that you could look at glucose and quantify glucose metabolism using the deoxyglucose technique.  The radiochemist Al Wolf and colleagues at Brookhaven National Laboratories then synthesized the fluorine-18 to fluoro 2-deoxyglucose that we now use for the PET scanning.
		You have heard this gone through a couple of times today, that the similarity of the behavior between the fluorodeoxyglucose and glucose is the basis upon which this imaging principle works.  Just a couple of points that have been brought out here, is that the PET scans are done with the patient in the fasting condition.  We want the blood glucose level to be at the lowest level it can be but we don't want the insulin levels to be sky-high either.  That is, if you inject insulin at the same time you inject FDG, most of that FDG is going to go intramuscularly.  And so it is a balance between the serum glucose, serum insulin, and the fluorodeoxyglucose.
		So, typically, we have our patients fasting four hours before having the study.  If they are scheduled first thing in the morning, they are fasting over night.  If they are scheduled later in the day, it is a four-hour fast.  If the patient is diabetic, we want them to be at as uglycemic normal glucose levels as they can be.  And, typically, what we have used as a cut-off in our laboratory is a blood glucose of 200.  And for patients who are diabetics, we ask them to have their glucose under control without having any regular insulin within four hours of coming to the PET laboratory.  Patients these days are very knowledgeable about their glucose levels and they can get their own glucose levels to the point where it will be at an acceptable level when they come to the PET facility.
		If for some reason a patient is diabetic and did not know that they were supposed to be fasted or what their glucose level was going to be, we will check the glucose level in the laboratory.  But we do not do it routinely.  It is only if they are diabetic, if there's any question of not fasting for four hours, or any question of glucose intolerance, then we will get a serum glucose.  And we do not do the FDG study if the serum glucose is greater than 200.
		This shows what has been happening to PET imaging at our center, Department of Radiology, Duke University Medical Center, going back to December 1996.  The yellow are the total studies, the orange-ish line here is the clinical studies.  And you can see back in 1996 we were doing 40 to 60 a month.  Now we're up to 180 a month, and this year we will be doing about 2,000 clinical PET scans.  So this is a timely topic.  It is a very important topic for us in nuclear medicine, in radiology and PET imaging to make sure that we do have these radiopharmaceuticals approved and that they are being used under the right regulatory authority.
		What I'm going to do now is go through the patients that we did last Wednesday.  We do eight to ten clinical patients a day.  I thought it may be useful for this panel just to see what types of patients does a PET center see in a day of activity.
		This first patient is a patient with a history of a brain tumor.  He has had resection, and the question now is does the patient have a recurrent tumor or not.  The data on supporting this indication was the first clinical PET data in the literature.  And really, clinical PET was started by Giovanni Di Qierro and his colleagues at the NIH.  Giovanni did some very careful and important work on looking at FDG accumulation in brain tumors and in differentiating necrosis from recurrent tumor after therapy.  During the discussion, there was some discussion related to the metabolic information and the prognostic information in the imaging studies.  Well, Giovanni Di Qierro many years ago demonstrated very clearly that the more metabolically active the tumor, the shorter the prognosis, and regardless of what the histologic characterization was, the metabolic information provided better prognostic information than did any other parameter.
		We have shown in lung cancers, and this was published in Cancer this year, that lung tumors that are more metabolically active, have higher SUVs, have a much worse prognosis than those that have low SUVs.  And there is similar data, again from the NIH and other institutions, on soft tissue carcinomas.  The higher the amount of FDG uptake, the more malignant carcinoma it is.  So there is data out there in certain tumor types on using FDG from a prognostic standpoint.
		What I am showing on this slide is a patient who has had surgery.  The question, recurrent tumor.  On the left is the patient's MRI, contrast enhanced MRI, and on the right is the registered PET image.  That is, we've take the PET and MRI and matched the surfaces so that we can move from one to the other and look at the exact same structure.  And this image is two-thirds MRI, one-third PET.  This is two-thirds PET, one-third MRI, and then 100 percent PET.  What we're seeing is there is some glucose metabolism, not great, but in this little nodule of enhancement here just posterior to the cystic cavity.  The other are radiation changes, enhancement from necrosis, but there is recurrent tumor in this patient.  And this is the combination of the findings from the MRI and PET that permit us to make that diagnosis.
		This is an interesting patient that I don't have pathology back on as yet; I checked yesterday before I left to come here.  She has had two lymph node biopsies and neither one has been diagnostic.  She was referred to Duke earlier this week with some shoddy adenopathy in the neck, she had a right axillary node, and on chest x-ray has a mediastinal mass.  Certainly highly suspicious for lymphoma.
		Before she got to the PET facility, they had biopsied a right axillary node that came back non-diagnostic, maybe slightly increased plasma cells but no characteristic lymphoma.  We did the PET scan, and you can just see nodes, 50 to 100 of them in the neck, mediastinum full of nodes, superclavicular fascia, both axilla, mediastinum into the hyla areas, spleen is involved, periaortic, abdominal lymph nodes, iliac, and inguinal lymph nodes.  So, certainly, this should be lymphoma.  I notice on Friday they biopsied one of the abdominal nodes under ultrasound guidance, and, again, that had come back nondiagnostic.  But this very likely will be lymphoma, and very likely a Hodgkin's lymphoma.
		This next scan is a 52-year-old gentleman, actually an administrator at the hospital, that has been a very active runner, very avid athlete for many years.  Over the last couple of months, he has had the insidious onset of back pain.  He was treated conservatively for six weeks or so.  Back pain continued to get worse.  Started having some fever, just general not feeling well.  And was admitted to the hospital last Sunday night mainly for pain control.  On Monday, he had an MRI that shows diffuse increased T-2 signal in T-11.  Worrisome for myeloma, worrisome for lymphoma, unlikely to be trauma, doesn't look like a fracture.  He actually got his CT scan.  The CT scan was negative.  I should say there was slight contrast enhancement on the MRI.  He got a CT scan that was negative.  Had a biopsy of that vertebral body.  It came back normal bone and bone marrow.
		Got the FDG PET scan.  It shows increased signal, increased FDG localization in the T-11 vertebral body, on coronal sections, we're seeing the increased FDG accumulation there.  The patient went to open biopsy on Friday, and those results are not back as yet.
		This is a patient that recently presented.  On a chest x-ray had two nodules, one in the left upper lobe, one in the right upper lobe.  The left upper lobe nodule was biopsied.  A small cell lung cancer.  We also see hypermetabolism in the right upper lobe nodule, suggesting another lesion.  Here it is on the transaxial sections.  The right upper lobe nodule.  The left upper lobe nodule was actually right up next to the aorta.
		What the PET scan was able to show here were two lesions in the liver; a small lesion here in the right lobe, and a larger lesion in the left lobe.  The left lobe lesion on CT scan was seen and thought to be possibly a cystic lesion and not definitely a metastatic lesion.  The right lobe was not see on the CT scan.
		This is a patient that presented to the thoracic surgeon with a barium swallow showing an esophageal mass.  This is presumed to be esophageal cancer.  What we're seeing on this coronal section is increased uptake in the distal esophagus.  We're seeing it here.  On a more localized view of that area, we're seeing the FDG accumulation in the esophageal cancer.  We're seeing a lymph node right below the gastro-esophageal junction that had not been caught on the CT scan.  In retrospect, you could go back and see that lymph node.  But the tumor is also extending into the superior portion of the stomach, and, again, suggested on the barium swallow but had not been called at the time of the barium swallow.
		This is a patient with rectal cancer with a known three centimeter lesion in the liver.  The patient is being considered for operative resection of the metastatic disease in the liver.  It has been found that a third to maybe as high as 50 percent of patients that have colorectal cancer metastatic to the liver may significantly benefit and have prolonged survival with removal of these lesions if the tumor is not elsewhere.
		And so this patient had a CT scan showing the one large lesion.  There was an equivocal abnormality lateral to that, which we're seeing here on the PET scan.  There are two lesions here.  And again on these images you can see the larger lesion and then the smaller lesion is seen a little better postoral.  There are several studies in the literature now that show the accuracy of PET scanning in detecting metastatic cholorectal disease and the advantages of its use for the surgeon in defining the disease.
		This is a patient that had had colorectal cancer metastatic to the liver that had had a hepatic resection of the metastases, and this was being for follow-up is there recurrent tumor on these whole-body coronal sections.  This is a normal study.  As we look a little more postoral, we can see the evidence of the resection.  We're seeing evidence of resection here.  But there was no evidence of recurrent or persistent tumor at this time.
		This is a PET scan of a 19-year-old boy with malignant melanoma that had recurred in his axillary lymph nodes right axilla.  He had had surgical removal of those.  Now this was being used to determine is there any persistent or recurrent disease.  And we see no abnormalities to suggest recurrent melanoma on this patient.
		The next patient is an older patient than the last.  This patient is in his 50s.  Very similar story.  Had a melanoma removed several years ago, then developed axillary involvement, had surgery, now coming back six months later is there any evidence for metastatic disease.  And in this patient we have right upper lobe metastases, left iliac wing metastases, and a left adrenal metastasis.  So this is being used to for surveillance of these patients to determine when the disease has recurred.
		And then, just in closing, to show FDG in determination of cardiac viability.  Dr. Raczkowski and others have pointed out that we compare the FDG images, which are these three images, with the ammonia images, which are these three.  On the vertical long axis views on this ammonia image, this should look like a horseshoe.  And so this portion of the myocardium is hypoperfused.  If you look at it on the glucose, it has FDG accumulation within it.  So that shows that it is ischemic, decreased blood flow, but viable, having glucose accumulation within it.
		This particular patient is a 60-year-old woman, 8 years post-bypass grafting surgery, 6 months post-anterior wall infarction, heart failure EF-22.  The images revealed this mismatch consistent with viable anterior wall.  Coronary angiography revealed an occluded graft.  A second bypass was performed.  Six months later the patient was asymptomatic.  Ejection fraction 47 percent.
		And then the last one is a 30-year-old man.  Family history of heart disease.  Anterior wall infarct.  Angioplasty attempted.  Unsuccessful.  The PET FDG and ammonia images show a match consistent with scar.  Because of the age, 32, they chose to go ahead and bypass the patient.  Two months after cardiac surgery, the pre-surgical ejection fraction of 20 percent was unchanged, wall motion not improved.  The patient died six months after the surgery.
		This shows the images in this patient.  Again, this should look like a horseshoe.  A large defect here in the anterior anoapical-infloapical wall.  But the FDG images look identical to the perfusion images.  So this is a match and shows infarcted myocardium, not ischemic myocardium.
		Thank you.
		DR. RAMSEY:  Thank you, Dr. Coleman.
		We have time for questions now for the speakers from this morning as well as Dr. Coleman.
		DR. KONSTAM:  Dr. Coleman, could I just ask you about that cardiac case with the viability.  I think I noticed that there didn't seem to be an increase in FDG uptake in the ischemic, it just looked homogeneous relative to the flow which was clearly not.  I guess the question I have is, to what extent is the diagnostic capability of FDG for viability a function of increased uptake versus just simply a mismatch with flow or wall motion?
		DR. COLEMAN:  The FDG images have been evaluated in several ways.  As Dr. Raczkowski pointed out, there have been criteria based upon if it is greater 50 percent of otherwise normal myocardium, there have been pooled data to use as a background upon which to compare the FDG accumulation, and there has been visual interpretation.  And I think most of us in our clinical practice look at the images and say is there more FDG accumulation there than perfusion, suggesting that there is ischemic viable myocardium.  So it is a comparison with the amount of FDG in a region as compared to the perfusion to that region.
		DR. KONSTAM:  So the diagnosis doesn't really require an excess FDG uptake relative to normal?
		DR. COLEMAN:  No, it does not.  Any FDG uptake there suggests some degree of viability.  And then you have got to compare it to the amount of muscle there that has perfusion.  So, the answer is, yes.
		DR. MALCOLM:  I had a question for Dr. Coleman.  Just a very simple question.  I just wanted to know how do you report those positive studies in the oncological patients?  If I was a clinician looking at any of those studies, what would the readings say?
		DR. COLEMAN:  The readings would say, for example, in a patient with a solitary pulmonary nodule, if I have FDG that looks like the one I showed you, these are the findings suggesting cancer.  In the multiple abnormalities, these findings would be most consistent with metastatic disease.  In the patient that I presented with the lymphoma, that distribution would be most consistent with lymphomatous disease.  So that's the way my interpretations would be.
		DR. TATUM:  I'm Dr. Tatum.  Another question for Dr. Coleman, because I think it is really important for this panel to understand, and a question that has come up several times, in comparing why there is not a sponsor.  If this were another type of a drug with a broad dissemination and profit margin that was more extensive, we would expect to see a sponsor.  So that becomes a very critical point.  And I would like to hear, I know you've been in the area for a long time, your comments on why you think there isn't sponsorship, and what impact it has on our decisionmaking process.
		DR. COLEMAN:  Well, I think that to go through the NDA process, to go through the clinical trials is a very expensive process.  There is no company out there that is going to make the amount of money that is generally made on drugs that receive an NDA, so there is no impetus for any one company to support the clinical trials that are used to have an NDA for a drug like this.  The ICP in its very inception met with the FDA to go through this type of process for approval for FDG just because of that reason.  And so I think this is a very reasonable process to go through for the PET radiopharmaceutical drugs where there is no proprietary nature to the drug.
		DR. AMENDOLA:  I'd like to ask a question to Dr. Coleman regarding his experience on the use of this agent in breast cancer.  There is a very specific set, a patient with a negative mammogram, a positive MRI, the patient cannot be biopsied.  It seems that that would be a pretty good indication for this.
		DR. COLEMAN:  The data on using PET imaging for characterizing breast lesions is relatively sparse at this time.  The initial data are somewhat promising.  I think that for breast imaging what we are going to find is the development of specific devices that will improve the resolution for detecting breast lesions, so-called positron emission mammography.  And several centers now are working on such devices to be able to improve the resolution for detecting breast lesions.  So the preliminary data look quite good for breast cancer, look quite good for looking in the axilla.  But I think that it is going to get better when we have the dedicated devices.
		DR. RAMSEY:  Dr. Coleman, you will be here this afternoon if there are any more questions?
		DR. COLEMAN:  I will.
		DR. RAMSEY:  Okay.  Does anybody have any more questions?
		Yes?
		DR. HAMMES:  Dr. Coleman, your experience with FDG, in particular, but also the ammonia and water, have ever witnessed any adverse effects?
		DR. COLEMAN:  I have never witnessed an adverse effect.  I called Dr. Ted Silverstein, who chairs the Pharmacopeia Committee of the Society of Nuclear Medicine, who surveys all PET centers, and I think it is on a monthly basis, I think we send in monthly reports, but he surveys and he has never received a single adverse event from a PET radiopharmaceutical.
		DR. HAMMES:  Also, does the FDA have any reports of adverse effects from any of these agents we're talking about?
		DR. COLEMAN:  In his letter to me, he said they did not.  But I don't know.
		DR. LOVE:  Since water or ammonia at this moment are not under NDA, we would not normally receive reports from them, it would only be from FDG.  And to my knowledge, we have not received any report on FDG.
		DR. CHOYKE:  Dr. Coleman, could you say what the relative percentage of oncologic versus cardiac use is in your place, and then overall.
		DR. COLEMAN:  The overwhelming use of FDG clinically is in oncology.  Of the 2,000 clinical PET scans we do at Duke, this year the number that will be cardiac will be somewhere between 50 and 100 out of those 2,000.  And I think that that's not too dissimilar from most active PET centers.  There is going to be a few, like UCLA, that has done a lot with cardiac PET and will have a little different ratio and use it more for cardiac.  But most of my colleagues that have active PET centers where there is a lot of oncology and cardiology, it is heavily weighted in favor of oncology.
		DR. RAMSEY:  Any other questions?
		DR. KONSTAM:  Just to follow up on that, and it gets into a question of physiology that I have.  I wonder why it isn't used more in cardiac, in your experience anyway.  I guess I want to couple that with sort of a quandary that I have about the dataset in general; which is, there's a significant nuclear medicine literature on myocardial perfusion imaging as an indicator, and maybe I can address this to Dr. Raczkowski as well, as an indicator of viability, that is perfusion as an indicator of viability.  And there is extensive literature about this.  And yet when you turn to the PET literature, you're looking for a mismatch that is under perfusion relative to FDG.
		I guess let me perhaps partly answer the question relative to what we said earlier, is that, well, but maybe there is increased uptake of FDG in the ischemic area, so it is going to be still increased relative to perfusion even if perfusion is relatively normal at rest.  But then, on the other hand, you showed us a case that didn't have increased FDG perfusion.  So, I guess I'm not sure it matters in the end of the day in terms of the data that Dr. Raczkowski showed which seemed to show that it is useful.  But I just wonder if either of you, or anyone else, can comment about this I think little bit of a paradox.
		DR. COLEMAN:  Let me say a few things, and then maybe Dr. Maddahi will want to say something, too.
		Why is this not used more?  I think that there is a lot of competing techniques out there that are pretty darned good right now.  Thallium redistribution is pretty good.  Low dose dobutamine echo is pretty good.  FDG PET is probably a little better than those but it is not as widely available.  Cardiologists are more used to using the low dose dobutamine echo or thallium.  And so it just hasn't been used that much.
		Now concerning the use of perfusion alone in predicting viability, certainly if you get below a certain threshold of perfusion, you are not going to have viable myocardium.  And this has been shown in dog studies as well as in people.  But above a certain level, it is difficult to know whether that is going to be ischemic or infarcted.  And I think that that's the group where the wall motion stops, the wall stops functioning, the perfusion is decreased, it is not zero, there is some chance for viable myocardium but it also may just be ischemic and viable.  And so that's where the PET technique helps.
		Dr. Maddahi, did you want to say something there?
		DR. MADOO:  Can you identify yourself and your affiliation, whether you are being sponsored.
		DR. MADDAHI:  Yes, my name is Jamshid Maddahi from UCLA, and I am sponsored, like Dr. Coleman, by ICP to appear here.
		I agree with the comments that Dr. Coleman made about the two issues.  But I would like to add a little bit to it.  Why isn't it used as much?  I think that part of it is because of the fact that there are other techniques that do the job.  But also we have got to keep in mind that even in centers that do cardiac studies, 20 cardiac studies a day with nuclear techniques, the ones that directly and specifically relate to myocardial viability are not many studies.
		Even in those centers, only about two a day are related specifically to myocardial viability because we're looking at a disease that the prevalence of the patient population that would require a specific question of myocardial viability is much less than it is for detecting coronary artery disease.  So later on when we'll be talking about detecting disease with just ammonia, those are the type of studies that, if they are used, they will be used in the ratios, in the higher ratios than viability assessment.
		The second question was related to perfusion and relationship to viability.  We published a few months ago an article that we looked at actually the specific question of relationship of perfusion to myocardial viability.  What we found was that below a certain amount of perfusion, generally there is not much viable tissue because there has to be at least a minimum amount of perfusion to keep the tissue viable.  And also, when you get to very high perfusion levels which is close to normal, 80 percent or more, or 20 percent only reduction in perfusion, then you'll see that those areas are also often viable and there's no problem there.
		The clinical problems in perfusion levels are in the intermediate zone of somewhere between 20-25 percent to 70-80 percent.  In those intermediate zones, then perfusion alone cannot distinguish the three different patterns of viability which we call hibernation, or stunning, or presence of the myocardial infarction, transmitter or nontransmitter infarction.
		So I think that in clinical decisionmaking, when I see the perfusion defect that is very, very severe, very much reduced, I don't really need anything more to tell me that it is nonviable.  And when perfusion is normal, I don't need anything else to tell me it is viable.  But when it is in the intermediate zone, that is where the clinical problem starts and we need a metabolic marker to tell us whether it is viable or not.
		DR. RAMSEY:  Let's have one more brief question or comment, and then we'll break for lunch.  We can continue the discussion after lunch.
		DR. RACZKOWSKI:  Victor Raczkowski.  The only thing I wanted to add to that is some of the agents that we're referring to as perfusion agents, such as thallium, have other properties besides just assessment of perfusion.  Thallium requires an intact membrane in order for it to be taken up.  So, in that sense, it could be viewed as a potential marker for viability as well, not just perfusion.
		DR. RAMSEY:  Thank you.
		Again, I want to thank all the speakers and presenters this morning.  I think we all learned a lot.  Everybody did a very nice job.
		Let's take one hour for lunch.  We'll reconvene here at 1:30.  We can continue our open discussion, and then we'll go right into the presentations.  So have a nice lunch and I'll see you at 1:30.
		(Whereupon, at 12:30 p.m., the meeting was recessed for lunch, to reconvene at 1:30 p.m.)

	AFTERNOON SESSION	(1:35 p.m.)
		DR. RAMSEY:  I sent Mr. Madoo out there to ring the bells.  So we will see if we can get everybody back in here.  All our good question people are out enjoying themselves.  We have to get them back in here.  Mr. Madoo is out rounding up the last members.  But I think it is time, it's a few minutes past time, so why don't we go ahead and get started.
		First, I would like to ask if there are any questions of any of the speakers this morning, or further conversation or comments regarding their presentations?
		Dr. Hertzberg?
		DR. HERTZBERG:  What I'm struggling with right now is that for FDG for malignancies there is no restrictions with regard to safety, but for cardiology uses you've indicated a safety hedge, if you would, for individuals with impaired glucose metabolism.  And I was just wondering if you can help me straighten out it should be in one and not the other, or why they should differ in that respect.
		DR. RACZKOWSKI:  I'm not sure that they should be different.  One of the speakers, Dr. Coleman I believe, this morning indicated that in his experience generally patients are uglycemic or near uglycemic when they are considered to be candidates for PET scanning.  Our anticipation would be that the labeling would be similar for both indications.
		DR. HOUN:  I don't think that there was enough data to actually comment on its use in diabetic patients.  So I'm not sure, if you saying there was no restriction in oncology, it is no data was presented on how hyperglycemic patients would react with a PET scan, what the efficacy would be with hyperglycemic patients.  And in four studies, they specifically excluded patients with glucose over 100.  So some of that would be reflected in the labeling.
		DR. RACZKOWSKI:  Right.  And, actually, I raised it more also as a theoretical concern.  It wasn't anything that I had seen adverse event reports that was resulting from data.
		DR. LINKS:  Jon Links.  Just to also clarify.  In the case of FDG, you have to make the distinction in these conversations between issues arising from the preparation of the patient versus an actual pharmacologic effect of the tracer itself.  And in this context, there is no pharmacologic effect of the tracer itself.
		DR. PONTO:  Laura Ponto, the University of Iowa.  I guess I would like to address this question to Dr. Love, Dr. Houn.  How extensive do you anticipate the labeling to be with respect to patient preparation?  Those of us who work with FDG know the importance of monitoring the glucose, of having different types of glucose state, whether it is a fasting state for a neurological study or oncologic study, the fed state for a cardiac study.  How extensive do you anticipate the labeling will be, and how much do you anticipate you would need to advocate that the glucose levels be monitored?
		DR. HOUN:  I think in looking at the studies that were reviewed, we would have enough to put in the label that the studies were done in uglycemic conditions.  We don't have enough information about how it would be performed in a diabetic population, what the results would be.  I think we would recommend in terms of dosing administration at least four hours or more fasting prior to the IV injection for the oncology indication.
		What were the other kinds of concerns in terms of patient preparation?  Should glucose be monitored?
		DR. PONTO:  Yes.  Would you have them monitor the glucose?  And would you put a precaution on for diabetic patients?
		DR. HOUN:  I would welcome your advice on that.  I think we certainly would state that there was a lack of data to say what efficacy could be found in diabetic patients.  One study specifically said four of their patients were diabetics.  But the results from the other studies we don't really have.  So whether that's a precaution or a statement in the clinical trials section, it certainly I think deserves consideration.  In terms of precautions, what we would be cautioning about was that there wasn't information to state about its effectiveness in this population.
		DR. TULCHINSKY:  If I may add to this just for a moment.  Currently, as we're doing myocardial perfusion imaging with thallium, there is also very specific preparation procedure.  Patients should be fasting, for a number of reasons into which we're not going to go at the moment.  But would it be reasonable to leave that as a practice of medicine for an individual center to decide?  It has not been really a safety problem.  As a nuclear medicine physician, that would seem reasonable to me.
		DR. MALCOLM:  I was going to say this issue of safety and preparation is a medical problem and the referring physicians and the physicians doing the study should have information with regards to the patient's metabolic state.  This has nothing, as I see it, to do with the drug itself.  The drug has no "effect" on a patient that's diabetic.  It is the fact that the patient may be a diabetic and can that patient fast, et cetera, et cetera.  So that has to be a clinical decision that should be made prior to the patient having the study that the physician should be aware of.  Aren't we all saying the same thing?  So it's kind of a different issue.
		DR. TULCHINSKY:  Exactly.
		DR. KONSTAM:  No, but the efficacy question, she's saying, if I'm catching it, that in your review of the literature you would raise a question as to whether the data are as clear in a diabetic population.  Is that ‑‑
		DR. HOUN:  Yes, exactly.
		DR. KONSTAM:  So that that ought to be stated.
		DR. HOUN:  I don't know, the effectiveness in the diabetic population who are suspected of having tumors, that was not very well demonstrated and documented.
		DR. TULCHINSKY:  Yes, and that's very well understood.  I am not contradicting in that respect.  All I am saying is it hasn't been demonstrated to be effective, or it hasn't been demonstrated not to be effective.  I would leave it to an individual pair of physicians on both the management team and diagnostic team to sort it out.
		DR. KONSTAM:  Maybe this does need a little bit more discussion because I'm worried that we're on a slippery slope.  You know, we're here to determine the efficacy of the agent for the indication shown.  And the presumption is that the agent is effective in the population in which it is going to be studied.  And this needs to be data-driven.  And to the extent that we're sort of falling back on criteria for data, there may be reasons for that, but if, in fact, there might be some reason to suspect there might be less efficacy in diabetics and we don't have a dataset to deny that, then I think that that's a population that has not been studied and that needs to be reflected in the packet insert.
		DR. TULCHINSKY:  In what sense?  Like what would you suggest?  How?
		DR. KONSTAM:  Like what I just said.  That the efficacy has not been demonstrated.  And I don't know the data well enough, but what I gather just in listening to the presentation and reading it, is you're saying the efficacy has not been established in a diabetic population.
		DR. TULCHINSKY:  That sounds fine.  It's a little bit troublesome though, because there are so many other conditions I guess that it hasn't been demonstrated.  Should we list those too?
		DR. RAMSEY:  Mr. Hammes?
		DR. HAMMES:  At least in terms of cardiology, I had a discussion with a cardiologist before I came to this meeting and they expressed a very strong concern in terms of any kind of limitation on FDG for that population just because that's the population that has a great deal of cardiovascular disease.  And along with that, they passed along to me an article, which I did bring along, from the April 1999 Journal of the American College of Cardiology, that specifically looked at the use of FDG to assess left ventricular contractile dysfunction in a diabetic population with very good results.  I think that is something we need to consider in these deliberations.  There now is data out there.
		DR. RAMSEY:  Any other comments, questions?
		DR. KONSTAM:  I wanted to go back to Dr. Raczkowski's presentation.  To begin with, I would like to critique the indication or the draft indication in a couple of respects.  One is that I would urge taking the word "contractility" out of the indication.  None of the studies measured contractility.  Contractility is a specific indicator of myocardial function independent of load.  And so what was measured was systolic function.  And so that's really the way it ought to be stated.
		The other thing about the indication, and I guess I was sort of asking about this before, you're talking about altered glucose metabolism.  I'm not clear that altered glucose metabolism is the key element, or, if it plays a role, whether it is a necessary element in the diagnosis here.  At least to a great extent, the diagnosis is based on a mismatch between glucose uptake or FDG uptake and either perfusion or wall motion.  So I think that is really the key element.  I don't believe that we've shown that a key part of the diagnostic role is in identifying an abnormality of glucose metabolism; it may or may not be.
		So I redrafted it and it can just be played around with.  I said, "To examine myocardial glucose metabolism and to identify myocardium with reversible loss of systolic function, when used together with myocardial perfusion imaging."  Something like that to solve those problems.
		DR. RACZKOWSKI:  I absolutely agree with you about the contractility statement and systolic function.  One of the reasons we put the glucose statement into the indication was just to have some statement in there reflecting the underlying biochemical.
		DR. KONSTAM:  Oh, yes.  But I'm just saying it is not necessarily an abnormality of glucose metabolism.  I would just restate it a little bit so that it's not ‑‑ that's why I said to examine myocardial glucose uptake or metabolism, however you want to say it.
		The other question I had, I just wonder whether, in looking at the data, again with regard to the myocardial indication, whether it might not be subject to a meta analysis.  Understanding that there are a lot of differences in there, but I think still there's a lot more similarity across those studies relative to comparatively to the cancer indication.  I think that might be very useful.
		In looking at the different studies, I just wonder whether one could not construct an ROC curve over the totality of data in some way.  I don't know, maybe somebody wants to comment from a statistical perspective on that, or whether you do.  But I would like to somehow be able to summarize everything we know.
		DR. RACZKOWSKI:  In my review, I did reference a recent pooled analysis that was published I think in the Journal of the American College of Cardiology in about 1998 or so which covered many of the same articles.  They, in fact, did do a pooled analysis.  I ended up not including some of the studies that were included there because I felt that the quality of the studies didn't merit being included.
		The issue of a meta-analysis is a much larger issue.  And I do agree that there are a lot of similar things across the different studies, including endpoints, that potentially would lend itself to that sort of analysis.
		DR. KONSTAM:  Well, I guess, just listening to your presentation, I'm left with a lot of questions about exactly what do we think is the sensitivity and specificity, about what are the correct or optimal diagnostic criteria that should be applied to the studies to get the most out of them.  If I'm a clinician and I'm looking to the FDA to an approval here, I guess I would like some help about that.  And I don't get it from looking at all the individual studies in isolation.
		I don't know if Dr. Maddahi wants to comment on that.
		DR. MADDAHI:  I agree that meta-analysis or pooled literature has some advantages.  But knowing some of the difficulties also, it is that you're dealing with some studies that are not exactly uniform.  If it would be helpful to the panel and to Dr. Raczkowski, I have done a recent rerun of that pooled data with emphasis or special attention to the differences of some of the studies and how they were done that I would be glad to get a copy of that for the panel; either today or later I can submit that to the panel.  I could actually ask my office to fax me a simple table of the average sensitivity or mean sensitivity and specificity that would help along those lines.
		But what we've found is that the sensitivity and specificity are positive and negative to the predictive values are in the range of 82-83 percent with this technique, that is quite good, looking at regional wall motion.  And we do have some other data for ventricular function improvement.  I would be glad to provide that data.
		DR. RACZKOWSKI:  I think that would be great.  One of the issues that I struggled with is the definition of segment is different in all the patients.  And given that difference, especially when the segments may not be mutually exclusive of one another in all the papers, how do you then go about pooling those data?
		DR. MADDAHI:  Right.  I think that the point is that if the segments are very, very small, then I think that it is going to create a problem.  And in fact, that would result into ‑‑ it has one advantage in that it provides more data for the investigator, but, on the other hand, it makes the misalignment of the segments between the various techniques much more difficult.  So I think what you are saying is absolutely correct.
		I think there is also other data, as you know, looking at ejection fraction changes, that is perhaps a better marker I think, and also prognosis.  There are about four or five studies that, again, have been alluded to by you in some other literature that will be appearing later on this afternoon about the prognostic aspects also, several publications along those lines.  So I think that if you look at four endpoints ‑‑ one being segmental wall motion improvement, the second being ejection fraction improvement, third being improvement of patient symptoms, heart failure symptoms, and fourth being improvement of patient survival and prognosis ‑‑ I think that among all of those we can get a common theme here that would help a clinician as to where this technique might be helpful.
		DR. TULCHINSKY:  I would like to mention to the panel members that in Volume 3, the first reference is on that very specific topic.  It is a meta-analysis.  It was published in the New England Journal of Medicine, a very reputable publication source, and by very reputable people.  They do cite all different tests and their sensitivity and specificity.
		I also would like to comment on Dr. Raczkowski's compilation.  It has been exclusively well-done given the problems we are addressing at the moment, especially the segments being difficult to follow.  The first article that you have brought to our attention, Dr. Baer's article, which kind of strikes funny for Dr. Baer to talk about hibernation.
		(Laughter.)
		DR. TULCHINSKY:  But I also notice that if you look at his drawings of segments, we in America usually refer to anterior walls and to the wall opposite as inferior wall, but Germans, being very logical, they term it posterior wall as contra distinction to anterior wall.  And it is sometimes very difficult to follow those different nomenclatures.
		In addition, you were talking about 50 percent above the maximal pixel as being a criteria that they used.  Now, for a moment, if one would think about it, 50 percent of maximal pixel activity, it is kind of like saying I jump about 50 percent in this room above the level of the ceiling, which is clearly impossible unless you have a pretty hard head, which many have posed to me as a possibility in my case.  But in any event, what the authors probably meant is a 50 percent above the mean pixel count.  But the way it came out seems to me to be a little different.
		Jon, do you know something different?
		DR. LINKS:  It's 50 percent or greater of the maximal pixel count.
		DR. TULCHINSKY:  But the maximal ‑‑ you can't get 50 percent above the maximum, can you?
		DR. LINKS:  No, 50 percent of half of it or greater.
		DR. TULCHINSKY:  That's not how the sentence reads.  But I think it is a translation difficulty though.
		DR. RAMSEY:  Any more questions or comments?  That's what happens when you read these things here.
		(Laughter.)
		DR. RAMSEY:  Okay.  Seeing no further questions at the moment, why don't we proceed ahead with the next portion of our program.
		DR. HOUN:  We were thinking that maybe we should vote on the FDG question, then we can move on so that each drug product is fresh in people's minds.
		DR. RAMSEY:  Oh, my goodness, a vote here.
		(Laughter.)
		DR. RAMSEY:  Okay.
		DR. MADOO:  Let me reiterate that apparently we have 12 eligible voters.  Our guest experts, sadly, will not be voting.  But our two august consultants from other committees will be contributing.  Of course, the options are affirmative, negative, or abstain.
		DR. KONSTAM:  What did you just say, Leander?
		(Laughter.)
		DR. MADOO:  What I'm saying is that apparently we're proceeding into the voting component of ‑‑
		DR. KONSTAM:  Who votes and who doesn't?  I don't get it.
		DR. MADOO:  You as a consultant are eligible to vote.
		DR. KONSTAM:  I am eligible to vote.
		DR. RAMSEY:  I think Mr. Madoo is also making a point that there are 12, so there could be a tie.
		DR. MADOO:  It's conceivable.
		DR. KONSTAM:  I don't think that's going to happen.
		Could we have a little more discussion before the vote?  I don't know how you want to do it, Ruth.
		DR. RAMSEY:  If you feel like discussing it, I think we should do that.
		DR. KONSTAM:  I would just like to hear a little bit more discussion around the oncology indication.  The issue about the diversity of the different studies and then merging them into a single indication, there really are two studies that you're really very happy with, those two are different, each one of them has problems.  We're going to say it is for cancer.  I don't know, do we need a little bit more discussion about what ‑‑ is there going to be actually a packet insert here, is that what happens? ‑‑ what the packet insert is going to say about this, which cancers.  I would like to hear more discussion about this.
		DR. HOUN:  The way that this is being proposed, and that's why I'm very interested in hearing the discussion, is to have this broad indication to help in the evaluation of malignancy through identifying areas of abnormal glucose metabolism.  We were not thinking of having a specific indication in terms of evaluating malignancy to identify lymphoma, or hepatic metastases, or small cell lung cancer.  We were not going to specifically indicate the names of the cancers that the studies came from in the indication section.
		However, in the clinical trials description part of the package insert, we are going to have the package insert for labeling for these products, we would describe the literature that was reviewed in terms of prospective studies, the number of patients all together, as well as the different types of cancers that these studies included.  I know some of the folks in the PET community were interested in getting more specific cancers in the clinical trials section, such as brain tumors.  But we didn't find, at least we weren't able to locate studies that were of a prospective nature, that had at least 50 evaluable patients, et cetera, et cetera.  So in the clinical trials section of the label, we were going to discuss some of the criteria that brought the studies into the review of this process.
		DR. KONSTAM:  Well, maybe it's just because I don't know anything about this field, but I just am uncomfortable about this because I'm looking to the packet insert to give me guidance on how to use this agent.  I understand there are people in the audience with a lot of experience and people with a lot of experience who just want to be able to use the agent.  But the indication is going to be data-driven and the data are very diverse.
		I just continue to be uncomfortable about an indication section that simply says diagnosis of malignancies without any kind of data-driven information or conclusions around what are the cancers where we're confident, what are the cancers where we're not confident or we don't have any data.  I don't know how the clinician is really going to be guided without that.
		DR. HOUN:  I'll ask for other members to help give FDA some direction.  I do think we need to state in the labeling that using PET is not a substitute for other diagnostic, for biopsy, and that we need to caution in terms of false-negatives and false-positives do occur with PET scanning.  But I'm interested in hearing the panel's views on how to handle this and what kinds of information doctors should be provided from the labeling to help them.
		DR. LINKS:  Jon Links.  I like the proposed indication.  The reason I like it is because it really represents, in terms of diagnostic imaging agents, the first attempt to move beyond the concept of diagnostic accuracy, per se, simple concepts of sensitivity and specificity, and to really acknowledge that in many nuclear medicine studies what you're trying to do is a functional characterization but in the setting of different diseases.  Now there's a challenge in that, and the challenge is that we seem, certainly within nuclear medicine, and certainly today in the studies that have been presented, to always fall back on sensitivity and specificity.  How are we to move beyond sensitivity and specificity and diagnostic accuracy if we keep falling back on those?
		The reason I like the indication is because it is a step away from simply looking at diagnostic accuracy.  It is certainly true that this morning we were not presented with any data, to use your term, on the accuracy of quantification of glucose metabolic rate in a given lesion.  But we know from other studies that we can accurately quantify metabolic rate.
		Here's my point.  My point is that the indication is not an indication focused on sensitivity and specificity, but rather on characterization when the presence of a lesion is already known.  That is the way the indication is written.  I favor it because that's what I think in clinical practice in oncology this agent is all about.
		DR. MALCOLM:  Arnold Malcolm.  I totally agree with what Jon just said.  We deal with this on a daily basis.  It is the same situation we have ‑‑ in fact, I've never looked at a label for tecnesium for bone scans for patients; I don't even know what it says.  But I know when a patient gets a bone scan and I have all the clinical information, I can make a clinical decision from that bone scan with tecnesium.  And I think we're talking about the same situation again here.  Maybe I'm simplifying it, I don't know.
		The studies that have been reviewed have talked about a variety of malignant diseases.  And if you try to pick it through, it just won't happen.
		DR. KONSTAM:  Well, I don't know.  I think people are bringing their own experience to the table, and that's always helpful.  I wasn't necessarily talking about identifying sensitivities and specificities.  It is one thing to say this thing is indicated, I have experience, I'm going to use it.  It is another thing to say the FDA is going to declare that it is effective.  And if the FDA is going to declare it is effective, to my way of thinking, I don't think it is so unreasonable to take a stab at asking what are the data to drive that, and where is the data in terms of what entities have been studies, what entities haven't been studied.
		I've heard comments to the effect that there are certain cancers that just don't pick this up ‑‑ renal cell, if I'm not mistaken, for an example.  Now, do you want that nowhere referenced?  Is it sufficient to tell the clinician it is indicated for the diagnosis of malignancies without some comment about the fact that there are clear discrepancies across the different cancers?  I'm not understanding.
		DR. MALCOLM:  I understand what you're saying.  I thought Dr. Houn was saying that the label would indicate which studies are being referenced for the disease type.  I thought that's what I heard her say.  Is that clear?
		DR. HOUN:  Yes.  The comments I made in terms of saying some cancers are less likely to be picked up by PET, including bronchial alveolar carcinoma, low grade non-Hodgkin's lymphoma, those are general comments that come from the literature but there is no study on the specific entity showing PET performance is less.  And so in that case, there is no data, except I guess there must be in terms of investigator experience and some ‑‑
		DR. KONSTAM:  Maybe we're going to be in a quandary.  But, I'm sorry, I just can't get away from the fact that what we I think are supposed to do around this table is act upon data.  That's all I'm saying.
		DR. PONTO:  Laura Ponto, University of Iowa.  I think we're going back to the problems that we have had with indications that we've been struggling with as a committee for a couple of years now.  Are we looking at a disease-specific indication, or are we looking at an imaging mechanism that tells us something about biochemistry.  And the indication that I'm seeing here is that we are looking at glucose metabolism, and we know that in a large number of tumor types, because of their general metabolic activity, that glucose metabolism will be "abnormal," and that that information then can tell the clinician where metastatic disease may exist, maybe give them prognostic information about the type of cancer that they are dealing with.
		If we have the indication, as we are looking at glucose metabolism, then I think that we have the data that tells us, basic science data that says this agent gives us a picture of glucose metabolism.  We know that tumors will have differences in glucose metabolism.  And if that is the indication, we can make labeling changes that say certain types of cancers do not have large metabolic differences from normal tissue.
		So I think that we're dealing with what is the indication, and the question is, is this effective for that indication?  If we're going with a specific type of cancer, is it good in lung cancer, in melanoma, or whatever, we do not have the data here to possibly get that specific a type of indication.  But a general, does FDG give us a picture of glucose metabolism in the body, and is it efficacious for that indication?  That is I think what we're trying to deal with today, and that is what I think this indication is trying to get at.  It may not be the correct wording altogether, but I think it is probably the correct one, at least in the ballpark.
		DR. TULCHINSKY:  Yes, I would like to echo that comment.  I totally agree with your assessment.  Again, just as a basic reference, going back to what we have been through and said and done, I brought a book with me of package inserts.  It's just my fun time reading before I go to bed.
		(Laughter.)
		DR. TULCHINSKY:  I was looking at the indications for the bone-seeking radiopharmaceutical, the bone scan agent.  Let me read it to you.  "Technetium-99m metronate injection may be used as a bone imaging agent to delineate areas of altered osteogenesis."  I suggest we keep those historical pieces in mind as we go forth here.
		Also, I have to say that I disagree that we're not acting upon the data.  I think we're very much acting upon the data.  If it is not, what is the reference book that I'm holding right under my left arm?  It's full of data.  And it is not simply our personal experiences.  I have to say I personally have no PET experience, so I don't have that.  But we are looking at a compilation of literature experience.  This is something that has been published, and most of it in very, very well peer-reviewed publications.  Credibility ought to be given to that.
		And I totally agree with the FDA's assessment for the labeling indication.  I'm perfectly happy with it.  Going back for a moment to the bone tracer, we all know that the bone scan is less sensitive in patients with multiple myeloma.  And that is not in the indication that it is less sensitive in multiple myeloma.  I'm not sure it belongs there.  It belongs in a text book.  And we practice medicine not by package insert, we practice it by compilation of the textbook and our collegial and personal experience.  So I would suggest we keep that in the background as a framework as we move forward.
		DR. PONTO:  To follow up my comment, I work in a PET center and I firmly believe in what I do.  I think there is evidence that says that this is an incredibly useful technology.  But I'm saying that in the two studies that were cited here, I can see where some people around this table would say this is not up to the same level that we're used to approving an indication for.  But if we look at the literature as a whole, not only the disease-specific literature but malignancy as a whole, as well as the basic science literature, there is data that says that this agent gives us a picture of metabolism.
		DR. TULCHINSKY:  Again, I totally agree.  I think we came prepared for this meeting to look at it in that particular way.  That's why it makes it different.  So I totally agree with you.
		DR. ZIESSMAN:  Harvey Ziessman.  I think that the medical community in general has been urging the FDA to get away from the specific one drug, one diagnosis indication approach.  And this is I think a major advance.  We don't want the FDA to be telling us how to practice medicine.  I doubt very much whether you look at the package insert to decide what the indications are for treating patients, because I know most physicians don't.
		This is an approach that I think many have been urging on the FDA for some time.  I think they are to be commended for it.  And I'm in favor of it.
		DR. KONSTAM:  Can I respond to that?  First of all, I would say that I disagree.  I think that the FDA is very specifically here to tell us what are the data that support the practice of medicine.  And if you as a clinician want to go beyond that, that's your prerogative; nobody is stopping you from doing that, the FDA isn't stopping you from doing that.  The FDA hasn't been stopping us from using FDG for quite a while now.
		But I specifically think the FDA has a major role to educate the clinician, to tell you, okay, what do the data show.  This is proof, this is what we know about this.  Now if you want to go beyond that, that's fine, but this is what we know about this.
		Now I think this situation is odd.  And we're going to resolve this.  I think this agent needs to be approved and go beyond it.  But I think it is odd because everybody around the room knows there is no such thing as malignancy, that we're talking about an assortment of scores of diseases.  And so I guess I have a very different reaction from people around the room.  My reaction is that to not find some way to acknowledge that, and I'm not sure what the way is, but my feeling is to not find some way to acknowledge that in the written indication is as if to say all cancers are the same.  And that's what I feel you're saying to the clinician.  So I guess I have a very different interpretation.
		DR. ZIESSMAN:  But I don't think the purpose of the FDA is to educate, as you're saying.  I think the purpose is to tell us that drug is safe and efficacious.  And if it is, then it is up to the physician to use the drug appropriately.
		DR. TATUM:  Could I just suggest that maybe we change a little bit the verbiage to try to reflect the statement with the data that we have.  And maybe just think about this, it is really a subtle change, "Detection of enhanced glucose metabolism associated with known or suspected malignant tumors," which after that could follow the statement that you would enclose.  That would flow quite nicely.  Just a suggestion.
		DR. LINKS:  I was going to suggest something similar.  I strongly support that.  Take, for example, a tumor that may or may not express a certain receptor and you have a receptor imaging agent, and I'm predicting something that will probably come before this committee at some point, and if all you were to do is to ask the question, "What is the sensitivity and specificity of that receptor binding radiopharmaceutical?"  In my opinion, it would be a grossly misleading kind of study because the point of using that radiopharmaceutical is not to detect the lesion but to characterize the lesion.
		I think where we're getting sucked into this confusion and the fact that different types of tumors may or may not take up FDG to the same extent is because we're focusing again on the detection part.  What we're really talking about here is assessment of glucose metabolism in lesions.  And the way the indication is written here, it is known.  I like your addition of "or suspected."  But, quite frankly, the name of the game in this indication is not raw detection, per se.  And the name of the game of FDG is not raw detection, per se, necessarily, but rather assessment of metabolism.
		DR. TULCHINSKY:  Would you consider also adding "and extent of the tumor."  Because oftentimes once we characterize the lesion, we would like to also see if there are others.  So I would wonder if that would be useful to incorporate.  But, in general, I was, frankly, perfectly happy with the way it was written in the beginning.
		DR. HAMMES:  Just a comment along these lines.  From reading the indication as it is written, we're basically just saying that, yes, FDG can measure glucose metabolism, that it is known that some malignancies to a greater or less extent use more glucose, and hence, by extension, we can make some determinations clinically about that.  But it is very clear to me that we're not operating in a static vacuum here.  What we know about it in terms of cancers is going to change, and that is the practice of medicine.  We expect our physicians to stay current with the current literature about what is known about things.  And that doesn't belong in a package insert.  I'm very happy with it as written.
		DR. RAMSEY:  Any other comments?
		(No response.)
		DR. RAMSEY:  A suggestion has been made that we vote on these.  And I guess that's appropriate then at this time.  Is that then Questions 1 and 2.  And this is in your handout.  I numbered it as page 5.
		DR. LINKS:  We've now had recommendations for wording changes on both indications.
		DR. RAMSEY:  Would that come under discussion or ‑‑
		DR. LINKS:  I personally like most of the wording changes I heard about for both indications.  I would just as soon vote on the changed ones rather than the original ones.
		DR. RAMSEY:  Okay.  All right.  Let's go to Question 1.  Question 1 is:  Based upon the presented literature review, do you think fludeoxyglucose F-18 injection is safe and effective in positron emission tomography (PET) imaging for identification of abnormal glucose metabolism to assist in the evaluation of malignancy in patients with abnormalities found by other testing modalities, or in patients with existing diagnosis of cancer?
		That is the statement before us.  And now if we want to modify it, why don't the modifiers suggest their modifications again.
		DR. TATUM:  Mine was to change it to "detection of enhanced glucose metabolism associated with known or suspected malignant tumors."  I'm just replacing the original, not with a question.
		DR. RAMSEY:  Just a little slower.
		DR. TATUM:  Detection of enhanced glucose metabolism associated with known or suspected malignant tumors.
		DR. KONSTAM:  Can I just ask the FDA, just in terms of what ‑‑ I guess I'm not picturing what an indication section of a packet insert looks like.  In other words, this is the indication, but then there is a discussion within the indication.  Can you comment?
		DR. LOVE:  The package insert generally, in relationship to what we're talking about, would have something called a clinical pharmacology section which would describe mechanism of action, pharmacokinetics, and what is known about the drug itself, a clinical trials section that would discuss the database essentially, the key studies usually, and then an indication section which is just a discreet one or two sentences most often.
		DR. KONSTAM:  So this would be the entirety of the indication section.
		DR. LOVE:  The indication section.
		DR. ZIESSMAN:  I would suggest that Jim's suggestion "detect," I would rather use the word "evaluate" or "assess," something rather than detect.
		DR. RAMSEY:  Dr. Tatum, would you accept that?
		DR. TATUM:  Yes.
		DR. LINKS:  And I would just as soon eliminate the word "enhanced."  It is assessment of glucose metabolism.
		DR. TATUM:  That's what you do by changing detection to enhance, it becomes value.
		DR. RAMSEY:  Okay, I got lost there.
		DR. MADOO:  Would someone read the concrete new statement.  I guess I'm experiencing abnormal glucose metabolism.
		(Laughter.)
		DR. RAMSEY:  Start from PET imaging in line 2.
		DR. LINKS:  Okay.  So I am modifying the questions for MIDAC, right?
		DR. RAMSEY:  Right.
		DR. LINKS:  So, is safe and effective in PET imaging for "assessment of glucose metabolism to assist in the evaluation of malignancy in patients with known or suspected abnormalities found by other testing modalities, or in patients with existing diagnosis of cancer."
		DR. RAMSEY:  Comments?
		DR. KONSTAM:  I don't suppose anybody would go for saying "certain cancers."
		PARTICIPANT:  No.
		(Laughter.)
		DR. PONTO:  This may be opening an entire can of worms that we don't want to, but do we want to leave positron emission tomography in there since individuals are sometimes imaged using SPECT technology?
		DR. HOUN:  The data reviewed was for PET technology.
		DR. TULCHINSKY:  Since the technology is evolving quickly, I don't see a very compelling reason to include that at all, frankly.  Does anyone feel different?
		DR. RAMSEY:  Is that appropriate?
		Yes, go ahead.
		DR. CONTI:  You can actually consider an imaging adjunct for the assessment and take out the specific technology.
		DR. MADOO:  Please identify yourself.
		DR. CONTI:  Peter Conti from USC. "Effective as an imaging adjunct for the assessment..."  That's another possibility.  And take out the word "PET."
		DR. RAMSEY:  Any other comments?  But we are discussing PET, right?  I think they want it in there.
		DR. HOUN:  I don't think you will get very far without us talking about PET, as mandated by Congress.
		DR. RAMSEY:  Okay.  So, Dr. Conti, can we leave that in there?
		DR. CONTI:  That's fine with me.
		DR. RAMSEY:  Thank you.
		Any other?
		MS. BEAMAN:  Carolyn Beaman, consumer representative.  I think that we've stretched some things beyond their elasticity point already.  And now if we go back and start trying to rename the method of imagery and on and on, then we might as well just make up a whole lot of data, just make it up and play it by ear as we go.  We can't reach in there and pull PET out like that, or we shouldn't.
		DR. RAMSEY:  I think it will be left in there.  I think that's what we're talking about.  That's what they want us to do.  So, right now it is in there.
		Any other questions?
		(No response.)
		DR. RAMSEY:  Maybe we should read what we're voting on again.  Who knows what we're reading here?
		(Laughter.)
		Jonathan?
		DR. LINKS:  Okay.  So, F-18 FDG injection is safe and effective in positron emission tomography imaging for assessment of glucose metabolism to assist in the evaluation of malignancy in patients with known or suspected abnormalities found by other testing modalities, or in patients with existing diagnoses of cancer.
		DR. RAMSEY:  All right.  That is what we're voting on then.
		Mr. Madoo, would you help me verify whoever is eligible to vote here?
		DR. MADOO:  Certainly.  Okay, again, the 12 eligible voters proceed.
		DR. RAMSEY:  Do we have to call for the question here, or how do we do this?
		DR. HOUN:  We would appreciate also hearing from non-voting members their views.  But that wouldn't be counted as a vote.  Just to hear their views.
		DR. RAMSEY:  So before we vote, do we want to hear those views?  Because it might change somebody's vote.  I think they wanted comments from non-voting members, if anybody has any.  Somehow I think this is not a shy group here.
		DR. HOUN:  If the non-voting members could comment whether they are supportive or not supportive, that would help us.
		DR. RAMSEY:  Okay.  Why don't we just start with Dr. Herscovitch.  And make a comment why you either support it or don't support it.
		DR. HERSCOVITCH:  I'm supportive of the question as amended.  I still have reservation about the perhaps mismatch between the original question and the data, but that's perhaps a minor reservation because the ultimate issue is its use as a metabolic agent in the specific cases that have been very well documented both in the literature and by the FDA reviewers.
		I think that it is important to realize that many of these tracers are physiologic tracers, and that it may be a bit of a mindset or a paradigm shift, to use another cliche, but I think increasingly in the field of nuclear medicine, definitely in the field of PET, there are going to be tracers based on biochemical mechanisms not more physicochemical mechanisms.
		And I think it is important for what we're doing today that we not only realize that we, or you, not me because I'm not voting, that you all are deciding on an indication, but also that you are establishing a process for how these agents, especially PET agents in the future, might be assessed.  And in that regard, not being familiar with this process, I do have to give some credence to the views expressed by Dr. Konstam about the level of proof that is needed for these agents.  But that aside, I would, if I were voting, vote in favor of this indication.
		DR. TATUM:  I obviously support the way it was amended.  I think there are a couple of things I would like to say since I'm not voting that are important.  Jonathan pointed out that this is probably the start of a process where we're going to be dealing with a number of agents in the future.  And I don't think they are all just PET agents.  As we begin to look at molecular probes, we're going to have this same problem.  We're going to have things that do not have sponsors because they do not commercially have a large enough target audience, but yet they may have a very valuable asset to programs and to development.
		One of the things that is an issue at NCI right now is in mechanistic drug design and trying to get probes, and PET is one of the areas where it is difficult.  And to get the number of clinical trials to answer the secondary questions you're coming up with, we really need more sources of these.  And without approval, I think it is going to be extremely difficult.
		So, again, I do support this.  I do think you're setting a precedent that also is a slippery slope because it does in fact say how in the future these are going to be evaluated and tested.  And maybe we should keep in mind that the data needs to look a little bit more like a regular commercial application in the future at the same time.  So, I think it is important for this particular course, but it also sets a precedent for the future.
		DR. KONSTAM:  I probably shouldn't be allowed to vote because I don't know anything about this.  But then, again, maybe I'm thinking that it's good to have somebody who doesn't know anything about it so he's forced to sort of make his decision purely based on the data that he's seeing.  And I guess I'm going to hold out.  I'm going to vote no to this.  I think that it should be approved, even though I'm confused about what the standard is.  But what the heck?  It's been around for a long time.  I do believe it works based on looking at the totality of the data.
		However, I just want to express my deep concern about an indication that talks about cancer as if it is some homogeneous process and where the data are sparse to absent to negative in some areas.  And so what I would urge the FDA to do is simply amend whatever specific wording you're coming up with to include a term like certain malignancies, or certain cancers, or selected ‑‑ I guess that's the best way I can come up with it ‑‑ certain malignancies and certain cancers.
		DR. MADOO:  Dr. Konstam's vote duly recorded as a no.
		MS. BEAMAN:  Carolyn Beaman again.  I think that it is clear that the FDG or PET can detect changes in glucose utilization patterns.  I would, however, suggest that in the future when pharmaceuticals are brought before this or other similar committees that we definitely need a more detailed guideline for interpretation.  I think that goes without saying.  But having said that, I reluctantly support the question as amended.
		DR. MADOO:  Duly recorded as a yes.
		DR. HAMMES:  Richard Hammes, University of Wisconsin.  I think by all accounts this has been shown to be about the safest drug ever considered.  There has never been an adverse effect reported, so we're only talking about efficacy.  It has been well accepted for over 20 years in the nuclear medicine PET community as being a good marker of glucose metabolism, with some very thorough animal work to back that up.
		The only reason that we're going through this strange process is because there hasn't been a sponsor, there hasn't been enough money, it hasn't been patentable.  I don't think this necessarily should be the model for the future.  I think the PET community needs to learn what kind of data would convince everybody who perhaps isn't an expert in the field out there and that is the kind of studies that need to be done in the future.
		But this is an indication that needs to be approved.  The people that can afford it have been getting it for 20 years.  All we're doing is making it effectively available to the Medicare population, the Medicaid population, the poor population, and maybe allow them to get reimbursement support so that they can also benefit.  I vote yes.
		DR. HERTZBERG:  Likewise, I vote yes, although I share some of the reservations about the specific concerns expressed about the disease entity.  I don't know what disease entity it is being indicated for.  But I do think that it is efficacious.  I do think there are issues with regard to patient preparation for the procedure that need to be cautioned about.  But I do vote a yes.
		DR. TULCHINSKY:  I guess there is no suspense, my vote is yes.  I have no reservations, frankly.  I think we are not doing anything that is terribly unusual given other indications I've read through in the package inserts that I've gone through.  I have to tell you that I do go through package inserts on everything that I use.  I think there is a great deal of useful data in it and I respect that very much.
		I think it is a milestone though that we have come upon because today we have used a bit more of scientific, logical thinking in synthesizing the data to support our yes for this particular vote, at least those who are voting yes.  I think it is a step in the right direction.
		DR. CHOYKE:  I'm going to try to get the brevity award.  I'll vote yes for all the reasons stated.
		DR. MALCOLM:  Bet you I can outdo you.  My vote is yes.
		DR. RAMSEY:  I vote yes as well.  I also concur with everything that has been said.  I think this is something that is being used very commonly, although there are not as many PET scanners as there are CT scanners and MR scanners.  I think if agents like this are approved, I think we'll see the data that people have expressed some concerns about and it will allow us to go forth in a more widely and freely way to further evaluate this new agent.
		DR. PONTO:  I obviously also vote yes.  I would like to urge the FDA though to write very detailed use instructions.  Specifically, I would like to urge them to have patients monitored for their glucose levels, because I think that very importantly can impact the efficacy of a particular scan.
		DR. AMENDOLA:  I think that based on the evidence presented here, a little bit of my personal experience with this agent, my vote is a qualified yes.  I share some of the reservations that were expressed.  But I think this is a really valuable addition to the practice.  So my vote is yes.
		DR. ZIESSMAN:  I think this radiopharmaceutical is clearly safe and effective.  And I think this new approach is a major step forward.  I don't agree that we ought to be closely monitoring glucose levels routinely, as you suggested.  In fact, I think Dr. Coleman mentioned earlier that they do not check them routinely except under certain exceptions.  And I don't think that ought to be part of the package insert, other than a comment that it may be indicated in some instances.
		DR. LINKS:  Yes.
		(Laughter.)
		DR. MADOO:  I have the official vote tally.  It appears to be 11 yes, 1 no.  And I duly respect Dr. Konstam's viewpoint.
		DR. RAMSEY:  Thank you all.
		I think there is Question 2 also under this agent.  "Based upon the presented literature review, do you think fludeoxyglucose F-18 inject is safe and effective in positron emission tomography (PET) imaging in patients with coronary artery disease and left ventricular dysfunction, when used together with myocardial perfusion imaging, to identify left ventricular myocardium with altered glucose metabolism and reversible loss of contractility?"
		DR. KONSTAM:  Could I just re-read my suggested change to that?
		DR. RAMSEY:  Please.
		DR. KONSTAM:  All the stuff you said at the beginning, Ruth, and then where it goes "to identify left ventricular myocardium," I've jotted down "to examine myocardial glucose metabolism and identify myocardium with reversible loss of systolic function," and then to continue, when used together with myocardial perfusion imaging, et cetera.  So the two changes are just changing the word "contractility," and just taking out the "altered glucose metabolism" part.
		DR. RAMSEY:  Are there any comments on that suggested change?
		(No response.)
		DR. RAMSEY:  In general, are there any comments or discussion?  FDA, would anyone like to make any?
		DR. ZIESSMAN:  I'm in favor of that change.
		DR. RAMSEY:  Would you like the same thing again, a vote and comments.  Are we prepared to vote then.
		Why don't we use the same method again.  Dr. Herscovitch, you can go first.
		DR. HERSCOVITCH:  I would vote in favor.  I think this is a lot more clear-cut than some of the earlier discussions we were having.  Perhaps one thing to clarify it.  I think it is fairly obvious to everyone in the room that the myocardial perfusion imaging is not necessarily with the other PET agent N-13 ammonia, but other agents as well, more conventional agents.  Because especially in some facilities, FDG will be available from other providers but the ammonia won't because of absence of an in-house cyclotron.  So, I think just to make that clarification, although it was probably clear to everybody before I said that, in this room at least.
		DR. TATUM:  A straightforward yes on this one.  Well supported, well documented.
		DR. MADOO:  Excuse me.  Before we proceed with the vote, some of us are experiencing Y2K problems.  We would like to have the rephrasing of the question again.  Read the question, please, the entire question.
		DR. KONSTAM:  Well, I don't have the beginning of it.  Okay, I got it.  "Based upon the presented literature review, do you think fludeoxyglucose F-18 injection is safe and effective in positron emission tomography (PET) imaging in patients with coronary artery disease and left ventricular dysfunction, when used together with myocardial perfusion imaging" ‑‑ I'm sorry, the wording is just backwards.  That's fine.  So, "when used together with myocardial perfusion imaging, to examine myocardial glucose metabolism and to identify myocardium with reversible loss of systolic function."
		Oh, yes.  The only thing is I would urge the FDA I think to develop some kind of advice in the packet insert regarding what we think the true boundaries of sensitivity and specificity are with selected methodology, because I don't have a clear sense of that right now and I think it could use a little work.
		DR. MADOO:  So you vote yes I take it?
		DR. KONSTAM:  I vote yes.
		MS. BEAMAN:  Yes.
		DR. HAMMES:  Yes.
		DR. HERTZBERG:  Yes, again with the language about appropriate patient preparation.
		DR. TULCHINSKY:  Yes, as modified.
		DR. CHOYKE:  Yes.
		DR. MALCOLM:  Yes, as modified.
		DR. RAMSEY:  Yes.
		DR. PONTO:  Yes.
		DR. AMENDOLA:  Yes, as modified.
		DR. ZIESSMAN:  Yes.
		DR. LINKS:  Yes.
		DR. MADOO:  It appears we have a sweep, 12-0.
		DR. RAMSEY:  Thank you all.
		We will now move on in the agenda.  The next agenda item is FDA presentation on safety and effectiveness of nitrogen N-13 Injection.  Our first presenter I believe will be Dr. David G. Udo, Ph.D., on clinical pharmacology, pharmacology, and toxicology.  Thank you.
		Oh, a break?  We have a question for a break here.
		DR. MADOO:  What time was the scheduled break?  Is there a motion to have the break now, or would you like to proceed with all due purpose into the N-13 world?  The committee requests a break.  Dr. Ramsey, is that appropriate?
		DR. RAMSEY:  Yes.  Let's take ten minutes, and we'll come back here at five minutes to the hour.
		(Recess.)
		DR. RAMSEY:  We're going to go ahead and begin with our afternoon presentation.  So if everyone would please come in and take a seat, we're turning the podium over now to Dr. Udo, who will tell us about nitrogen-13 clinical pharmacology, pharmacology, and toxicology.
		Thank you, Dr. Udo.
		DR. UDO:  Thank you.  Good afternoon, ladies and gentlemen.  I am David Udo, a reviewer with the Office of Clinical Pharmacology and Biopharmaceutics of CDER.
		The information I'm going to present today is from reviews of literature articles on pharmacology, toxicology, and clinical pharmacology of N-13 ammonia.  The pharmacology/toxicology review was done by my colleague, Dr. Adebayo Laniyonu.  The clinical pharmacology review was done by me.
		These reviews were focused on the use of N-13 ammonia for measurement of myocardial blood flow by the PET technique in patients with known or suspected coronary artery disease.
		In this presentation, we will cover the following aspects of N-13 ammonia:  The concept of blood flow measurement, pharmacokinetics, and metabolism.  An attempt will be made to relate pharmacokinetics or metabolism to safety.  And then in the end a summary will be provided.
		Following intravenous administration of N-13 ammonia, the blood takes it to the coronary vasculature.  And for our purpose, I'm going to say that we're going to find in the myocardium N-13 ammonia in the blood flowing in the coronary capillaries from where it entered the extravascular compartment of the myocardium and, finally, into the intracellular compartment where, in a reaction mediated by glutamine syntheses, it is transformed into glutamine and trapped therein.  That is, inside the cell.
		And so we can see that we have three distinct compartments in the myocardium where you can find N-13 ammonia for kinetic purposes.  This can be presented schematically, as shown.  K1 and K2 are intercompartmental real constants for the blood in the capillary and the extravascular space of the myocardium.  K3 represents the rate of metabolic conversion of N-13 ammonia to N-13 glutamine.
		Our focus is K1.  K1 is a composite rest constant which represents blood flow and the single pass extraction of ammonia from the capillary into the extravascular space.  Since the extraction is very close to 1, then K1, which is a product of E and F, already defined, approximates F, and therefore provides an estimate of measurement of blood flow.
		Now how do we obtain the value of K?  K is obtained by solving the three-compartmental equation which described the time course of N-13 ammonia in the myocardial tissue.  And we have said K1 is the blood flow.  So, by obtaining data and putting in the appropriate concentrations, K1 can be determined which approximates blood flow.
		Now, let us examine the pharmacokinetics aspects of N-13 ammonia.  In the literature, articles revealed that doses that were administered were mostly in the range of 10 to 20 millicuries.  This was associated with a mass dose of 0.05 to 0.1 micromole of N-13 ammonia, which translates to 0.80 to 1.60 micrograms.
		The physical half-life of N-13 ammonia is approximately ten minutes.  It's half-life in the blood, as determined by accurately taken blood samples, is approximately three minutes.  It's half-life for myocardium and the brain, as determined from imaging data, are no more than two minutes and three seconds, respectively.
		Now how is N-13 ammonia handled in the body so as to show it its way out?  That brings us to the subject of metabolism.  N-13 ammonia is metabolized to N-13 urea, which is its major metabolite.  Other metabolites of this imaging agent include neutral amino acids, and traces of acidic amino acids, mainly glutamate and aspartate.
		Now, could anything that relates to pharmacokinetics effect the safety of this imaging agent?  And so we get back into examining what really is the amount of ammonia that is already in the body produced by various metabolic processes.  The normal range of ammonia in humans is 12 to 55 micrograms per deciliter, which translates to 720 to 3300 micrograms in a 70 kilogram man.  And so, if you throw in this 0.80 to 1.60 into that amount, it appears to me that it is like throwing a teaspoon full of salt into an ocean; it will not change the salinity.  So I think that this amount would not cause any significant increase in the amount of ammonia in the body and, subsequently, would not effect a net drug imbalance of the body.
		In reference to metabolism and safety, we find that urea is readily eliminated in urine.  And the small amount that is generated from the small dose of N-13 ammonia then would not be a real problem, in my opinion.  Amino acids are normal components of body tissues.  So based on this, it is reasonable to expect that the metabolic products of N-13 ammonia would not significantly affect the safety of this imaging agent.
		And so the next thing I had to look at was radiation absorbed doses to various organs of the body.  I had to go to the information that is published by the ICRP and then generate a dosimetry table in the units we usually use in regulatory arena; that is, rem per millicurie.  And so this would do is that the clinician can use the dosimetry table as a calibration curve to determine the radioactivity dose that would cause acceptable radiation exposure in different tissues.  This is only a small part of the table.  The whole table is in the review that has been put in the files of the  FDA.
		And to summarize, we can say that due to the high extraction of ammonia from coronary capillaries into the myocardial extravascular space, the value of K1 obtained via the three-compartmental equation that describes this time course in the myocardium can yield a reasonable estimate of myocardial blood flow.  As we see, ammonia is effectively eliminated from the body.
		I've already talked about the dosimetry thing, that it would be a calibration curve which allows the physician to determine a dose that is appropriate for a given population.  And finally, we can say that the pharmacology, toxicology, and pharmacokinetics of N-13 ammonia do support its use for myocardial indications.  Thank you.
		DR. RAMSEY:  Thank you very much.
		I think we will hold questions until after the second presentation, and the second presentation is entitled "Safety and Effectiveness in Oncology," by Dr. Florence Houn.
		DR. HOUN:  Good afternoon again.  I'm going to be talking about N-13 ammonia in use of PET for myocardial perfusion.  My teammates include Sonia Castillo, who helped with the review.  She's a Ph.D. from the University of Washington in Seattle, and a postdoctorate from the Harvard School of Public Health, and she's been with the FDA for three and a half years.  Also, Ms. Kaye Cho was the project manager.  David Hussong was our microbiologist.  Ravi Kasliwal was the chemist.  Dr. Laniyonu was the pharm/tox reviewer.  Dr. Udo did the biopharm.
		My preliminary conclusions are a finding of effectiveness to assess myocardial perfusion in the evaluation of coronary artery disease in patients with known or suspected coronary artery disease through stress and rest testing.  In the literature, single doses of up to 25 millicuries were studied, usually administered as two IV doses, during rest and then at stress, up to 20 millicuries each.
		I'm going to kind of run through these slides because I've talked about them before in terms of the general structure of the talk.  You've heard about our guidances and how we've been using them.  I'm going to discuss the intended use of N-13 ammonia, the external standards of truth for the studies, our search methodology, selection criteria, review of findings, and conclusions.
		I'm not going to talk very much on this.  Again, the guidance for clinical effectiveness was discussed, when studies in the literature could be used to support indications.
		The draft medical imaging guidance also provided some structure for me in terms of looking at what should be included in studies in terms of adequate and well-controlled design.
		In terms of its intended use, a cursory review of the N-13 ammonia literature found a couple of different uses for this drug, including identification of malignancy, perfusion of various organs, and the assessment of myocardial perfusion.  The bulk of the literature focused on myocardial perfusion, and that's what I focused on in terms of trying to find effectiveness.
		The advantages for this agent in terms of evaluating myocardial perfusion include that it's minimally invasive, there are kinetic models available to allow for quantification, there is the ability to correct for photon attenuation because of body habitus.  Also, it provides a functional or physiologic claim in terms of looking at perfusion, and ammonia tissue concentration almost linearly relates to the flow over zero to 300 CC's per minute per 100 grams of tissue.  It's highly extractable, as Dr. Udo was talking about, from the circulation into myocardial cells, where it's rapidly metabolized.
		In terms of an external standard of truth for myocardial perfusion, many studies were done comparing to coronary angiography.  Angiography is typically viewed as a gold standard for anatomy, for coronary artery disease, and at times for blood flow.  We know it's good in terms of identifying anatomy.  It presents two-dimensional information, but there are problems with coronary angiography in that the endpoint in terms of percent stenosis on an angiogram doesn't take into account many factors, such as the geometric complexity of the actual atherosclerotic vessel.
		There are variations in terms of the extent of the length of the stenoses, diffuse disease.  There's collateralization, viscosity.  Angles of various takeoffs of vessels affect flow rate, hypertension with or without hypertrophy, and even heart rate.
		So in trying to address what can be used as a standard to look at myocardial perfusion, one solution that authors had looked at was the use of quantitative angiography through validated software programs to try to eliminate observer bias and allow calculation of coronary perfusion as a function of flow.  In some of the papers I'm going to talk about, the use of stenosis flow reserve is presented, and that's defined as the flow at maximum vasodilation versus at rest.
		The search criteria you've heard earlier:  the same time period, from 1990 to 1998; online databases that were in English and that dealt with human clinical trials information.  We got a lot of assistance from ICP in finding articles as well.  In all, 76 articles were generated from the above search criteria.
		In terms of selection criteria, we looked at N‑13 ammonia PET studies that compared to an appropriate clinical standard of truth.  Some of this would be in terms of anatomy relating it to angiography.  In terms of a functional standard for microperfusion, we looked at various other comparators, such as wall motion through echo or through ventriculography, exercise testing.  A variety of other standards were used in terms of trying to assess microperfusion.
		We also looked at articles that had a relevant clinical study question and were not experimental in design.  A well-described clinical population was included, and there were some types of procedures to reduce bias, such as masking, randomization.  In all, the selection criteria generated 14 articles.  Two of them I'm going to discuss at greater length.  These were the larger studies.  One is a feasibility study that led into the larger published studies, which I'll talk more about.
		I'm also going to be going through some of the other controlled published studies.  These had various study hypotheses.  Some of them had retrospectively selected patients.  Others used normal volunteers and assumed that they would have angiographically-defined negative disease, although these normal volunteers did not undergo angiography.  These were smaller studies.  There were nine other published studies that had a wide variety of hypotheses but still supported the idea of using N-13 ammonia to define coronary perfusion.
		Also in my review I included myocardial blood flow quantification algorithm papers, much as what was summarized by Dr. Udo earlier.
		The two studies I'll focus in on are Gould, published in 1986, which is a feasibility study, and Demer, published in 1989 as the follow-up larger study to the Gould study.
		Other controlled studies are listed here:  Schelbert, Di Carli, Gerwitz, and other supportive studies are listed in alphabetical order.   You see them here and on the next slide.
		The quantification algorithms are listed here, three studies that I really will not be talking about, but they're included in the review for completeness.
		In terms of the first study we'll spend some time on, Gould in 1986 published this from the University of Texas Medical Center.  It was a feasibility study for diagnosing coronary artery disease with rubidium and ammonia N-13 using rest and stress testing with IV dipyridamole and hand-gripping.  Now, 23 of the 50 subjects received ammonia in this study, and these people were presenting for work-up of chest pain.  They were being evaluated status post-MI.  Some of them were pre- and post-angioplasty patients.  Some of them were pre- and post-plasmapheresis for cholesterol control patients.  So a variety of types of patients were in the study.
		It was a prospective study, and it compared angiography results to PET results.  The image protocol involved masking.  PET images were re-read three times using three presentations.  There was gray-scale presentation, a tri-color presentation, and an isocount color format which ended up to be what the investigators felt most correlated between PET and angio results.  The isocount color format had defects defined by the color format and the continuum of changing count densities being reflected in hue gradations in each of five primary colors corresponding to steps of about 3 percent maximal counts at rest and stress images.
		The dosage of N-13.  People got between 10 to 20 millicuries two times, at rest and at stress, of either N-13 ammonia or rubidium.  It depended on what was available from the generator.  X-rays were digitized and allowed for the measurement of stenosis dimensions and allowed for calculation of coronary flow reserve.  That was scored between zero to 5, zero being no flow and 5 being normal.  They defined having a significant coronary flow reserve problem as less than 3.0 on the angiography, and this was defined prospectively.  There were 22 patients that met this definition of having significant coronary artery disease.  There were 9 patients without coronary artery disease defined as greater than or equal to a score of 4, and there were 13 patients with mild disease, between 3 and 4.
		The paper stated in a caption that the percent isocount reduction on PET was proportional to the percent decrease of coronary flow reserve.  So I'm making the assumption that this is the equation in terms of relating coronary flow reserve and PET scores.
		The sensitivity of this study showed 21 out of 22 patients who were identified as having significant CFR picked up by PET, and a specificity of 9 out of 9 who were disease-free were picked up as PET-negative.  The qualitative comparison of N-13 ammonia and rubidium-82 was just stated in the study to be comparable.  There was no separate stratified data on how each of these agents performed.
		The Demer study also came out of the same university as a follow-up to the Gould study.  The specific objective was to look at accuracy of N-13 ammonia in evaluating coronary artery disease using rest and stress testing compared to coronary angiography.  The sample size included 111 patients who received ammonia.  The remaining patients received rubidium.  There was a total of 193 patients, of which 174 were analyzed.  Nineteen patients were excluded from the analysis, and the reason stated was the infarct-related stenoses they had had undergone acute revascularization, and they were excluded because residual stenosis severity would not be comparable to perfusion defect on PET.
		The inclusion criteria were all patients who were undergoing catheterization, and this included the population suspected of having the disease, and including some that were disease-free.  There were 143 men, 50 women.  They included people undergoing work-up for chest pain, abnormal stress test results, thrombolytic therapy.  They were being evaluated for renal transplant.  There was also a cholesterol lowering program involving coronary angiography and PET testing, and these patients were also enrolled.
		The design of the study was comparing stenosis flow reserve, which resulted from digitized angiograms that allowed calculation of SFR, and they defined SFR as the intersection of flow at maximum coronary vasodilatation relative to rest flow.  They compared this score to PET defect scores.
		The endpoints were continuous scales.  SFR was measured from zero to 5, and I have here 5 being normal, but it's actually greater than or equal to 4 being normal, less than 3 being significant coronary artery disease.  The PET defect scores were also zero to 5, but going in the reverse direction, 5 being severe perfusion defect, zero being normal, 1 being possible, 2 being probable, 3 being mild, and 4 being moderate.  So significant coronary artery disease was defined as a PET score of greater than 2 and an SFR of less than 3.
		The image protocol involved masked readers.  They were independent in reading.  Each image was re-read twice.  The rest and stress images were read side-by-side using the isocount format.  Scores for PET were averaged.  This study talked about tracking inter-observer variation.  Dispute resolution was described for eight cases.  These cases were re-read, and either there was an agreement in two cases or they averaged the scores in six cases.
		The dose and administration section of the study was supplied, and the results were presented as a Spearman correlation coefficient of 0.77 per patient, scores with the most severe PET score and SFR score.  What that meant was for each patient, regardless of the location of the vessel that was being considered, the most severe score for PET and for SFR was correlated.  So these may not be of the same regions in the testing modalities.
		Also, per-vessel analysis done by 243 stenosis defect pairs was correlated, to have a Spearman correlation coefficient of 0.63.  In terms of rubidium and ammonia use, the study stated the following concerning the two agents:  "Images obtained with rubidium-82 and N-13 ammonia tracers were qualitatively similar."  There was no breakdown in data of how rubidium performed relative to ammonia, but there was some information in terms of the total enrolled patients of 193.  There were two false-positives, of which one was from rubidium, one was from ammonia, and there were seven false-negatives, of which two were from rubidium and five were from ammonia.
		This 193 and the two false-positives and seven false-negatives was not the actual data set they analyzed, which, if you recall, was 174, because they excluded 19.  So in trying to use the data that was presented, I know Dr. Links was hoping FDA would move away from sensitivity and specificity.  Nevertheless, we moved towards it in this study, to trying to use Figure 3 in the study, which I'll show you in the next slide, which is a graphical representation that does permit some estimates of N-13 ammonia PET sensitivity and specificity using the data of the plot versus mean stenosis flow reserve score versus subjective PET defect severity score.
		So if you go to the next slide, I think it's kind of hard to see but it is included in your review.  The upper representation is the per-vessel analysis.  If you total the N's here, it deals with 243 vessels.  I'm going to first talk about the lower representation, which is the per-patient analysis, which, if you totaled all the N's here, comes to 174 patients.
		I'm going to orient you.  This is the PET score severity, zero to 5, zero being no disease or PET-negative, and a score of 2 or more being significant artery disease as defined by PET.  So a PET-positive score is 2 to 5.  So all these people here are PET-positive.  These are the numbers of the people and their average scores.  These are the error bars associated.  There are 106 patients here in the study that were defined as PET-positive.  Over on the right-hand side, these are the PET-negative people.  There are 68 patients here defined as PET-negative.
		Now, if you go on this axis, stenosis flow reserve score, it's the reverse, where zero is severe disease and 5 is considered non-disease.  Here a score of 3 or less is considered significant disease based on the angiography results.  So this box of people are considered disease-positive based on this gold standard of angiography stenosis flow reserve, and the people below a score of 3 on SFR are considered normal.
		So what we have here is the making of a 2x2 table, except that there are some overlaps.  The number here is 4, and there is some overlap in that probably two out of four of these patients are false-negatives, meaning that the PET score is less than 2 but their stenosis flow reserve score is greater than 3.  We also have patients here who are false-positive, where their PET score is greater than 2, meaning they're PET-positive, but their angiography results are less than 3, meaning that they're not diseased according to angiography.
		So what you have is the makings of the 2x2 table, and if we advance one slide we have the totals based upon that graphical representation.  We have one degree of freedom, in that if I fill in one box, everything else must add up.  So if I fill in one box, I'm obligated to come out with the totals on the end.  What I've done is I've estimated that error bar that was a false-negative, two out of four, putting the 2 here as a false-negative score, meaning that the PET score was less than 2 but the stenosis flow reserve was less than 3, signifying disease.
		Based on that 2x2 table, we get a sensitivity of 98 percent and a specificity of 85 percent.  This is the per-patient analysis.
		Now, if we go back to the graphical representation, I've done the same thing also for this per-vessel analysis, using this corner as the PET-positive/disease-positive cell for my 2x2 table.  This would be my PET-negative/angiography-negative cell in my 2x2 table, and the offsetting two boxes would be my discordant cells, meaning PET-positive/angiography-negative, and here would be PET-negative/angiography-positive.
		Using an estimate of the error bar here, saying that that's about two out of the five total patients, if you go forward two slides, I've put in two here, and again with one degree of freedom, all the other cells fill in, and I can estimate a sensitivity of 99 percent and a specificity of 74 percent.  So if you advance one more slide, these are the numbers that we got with the confidence intervals figured in.  For patients, 98 percent sensitivity with a 95 percent confidence interval between 92 to 99.7, a specificity of 85 percent with a confidence interval between 75 to 92 percent.
		The strengths of the Demer study were that the inclusion criteria were rather broad and allowed for diseased patients and non-diseased patients to be entered in.  The images were read by two readers independently.  They were masked to the angiography results.  Inter-observer differences in PET readings were tracked and analyzed.  There was graphical data with enough detail to look at the sensitivity and specificity.  Dispute resolution was defined.  There was detailed information on readers' performance, on the reader variability, and there was a relatively large number of patients.
		In terms of weaknesses, we do not actually have a stratified study of rubidium versus ammonia results.  We have some indication from the false-negative and false-positive of the total 193 patients what false-positives and false-negatives did occur.  We know that in terms of sex and age distribution, age was not presented.  There were certainly more men, 143 compared to 50 women.  Nineteen patients were excluded from the analysis, so this was not an intent-to-treat analysis.
		In terms of other controlled studies, these were more variable in their hypotheses.  Their patient populations were selected retrospectively at times.  There were small numbers in sample size.  Normal volunteers were selected to represent coronary artery disease-free patients in some of the studies.  Schelbert in 1982 from the University of California-L.A. published a study to try to correlate angiography and N-13 ammonia PET results.  It was a very small study of 32 patients who had coronary artery disease on angiography, and there were 13 normal volunteers who underwent PET imaging, rest and stress testing, but who didn't undergo angiography, and they were assumed to be normal in terms of disease-free for angiography.
		Eleven patients with coronary artery disease did also have stress thallium testing as a small sub-study.  There were two readers reading through consensus.  They were masked to the findings of the angiography.  The agreement of these readers were tracked.  We have dosage and administration, as well as acquisition information from the study.
		The results show a sensitivity, based on a percent stenosis of 50 percent or more, of 97 percent, 31 out of 32 patients, and a specificity of 13 out of 13 patients.
		The major weakness in this study was that it was a retrospectively selected study population, and it really didn't test how the diagnostic test is going to be used in a clinical population.  The same size was very limited, but nevertheless it was a study that could be viewed as providing information on proof of concept.
		Di Carli in 1994 from the University of California at L.A. School of Medicine published an article on the relationship of collateral flow, wall motion, and viability as defined by metabolism of F-18 FDG.  The sample size was 42 consecutive patients, with a total of 78 vessels, with coronary artery disease defined by angiography with LV dysfunction.  This was a comparative study of PET viability patterns and the severity of perfusion defects between three groups of angiographic collateral flow grades.
		The findings were that there seemed to be separate information provided by angiography from PET and that they were contributing different types of information about flow.  Fifty-eight percent of patients that had collaterals on angiography had decreased N-13 flow, and 50 percent with no angiographic collaterals had N-13 flow.  This study was included in the review as providing information on this aspect of microperfusion that is above and beyond what angiography can provide, because angiography will not be imaging vessels less than 100 meters in diameter.
		The next study was in 1994 by Gerwitz from the MGH in Boston, and it was to try to determine a minimum level of myocardial perfusion, and this I think was referred to earlier in discussions about is there a flow rate beyond which viable myocardium cannot be sustained.  This looked at 26 patients with chronic MI referred for thallium and PET testing.  It compared wall motion in the PET FDG study with N-13 ammonia perfusion.
		The results of this study showed that perfusion correlates with wall motion and that in patients with chronic myocardial infarction, myocardial viability is unlikely when a basal regional myocardial blood flow was less than 0.25 ML's per minute per gram.  Again, this information, although the study was small, provided proof of concept of how to use N-13 ammonia as opposed to anatomical definition that's traditionally looked at from angiography.
		Other studies that were reviewed ‑‑ and I don't intend to really go into detail because these also were wide-ranging in their hypotheses.  Some of them were uncontrolled.  Some of them had very small sample size.  In some of them, experimental intervention was the goal of the study, and PET testing and angiography results were part of looking at how well intervention worked for the patients.  Most of these studies were retrospective in nature.
		The results of these studies talked about either how angiography correlates with PET or, in severely diseased patients, how PET detects microperfusion when angiography is negative.
		Beanlands in 1995 from the University of Michigan Medical Center studied myocardial blood flow reserve and angiography and did a correlation in terms of lumen diameter and flow rates.  There was detailed patient information in this study.
		I know I'm going to slaughter many people's names here.  Dr. Czernin in 1995 from the University of California School of Medicine studied myocardial perfusion's response to conditioning, exercise conditioning.  There were 13 volunteers, of which four had coronary artery disease, and there were eight non-randomized, non-concurrent controls that were normal volunteers.  This study showed an improved flow in cardiac endpoints with conditioning.  What this study allowed us to do was to look at the pressure heart rate product and exercise as a reflection of flow and microperfusion as a functional comparison.
		Di Carli in 1994 from the University of California Los Angeles School of Medicine used PET and angiography to try to predict survival.  Ninety-three consecutive patients with severe left ventricular dysfunction were studied, but this was not a randomized assignment in terms of 50 getting medical treatment, 43 getting revascularization.  Rather, treatment was based on the referring physician who was aware of the PET results.  Management decisions in terms of how the referring physicians used PET to change patient management was not tracked, but the results in terms of survival were tracked.
		The next study by Gould in 1994 from the University of Texas Medical School was of 15 patients with greater than 50 percent stenosis to try to assess perfusion after a cholesterol reduction program, and they were randomized to three 90-day programs to decrease cholesterol.  It was a treatment-control sequential trial, and PET was correlated with better cholesterol results, better exercise capacity.
		Gould in 1995 published in JAMA his randomized clinical trial of 20 patients who received active risk modification for coronary artery disease, along with 15 patients who received usual care.  Quantification of PET and angiography results were done initially, and then after five years, and there was a correlation of PET results in terms of size and severity of defect and angiography results in terms of percent stenoses, absolute lumen area, and SFR.
		Haas in 1997 from the University of Munich, Germany, published a study to assess PET's correlation with outcomes of CABG decisions.  This again was a retrospective study.  It was non-randomized in terms of treatment.  There were 76 patients, of which 35 were selected to undergo a CABG based on angiography, and 34 of 41 underwent CABG based on angiography and PET results.  This study also tracked survival.
		Laubenbacher in 1993 from the University of Michigan published a study involving 29 patients with coronary artery disease on angiography and 23 controls to evaluate automated analysis of 3-D myocardial blood flow algorithms.  ROC curves were generated from this study.  Agreement of software and observers' interpretation also resulted.
		Sambucetti in 1995 from Pisa, Italy, studied myocardial perfusion in collaterals.  There were 19 patients with coronary artery disease, 13 normal patients.  PET results were compared to angiography at rest and stress, and the results of this study again supported that angiography and PET provide different information when it comes to collaterals, that collateral-dependent myocardium maintains a residual blood flow reserve at stress not appreciated by angiography at rest.
		Soufer in 1995 from the West Haven VA Medical Center studied reverse redistribution in thallium studies.  A new or increased defect was defined as reverse redistribution after thallium stress testing.  Basically, the study results of the 32 patients with coronary artery disease and reverse redistribution contributed information on PET wall motion and microperfusion correlations.  There were 50 segments with reverse redistribution.  Thirty-six of the 50 ‑‑ that's 72 percent ‑‑ were PET-positive for a perfusion mismatch, and after a mean follow-up of 14 months, 50 percent with cardiac events had reverse redistribution and PET viability ‑‑ that's 5 out of 10 ‑‑ compared to 9 percent, 2 out of 22, who didn't have a cardiac event.
		We've talked about the weaknesses of the literature.  In the ammonia data set, the studies were certainly a lot smaller than the ones that were reviewed for FDG oncology, and also in terms of consistency, there was much more variability than for FDG in myocardial hibernation that Victor reviewed.  The data set was much smaller, and the hypotheses were much more variable in terms of supporting myocardial perfusion.
		Nevertheless, some of the data did suggest support for the intended use to assess myocardial perfusion.  These findings were consistent with the perfusion indication not only from an anatomical point of view but also from a microperfusion point of view for functionality.  The studies were done in diverse populations.  We were able to calculate sensitivity and specificity based on the larger Demer study, and we did have information not only on blood flow as defined by anatomical blood flow but also functional blood flow in terms of microperfusion.
		The safety information has been discussed by Dr. Udo.  A small amount of ammonia is introduced to the body, with known metabolism and excretion, a very short half-life.  Dosimetry information was given to you earlier.
		So in my preliminary conclusions, I would invite the advisory committee to help us in terms of discussion of effectiveness to assess myocardial perfusion in the evaluation of coronary artery disease for patients with known or suspected CAD.  Again, this is not a screening test.  This is done specifically in a diagnostic population, people with symptoms or people with known CAD.
		Thank you very much.
		DR. RAMSEY:  Thank you, Dr. Houn.
		I think we'll go on to the next presentation, and this is Dr. Jamshid Maddahi from the University of California in Los Angeles.  This is part of the open public hearing portion of the program.
		By the way, we will not take up tomorrow's program today.  That will be presented tomorrow.  Thinking ahead while we set up, we probably will not take all day, probably just the morning.  We should be done by noon.  I imagine so, but obviously you can never predict.  But that would be what we're looking at, without holding me to that, please.
		But nonetheless, Dr. Maddahi.  Thank you.
		DR. MADDAHI:  Thank you very much for the opportunity to be here.  I thought that I would show some case examples of how this test is used at our clinical PET center at UCLA and how we make patient management decisions based on this.  Also, I thought that, as Dr. Ed Coleman drew cases from last Wednesday, I'll draw cases from several years ago because I wanted to show you how these tests actually help the prognosis of patients as well, in addition to diagnosis.
		The first case that we'll be looking at ‑‑ could we please have the slides on?  This first case is a 58-year-old physician, a radiologist actually, who was admitted with severe resting anginal pain, and myocardial infarction was ruled out in the hospital.  On the resting electrocardiogram, there was some T-wave inversions in ADL.  In order to find out whether this pain is cardiac, the patient had an exercise test, did very well, went for 10 minutes with a good heart rate response, good blood pressure response, no chest pain, but there was some questionable ST segment depression on the treadmill test.
		Because of the fact that the patient did have a recent onset of angina and had some questionable ECG changes, then the decision was that we needed some more information, at least non-invasively, as to whether this patient has coronary artery disease.
		I'm going to show you in two different formats the slices.  These are all the slices that we get, and I'll reorient them in the short axis.  The red is the myocardium that is perfused from apex to the base of the heart in the resting condition and stress condition, and vertical long axis the same way, and axial cut.  In order to appreciate what the abnormalities are, these are the selected cuts in the vertical long axis at the time of stress and rest, short axis stress and rest, and axial stress and rest.  That shows normal myocardial perfusion in this patient, absence of stress-induced ischemia.
		Based on the data that you already heard from Dr. Houn that the specificity and sensitivity of the test is quite good based on several published literature, although they used different criteria, here you obviously cannot, based on a negative study, you cannot ever on a non-invasive test draw the presence of coronary disease with 100 percent, but the sensitivity of the test is in the 95 percent range, and the specificity is in the same ball park.  Therefore, we were quite confident that the likelihood of coronary artery disease in this patient is quite low.
		Treating this patient was not very easy.  For those of you who have had physician patients, you'll appreciate my comments.  So the patient insisted on having an angiogram also, as a gold standard, just to see what's going on.  And sure enough, my arms were twisted to refer him for coronary angiography, which actually turned out to be completely normal, to confirm that the results were okay.
		This patient actually has done quite well.  This study was done in 1992, I believe, and he's done quite well for these past seven years and has not had any problems.
		We'll go to the next patient.
		I'd like to point out before we go to the next patient that we do actually do quantitation with a polar map approach.  This is the flattened-out myocardium.  If you imagine the myocardium being like a semi-open umbrella, a cone-shaped structure, we're opening it up, looking at the entire myocardium, with the apex at the center, and then the atrium ventricular group in the periphery, and the different colors indicate different degrees of uptake of ammonia in this case, which is entirely normal, except for the apex, which has a normal pattern of apical thinning that we see in patients.
		The next patient is a younger gentleman.  He is about 48 years old.  He also presented to the emergency room, also with a similar kind of scenario, with several hours of chest pain, and the myocardial infarction was ruled out, and a subsequent rest and stress PET study was done.  Here I'm showing it to you in black and white.  This is the way we analyze these images.  They're either in the gray-scale color or in color scale.  Here you can see again that there's a normal perfusion throughout the myocardium, and everything was normal at rest and during pharmacologic stress.
		Here is the representation of the color slices of the same patient, showing normal myocardial perfusion, and the polar map display quantitation shows again some apical thinning and normal perfusion in the myocardium.
		This patient agreed that he's not going to have an angiogram.  He took the suggestion that this is a low likelihood of having coronary disease.  Even more importantly, this is a low likelihood of having coronary events in the future.  This patient has been now for five years after the study and he has not really had any coronary events or any problems.  He is one of 173 patients that we have followed for a period of about two and a half to seven years now, with negative studies, and we were curious to know what the prognostic indication or the prognostic significance of a negative study is in these patients, and we found in the 173 patients that there was no mortality in these patients.  The event rates were quite low, about a quarter percent per year, which is a 0.28 percent per year event rate in patients with a negative test.
		Now, we know from nuclear cardiology, from thallium testing, and from the sestamibi testing literature also, that the event rate in patients having an entirely normal study is quite low, is in the less than 1 percent range.  This, in fact, appears to be slightly better, meaning that it is more predictive of lack of events in these patients.
		The way we would use this information, obviously, is that we could, based on the strong negative predictive value of the test, which is over 99 percent ‑‑ when we're talking about a quarter percent event rate per year, we're talking about a negative predictive value that exceeds 99, is 99.7 percent negative predictive value.  This becomes a very, very powerful test in patient management.  I think we have avoided coronary angiography in many patients who have had negative studies, even though they have presented with symptoms that were suspected of having coronary artery disease, and they have had good prognosis.
		Here is an example of another individual who has had some pain, and his physician, with repeated treadmill testing over a period of time, he has only seen a very slight and insignificant ST segment depression on the treadmill, and he wasn't convinced that this patient's chest pains are cardiac and has been assuring him that his pains are not cardiac, until he insisted that he needs another step beyond treadmill testing to find out what's going on with him.
		Here you're looking at the stress perfusion with pharmacologic stress and the resting ammonia distribution.  The resting study is normal, as you can see, a complete doughnut-shaped pattern in the short axis and the horseshoe pattern in the vertical long axis and axial planes, but there is a significant reduction of perfusion in the lateral wall that extends to the inferior wall.  It involves approximately 30 percent of the myocardium.  This was interpreted as indicating the presence of a very severe proximal disease in this patient.  The patient subsequently went to coronary angiography and was found to have 95 percent proximal stenosis, which then subsequently underwent angioplasty, and that resulted in the resolution of this patient's chest pain.
		Now, whether we need to do a prospective study of whether these defects, if they are left alone, would cause more events, I think this goes back to another issue that was brought up earlier today, that although ideally we want to have prospective randomized studies to evaluate the effectiveness of various prognostic indicators, I believe that we have learned enough in the field of PET, and perhaps even with some other agents, that it becomes increasingly difficult and perhaps unethical to conduct prospective studies and randomize these type of patients.  If I was a patient who had such a defect, I would not want to be randomized to no treatment in order to provide data to support that this kind of an abnormality is associated with higher incidence of death or myocardial infarction.
		So I'd like the group to keep in mind that we have a dilemma as researchers, that we cannot actually conduct in certain areas randomized studies anymore because of the fact that the knowledge is out there and it has become unethical to conduct these types of studies.
		Here the polar map display also shows very nicely that a big chunk of the myocardium, one-third of the myocardium is severely hyperperfused during stress, while the resting perfusion is normal, indicating that this patient has not suffered prior infarction, but these are all areas that become hyperperfused during stress, indicating coronary disease.
		I'd like to move on to another challenging case.  This was a patient who presented after acute myocardial infarction.  The first three cases that I discussed with you were cases who were suspected of having coronary disease but they did not have known coronary artery disease.  But the role of the myocardial perfusion imaging with PET and ammonia goes beyond this group of patients and extends into patients with known coronary artery disease.
		This is an example of a patient with a prior known anterior myocardial infarction, and he was complaining of chest pain about two weeks after an acute myocardial infarction.  He was a patient who presented with his MI with sudden death.  So he was resuscitated at that time.  He is now complaining two weeks after resuscitation and after acute myocardial infarction with chest pain.  The question was whether something should be done about this patient.
		The patient went to coronary angiography first, and what was seen was a single 80 percent lesion in the left anterior descending coronary artery.  This is when I think most cardiologists, especially the catheterizing cardiologists ‑‑ I may say these things because I'm a cardiologist myself, so I'm sure they will not be taken wrong by anybody ‑‑ they may go by this reflex that we call the occluding dilating reflex, that they see stenosis and they want to dilate the stenosis.  They think that this will cure the problem.
		Now, in this case they asked my opinion of what should be done, and as a consultant I decided that we need some functional information in this patient to know whether that 80 percent stenosis is supplying viable tissue, that by opening that stenosis up, we're going to help this patient.  There's 80 percent stenosis.  Is this supplying dead tissue or viable tissue?
		Here, looking at the resting, first we looked at the viability pattern with FDG and ammonia.  The resting ammonia shows a big hole in the distribution of the left anterior descending coronary artery.  We no longer see the doughnut-shaped pattern, and the apex and the anterior wall is missing, and you can see a match to defect.  That was the pattern that was discussed earlier today with FDG.  There's a match to defect in exactly the same area, with almost absence of perfusion and absence of FDG uptake.
		This indicated to me that there's really no viable tissue within this area that would benefit from opening up that artery.
		Another question that may come up in this situation is that these are all resting images.  Do we know whether we're going to make other portions of the left anterior descending coronary artery ischemic during stress?  So we proceeded to do also the protocol of stress/rest study.  The resting study is the same one that you saw before, and then we did pharmacologic stress, and we see absolutely no change in the pattern of perfusion.  These were quantified, and the size of the perfusion abnormality was identical to the resting size of the perfusion defect.
		The conclusion here was that not only is there no viable tissue within the infarct zone, but there's no stress-induced ischemia in this patient, so the patient really would not benefit from angioplasty, and I resisted that.  Now it is about four years after this test and the patient is doing quite well.  There is no problem with that stenosis.
		Now, where did the chest pain come from?  It turns out that after a while we did some x-rays of the chest, and we found out that during the initial resuscitation, the patient had a fractured part of the junction, and it was the reason for the patient's chest pain, not myocardial ischemia.
		I'm going to show you two more cases.  The two more cases are again patients with known coronary artery disease, and the orientation, now that you are quite familiar with what these look like, I'm going to show you a whole row of data.  Here the resting study is on the top and the stress study is on the bottom.  We're looking at a patient here ‑‑ perhaps this is the clearest view, the vertical long axis, that shows an area of severe decrease of activity in the anterior wall and apex, which is normal at rest.  Here you can see the same thing, that the apex that is missing during stress is normal at rest.
		This is a patient who has had angioplasty of the left anterior descending coronary artery, and because it was a high-risk angioplasty, meaning that the lesion was quite complex and statistically there was a high chance of recurrence, the physician who did the angioplasty was quite concerned that this patient would have a high likelihood of re-stenosis.  But the patient was asymptomatic, so the dilemma was whether there's anything we can do to evaluate this patient non-invasively rather than doing another angiogram, and we proceeded to do a PET study.
		As you can see clearly, there is evidence of significant stress-induced ischemia in the left anterior descending coronary artery territory.  Here are the polar maps at rest, resting perfusion, and stress perfusion, which is significantly worse than the resting perfusion in the left anterior descending coronary territory.
		We also see that even resting perfusion is not entirely normal, indicating that perhaps during the first angioplasty the patient had suffered a non-transmural myocardial infarction, perhaps as a result of dislodgement of the placque distally.  There is a small apical myocardial infarction in this patient as well.
		This led to a repeat angiogram in this patient that confirmed that there has been significant re-stenosis in this patient.
		Another case is a patient who has had bypass surgery already and comes about four years after bypass surgery with a chest pain episode that again statistically puts the patient in the category that, knowing from the literature that vein grafts may close, about 50 percent chance of closure about five years out after bypass surgery.  This patient is in an intermediate likelihood of having one of the vein grafts having a problem and is presenting with chest pain.
		Doing a nuclear evaluation with PET ammonia, resting images are shown on the top, and stress images are shown on the bottom.  At first glance things look to be okay, except for a very, very small area here in the posterior lateral wall that is a non-reversible defect.  I'll show it on the polar maps.  There's a very, very small area of lack of perfusion at rest that remains unchanged during stress.
		This patient had a known occlusion or infarction in the distribution of a branch of the circumflex coronary artery, which is the second obtuse marginal branch, and that correlates perfectly well with that old known small myocardial infarction that did not even show on the resting electrocardiogram.  But it was known that the patient had a second marginal branch occlusion.  But beyond that, we don't see any evidence of stress-induced ischemia in this patient, and this was a reassurance that this patient was in a low-risk category for development of events.
		There is, again, nuclear data, not necessarily with ammonia, but rest and stress perfusion has been excessively used in the single photon arena.  I've shown this concept that the negative test after revascularization is indicative of good prognosis in these people, and currently data with PET is accumulating in order to establish the prognostic significance of these findings, similar to what we know from the single photon data in the PET data in patients following acute myocardial infarction or in patients who have had bypass surgery.
		Thank you very much for your attention.
		DR. RAMSEY:  Thank you very much.
		I want to thank all the presenters this afternoon.
		Now we are in open discussion and the question and answer period.  Specifically, I'd like to ask if the FDA individuals have any specific questions or any specific things you want addressed.
		DR. HOUN:  I'd like to hear the committee's comments on their evaluation of effectiveness.  I mean, I think the studies that I've presented are certainly smaller in sample size, very diverse in their hypotheses, but as a whole I'm just interested in hearing the positives and negatives about the group of studies reviewed and how people are feeling in terms of effectiveness for perfusion with N-13 ammonia based on the data.
		DR. CHOYKE:  Can I just begin with a technical question, because I'm perplexed by it.  Perhaps you can address it.
		You have an agent with a 10-minute half-life, and I'm trying to figure out how you can do rest and stress and do all these things while the decay is happening.  How technically demanding is this study, and is it really reserved for a sophisticated center, or could an average center do it?
		DR. RAMSEY:  I have a corollary to that, too.  That is, I also don't do cardiac imaging, so coming from lack of knowledge here, how often is it done?  Who does it?  Where is it done?  How many cases per year or per week or whatever?
		DR. MADDAHI:  I think these are all very important questions.  It is a technically demanding type of study.  It requires certain things.  One is that the cyclotron that produces ammonia has to be on site.  Unlike FDG, that has a future and is currently being used as having regional cyclotrons that can ship FDG to remote sites within a two-hour distance from the sites, with N-13 ammonia, we cannot do it that way.  The cyclotron has to be on site.  Because of that, it creates a technical difficulty there.
		The second thing is that timing is very important.  We have pneumatic tubes that connect the cyclotron directly to where the patients are being imaged.  We're in contact with them to know when the ammonia is introduced, and then we will just have the patient ready to inject.  So it is technically demanding as well.
		At the present time, there are not many studies being done because of these technical difficulties.  But whether there will be more of them done in the future, I would guess that the use of ‑‑ this is not going to be the type of procedure that would be done 5 or 10 a day or anything like that.  I think that this is going to be perhaps much more limited than that, and the reason is not that the disease is not common.  We all know that coronary artery disease is very common, and centers that do non-invasive evaluation of coronary disease with other techniques such as single photon imaging, they often do 10 patients a day, 15 patients a day.
		But here I think that we're not going to be getting to that.  I think that for centers that have access to both ammonia and to other agents, the first choice would remain those that are more practical, and then ammonia would be perhaps reserved for a very specific type of patient population, perhaps those where attenuation correction is very important.  We know that one of the sources of artifact with imaging is breast attenuation in women and diaphragmatic attenuation in both women and men.
		Attenuation means that the activity that is coming from the heart going through the tissue would register on the camera as being an area that has decreased activity, and the more tissue it goes through, the less activity would show.  So it becomes confusing at times to interpret.  So I think that perhaps is one of the fortes of this technique.  But I think that the use of it is not going to be very widespread because of these technical limitations.
		DR. CONTI:  Can I interject?
		DR. RAMSEY:  Yes, please.
		DR. CONTI:  This is Peter Conti from USC.  I'd also like to just mention that, of course, we do rubidium in the field, which has a shorter half-life, and also is technically challenging.  So this is not necessarily something that's novel to the PET community.  I would also add that the technologies that we currently use for stress/rest are not necessarily that technologically undemanding either.  It requires a fair number of visits to the scanning suite, the studies are more protracted, and when the systems are down, they can actually be quite simple with 13 ammonia, as long as there's a reliable delivery system in-house.
		DR. RAMSEY:  Any other questions or comments?  Jonathan?
		DR. LINKS:  Just one point of clarification.  When you do a stress and a rest, it's two administrations.  So you're not trying to fit two different imaging protocols into a 10-minute half-life.
		DR. CHOYKE:  Could we maybe change the subject a little bit back to your question?  I'll pose it back to you a little bit, because I was confused about what is the ideal gold standard in these tests.  I mean, you've reviewed all the literature, and I was confused.  I mean, if you had to design the ideal study, what would it be, and how far away are we from those ideals?
		DR. HOUN:  I think that for N-13 ammonia, it's been studied in the literature according to a variety of standards because the indications that these investigators were studying were of a wide variety.  Some of these investigators were focused in on correlating N-13's use in terms of revealing anatomic information.  In that case, coronary angiography was used.  In other cases, investigators were trying to look at N-13's ability to detect microperfusion where people would be angiographically negative, and they compared microperfusion as detected by N-13 ammonia to other kinds of functional standards, such as exercise endurance.  They looked at wall motion by echo or ventriculography.
		So I guess there are a variety of standards used because the hypotheses about what this agent is trying to indicate, what it's trying to be used for are varied.
		In my review, I wanted to try to encompass both types of indications, an anatomical indication, which is certainly supported by the Demer paper, as well as a functional indication that's supported by the various studies that used wall motion, exercise endurance, and those other kinds of standards.
		Now, perhaps I'm stretching too much.  If people are more comfortable with an anatomical description, I'd like to hear that.  If people feel that the stretch is okay, I'd like to hear that too.  But that is the struggle, you're right.  I do think this agent is able to do more than just anatomical information, and I'm just wondering whether the studies support the microperfusion and functional indications.
		DR. KONSTAM:  Maybe I can comment.  First of all, I think that this, with the caveats that we discussed this morning about not having an NDA before us, I think that this application is extremely strong.  I actually favor the wording that you've used very much.
		I think that in terms of an ultimate gold standard of what you would want, I guess what we're seeking is something resembling clinically relevant abnormalities of myocardial perfusion.  I guess that's sort of what we're trying to capture.  There is no gold standard of that, as far as I know.  Actually, I think if you look through the literature, there are many places where the combination of N-13 ammonia and FDG has been used as the gold standard for that.  So what gold standard do we have outside of that?  I think we don't really have one.  So what do we know?
		I mean, we know that this agent follows myocardial perfusion based on other markers of myocardial perfusion in experimental models and in patients.  So I don't think that there would wind up being any doubt about that.  The next thing you get to, and that's really the analysis that you focused on in your review, is how does it relate to abnormalities in the epicardial coronary circulation, and the answer is pretty well.  So even if you sort of set that up as what you're after to identify anatomic large-vessel coronary artery disease, I think it does pretty well at that, and that's useful because there's a lot we know about the clinical importance of epicardial coronary disease.
		So if that was all it did, I think that would be okay, and I think getting beyond that, again in the absence of any external gold standard for clinically relevant myocardial perfusion abnormalities, which is not provided by the coronary angiogram really, I think the next thing you get into is outcome studies.  For whatever reason, there has not been ‑‑ and Dr. Maddahi touched on this ‑‑ there has not been randomized data to really look at outcome information in the best possible way, but there's been a wealth of cohort analyses looking at clinical outcomes of patients who have undergone revascularization versus those who have not, and looking at it in cohort analysis, this agent, often together with FDG, tends to mark those patients who are better served by bypass surgery than not, within the caveats of the cohort analyses.
		So, I don't know.  I think without a sponsor doing a large amount of other work in this area, I think it's a pretty strong indication.
		DR. RAMSEY:  Dr. Herscovitch?
		DR. HERSCOVITCH:  I would agree, and although I don't vote, I'm not voting, I would not vote yes on this application with this wording.  I understand your reservations about the literature review and the fact that perhaps some of these papers weren't as extensive in terms of the patient population as the earlier ones, but I still think there's a tremendous amount of supporting data that you presented.
		But there's another whole body of data that I might suggest be considered in this type of application, and that is the use of animal data or clinical research studies to show that in this case, it's an effective agent for myocardial perfusion, and this speaks to the more general issue of how the FDA in the future will study radiopharmaceuticals, not just PET radiopharmaceuticals, in which the indication has at least a partial functional basis, and that is for virtually all PET radiopharmaceuticals, there usually is a rather large and often very well done literature with basic studies in which the measurement being made has been validated against another gold standard, and also various physiologic manipulations have been made to show that whatever it is you're measuring with the agent varies appropriately.
		I would suggest, or urge almost, the FDA to include in their evidence for proposals such as this not only the clinical studies but also the basic physiology studies.  In this case, there is a large literature going back 15 or 20 years on the suitability and the limitations of N-13 ammonia as a myocardial perfusion agent.
		There is perhaps another caveat.  If you had trouble selecting appropriate papers to include in your review as a surrogate for NDA-type protocols, selecting appropriate research papers might be even more difficult but not at all insurmountable.  So again, I would just urge you to look at animal studies which have been done with most PET agents to validate the physiological function of these tracers.  In fact, on page 13 of the guidance ‑‑ it says "Draft," so I don't know if I'm allowed to quote from it, but really there's a very nice paragraph, the second paragraph, which shows how animal data might and even should be used in applications such as these.
		DR. HOUN:  The animal data and preclinical data reviews are included in the pharm/tox and biopharm reviews.  So that has been considered.
		In terms of putting them as part of the clinical effectiveness review, usually the human studies are looked at at that point.  But certainly the animal data is considered in terms of the overall package for the drug.
		DR. HERSCOVITCH:  Peter Herscovitch again.  I might add, though, that there is considerably more data supporting the use of ammonia as a myocardial perfusion agent than was addressed in this package, and I guess we'll discuss this tomorrow, but the O-15 water package had really minimal, if any, animal data supporting the use of O-15 water as a cerebral perfusion agent.  Again, if part of the indication is based on the function of the radiopharmaceutical, I would suggest that those data be included, not to the exclusion, of course, of the clinical data, but to buttress or lend further support to the clinical evidence.
		DR. KONSTAM:  I don't know if I take a little bit of issue with what you're saying.  I mean, I think that, to me, a clinical application has to be supported by the clinical data, period, except that I think that the mechanism by which an agent works or a drug works can be very important in going beyond the clinical data and saying, well, where else might it work, are there concerns we might have about what's the population?  I think it's very helpful.  But, to me, I think that a clinical application really stands on the clinical data.
		I mean, I agree with everything you say, but it doesn't surprise me that we wouldn't spend a lot of time on it.
		DR. HERSCOVITCH:  Just two things.  First of all, I'll quote Lou Sokoloff, who is the developer of the deoxyglucose method, which went on to FDG.  Taking a purely clinical approach ‑‑ and I hope nobody will be offended by this word, but it wasn't my invention ‑‑ one could, in fact, using radioactive shoe polish, and showing it has a certain sensitivity and specificity, but without a firmly based understanding of how the tracer behaves, you're only doing a correlational work and specificity and sensitivity.  Understanding how the tracer behaves not only supports an indication which says here, "Imaging of myocardial perfusion," but it also helps you understand those conditions or diseases where the tracer may or may not be valuable.
		For example, with FDG, it's been shown not to be particularly valuable looking at brain metabolism in ischemia, for a lot of theoretical reasons which have been experimentally justified.  So knowing how the tracer behaves I think will not only buttress the clinical indications but also help support certain caveats as to how the tracer may or may not be used in certain diseases or when you have physiological or pathological variance, such as diabetes.  The whole concept of why one should even look at diabetes and blood sugar came from an understanding of how deoxyglucose and fluorodeoxyglucose behaves, issues which one wouldn't be concerned about if one were only looking at radioactive shoe polish.
		DR. LINKS:  To follow up on this a little bit, I think we have to be careful about the phrase "clinical indication," because basically what we have here is a set of four categories of clinical indications, and assessment of myocardial perfusion falls under one of those categories as intrinsically, now, a "clinical indication."  It seems to me that if that's going to be the case, then the challenge is to expand our thinking on what it means to validate it.  For me, if I want to know if this agent measures perfusion, I'll do microspheres.  I'm going to have a hard time doing that study in humans, but that to me would be an obvious study to do.  Of course, it's been done, and it does track with microspheres.
		So I think if we're going to expand what we mean by a clinical indication, we have to correspondingly expand our willingness to accept all sorts of very different types of data than we have in the past when clinical indication was more narrowly defined.
		DR. KONSTAM:  I guess I'd respond to that by saying ‑‑ and I sympathize, and I agree with almost everything you said.  So I sympathize with the concept.  But I guess I'd respond to what you said by saying that if I did a microsphere study in rats with the agent and found that it was a good marker of myocardial perfusion, that would not be sufficient for me to support a clinical indication.  When I say clinical indication, I'm talking about an indication in patients.  That's what I mean.
		Now, I understand the nuance of saying that an indication can be, in the case of tracers, let's say, physiologically based, if we can identify something that would fit into that category.  But nevertheless, I'd like to at least know that in patients.
		DR. RAMSEY:  I'd just like to ask for clarification since I think we're getting to where we have to vote on Question 3.  Dr. Herscovitch, you said you would vote against it.  I think I heard you say why, but could you say why you would vote against it again?
		DR. HERSCOVITCH:  Perhaps I was being too smart by half.  I was saying that I'm not allowed to vote, but my non-vote would be yes, and I strongly support this application as it is worded.
		DR. RAMSEY:  I totally misunderstood you.  Boy, am I glad I asked that question.
		DR. HERSCOVITCH:  I apologize.
		DR. RAMSEY:  Any others?  Mr. Hammes.
		MR. HAMMES:  If you were to draw up a lecture and describe the ideal human radiopharmaceutical to do perfusion imaging, you would probably describe ammonia.  You have an endogenous substance, you have a very favorable energy in the particle, you have a high specific activity, and you have a short half-life so you can do repeat studies.  The only limitation is that you need the cyclotron there.
		I mean, we are looking at what we will consider the gold standard in the future, I think.  The only real limitations are with the instrumentation and what you can image.  So in terms of the drug, I think this is the biggest no-brainer in terms of approval you're ever going to run into.  What its use will be I think is going to be determined by the requirement that you have the cyclotron right there.  But I think we're looking at the gold standard.
		DR. HERSCOVITCH:  I just have a question of clarification.  The first presenter gave a table of dosimetry which also included pediatric patients, and that just led me to think will there be any guidance or discussion of the use of this agent or the other agents in the pediatric population.
		DR. HOUN:  None of the studies reviewed had pediatric population in them.  So the indication would be supported by the literature for adults.  I guess in terms of the pediatric section of the label, we would indicate that no information is available from the literature review that we did.
		DR. RAMSEY:  Dr. Conti?
		DR. CONTI:  Let me just address this issue of dose.  This actually is available, this material, in N-13, FDG, and water.  So I think we can get that for the label.
		DR. RAMSEY:  I'm not sure I heard the answer there.  It's available for adults or children?
		DR. CONTI:  For children.
		DR. RAMSEY:  Or both?
		DR. CONTI:  For children and adults.  There's a scale, basically, that's available for reducing the injected dose based on radioactive exposures for children for all those isotopes.
		DR. RAMSEY:  But that's extrapolated data, or it's been done in children?
		DR. CONTI:  We do it every day in the clinic.  I mean, it's done.  It's based on doses, radioactive doses.  So this material is available.
		DR. RAMSEY:  Thank you.
		DR. MALCOLM:  But I think the question is, I think the review had no children in the studies.  That's what we're asking.  There are no children.
		DR. CONTI:  That actually doesn't matter.  It's the radioactive material that's given and how much exposure the child gets versus the size of the child.  It's not a dose of ammonia per se.  It's a dose of the radioactive material.
		DR. MALCOLM:  I understand extrapolation.  I don't have a problem with that.  But what I'm saying is, I think what the FDA is saying is that the studies that they reviewed and what we're approving, from the information, is in adult patients.  It's not in children.  So I think the question is, are we going to use this material in children?  I think that's the question.
		DR. HOUN:  I think the question for approval does not include children, and certainly if there is more information, it can be submitted as a supplement to get pediatric labeling.  But at this point in time, the literature doesn't comment on its effectiveness in children.
		DR. CONTI:  Well, let me be the child's advocate in this case.  There's no reason for it not to be applicable in a child with ischemic heart disease.  What is the difference between a child with ischemic heart disease, Kawasaki's disease, which we study all the time, with conventional nuclear isotopes, which give a higher radiation dose, and with N-13 ammonia?
		DR. RAMSEY:  I'll jump in here on that.  As a neuroradiologist, the myelographic concentrations were utilized for a long time and approved only for adults.  We used it in children all the time, but it was not approved.  I think that's the same thing we're looking at here.
		Correct me if I'm wrong from the FDA side.
		DR. HOUN:  There's a labeled indication, and how physicians want to use the drug in their practice is up to them.
		DR. CONTI:  This would apply, then, to all the radiotracers we're discussing today as well.  But I will tell you again that radiation information is available.
		DR. RAMSEY:  Thank you.
		Yes?
		DR. MADDAHI:  I just want to make sure that I haven't misled the committee here about the complexity that I spoke about.  I think the issue of complexity that I referred to was the issue of the need for an on-site cyclotron.  But I just want to tell you that in our experience of thousands of these perfusion studies that we have done of rest and stress, even in the pediatric population, I don't recall any study that we couldn't read because it was technically unreadable or it was not good quality.  These are excellent images, excellent studies, although it requires, obviously, technical ability of the people who work with this technique, like anything else.
		The complexity I was talking about is the instrumentation complexity, not the agent itself, and not the quality of the images that we get.
		DR. RAMSEY:  Thank you.
		Any other questions or comments?
		(No response.)
		DR. RAMSEY:  Okay.  I think we'll move to the question, then.  This is Question 3.
		"Based upon the presented literature reviewed, do you think ammonia N-13 injection is safe and effective in positron emission tomography (PET) imaging of the myocardium under rest or physiological stress conditions to evaluate myocardial perfusion in patients with suspected or existing coronary artery disease (CAD)?"
		I think we'll again follow the vote, your vote and your comments.
		Dr. Herscovitch.
		DR. HERSCOVITCH:  Yes, and I think I've made all the comments that I have to make.  Thank you.
		DR. TATUM:  I would also say yes, mainly because I do think the data does show it's safe, and it's quite effective.  But in addition, there's been a lot of discussion of gold standard, and it's probably the most likely candidate for now for giving us something that's quantitative, which is a badly needed tool in the approved arena for other reasons.  So I would definitely support it.
		DR. KONSTAM:  Yes.
		MS. BEAMAN:  Yes.
		MR. HAMMES:  Yes.
		DR. HERTZBERG:  Yes.
		DR. TULCHINSKY:  Yes.
		DR. CHOYKE:  I'd just like to be a little more wordy.  I think I'm a little hesitant about the data, frankly, because I saw it all over the place, ranging from 99 percent to 50 percent correlations.  But even in that range, it seems like we definitely have some kind of correlation, that it is a meaningful agent.  It may very well be that the gold standards that are used in the test are just not adequate to measure this, and that's supported I think by the animal data, or what we hear of the animal data.  It's certainly a harmless agent.
		So for those reasons, I'm voting yes.
		DR. MALCOLM:  My answer is yes, and I completely agree with Pete's comment.
		DR. RAMSEY:  Yes.
		DR. PONTO:  Yes.
		DR. AMENDOLA:  Yes.
		DR. ZIESSMAN:  Yes.
		DR. LINKS:  Yes.
		MR. MADOO:  We have a total agreement on the committee, 12-0.
		One other comment.  Dr. Love, when we leave, are you comfortable with us keeping our materials on the desk in a locked room, or ‑‑
		DR. LOVE:  Yes.
		MR. MADOO:  Okay.  That's probably relevant to people.  You don't have to tote your stuff.
		DR. LOVE:  All of these data are publicly available.
		DR. RAMSEY:  Any other questions or comments?
		(No response.)
		DR. RAMSEY:  Okay.  I want to thank the presenters all for coming in.  I know sometimes it's hard to get here.  I really appreciate your coming and sharing your information.  I want to thank all of you for participating.
		We will begin tomorrow sharp at 8:00 in this room, where we will have the presentations regarding nitrogen N-13.  Am I right?  No.  Presentations on water O-15 beginning at 8:00 tomorrow morning.  So I'll see you here.  Thank you all.
		(Whereupon, at 4:40 p.m., the meeting was recessed, to reconvene on Tuesday, June 29th, at 8:00 a.m.)