1 DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION CENTER
		FOR DRUG EVALUATION AND RESEARCH
					THE PEDIATRIC SUBCOMMITTEE

OF THE ANTI-INFECTIVE DRUGS ADVISORY COMMITTEE
IN JOINT SESSION WITH
					THE PEDIATRIC SUBCOMMITTEE

OF THE ONCOLOGIC DRUGS ADVISORY COMMITTEE
										(ODAC)
				Tuesday, September 12, 2000

									8:00 a.m.
		Hyatt Regency Bethesda One Bethesda Metro Center
								Bethesda, Maryland
		2 PARTICIPANTS
			P. Joan Chesney, M.D., Chairperson
			Karen M. Templeton-Somers, Executive Secretary
THE ANTI-INFECTIVE DRUGS SUBCOMMITTEE
MEMBERS:
			Judith O'Fallon, Ph.D.
			Keith Rodvold, Pharm.D. (Consumer Representative)
SGE CONSULTANTS:
			David Danford, M.D.

Robert Fink, M.D. Susan
Fuchs, M.D. Barbara Geller, M.D.
Richard Gorman, M.D., FAAP Mark Hudak, M.D.
Naomi Luban, M.D.
Robert Nelson, M.D., Ph.D. Victor Santana, M.D.
GUESTS AND GUEST SPEAKERS:

		Ralph Kauffman M.D. 
Steven Spielberg, M.D., Ph.D. Robert Ward, M.D., FAAP, FCP

						THE ONCOLOGIC DRUGS SUBCOMMITTEE
MEMBERS:
			Victor M. Santana, M.D.
Donna Przepiorka, M.D., Ph.D.
AD HOC MEMBERS:
			James M. Boyett, Ph.D.

			Susan L. Cohn, M.D.
Alice Ettinger, MSN, RN, CPON, CPNP Jerry Z. Finklestein, M.D.

Henry S. Friedman, M.D.
			C. Patrick Reynolds, M.D., Ph.D.
PATIENT ADVOCATE:
Susan L. Weiner, Ph.D.
GUESTS AND GUEST SPEAKERS:
			Frank M. Balis, M.D.

Malcolm Smith, M.D., Ph.D.
FDA:
Steven Hirschfield, M.D., Ph.D. Richard Pazdur, M.D.

			Dianne Murphy, M.D.
	3 C O N T E N T S
Call to Order/Introductions, P. Joan Chesney, M.D.	4
Conflict of Interest Statement,
	Karen M. Templeton-Somers, Ph.D.	7
Introduction to the Issues, Dianne Murphy, M.D.
	and Steven Hirschfield, M.D., Ph.D.	9
The Application of Evidence-Based Medicine to
	Achieve Progress in Pediatric Oncology,
Malcolm Smith, M.D., Ph.D.                             21
Lessons and Challenges of Participation in
	Clinical Trials -- a Family Perspective,
Susan L. Weiner, Ph.D.                                 46
FDA Initiatives in Pediatric Oncology -- Adaption

	of the General Case to Special Circumstances,
	Richard Pazdur, M.D.	                                60
Open Public Hearing:
	Dr. Greg Reaman	                               103
Discussion		                               104
									4
 1						             P R O C E E D I N G S
 2							  Call to Order
 3						    DR. CHESNEY:  Good morning.  I think we are ready
 4   to start, and before we get into discussion I would like to
5   just say thank you to Dr. Murphy and all of her staff at the
 6	FDA who have done such an incredible job of organizing these
 7	two days with four totally unrelated subjects, except that

 8	they all relate to pediatrics, and also to let you all know
 9	that in the "Science Section" of The New York Times today,
10	in the middle, there is a full-page article, with a big
11	picture of Dr. Murphy, and all addressing the use of drugs
12	in children.  So, I think that is a real tribute to her and
13	to all of the efforts of the  FDA in this regard.

14		We are going to start by having everybody
15	introduce themselves, and also to remind you all that when
16	you ask a question or make a comment, please be sure to give
17	your name so the transcriber will know who it is and, for
18	those of you who weren't here yesterday, the way to turn on
19	your microphone is to push the green button.  So, let's
20	start over here, on the left-hand side.  I think Dr. Murphy
21	is the first.
22		DR. MURPHY:  Dianne Murphy, Associate Director for
23	Pediatrics at CDER, and I haven't read the article so I
24	don't know if I am infamous or not.
25		[Laughter]
			5
 1		DR. PAZDUR:  Richard Pazdur, Division Director,
 2	CDER.
 3		DR. HIRSCHFIELD:  Steven Hirschfield, medical
 4	officer, Division of Oncology Products.  I read the article
 5	and it is very favorable.
 6		DR. SMITH:  Malcolm Smith, head of the Pediatrics
 7	Section of the Cancer Therapy Evaluation Program and
 8	pediatric oncologist.
 9		DR. BALIS:  Frank Balis. I am a senior
10	investigator at the National Cancer Institute, Pediatric
11	Oncology Branch.
12		DR. BOYETT:  James Boyett, chairman of the
13	Department of Biostatistics at St. Jude Children's Research

14	Hospital.
15		DR. COHN:  Susan Cohn, and I am on staff as a
16	pediatric oncologist at Children's Memorial in Chicago.
17		DR. PRZEPIORKA:  Donna Przepiorka, marrow

18	transplanter, Baylor College of Medicine, Houston.
19		DR. WEINER:  I am Susan Weiner.  I am president
20	and founder of The Children's Cause.  I was a parent.
21		DR. REYNOLDS:  I am Patrick Reynolds, Children's
22	Hospital of Los Angeles.
23		DR. FRIEDMAN:  Henry Friedman, Brain Tumor Center
24	at Duke.
25		MS. ETTINGER:  Alice Ettinger.  I am a pediatric
				6
 1	nurse practitioner in New Brunswick, New Jersey.
 2		DR. FINKLESTEIN:  I am Jerry Finklestein.  I am a
 3	pediatric oncologist in Long Beach, and also chair
 4	hematology oncology for the American Academy of Pediatrics.
 5		DR. CHESNEY:  Joan Chesney.  I am in infectious
 6	diseases at the University of Tennessee, in Memphis, and
 7	also in academic programs at St. Jude.
 8		DR. TEMPLETON-SOMERS:  Karen Somers.  I am the
 9	executive secretary to the Oncologic Drugs Advisory
10	Committee, FDA.
11		DR. SANTANA:  Victor Santana, pediatric oncologist
12	at St. Jude Children's Research Hospital in Memphis,
13	Tennessee.
14		DR. NELSON:  Skip Nelson.  I am a pediatric
15	clinical care physician at the Children's Hospital in
16	Philadelphia.
17		DR. GORMAN:  Richard Gorman, general pediatrician
18	in private practice in suburban Maryland.
19		DR. O'FALLON:  Judith O'Fallon, group statistician
20	for the North Central Cancer Treatment Group.
21		DR. RODVOLD:  Keith Rodvold, professor of pharmacy
22	practice, colleges of pharmacy and medicine, University of
23	Illinois, Chicago.
24		DR. GELLER:  Barbara Geller, professor of
25	psychiatry, Washington University in St. Louis.
			7
 1		DR. DANFORD:  Dave Danford.  I am a pediatric
 2	oncologist at the University of Nebraska Medical Center and
 3	Creighton University in Omaha.
 4		DR. FUCHS:  Susan Fuchs, pediatric emergency
 5	medicine physician in Children's Memoria Hospital, Chicago.
 6		DR. HUDAK:  I am Mark Hudak.  I am chief of
 7	Neonatology at the University of Florida at Jacksonville.
 8		DR. FINK:  Bob Fink, pediatric pulmanologist,
 9	Children's Hospital, Washington, DC.
10		DR. LUBAN:  Naomi Luban, pediatric hematologist-
11	oncologist, for this group mostly a hematologist, Children's
12	Hospital, Washington, DC.
13		DR. SPIELBERG:  Steven Spielberg, head of
14	pediatric drug development at Johnson & Johnson,
15	representing PhARMA.
16		DR. KAUFFMAN:  Ralph Kauffman, pediatrician,
17	clinical pharmacologist, Children's Mercy Hospital, Kansas
18	City, Missouri.
19		DR. WARD:  Bob Ward, neonatologist and professor
20	of pediatrics, University of Utah, and chair of the American
21	Academy of Pediatrics Committee on Drugs.
22		DR. CHESNEY:  Thank you.  Karen Templeton-Somers,
23	our executive secretary, is going to read the conflict of
24	interest statement.
25		     Conflict of Interest Statement
			8
 1		DR. TEMPLETON-SOMERS:  The following announcement
 2	addresses the issue of conflict of interest with regard to

 3	this meeting, and is made part of the record to preclude
 4	even the appearance of such at this meeting.
 5		Based on the submitted agenda for the meeting and
 6	all financial interest reported by the committee
 7	participants, it has been determined that since the issues
 8	to be discussed by the subcommittee will not have a unique
 9	impact on any particular firm or product but, rather, may
10	have widespread implications to all similar products, in
11	accordance with 18 USC 208(b), general matters waivers have
12	been granted to each special government employee
13	participating in today's meeting.  A copy of this waiver

14	statement may be obtained by submitting a written request to
15	the agency's Freedom of Information Office, Room 12A-30 of
16	the Parklawn Building.
17		With respect to FDA's invited guests and guest
18	speakers, Dr. Ralph Kauffman, Dr. Steven Spielberg and Dr.
19	Robert Ward have reported interests which we believe should
20	be made public to allow the participants to objectively
21	evaluate their comments.
22		Dr. Kauffman would like to disclose that he has
23	grants with Bristol-Myers Squibb and is involved in research
24	for Bristol-Myers Squibb, Astra, Zeneca, Janssen, Merck,
25	R.W. Johnson and Adventis, and is a scientific advisor for
			9
 1	Bristol-Myers Squibb, Johnson & Johnson and Purdue PhARMA.
 2		Dr. Spielberg would like to disclose that he is an
 3	employee of Johnson & Johnson.  Dr. Ward would like to
 4	disclose that he owns stock in Ascent Pediatrics and
 5	Viropharma; has grants with Wyeth-Ayerst, Novardis, Ascent

 6	Pediatrics, Adventis Pharmaceutical and Sepracor; receives
 7	consulting fees from Janssen Pharmaceutical and is a
 8	scientific advisor for McNeil Consumer Products.
 9		In the event that the discussions involve any
10	other products or firms not already on the agenda for which

11	an FDA participant has a financial interest, the
12	participants are aware of the need to exclude themselves
13	from such involvement, and their exclusion will be noted for
14	the record.
15		With respect to all other participants, we ask in
16	the interest of fairness that they address any current or
17	previous financial involvement with any firm whose products
18	they may wish to comment upon.  Thank you.
19		DR. CHESNEY:  Does anybody have anything that they
20	haven't yet declared?  Hearing none, Dr. Murphy will give us
21	our mission for the morning.
22		       Introduction to the Issues
23		DR. MURPHY:  Actually, I am going to try to do a
24	little more than that -- I try not to tell the chair what we
25	are going to do.
			10
 1		[Laughter]
 2		It is basically part of our responsibility, under
 3	the Pediatric Rule, to provide an update to this pediatric
 4	subcommittee on an annual basis.
 5		[Slide]
 6		As yesterday was even busier with a packed
 7	schedule, I chose this morning and I would like to take
 8	about five minutes of today's time to update the pediatric
 9	subcommittee on where we are.
10		[Slide]
11		I am leaving this up because I don't want to have
12	slide after slide of the statistics of what has been going
13	on because you heard some of that yesterday as far as over
14	150-some written requests that we have issued under the Food
15	and Drug Modernization Act and the fact that we expect 85

16	percent, approximately 75-85 percent of those studies to be
17	completed.

18	          The other activities that have been ongoing in the
19	meantime are rather significant and I would like to take a
20	moment and introduce Dr. William Rodriguez.  Dr. Rodriguez,
21	would you stand up, please?  He introduced himself
22	yesterday.  He has come to us as our science advisor because
23	it has become quite clear to us, as we move into the whole
24	area of drug development, that we have a tremendous number
25	of questions as we go forward in how we do drug development
		11
 1	in children and the science gaps are significant in certain
 2	areas.  Dr. Rodriguez was a professor of pediatrics at
 3	Children's Hospital in Washington for 29 years and is now
 4	professor emeritus, and we are delighted to have him join
 5	us, and you will be seeing more of him as he begins to
 6	address some of the issues that we know exist.  As a matter
 7	of fact, I think Thursday is his first internal
 8	brainstorming session for us in the agency, and we will have
 9	a number of those.
10	          The other aspects that I wanted to inform the
11	committee about were the fact that we have a congressional
12	report that is due January 1 on the effectiveness and
13	efficacy, if you will, of the legislation, and we will have
14	that report out of the Center by the end of this month and
15	anticipate that we will be bringing that report to you next
16	year, after it is made public, that answers the questions

17	that we were mandated by Congress to answer about the
18	implementation of the Modernization Act.
19	          I said to Rosemary this is beginning to get
20	embarrassing, and she said, what do you mean, beginning to
21	get?  -- Dr. Roberts told me it is embarrassing.  We had

22	stated last year that we thought we would have the guidance
23	on the Pediatric Rule out by June.  It is not.  We are

24	pushing very strenuously to have it out before December.
25	The Pediatric Rule went into effect for the agency as far as
		12
 1	our responsibility to inform sponsors that they must have

 2	either studies in their applications or they must have a
 3	waiver or deferral from us -- that began in April of 1999.
 4	We could not require studies until this December.  So we

 5	were informing them but we could not require they submit
 6	them.  We can require them to have those studies as of this
 7	December.  We hope to have the guidance out before that
 8	point.
 9	          One last thing for the committee to be aware --

10	you heard yesterday that there are continuing ethical issues
11	that we may need to bring to you but, in particular, we will
12	be bringing some of the issues attendant to extrapolation
13	and the algorithms that we are developing are building upon
14	some of the data that is coming in and experiences we have
15	had with concentration response studies and the use of PK/PD
16	in our development program.  So, we hope in the upcoming

17	year to be able to bring some of that information to the
18	committee.  At this point, we have had -- and this is all
19	available as public documents on the web, the address of
20	which the committee is very familiar with at this point --
21	we have had 24 products bring their studies in for an

22	exclusivity determination, and we have 11 of those products
23	already labeled.  And, people say, "why do you say already?"
24	I don't need to explain to this group that from the time we
25	issue a written request to the time that the sponsor has to
		13
 1	develop the protocol, recruit the researchers, put the study
 2	in place, collect the data, submit it, review it and then
 3	send it in to us we have 10-12 months to review it.  That is
 4	fairly phenomenal since the first request was in July of

 5	'98.  So, in the last two years we have had 24 products
 6	submitted for exclusivity determination and have already
 7	been able to label 11, and we have another one and I was

 8	hoping I would be able to tell you an even dozen but it is
 9	close.  So.
10		Now, as far as the Pediatric Rule is concerned, as
11	I said, it went into effect April, 1999.  We are requiring
12	the studies as of December.  What has happened with waivers
13	and deferrals thus far?
14		[Slide]
15		This is an overview, and I really would tell the
16	committee at this point that my intent this morning is not
17	to provide you any details on these but to give you the
18	broad-brush overview as to what is happening because, again,
19	we can't require the studies to come in.  So, in the
20	categories of diseases where are we waiving and where are we
21	deferring products this coming year we will provide more
22	detail as to what is happening within some of these
23	categories.
24		You can see that in cardiorenal, which leads the
25	pack as far as written requests and/or exclusivity, we have
			14
 1	had two waivers -- usually this is because of a disease that
 2	would not exist in children -- and one deferral.  The areas
 3	of activity under exclusivity are cardiorenal, neuropharm.,
 4	metabolic, anesthetic and antivirals.  So, right now it
 5	would appear that most of the studies that are being
 6	deferred are in metabolic, and as we discussed yesterday,
 7	what that means is really a spectrum of activities.  It may
 8	mean that we know really what the protocol is.  It may even
 9	be as developed as a Phase IV requirement.  Or, it may be,
10	as we discussed yesterday, that we think pediatric studies
11	will be required but we are at that point that I mentioned
12	earlier where we don't feel competent enough; there is not a
13	level of certainty that we want to proceed in asking or
14	demanding that these studies be done until we have

15	additional data.  So, we have a large category of deferrals
16	at this point as we build up some of the information bases
17	that allow us to design those studies that we are going to
18	be requiring.
19		[Slide]
20		As I said, in antivirals are studies that have
21	come in.  So, you aren't seeing the studies that have come
22	in.  Even though they are not required, they have come in
23	under the FDAMA.  Because this process has turned out to be
24	much more complex than I am sure any of us anticipated, in

25	any one application that is in-house we may have a waiver, a
			15
 1	deferral and studies.  All three things can be happening

 2	with the same product.  Depending on whether that disease
 3	occurs in the entire spectrum of pediatrics, you may have
 4	some part that you are waiving; you may have another part
 5	which you are deferring because you are waiting on the
 6	information that you have on the studies that you have in-

 7	house.  So, all three things may be happening in some areas.
 8		[Slide]
 9		This is to give you a feel for the activity.  We
10	are trying to present this in a less crowded way.  We
11	normally send you these statistics as they are up on the web
12	and they are not particularly viewer friendly, but these
13	slides now break out for you the various disease categories
14	which are really our divisions, and the numbers of proposals
15	that sponsors have sent in to us, in the left-hand column,
16	and the number of written requests that we have issued for
17	studies to be done in these areas.  Again, this is under

18	exclusivity.  I just finished going over the rule.
19	Exclusivity has been effective since 1997.  In July of '98
20	we had our first written request issued.
21		So, quite a few studies have been asked for in
22	cardiorenal and neuropharm.  I iterate one more time that

23	these are voluntary.  The sponsors do not have to do them,
24	but we have some changes from last time in some of these
25	categories in that we have had increased activity in
			16
 1	metabolic, endocrine and anti-inflammatory, and
 2	gastroenterology, special pathogens and oncology.
 3		[Slide]
 4		This slide is to lead me into the topic for this

 5	morning.  In the implementation of FDAMA, it is quite clear
 6	that not only do all diseases have their own special needs
 7	and areas of development as far as the science base and as
 8	far as the clinical trials base, in the area of oncology it
 9	is -- how should I -- I am told you can't be "very" unique;
10	you are just unique -- they are unique, and we have -- I

11	will use the word struggled because we have to treat all
12	diseases the same in that many a parent who has a child with
13	a severe neurologic disease, a parent who has a child who is
14	dying from heart disease -- these are all as serious and
15	important to them as any disease.  So, we need to do things
16	that are consistent with an even playing field for the

17	development of all of these areas.  We found there were
18	unique aspects that we needed to address for oncology, and
19	to do that we really discussed it with a number of external
20	experts.
21		[Slide]
22		And, the American Academy of Pediatrics put
23	together an invitational meeting in February of this year
24	and invited a number of academic researchers, National

25	Cancer Institute, PhARMA, pediatric cooperative groups,
			17 1
 advocacy representatives and, of course, the FDA.  We
 2	discussed the issues surrounding pediatric drug development
 3	in the area of oncology, and felt that we were able to
 4	define a process and that is one of the things that we hope

 5	to accomplish this morning, to present this approach to you.
 6	There is a guidance, in contrast to the Pediatric Rule
 7	guidance, just to let you know the level of priority that
 8	was put on this.  We got this guidance out in record time
 9	because we did not want this to continue without information
10	for the researchers and the sponsors in how we were looking
11	at the development of this area because it is different.

12	And, that is what will be explained to you this morning.
13	          In addition to the process, there is a new
14	committee that has been put in place and I will ask Dr.
15	Hirschfield to, please, come up here and explain to you the
16	development of an additional -- let me back off; I am not
17	allowed to say we have a new advisory committee, so an

18	additional panel of experts which we are utilizing to advise
19	us.  Thank you.
20	          DR. HIRSCHFIELD:  Good morning.  I would like to
21	acknowledge the efforts and the support that Dr. Mack
22	Lumpkin, our Associate Center Director, Dr. Dianne Murphy,
23	our Associate Center Director for Pediatrics, and Dr.
24	Richard Pazdur have provided on behalf of and in support of
25	pediatric oncology, and none of what we are going to discuss
		18
 1	over the course of the day would have gone forward without
 2	their efforts.
 3	          We recognized, and you will hear several times
 4	during the course of the morning and those who go to the
 5	afternoon session on pediatric oncology, how pediatric
 6	oncology has characteristics that are different than other
 7	areas in pediatrics.  The diseases are relatively rare.
 8	They are life-threatening.  There is also a long history of
 9	evidence-based medicine, going back essentially fifty years.
10	Most of the children are treated on protocols in cooperative
11	group studies and there is a recognition that research is

12	the standard of care for pediatric oncology.  You will hear
13	these themes again, but these themes made us examine very
14	carefully the approaches that were taken to other pediatric
15	diseases and ask how can we adapt the tools that we have,
16	which are new in the history of regulatory science, to the
17	pediatric oncology situation?
18	          And, one of the mechanisms was to look at how we
19	could apply the Pediatric Rule.  The Pediatric Rule states
20	that if a disease in adults is similar to a disease in

21	children, or vice versa, there is a mandate to perform
22	studies in the pediatric population.  There is also an

23	incentive in the sense that it is possible, if efficacy is
24	demonstrated, to apply the adult efficacy data to the
25	pediatric population.
		19
 1	          Pediatric oncology has yet another difference,
 2	aside from the differences just enumerated and that is that
 3	the biology of the tumors tends to be quite different from
 4	the tumors which are seen in adults.  Adults typically get
 5	tumors associated with the skin, the lining of the skin, the
 6	lining of the lungs, breast, and pediatric tumors tend to
 7	have different tissue origins.  So, on the surface it looked
 8	like the Pediatric Rule would be extremely limited in its
 9	application, perhaps to some brain tumors; perhaps to some
10	hematologic tumors.  But otherwise we would have the
11	inability to utilize what we perceive as a very important
12	tool.
13	          However, we decided to examine that question.  So,
14	we convened a panel of experts and supplemented what we
15	consider our core group of experts with experts who will be
16	coming for today to assist us in describing the
17	characteristics of tumors, and we will be spending the

18	afternoon asking the question how do we describe tumors?
19	What is it we know about tumors?  What are the principles

20	that we can use to extend our knowledge of one tumor type to
21	another tumor type?
22	          In that regard, aside from the distinguished panel
23	that has introduced themselves to you this morning, we will
24	have Dr. Todd Gollup from the Whitehead Institute join us.
25	Dr. Gollup, for those of you who happen to have read this
		20
 1	week's Science magazine, was featured in the "News and
 2	Views" for his work on DNA micro arrays in describing
 3	tumors.
 4	          Dr. Michelle LeBeau, of the University of Chicago,
 5	who is an authority on cytogenetics, will discuss with us
 6	this afternoon the application of cytogenetics to tumor
 7	characterization.  Dr. David Parma, of the University of
 8	Arkansas, who is a world recognized expert in the
 9	histopathology of tumors; Dr. Peter Berger, of Johns Hopkins
10	University, who is internationally recognized for his work
11	on pediatric and adult brain tumor pathology.  In addition,
12	although he is part of our regular panel too, Dr. Frank

13	Balis, of the National Cancer Institute, will offer his
14	perspectives on the application of development of
15	therapeutics.
16	          This panel, we hope, will stretch the boundaries
17	of what is now only known about pediatric oncology but help
18	set a precedent for the examination of how one may
19	extrapolate our knowledge of adult diseases to pediatric
20	diseases, not only for the regulatory purpose but for
21	scientific purposes that we can think of different
22	paradigms, perhaps new paradigms in terms of combining

23	studies in certain cases between adults and children,
24	looking at the types of information that we would need to
25	make not only regulatory decisions but therapeutic and
		21
 1	scientific decisions.

 2		I look forward, and feel honored to be part of
 3	this day today.  Thank you very much.
 4		DR. CHESNEY:  Thank you, Dr. Murphy and Dr.
 5	Hirschfield.  Our first speaker this morning is Dr. Malcolm
 6	Smith, from the National Cancer Institute, and he is going
 7	to talk to us about the application of evidence based
 8	medicine to achieve progress in pediatric oncology.
 9	   The Application of Evidence-Based Medicine to Achieve
10		     Progress in Pediatric Oncology
11		DR. SMITH:  It is a privilege to speak to you

12	today on the application of evidence-based medicine to
13	achieving progress in pediatric oncology.
14		[Slide]
15		In many ways, I am speaking to you today on behalf
16	of the hundreds of clinical researchers who, over the past
17	four decades, have designed and conducted the clinical
18	trials that have led to the progress that I will be
19	describing, and speaking on behalf of the thousands of
20	patients and their families who have participated in these
21	trials.
22		[Slide]
23		As an outline of what I will be speaking about,
24	first I will give an introduction and historical
25	perspective.  Then, I will speak about the importance of
			22
 1	Phase III randomized clinical trials to the progress that we
 2	have achieved in treating children with cancer.  I will talk
 3	about the importance of risk-adjusted therapy to developing
 4	better treatment strategies for children with cancer.  I
 5	will talk about the clinical trials research infrastructure
 6	that has been essential to this progress, and I will end by
 7	talking about unmet needs and future directions.  The
 8	handouts that you have, have additional details beyond the

 9	slides that I will be using today.
10		[Slide]
11		First in terms of childhood cancer basic
12	introduction, a few points:  There are 8700 new cases of
13	cancer diagnosed annually among children younger than 15;

14	over 12,000 when you extend the age limit up to younger than
15	20 years of age.  There are approximately 1700 children who
16	die each year of cancer younger than 15 years of age, and
17	over 2000 when you extend the age to up to 20 years of age,
18	making cancer the leading cause of disease-related mortality
19	among children over one year of age.  Finally, most of the
20	cancers of children differ from those of adults in their

21	histology and in their biological characteristics.
22		[Slide]
23		This slide shows the distribution of cancers that
24	occur in adults, and you will recognize prostate cancer,

25	breast cancer, lung cancer, colorectal cancer.  These are
			23
 1	the carcinomas that predominate in adults.
 2		[Slide]
 3		Whereas in children, this slide shows the
 4	distribution and approximately half of the cancers among
 5	children are divided between the leukemias, acute
 6	lymphoblastic leukemia predominating, and the brain tumors.
 7	Then, there are tumors like neuroblastoma, Wilm's tumor and
 8	retinoblastoma that have no equivalent among adults.  Even

 9	the tumors that have the same name, like non-Hodgkin's
10	lymphoma or acute lymphoblastic leukemia -- the subtypes

11	that occur in children are often distinctive from the types
12	that occur in adults.
13		[Slide]
14		So, in terms of childhood cancer clinical
15	research, one basic principle is that national efforts are
16	essential for studying the specific childhood cancers

17	because of the limited numbers of children with individual
18	cancer types.  So, in recognition of this fact, the NCI has
19	supported, since the 1950s, a nationwide clinical trials

20	program specifically designed to improve the outcome for
21	children with cancer.
22		[Slide]
23		A second basic principle is that we need to have
24	separate studies and we need to have a separate research
25	structure for studying the cancer in children.  Again, the

			24
 1	cancers of children are biologically distinctive in most
 2	cases from those that occur in adults, and so the response

 3	of children to anti-cancer treatments may be qualitatively
 4	or quantitatively different from response of adult cancers.
 5		Second, the ability of children to tolerate anti-
 6	cancer treatments may differ from that of adults.  Children
 7	may be more sensitive or less sensitive to specific drugs
 8	and it may depend on age, different doses of drugs, and
 9	different schedules of drugs may need to be used.
10		Also, the investigators with special expertise in
11	pediatric oncology are the ones that are really best
12	qualified to prioritize, design and implement the clinical
13	trials for children with cancer.
14		[Slide]
15		We, in part, are still invested in our system of
16	clinical research because of the results that have been

17	achieved with this system.  When we looked at the early
18	1960s, only a small minority of children were cured of their
19	cancers.  However, currently the survival rates for children
20	with cancer approach 75 percent.  The mortality rate from
21	childhood cancer has decreased nearly 50 percent from 1973
22	to 1996, and this decline in mortality rate has continued in
23	the 1990s at a rate of approximately 3 percent per year.
24		[Slide]
25		I will give two specific examples of these
			25
 1	improvements in outcome.  The first is the example of
 2	leukemia.  Mortality remained relatively constant through
 3	the 1950s and the mid-1960s.  Since the mid-1960s mortality
 4	rate for leukemia has declined.
 5		[Slide]
 6		And, the reason for this decline is not that the
 7	incidence of leukemia has changed but, rather, that there
 8	have been significant improvements in the survival rate for
 9	children with acute lymphoblastic leukemia in particular.
10	Cure virtually did not occur in the early 1960s but with
11	each succeeding decade there have been incremental advances,
12	to the point where in 1990s over 80 percent of children are
13	surviving at 5 years from their ALL diagnosis, and most of
14	these children are cured.
15		[Slide]
16		Another example is the lymphomas as well.  In the
17	1950s, there were little changes in mortality.
18		[Slide]
19		By the mid-1960s a decline in mortality rate
20	began, and this decline has continued into the '90s so that
21	from a rate of over 6/million we are now below 2/million in
22	terms of the mortality rate.  Again, this has been achieved
23	by the identification of new treatments that have improved
24	the survival rate from less than 20 percent in the early
25	1960s to approaching 80 percent today.
			26
 1		[Slide]
 2		What have been the contributions of the NCI
 3	supported nationwide clinical trial system to improve the
 4	outcome?  First, and perhaps most important, is by
 5	conducting randomized Phase III clinical trials that

 6	reliably identify superior new treatments, and I will talk
 7	about this more in a few minutes.
 8		Second, by providing children with cancer
 9	throughout the United States and Canada with access to
10	state-of-the-art treatment protocols that are developed by
11	national experts, and that have multiple levels of review
12	for scientific quality and multiple levels of review for
13	patient safety.

14		Also, by providing central review of pathology and
15	imaging, leading to nationwide improvements in diagnosis and
16	staging, and another contribution, by supporting the
17	research studies that have led to the identification of

18	reliable clinical and biologic prognostic factors, and I
19	will come back later to talk again about the importance of
20	this.
21		[Slide]
22		First, let me emphasize the importance of
23	randomized Phase III clinical trials.  Why do we put such
24	emphasis on this?  One reason is because what is completely
25	logical and by all accounts should work, doesn't.

			27 1
 Identifying new superior treatments is an empirical and not
 2	a deductive process.
 3		One example comes from the cardiac literature.

 4	Anti-arrhythmic therapy to prevent mortality from fatal
 5	arrhythmias, and here is the logic: that elevated
 6	ventricular premature beats are associated with early death.
 7	Encainide and flecainide suppress ventricular premature

 8	beats, therefore, the application of these drugs should
 9	reduce mortality in patients with ventricular premature
10	beats.  That is absolutely perfectly logical and is

11	absolutely perfectly wrong.  The randomized clinical trials
12	supported by the National Heart, Lung and Blood Institute
13	demonstrated that the patients who were randomized to

14	receive these two drugs had higher mortality rates than the
15	patients randomized to receive placebo.  We have to subject
16	-- I am not arguing that we be illogical but, rather, that
17	we subject our logic to the empirical testing in
18	appropriately designed clinical trials.
19		[Slide]
20		Another reason we feel so strongly about these

21	trials is that we need reliable answers to questions of
22	therapy.  If we were to accept a more toxic therapy as

23	superior when it really is no better than standard therapy,
24	this would have serious consequences for future patients.
25	We would be treating future patients with therapy that is

			28
 1	more toxic and they would not be receiving any benefit from
 2	that more toxic therapy.  So, we need reliable answers to
 3	questions of therapy.
 4		The conclusions that are reached from single-arm
 5	and non-randomized clinical trials often have limited
 6	reliability, and they have limited reliability for several
 7	reasons.  One is that apparent improvements that are
 8	ascribed to a new treatment in a single-arm trial are often
 9	due to patient selection.  It is the patients that enter the
10	trial and not the treatment that are different and that

11	account for the apparent benefit for the new treatment.
12		Another reason is that the improvement that we
13	ascribe to our new intervention and the patients that we
14	have treated with our new intervention may not be due to

15	that but may be due to some uncontrolled factor, such as we
16	now have better supportive care; our surgeons are better;

17	our radiation oncologists are better at delivering radiation
18	oncology.  It may be due to those changes and not to the new
19	treatment that we are evaluating, and randomization avoids
20	these problems.
21		[Slide]
22		One example of the selection bias and how it can
23	give misleading answers -- over the last decade a number of
24	single-arm trials suggested high response rates and survival
25	rates for high-dose chemotherapy in women with metastatic
			29
 1	breast cancer.  At M.D. Anderson researchers looked at
 2	outcome for 1600 patients with metastatic breast cancer.
 3	All of these patients received conventional chemotherapy,
 4	standard doses of chemotherapy agents.  None received high-
 5	dose chemotherapy.  The patients who would have been
 6	eligible for a high-dose chemotherapy protocol had higher
 7	response rates and had higher survival than the patients who
 8	were not eligible, and the recent randomized studies
 9	comparing high-dose chemotherapy for breast cancer to
10	conventional chemotherapy have raised questions about the
11	true contribution of this approach to the treatment of
12	breast cancer.
13		[Slide]
14		So, what are the Phase III trials that we support,
15	and what are their characteristics?  First, the Phase III
16	trials that we support are large trials.  They are expensive
17	trials because of their size.  They require hundreds and, in
18	some cases, over a thousand patients to reliably identify

19	clinically meaningful differences between treatments being
20	compared.
21		In our Phase III randomized trials, patients are
22	randomized to receive what is considered best available

23	therapy or to receive some new treatment, and the new
24	treatment is prioritized for evaluation based on preliminary
25	data suggesting its potential for improving outcome, and
			30
 1	improving outcome could either mean better survival and, in
 2	some cases, diminished toxicity.
 3		These trials address important questions of
 4	therapy and we don't know the answer to them.  I may have my
 5	hunch a bout which arm is better, and Dr. Brown may have a
 6	different hunch about which arm is better.  We truly don't
 7	know the answers to which treatment is better.
 8		[Slide]
 9		An important point, and Dr. Hirschfield alluded to
10	this, in the culture of pediatric oncology research is that
11	participation in Phase III trials is considered an
12	appropriate standard of care for children with cancer.  The
13	rationale for this is that our standard treatments, none of
14	them are perfect.  They either don't have sufficient
15	efficacy, or they have excessive toxicity.  So, for most of
16	our cancer types we are looking for better treatments.

17		Secondly, this is in the context of multiple
18	safeguards for patient protection, including the multiple
19	levels of scientific review and review for patient safety
20	and, of course, is in the context of appropriate informed
21	consent and assent.
22		So, given these, it is felt appropriate in most
23	circumstances to ask families to consider participation in
24	Phase III trials and historically most families have
25	accepted participation.

			31
 1		We generally have Phase III trials available for
 2	most types of childhood cancer.  There are 25 to 30 Phase
 3	III trials open at any given time for the different types of
 4	childhood cancer.
 5		[Slide]
 6		I will describe a couple of examples of Phase III
 7	trials that have changed standard therapy for specific types
 8	of childhood cancer.
 9		This is an example for a pediatric acute
10	lymphoblastic leukemia, the Children's Cancer Group-1922

11	trial for standard risk ALL, a population that before this
12	trial had about a 75-80 percent 5-year event-free survival.
13	In this case, what I will be focusing on is the comparison
14	of which steroid is the best steroid for treating children
15	with standard risk ALL -- is it prednisone, with half the
16	patients on the left receiving prednisone; or is it

17	dexamethasone, with half the patients on the right receiving
18	dexamethasone?
19		There was a second randomization as well, and that
20	question was whether the drug 6-mercaptopurine, or 6-MP, was
21	better by the standard oral route or whether a new way of
22	administering that drug, intravenously, was superior?
23		[Slide]
24		The results are shown here.  The two lines
25	represent patients ID and OD, patients who received
			32
 1	dexamethasone, and these patients had a significantly
 2	improved outcome compared to the patients in the two lower

 3	curves, the OP and the IP curves, who received prednisone,
 4	and this established a new standard therapy for children

 5	with standard risk ALL, that dexamethasone is a preferred
 6	steroid.
 7		Before I leave this slide, as an aside, if you
 8	compare the blue and the red lines, the blue line is the

 9	patients who received the old way of delivering 6-MP, oral
10	6-MP.  The red is below that.  It doesn't look better.  The
11	IV, the new way, wasn't better.  Comparing for patients who
12	received prednisone, again, the yellow line received the old
13	way and the light blue line received the new way.  So, what
14	we try, what is new doesn't always work but we subject it to
15	the test.  We carried forward the dexamethasone; we
16	discarded the IV 6-MP.
17		[Slide]

18		The other example of a randomized Phase III trial
19	that I will present to you illustrates the concept that
20	pediatric oncology drug development is a long-term
21	commitment, and this example is of ifosfamide and etoposide
22	for Ewing's sarcoma, a cancer of the bone primarily in
23	adolescents.
24		In the mid-1980s ifosfamide was first studied in
25	children.  It was identified, as a single agent, to have

			33
 1	activity for Ewing's sarcoma.  By 1987, there were reports

 2	that the combination of ifosfamide and etoposide, two anti-
 3	cancer drugs together was very effective against Ewing's

 4	sarcoma.  These were patients who had relapsed with their
 5	Ewing's sarcoma.
 6		A Phase III trial was initiated that evaluated
 7	ifosfamide and etoposide for Ewing's sarcoma.  This trial
 8	took a number of years to complete.  By 1994 the trial
 9	closed, and by 1995 the results were available that

10	ifosfamide and etoposide improved outcome for Ewing's
11	sarcoma.
12		[Slide]
13		This just shows the schematic for that study,
14	illustrating, again, that patients were randomized for what
15	was, before this trial, the best available standard therapy,
16	three drugs, or to those three drugs that alternated with
17	ifosfamide and etoposide.
18		[Slide]
19		And, the benefit for the patients receiving
20	ifosfamide and etoposide, 69 percent versus 50 percent, was
21	3-year event-free survival, and this, like the previous

22	study, established a new standard of therapy for children
23	with Ewing's sarcoma, the standard including ifosfamide and
24	etoposide.
25		But identifying this new therapy required a

			34
 1	commitment of resources for over a decade from the initial
 2	evaluation of ifosfamide in children to the eventual
 3	demonstration that this drug actually improved outcome for

 4	children with Ewing's sarcoma, and our systems have to be
 5	able to accommodate this long-term commitment.
 6		[Slide]
 7		I will just note that you have in your handout
 8	other examples of recent Phase III trials that have made

 9	important findings in the treatment of children with cancer.
10		[Slide]
11		Also, in your handout you have ongoing or, in one
12	case, soon to be initiated trials of really important

13	questions of therapy that over the next 1-5 or perhaps
14	longer years will answer these important questions of

15	therapy for children with Hodgkin's disease or T-cell ALL or
16	neuroblastoma.
17		[Slide]
18		This is what we strive for in our system of Phase
19	III trials.  This slide shows outcome for children with
20	acute lymphoblastic leukemia treated on sequential series of
21	clinical trials in the Children's Cancer Group from the late
22	1960s up through the 1990s.  Each series of clinical trials
23	involved hundred and more recently thousands of patients,
24	going from one series of clinical trials to the next,
25	building on what worked in the previous trials, discarding
			35
 1	what didn't work and having ever increasing survival rates

 2	for children with ALL.  This is really what we strive for,
 3	for all of the childhood cancer types.
 4		[Slide]
 5		An important concept in pediatric oncology is the
 6	concept of risk-adjusted therapy, that is, classifying
 7	patients by prognosis.  This slide shows a patient

 8	population for which the survival rate is approximately 70
 9	percent, and our approach to treating this patient
10	population and designing clinical trials for this population
11	would be based on the 70 percent survival rate, and the risk
12	and the types of new treatments we would evaluate would be
13	based on this.
14		[Slide]
15		However, ifosfamide we could identify factors that
16	allowed us to determine which patients do well with current
17	therapy and which patients do poorly with current therapy,
18	essentially to split that first group into two groups, a
19	group that does poorly with the current treatments that we
20	have and the groups that do quite well with the current
21	treatments that we have, then this would be very helpful in
22	terms of increasing the efficiency with which we can
23	identify better treatments.
24		[Slide]
25		The patients who have low survival rates with
			36
 1	current treatments are the ones that may well benefit from
 2	novel, more aggressive therapeutic approaches that are
 3	associated with greater risk, and the patients with very
 4	good outcome with current therapy should be spared more
 5	intensive and toxic treatments and, indeed, we may focus our
 6	research efforts on minimizing acute and long-term
 7	toxicities for these patients.
 8		[Slide]
 9		In order to use risk-adjusted therapy, this
10	requires that we determine reliable prognostic factors for
11	determining which patients do well and which patients don't
12	with current therapy.  To do this requires analyzing outcome
13	for larger numbers of patients, preferably treated in a
14	uniform manner.  Since biology is so improvement in

15	determining prognosis for these biological prognostic
16	factors, it requires collection and analysis of tumor
17	tissue.
18		The protocol-treated patients in the Cooperative
19	Group tumor banks have been invaluable in identifying and
20	confirming these prognostic factors that we now use to
21	assign treatments for children with cancer.
22		[Slide]

23		So, let me take a few minutes now to describe what
24	this research infrastructure is that supported these Phase
25	III trials, that supported the identification of prognostic
			37
 1	factors to support risk-adjusted therapy.
 2		In terms of the scope, approximately 5000 children
 3	are entered each year onto treatment trials supported by the
 4	National Cancer Institute.  The majority of these are
 5	entering Phase III trials but we also have entries onto
 6	Phase II trials to identify activity of new agents and Phase
 7	I trials to identify safe doses of new agents.  For the
 8	tumor types listed here, ALL, acute myeloid leukemia, Wilms'
 9	tumor -- for some of these, most of the children diagnosed
10	with these cancer types in the U.S. and Canada will be
11	entered onto one of the NCI-sponsored clinical trials.
12		[Slide]
13		These trials are supported through the Cooperative
14	Groups.  Historically, these have been the Children's Cancer
15	Group, the Pediatric Oncology Group, a group for
16	rhabdomyosarcoma and Wilms' tumor.  Together, these
17	represent over 200 institutions throughout the U.S. and
18	Canada, banding together to development research protocols
19	for children with cancer, and it represents most of the
20	institutions that treat children with cancer.
21		I would add that in addition to the pediatric
22	groups here, we support the Pediatric Brain Tumor

23	Consortium, specifically focused on developing new
24	treatments for pediatric brain tumors; a neuroblastoma
25	consortium for focusing on new treatments for neuroblastoma;
			38
 1	as well, a number of investigator-initiated projects and
 2	program projects, for example at St. Jude's Children
 3	Research Hospital.

 4		[Slide]
 5		In terms of the Cooperative Group structure, the
 6	four historical groups are now merged into a single entity,
 7	the Children's Oncology Group, and the decision to do this
 8	was based on improving the efficiency and developing and

 9	conducting clinical trials to identify better treatments for
10	children with cancer.
11		[Slide]
12		An important characteristic of the clinical trials
13	program is its multi-modality.  To treat children with
14	cancer requires specialists from many different areas and
15	these must all be a part of the research system, including
16	the pediatric hematologist, oncologist, the surgical
17	subspecialist, radiation oncologist, pathologist, laboratory
18	researchers, nurses, epidemiologist, radiologist and the
19	clinical research associates, and others.
20		[Slide]
21		To do this work, to have 5000 children entering
22	clinical trials each year requires a commitment to
23	infrastructure.  This infrastructure includes an operations
24	office involved in the administration of these trials,
25	coordinating protocol and development and distribution.  It
			39
 1	involves the statistical center for the statistical design
 2	of protocols for data collection.
 3		[Slide]
 4		Of course, it requires the support of the member

 5	institutions in supporting the investigators at the
 6	institution, the clinical research associates for collecting
 7	data, and currently we provide approximately $1700 to
 8	institutions for patients entered that partially reimburses
 9	the research cost to enter patients on these clinical
10	trials.  It requires support for tissue collection so that
11	we are able to do biology studies, and support for
12	submitting things like radiographs and pathology specimens.
13		[Slide]
14		Then, there are the groups that actual do the
15	science, that develop the clinical trials, the disease and
16	discipline committees -- disease committees for all of the
17	different tumor types, discipline committees for surgery,

18	radiation oncology, the disciplines involved in treating
19	children with cancer, and then individual study committees
20	that design and implement each of the individual clinical
21	trials.
22		[Slide]
23		In addition to this commitment to ongoing support

24	of Phase III trials, we also recognize our responsibility to
25	survivors of childhood cancer.  Survivors are at risk for
			40
 1	long-term sequelae of therapy depending on their diagnosis,
 2	depending on the type of cancer that they had that could
 3	involve the heart or lungs; that could involve second
 4	cancers; impaired fertility effects among offspring, central
 5	nervous system dysfunction, and so on.
 6		[Slide]
 7		In part, to support research to identify these
 8	long-term effects and to identify ways to either prevent or
 9	ameliorate these, we support the Childhood Cancer Survivor
10	Study.  This is a retrospective cohort involving 13,000 5-
11	year survivors of childhood cancer who are surveyed for
12	their long-term health and psychosocial status.
13		[Slide]
14		The Childhood Cancer Survivor Study is currently
15	addressing important questions for survivors, looking at the
16	late mortality risk for survivors, looking at second cancers
17	developing and what the risks of second cancers are, looking
18	at pregnancy outcomes after treatment for childhood or
19	adolescent cancer, looking for cancer in offspring of
20	pediatric cancer patients, and following thyroid disease and
21	survivors of childhood Hodgkin's disease, and then looking
22	at smoking and other health-associated behaviors among
23	survivors of childhood cancer.
24		[Slide]
25		Let me spend the last few minutes talking about
			41
 1	unmet needs and looking towards the future.  In spite of the
 2	progress that we have achieved over the past four decades,

 3	there are still over 2000 children and adolescents who die
 4	each year from cancer in the United States.
 5		Some of the children who are cured with our
 6	current treatments experience diminished quality of life
 7	because of long-term effects of their cancer diagnosis and
 8	treatment, and our current therapies for many cancers are

 9	near-maximal intensity and we need new treatment strategies
10	to improve outcome for these children.
11		[Slide]
12		This shows the distribution of cancer mortality in
13	children younger than 20.  About a third of the deaths

14	result from leukemia, about a fourth from brain tumor.
15	Endocrine is actually neuroblastoma, and so on.  We need

16	better treatments, new treatment approaches in each of these
17	different cancer types.
18		[Slide]
19		The handout has some of the different approaches

20	that we are trying for some of these different diagnoses.
21	What I will focus on in these last few minutes is that we
22	are moving towards a new era in treating cancer both in

23	adults and children, and an era in which our treatments are
24	molecularly targeted and the treatments are based on

25	specific molecular characteristics of the cancer.  The
			42
 1	treatments that we have had to date have been, in large
 2	measure, are non-specific treatments that harm normal cells
 3	and cancer cells as well.  These treatments, in principle,

 4	will be more specific for processes required for tumor cell
 5	survival and growth but, as I mentioned early in the talk,

 6	what is perfectly logical and makes perfect sense may not be
 7	true and, of course, we will have to evaluate rigorously
 8	whether these new treatments actually do work for children
 9	with chancer.
10		[Slide]
11		There are a number of opportunities for
12	molecularly targeted therapies.  The example that I will
13	focus on is for Philadelphia chromosome positive ALL, but
14	there are also opportunities using monoclonal antibodies and
15	opportunities using growth factor receptor inhibitors.
16		[Slide]
17		This example -- Philadelphia positive ALL, is ALL
18	that develops because of a fusion protein resulting from
19	chromosomal translocation.  This has very poor outcome with
20	our treatments, 20 or 30 percent event-free survival.
21		This fusion protein that causes the leukemia has
22	an enzyme activity that is absolutely essential for the
23	leukemogenic effect of the translocation, and we now have a
24	drug, STI571, that is an inhibitor of this critical enzyme
25	activity.  This drug inhibits the proliferation of the
			43
 1	leukemia cells and induces them to undergo apoptosis or cell

 2	death.
 3		[Slide]
 4		This schematically illustrates the genetic change
 5	in the Philadelphia chromosome positive ALL with the 922

 6	translocation leading to the leukemogenic fusion protein
 7	that produces a Ph positive ALL.  Over, on the right, is

 8	what happens when STI571 inhibits the activity of the fusion
 9	protein and causes the leukemia cells to die, resulting in
10	restored normal hematopoiesis.
11		[Slide]
12		Phase I trials have been completed in adults with
13	chronic myeloid leukemia.  High levels of anti-leukemia

14	activity were observed.  Pediatric Phase I trials are
15	ongoing and will be completed shortly.  And, we are working
16	with the Cooperative Groups to develop a pilot study for
17	newly diagnosed patients to incorporate STI571 with
18	conventional drugs to treat these patients with a type of
19	ALL that currently, with current therapy, has such a poor
20	prognosis.
21		[Slide]

22		In closing, let me first emphasize that the public
23	health of children has been improved by the long-term
24	sustained NIH support of this ongoing infrastructure for
25	conducting clinical research for children with cancer.  As a
			44
 1	result of this long-term sustained NIH support, superior new
 2	treatments have been identified, identified based on
 3	definitive and reliable evidence, and these new treatments,
 4	and superior treatments, have been made widely available to
 5	children with cancer throughout the United States and
 6	Canada.
 7		[Slide]
 8		The second point I would emphasize is that
 9	progress in the past as well as progress in the future
10	depends on collaboration and cooperation among the pediatric
11	cancer researchers and healthcare professionals throughout
12	the country working together.  It depends on the families

13	and their advocates participating in these trials.  It
14	depends on the National Cancer Institute recognizing that
15	this is a priority area.  It depends on the academic and
16	pharmaceutical developers of new cancer treatments and on

17	the FDA and its regulations.  And, it depends on third-party
18	payers supporting the clinical care costs for treating
19	children with cancer, and then all of these groups working
20	together, so that the most promising therapeutic approaches
21	are expeditiously evaluated with the ultimate objective of
22	continuing to see improvements in outcome for children with
23	cancer.
24		I thank you and I would be glad to address any
25	questions that you have.  Thanks.
			45
 1		DR. CHESNEY:  Thank you very, very much, Dr.
 2	Smith.  That was an exceptionally complete and informative
 3	overview.  Let me just ask Dr. Hirschfield, should we accept
 4	questions now or wait until after the break?  Now?  Are
 5	there any questions?  Yes, Dr. Fink?
 6		DR. FINK:  Apropos yesterday's discussion, your
 7	data on Ewing's sarcoma showed a p value of less than
 8	0.00005.  Was there a data and safety monitoring board in

 9	place that could have led to earlier termination of that
10	study and let more children receive the optimal therapy?
11		DR. SMITH:  Yes, for all of our trials we have
12	data and safety monitoring committees.  The Children's
13	Cancer Group, the Pediatric Oncology Group have data and

14	safety monitoring committees that are looking at the interim
15	results from our Phase III trials, and the protocols are

16	written with guidelines for what the monitoring boundaries

17	should be for these trials.
18		I wasn't a member of the data monitoring committee
19	for that trial so I don't know the specifics for that trial,
20	I can remember in the past few years a number of trials that
21	have closed either for one arm being superior to the other
22	arm or closed because there was no chance that a difference
23	could emerge related to the question being addressed.  We
24	have described our data monitoring committee system in the
25	Journal of Clinical Oncology and I would be glad to provide
			46
 1	you with that reference.
 2		DR. KRAILO:  Mark Krailo, from the Children's
 3	Oncology Group.  There was a data monitoring safety board
 4	for that study.  We met three times while the trial was
 5	ongoing, and the differences in the therapies emerged later
 6	on in this trial.  So, they emerged after the study had
 7	completed all its accrual.
 8		DR. CHESNEY:  Are there any other questions for
 9	Dr. Smith?
10		[No response]
11		Thank you again.  As Dr. Smith pointed out, the

12	role of families as advocates for children is so important
13	in all studies but particularly in oncology studies, and we
14	are very fortunate this morning to have Dr. Susan Weiner,
15	from the Children's Cause, who will speak to us on lessons

16	and challenges of participation in clinical trials, a family
17	perspective.
18	    Lessons and Challenges of Participation in Clinical
19		     Trials -- a Family Perspective
20		DR. WEINER:  Thank you, Dr. Chesney and Dr.
21	Santana, for giving me an opportunity to speak this morning,
22	and we are grateful -- I figure in my next life I will use
23	Power Point but, somehow, in my generation it hasn't quite
24	caught on -- we are specially grateful in the parent
25	community for the increased attention that the FDA has been
		47
 1	paying to pediatric cancer under the leadership of Drs.
 2	Pazdur and Hirschfield.
 3	          As some of you know, I was the parent of a child
 4	with a brain tumor who was diagnosed in infancy and died

 5	just short of his fourteenth birthday.  Since then I have
 6	worked as a patient advocate in the brain tumor community
 7	and in the pediatric cancer advocacy community, building
 8	programs to serve patients and counseling hundreds of
 9	families who are trying to make rational decisions about
10	treatment and care in an irrational situation.  I have
11	founded the Children's Cause to devote more time to

12	strengthening the pediatric cancer community through
13	education and advocacy.
14	          The experience of children and families who
15	struggle with the diagnosis of childhood cancer is different
16	from that of other pediatric diseases and disabilities.
17	When I watched my son years ago in a special education class
18	interact with his class mates disabled as a result of a
19	variety of other diseases, I realized the uniqueness of his
20	experience and that of our family.  While they lived the
21	slow course of chronic illness and developmental
22	disabilities, we were living with an internal anti-personnel
23	bomb.  The uniqueness of the pediatric cancer experience
24	lies not in its threat of its incidence or as a public
25	health menace but, rather, in its uniquely destructive force
		48
 1	on children and families.
 2	          The uniqueness of pediatric cancer, of course, is
 3	inherent also in its diversity, namely that it represents

 4	many orphan diseases, often of embryonic origin.  Families
 5	affected by childhood cancer share a common goal with the

 6	pediatric oncology research community.  We want new
 7	treatments that are less toxic, that can destroy disease and
 8	spare healthy tissue with laser-like precision.  Despite
 9	extraordinary gains in the treatment of some childhood

10	cancers, many other childhood cancers, most notably solid
11	tumors and, of course, brain tumors, have not enjoyed the
12	same degree of improvement.  We are still a long way from
13	achieving our goal.
14		Our question as parents and patient advocates now
15	is what will it take to ensure that pediatric oncology
16	researchers can have rapid access to new agents so that our
17	children with cancer can receive what so many people call
18	the best possible treatment?  During the 1990s, FDA and

19	Congress, urged on primarily by the American Academy of
20	Pediatrics, created initiatives to generate pediatric

21	information on new and improved oncology drugs for purposes
22	of labeling, as well as to increase industry financed
23	pediatric research.
24		For children with cancer, both the Pediatric Rule
25	and the pediatric exclusivity provision of FDAMA have had

			49
 1	disappointing results.  While it has been successful for
 2	other diseases, the interpretation of FDAMA has resulted in
 3	relatively little pharmaceutical investment for our
 4	children.  Now FDA's emphasis for labeling for pediatric
 5	oncology drugs, by enforcing the Pediatric Rule, leaves a
 6	series of questions about whether this enforcement will slow
 7	and alter the course of pediatric cancer research, questions
 8	which I hope we will discuss later today.
 9		First, how can strict requirements for labeling

10	possibly keep pace with rapid advances and knowledge about
11	gene expression and molecular targeting?
12		Will the enforcement of the rule, in effect,
13	redirect the strategy of the cooperative groups that have

14	been responsible for the successes in children cancer
15	treatment from consensus development and layers of review in
16	clinical trials using available drugs off-label that
17	pediatric oncology researchers believe are the most
18	promising approaches?
19		Finally, why should research priorities in
20	pediatric oncology now be shaped by a regulatory requirement
21	that places first those diseases that may be judged the same
22	or similar in adults as in children?
23		As parents and patient advocates, we want clinical
24	research studies in children with cancer to be determined by
25	the medical need to answer the most important research
			50
 1	questions and, of course, by the most promising scientific
 2	opportunities, and not by ill-fitting regulatory
 3	requirements.
 4		Neither FDAMA nor the Pediatric Rule offer
 5	successful solutions to achieving the goals we all share for
 6	children with cancer.  We seem to have strayed from our
 7	point.  We have not yet struck the right balance between
 8	incentives and enforcement in pediatric oncology research.
 9	We should use industry's desire for exclusivity to encourage
10	them to invest in pediatric oncology research and, at the
11	same time, expect conforming to academic standards and
12	strict cooperation with the cooperative groups.  From the
13	FDA, while we depend on your watchfulness, there needs to be
14	a more flexible approach to regulation in pediatric cancer,
15	and when it is time to re-authorize FDAMA we may need to

16	craft special provisions appropriate to pediatric cancer
17	research.
18		If rapid advancements in basic science are to
19	translate into effective treatments for our children in the
20	foreseeable future, a new interactive paradigm is needed

21	whereby each constituency involved in pediatric oncology
22	research will need to show more flexibility, a greater
23	commitment of resources and a continuing awareness of the
24	uniqueness of our diseases.  Thank you.
25		DR. CHESNEY:  Thank you very much for articulating
			51
 1	the issues so clearly.  Are there questions for Dr. Weiner?
 2		DR. HIRSCHFIELD:  I would like to ask if there are
 3	any perspectives you would like to share with regard to
 4	family participation in the process?
 5		DR. WEINER:  Could you be a little bit more
 6	specific?
 7		DR. HIRSCHFIELD:  We have all stated that research
 8	is the standard of care, and it is a different paradigm when
 9	a child has cancer than going to the local pediatrician and
10	getting whatever the standard of care may be for that
11	particular community.  It is a process where one has to sign
12	consent forms, be made aware of protocols, and learn a new
13	vocabulary, and I would like to know if you would make some
14	comments with regard to these aspects which are different
15	than families have when they are treated typically for other
16	illnesses.
17		DR. WEINER:  There are two things that I think are
18	operating now.  One is that there is a great reliance on the
19	wisdom and the necessity of referral to centers of
20	excellence to be treated.  And, when families line up in a
21	pediatric neuro-oncology setting, there is an important kind
22	of bonding that takes place initially.  There is an enormous
23	need to assimilate a great deal of information under very,
24	very dire circumstances.  I believe that parents are helped
25	these days by the web, by the free and open availability of
			52
 1	medical information from reliable sources such as the NCI
 2	and the FDA.

 3		As every pediatric nurse knows, there is an
 4	initial phase of sort of being deaf, dumb and blind at the
 5	beginning and it is during that period where consent

 6	typically has to be signed over a period of days or
 7	understanding what needs to be done, and we are very much
 8	dependent on the good will and directness of the medical

 9	team.  Does that answer your question, Dr. Hirschfield?  No?
10		DR. HIRSCHFIELD:  Well, you have not only had your
11	own experience but the experience of talking to hundreds of
12	other families, and I wanted our colleagues to be able to
13	have a little better understanding of the impact of having
14	the diagnosis of a child with cancer on not just the type of
15	care but on the lives of the families.
16		DR. WEINER:  Well, it is a life-altering situation
17	and many families are, of cost, cast in disarray.  The

18	siblings are oftentimes neglected, and work is sometimes
19	entirely neglected.  There is a sense of unreality about

20	being in a hospital and not being in a hospital at the same
21	time.  That is, while the hospital environment is a menacing
22	phase, one relinquishes the care to strangers on the one
23	hand.  On the other hand, being out of the hospital means
24	that life should appear normal which, of course, it is never
25	again since a diagnosis of life-threatening illness means
			53
 1	that there is always imminent danger.
 2		Does that do it?  Let me try again?
 3		DR. HIRSCHFIELD:  I think you have shared some
 4	important information.  Would you just elaborate a little
 5	bit more on what types of supports and what types of crises
 6	are faced, and where do people turn when they face these
 7	crises?  Is it to the medical system?  Is it to each other?
 8	Or, what are the responses and what are the resources
 9	available?
10		DR. WEINER:  Well, there are many pediatric groups

11	that have formed support groups and produce information
12	materials but that typically is not accessible at the time
13	of diagnosis.  That usually comes after consent is signed

14	and after the first treatment decision is made.  It is often
15	most accessible at the point of occurrence.
16	          But with the Internet there are increasing
17	resources that are out there.  There are chat rooms, and for
18	whatever they are worth, they represent a community.  There
19	is no substitute for the experience of one parent with
20	another, and it is very important for children's hospitals
21	and medical settings to offer that opportunity.
22	          Finally, I think, you know, in terms of management
23	of the sort you are referring to, it is very important to
24	ameliorate -- it is difficult for me to describe the degree
25	of distress.  It is very important to have an intermediary
		54
 1	between the pediatric oncologist and the family -- not a
 2	research nurse, a nurse practitioner.
 3	          I guess I would like to leave this part of the
 4	conversation with something that I have recently called the
 5	"parents' double-bind,"  the parents of children with
 6	cancer.  That really amounts to a situation in which the
 7	diagnosis of cancer as a life-threatening disease really
 8	violates the first principle of being a parent, that is, you
 9	have failed to protect your child from disease and imminent
10	death.  However, in order to ameliorate that diagnosis you
11	have to relinquish your role as parent and fail to protect
12	your child from harmful and sometimes toxic treatments at

13	the hands of strangers.  So, in that situation you can't
14	maintain your role as a parent either originally or through
15	treatment, and it is an understanding of that kind of

16	paradox that is very important and really is unique to
17	participating in clinical trials.

18		DR. CHESNEY:  We do have some other questions for
19	you, Dr. Weiner, if you would like to stay at the
20	microphone.  Dr. Santana?
21		DR. SANTANA:  Susan, you made a comment that has
22	been resonating in my brain for a little while, and I would
23	like you to help me by giving examples or sharing your
24	thoughts further, and it is this concern that you have that
25	with new regulatory issues coming from the FDA as regards

			55
 1	pediatrics whether we will have to redirect the model of
 2	cooperative group research and how this potentially could
 3	impact it.  Could you elaborate on that?
 4		DR. WEINER:  Well, Jim Boyett and were sort of
 5	talking about this a bit yesterday.  It would seem perhaps
 6	unfortunate if there were studies -- let me start over
 7	again, there is a paucity of subjects available in pediatric
 8	oncology research.  They are a valuable commodity and
 9	prioritization of approaches is something that is, as you
10	know, critical towards progress.  Dr. Smith described how
11	long it takes to come up with a Phase III standard of care.
12	It would be, I believe, unfortunate if these resources
13	through the cooperative groups were to be used to establish
14	similarity equivalence of disease rather than really taking
15	account of scientific opportunity that perhaps looked more
16	promising for new treatments.  That is the context.
17		DR. CHESNEY:  Dr. Kauffman?
18		DR. KAUFFMAN:  I wanted to follow it up to try to
19	understand better if you have any specific suggestions how
20	changes in FDAMA might -- if it is renewed and if it is
21	possible to make changes.  In our discussions last February,
22	as I recall, the issue came up that maybe FDAMA is not an
23	appropriate vehicle to accomplish what we want to
24	accomplish, and there are some inherent characteristics of
25	the current law that make that so.
			56
 1		One is that many of the drugs that need to be

 2	studied in kids, usually in combination, no longer have
 3	exclusivity to which to attach the benefits of FDAMA.  So,
 4	FDAMA is irrelevant to those drugs.
 5		Secondarily, of the new drugs, new agents, they
 6	don't have the market size where FDAMA has had the most

 7	impact -- they just don't have the market size to bring
 8	FDAMA into play.  So, what do you see as concrete changes in
 9	the law that might help with the oncology agents for
10	children?
11		DR. WEINER:  Well, you know, I am not an attorney
12	and not someone who really is experienced in crafting the

13	concept-precise proposals that you are aiming at, however,
14	one suggestion that came up in discussion yesterday

15	afternoon might be the point that the six months of
16	exclusivity is more valuable -- you know, somehow or other,
17	the older the drug, the closer it is to going off patent,

18	the more likely it is that those six months are likely to be
19	valuable.  So, in some sense, FDAMA might take account of
20	the kind of history or newness of the drug, and how that
21	could be crafted I am not prepared to say right now, but the
22	phrase "sliding scale" has been used a lot but the exact
23	dimensions of that remain to be seen.
24		DR. CHESNEY:  Dr. Nelson, you had a question?
25		DR. NELSON:  Thank you, and thank you for your
			57
 1	remarks.  When you started talking about the double-bind it
 2	began to address the area I was interested in asking about,
 3	which is specifically the consent process.
 4		One of the things that is explored in the process
 5	of looking at informed consent is the ability of an
 6	individual to distinguish research from standard of care
 7	but, yet, we are in the process of conflicting that

 8	distinction by saying that the standard of care is to
 9	participate in research.  So, I am just interested in
10	hearing your reflections about how at some time in the

11	process a parent becomes aware of the research components,
12	and what suggestions you might have or directions for
13	looking at the quality of the information and the quality of
14	the decision that a parent makes to enroll in that kind of a
15	process.
16		DR. WEINER:  This is, of course, the heart of the
17	matter.  As those of us who are in the pediatric oncology
18	community really know in our heart of hearts, parents do not
19	make that distinction.  It is in some sense unthinkable and
20	many of us can report instances in which the most
21	sophisticated parents and family members will say, after a
22	course of treatment and after having signed consent, that
23	their child was not part of a research study.  I think that
24	that is evidence for the kind of power of the need to
25	believe that one is treating one's child, one is subjecting
			58
 1	one's child to harmful intrusions for the purpose of their
 2	getting better.
 3		There may be other ways around that.  The consent
 4	form, and as many of you have reviewed dozens of these --
 5	the consent form language is always contorted in a way that
 6	makes it difficult.  That can always be tinkered with.
 7	Sometimes, particularly for example in Phase I trials, it is
 8	useful to have the investigator and the physician care-taker
 9	roles distinguished between people.  I think there is no
10	easy solution but those are some of the strategies.
11		DR. CHESNEY:  Dr. Murphy?
12		DR. MURPHY:  Susan, you were at our February
13	meeting so you know that many of these issues were brought
14	up and we thought that we left that meeting with a way to
15	resolve many of these issues.  And, Dr. Pazdur is, you know,
16	going to be presenting the guidance outcomes for the group
17	here and the approach, and after he speaks and presents the
18	process to the group I think it would be helpful for us to
19	hear where you still think there are issues, particularly as
20	relates to the selection of products to be driven by
21	science, because that is the very concern we have, that
22	FDAMA be driven by science and not because there is a lot of
23	money to be made off of a block-buster product.
24	          And, the second issue is flexibility and that is
25	one of the goals of this approach, to provide flexibility
		59
 1	for the development of pediatric oncology products while not
 2	making it a complete free for all.  By that, I mean that
 3	every group ends up with administering things in a
 4	regulatory way and in a different way.
 5	          So, I would just like to say I would like you,
 6	after we hear Dr. Pazdur, to point out to us where you think
 7	this approach does not address those two issues in
 8	particular because I think one of the concerns we have at

 9	FDA is, as Dr. Smith has clearly articulated this morning,
10	that there has been a lot of success in this field because
11	of the cooperative groups and the standard of care, and we
12	don't want unintended results here where FDAMA drives the
13	process in a different direction.  So, we don't want to

14	disrupt something that is working.  I guess that is one of
15	our concerns, we keep moving in this area.  So, again, those
16	two issues, the flexibility and why this process won't help
17	that and why this process won't help the science approach,
18	would be questions I would ask you to come back and tell us.
19	Okay?  Thank you.
20	          DR. CHESNEY:  Our next speaker is Dr. Richard

21	Pazdur, who is Director of the Division of Oncology Drug
22	Products at the FDA, and he will speak on the FDA

23	initiatives in pediatric oncology -- adaptation of the
24	general case to special circumstances.
25		 FDA Initiatives in Pediatric Oncology
			60
 1	  Adaptation of the General Case to Special Circumstances
 2		DR. PAZDUR:  Good morning.  I somehow feel like a
 3	fish out of water.  I am not a pediatrician and I was
 4	thinking back on my pediatric experience and, I am ashamed
 5	to say, it has been about 25 years ago that I treated a
 6	pediatric patient.  So, if I make any major faux pas in the
 7	science and medicine of pediatrics, please forgive me.
 8		[Slide]
 9		I came to the agency about a year ago.  In fact,
10	the last week in September will be my one-year anniversary
11	as far as starting at the FDA.  My former job was as a
12	clinical professor at M.D. Anderson Cancer Center where I
13	was very involved with Phase I, Phase II and Phase III drug
14	development in colorectal carcinoma, a quite different
15	disease than one would see in pediatrics.  Nevertheless, in
16	my experience in interacting with my colleagues in
17	pediatrics at M.D. Anderson and in the greater Houston area,
18	I was always aware of a particular angst or a particular

19	distress that the pediatric oncologist had when we talked
20	about clinical trials, especially when the adult medical
21	oncologist had a wide array of new agents that they were
22	studying.  There was somewhat of an uncomfortable feeling
23	among the pediatric oncologists that they simply were not
24	getting those good drugs right away.  In other words, they

25	were somewhat relegated almost to a second-class citizen --
			61
 1	let's see how these drugs work in the adults and they maybe
 2	we will consider developing them in pediatrics.
 3		When I got to the agency, it was clear from
 4	Dianne's presentation and working with the pediatricians in

 5	our oncology group that the implementation of the FDAMA
 6	incentive program was simply not working in oncology, and I
 7	kind of stepped back because I was new and that always gives
 8	you a fresh perspective -- right? -- and I said, well, why
 9	isn't this working?  And, I said, really, you have to have a
10	whole plan of basically developing a drug in pediatric
11	oncology.
12	          When one takes a look at the applications that
13	come into our division of medical drugs, where are sponsors
14	developing drugs?  They are developing drugs in the big
15	markets for oncology drugs -- breast cancer, prostate
16	cancer, colorectal cancer, lung cancer.  Very few approaches
17	or very few applications are coming in for indications where
18	we would even think of extrapolating from an adult
19	indication to a pediatric indication.  It is very hard to

20	make that bridge between developing a drug in colon cancer
21	and saying, well, we now have to exert the Pediatric Rule
22	for development of this drug in pediatrics.
23	          So, there are some very unique characteristics
24	about the whole field of pediatric oncology that I thought
25	needed revision.  The difficulty in extrapolating adult

		62
 1	indications to the pediatric population in oncology is one
 2	that we will discuss this afternoon, and it is a very
 3	difficult decision and perhaps, as science progresses and we
 4	learn more about the biology of the diseases, we will have a
 5	greater flexibility in applying this rule.
 6	          But, as I stated before, the major disease
 7	categories that we receive applications for are in the
 8	common adult malignancies which makes the application of the
 9	Pediatric Rule very difficult.  Nevertheless, we know that
10	pediatrics has very special characteristics both in the
11	pediatric community in general and in the oncology

12	community, and we must be cognizant of these special
13	characteristics as we develop any plan in developing
14	pediatric oncology drugs.  And what are those special
15	characteristics?

16		Number one, as has been stated repeatedly, it is
17	the standard of care for patients, children, to participate
18	in pediatric protocols.  I wish I could say that about adult
19	malignancies.  In essence, with adults it is just the
20	opposite.  It is the exceptional patient that participates
21	in a clinical protocol.
22		Secondly, and most important, it is the
23	relationship that the academic and the practicing pediatric
24	oncologist has with the NCI and the Pediatric Oncology Group
25	structure that must be protected, and that was part of a
			63
 1	whole development plan that we have initiated, that we do
 2	not disrupt this relationship because it has worked; it has
 3	turned pediatrics really into a very successful model of
 4	producing curative therapies in our generation.
 5		So, in any implementation of any plan, I want to
 6	make it quite clear we are not attempting to exert a
 7	regulatory hammer on a near-perfect relationship that exists
 8	between the cooperative group structure, investigators and

 9	the NCI.  The scientific agenda must be established by the
10	physicians that are doing the trials, those that are

11	involved in the cooperative groups.  We are here as a
12	facilitator to get those drugs, to use "regulatory pressure"
13	via FDAMA regulations, to act as a funnel to get those new
14	agents into the pediatric structure.  It is not our decision
15	of what drugs should be studied.  That should be left up to
16	the experts in pediatrics.
17		[Slide]
18		This is the Food and Drug Modernization Act of
19	1997, and this is what we call the incentive program.  Some

20	people call it the carrot in contrast to the stick, which is
21	the rule, and it is a provision for a 6-month extension to
22	the existing marketing exclusivity or patent protection of
23	the entire line, and it can be granted to an entire product
24	line of an active moiety for providing new pediatric
25	information that will benefit public health.  The
			64
 1	submissions must come in response to an FDA written request,
 2	and I will go over this in a little more detail.
 3		[Slide]
 4		This slide provides you the Pediatric Rule, which
 5	I think you all have been briefed on as far as the
 6	membership of this committee yesterday.  In this rule, this
 7	is what we kind of refer to as the stick or a mandate, and

 8	it provides that a product under review must provide
 9	pediatric information if the indication under review is a
10	disease found in children.  If a disease is not found in
11	children a waiver may be granted.  And, this is one of the
12	major problems that we have with the application of the

13	Pediatric Rule, that we issue far more many waivers than we
14	implement this rule simply because many of the diseases, or
15	I should say most of the applications and products are being
16	developed in common adult malignancies that do not have this
17	ability to extrapolate into pediatric indications.
18		[Slide]
19		Most people or many people have difficulty in
20	comparing the FDAMA incentive versus the Pediatric Rule, and
21	what I have attempted to do in this slide is to provide you
22	a listing or a comparison of FDAMA versus the Pediatric

23	Rule.  FDAMA is a voluntary program.  It applies to the
24	entire product line, the incentive does.  There is no

25	restriction on eligible pediatric diseases.  It only applies
			65
 1	when there is an underlying patent or exclusivity

 2	protection.  Obviously, you need something to extend.
 3	Biologicals and some other products are excluded and orphan
 4	drugs are included.
 5		In contrast to the FDAMA, the 1998 Pediatric Rule
 6	has the following characteristics, and these include that it
 7	is mandatory if the disease is found in adults and children,
 8	it must be studied in children.  It only applies to the
 9	product and the indication under the review rather than to
10	the entire product line, and it only applies if the
11	pediatric disease is similar to the adult disease.  It

12	applies to biologics, and orphan products are excluded.
13		[Slide]
14		This gives you an indication of how pediatric
15	exclusivity comes into being the actual process of how the
16	FDA works with this.  A proposed pediatric study request is
17	usually generated.  Who can generate this pediatric study
18	request?  Virtually anyone.  It could be a cooperative

19	group; it could be an academic; it could be a commercial
20	sponsor; it could be any other interested third party.  A
21	written request is then generated from the FDA.  This
22	written request is very important because it has the exact

23	specifics that must be followed, and these specifics must be
24	followed to the detail to allow granting of the eventual
25	exclusivity.
			66
 1		So, in response to a proposed pediatric study

 2	request, a written request is generated from the FDA.  A
 3	sponsor, if they are willing to do it -- remember, this
 4	program is voluntary -- submits study reports after

 5	completing the required studies and then the FDA determines,
 6	as it would in any review of an application, the scientific
 7	validity of the material that is submitted to determine
 8	whether it meets the specifics of the written request that
 9	is generated from the FDA.  Because we have had a paucity of
10	proposed pediatric study requests, we have taken the
11	initiative to generate some written requests on our own from
12	the Division level of Oncology Drug Products recently.
13		[Slide]
14		Let me give you the idea or the concept of this
15	pediatric plan that we are asking you to consider here and
16	to comment on.  As I stated before, if somebody is
17	developing a drug in an adult indication, such as breast
18	cancer or such as prostate cancer, it is going to be hard to
19	say where do I go with this drug in pediatrics.  It requires
20	really, if you take a step backward, a whole plan to develop
21	this drug.
22		One has to take a look at the dose in pediatrics,
23	the toxicities in children that might be unique.  What
24	pediatric disease do you study it in?  Well, there might be
25	some diseases that may be applicable if you know a specific,
			67
 1	for example, genetic mutation such as in the STI drug that

 2	Dr. Smith referred to.  However, for the vast majority of
 3	cases we are dealing in an area where we don't know what
 4	pediatric disease this may work into.  So, therefore, you
 5	would need some type of screening Phase II study to

 6	determine the eventual activity of the drug, if it does have
 7	activity.
 8		This is a very risky process and we are aware of

 9	this, and this whole plan that we are devising is some way
10	of sharing the risk of developing an entire oncology drug
11	for pediatrics with the sponsor.  So, the following

12	provisions have been made:  An overview, dosing and
13	pharmacokinetics in the Phase I one study must be done.  We
14	need this information obviously to proceed further.  What is
15	the dose of the drug?  What are the toxicities?
16		Then, Phase II or pilot studies in a range of

17	potential indications can be performed, and these are
18	usually stipulated in the letter or there is some
19	flexibility and here, again, we would encourage strongly
20	sponsors or people that have received a written request to
21	discuss what Phase II studies they want to do with the
22	pediatric academic/cooperative group community.  Pediatric
23	patients are an important national resources.  We do not

24	want them to be used as a commodity.  They should be used i
25	the best -- and I shouldn't even use the word "used" but
		68
 1	they should participate in the best designed scientific

 2	studies, designed to ask the most important questions.
 3	          Here, again, this plan is to introduce either old
 4	agents that have not bee studies, and by old agents I mean
 5	approved drugs in oncology, or new molecular entities that
 6	have not been approved yet by the FDA.  It is important to
 7	note that this development plan is not a supplemental NDA

 8	since efficacy does not necessarily need to be demonstrated.
 9	Obviously, we would want efficacy to be demonstrated if the
10	drug is active and for us to label this drug as well as to
11	approve this drug for a pediatric indication if warranted.
12	This applies to both new agents and approved agents that
13	have not been adequately investigated in pediatric oncology.
14	          [Slide]
15	          Let's take a look at the first stage of
16	development, and this correlates basically with a classical
17	Phase I study in medical oncology or pediatric oncology.

18	Phase I studies would be done to determine the dose, the
19	pharmacokinetics and the toxicities -- pretty
20	straightforward.  Roughly, about 25 patients would be
21	planned to be entered, and here again we have some
22	flexibility.  Obviously, nobody knows a priori, before
23	starting the study, exactly how many patients would be

24	entered on a Phase I study.  So, there would be a range here
25	and some flexibility.
			69
 1		The important point here is if unacceptable
 2	toxicity occurs the development would stop and an
 3	exclusivity extension would be granted -- pretty generous,
 4	right?  The reason behind this is we look at this as an
 5	exceptional situation.  We feel that there would be very,
 6	very, very, very, very few drugs that would go to Phase I in
 7	pediatrics and would be stopped because of unacceptable

 8	toxicity.  Nevertheless, if somebody makes a good faith
 9	effort in developing this drug and proceeding with a

10	development plan to a point where they can no longer
11	proceed, then we believe that this has been a good faith
12	effort and, therefore, they should be rewarded by the
13	granting of exclusivity.  We view this as a very generous
14	concession, in a sense, but we realize this is an important
15	aspect to promote and act as a funnel of getting new drugs
16	to the pediatric oncology community.
17		The most important aspect, rather than
18	concentrating on an exception, is where we believe most of
19	the drugs will go, and that is if the toxicity is

20	acceptable, and here, again, that is a decision that will be
21	made by the pediatric, academic and cooperative group
22	community, the development of this drug should proceed to a
23	second stage and this is the vast majority of cases, and
24	let's go on to that second stage.
25		[Slide]
			70
 1		Here, again, it is rather general because we
 2	cannot dictate specific situations to a general plan such as
 3	this, what we are looking for in our Phase II studies is
 4	what is the activity of this new molecular agent or an
 5	existing approved agent in pediatric malignancies?  So, we

 6	would propose that Phase II studies would be done and here,
 7	again, it would depend on what disease one is studying.  If
 8	it was a very refractory situation one could take a look at
 9	single agents.  Perhaps we would take a look at window

10	studies, perhaps at add-on studies or pilot studies of
11	various combinations to demonstrate an agent's
12	characteristic and contribution to the following --
13	efficacy, perhaps using surrogate endpoints such as response
14	rates, such as time to progression, and this would also

15	provide justification for further development to examine
16	clinical benefit.

17	          [Slide]
18	          Possible outcomes after the Phase II portion --
19	well, if efficacy is demonstrated on the basis of a
20	surrogate endpoint, this may lead to a concept known as
21	accelerated approval or subpart (h), and for those of you

22	who are unfamiliar with this FDA provision, it allows us to
23	approve drugs on the basis of a surrogate endpoint such as
24	response rate, such as time to progression, with an approval
25	for marketing with a commitment that a clinical benefit such
		71
 1	as a survival benefit or a palliative benefit in terms of
 2	symptoms be subsequently studied in a Phase IV commitment.
 3	But, anyway, if efficacy is demonstrated there is a
 4	possibility for accelerated approval, allowing for full
 5	marketing of the drug.
 6	          If there is no beneficial effect that is observed,
 7	then the development is halted and stopped.  The drug simply
 8	doesn't work.  Here, again, a good faith effort has been
 9	made in the development of this drug and even if the Phase
10	II studies are what we would call negative in that they have
11	not shown anti-tumor activity in a particular disease to
12	warrant further development, exclusivity would be granted on
13	this attempt to provide further information.

14		We would hope the latter or the third portion is
15	the most common one, and that is if results are promising
16	but not sufficient to support approval a commitment to
17	further development would be made.  As stated here, in all
18	three cases granting of exclusivity extension can be made.
19	It is important.  We are interested in good quality data.

20	The granting of exclusivity on "negative" data whether it be
21	a negative Phase I study with prohibitive toxicity or with
22	negative clinical results does not mean that we are

23	accepting poor quality data, studies that are poorly
24	conducted.  We are interested in working with the

25	cooperative groups to guarantee the best scientific
			72
 1	integrity of the studies, and we will be looking quite
 2	closely at how these studies are performed in our review
 3	process.
 4		[Slide]
 5		The results of the completion of a pediatric
 6	development plan are listed here.  The results are
 7	summarized in a study report and submitted to the FDA where
 8	a determination based on meeting the proposal is finalized.
 9	Upon review, if the conditions of the initial written
10	request are met, regardless of outcome, a 6-month
11	exclusivity extension may be granted.  We are looking for
12	well designed, well executed studies where negative results
13	can qualify as long as these studies are well designed and
14	well executed.  Our intent is a prospective plan to produce
15	and to really introduce new information of importance to the
16	pediatric oncology community.
17		In the year I have been here, although as I have
18	stated before I am not a pediatrician, because of Dianne's
19	influence and because of Steve's influence, it has been on
20	our radar screen to make pediatric oncology an important

21	element at the FDA.  Not only have we written this plan up
22	in a guidance, which is on our web site and I would

23	encourage all of you that are interested to view that
24	guidance, but also we have taken an active recruitment
25	posture as far as recruiting two additional pediatric

		73
 1	oncologists to our review staff.  We have 20 medical
 2	oncologists, three of which are pediatric oncologists,
 3	really to underscore our commitment to the pediatric
 4	oncology community in developing drugs.
 5	          There is only a certain amount that the FDA can

 6	do.  We do not make legislation.  We can simply implement
 7	what has been done, and this is an attempt basically to
 8	introduce new agents into the existing structure.  To
 9	reiterate once more, we believe that the relationship
10	between the investigators, between the cooperative groups
11	and the NCI is an important one.  We are here as a
12	facilitator, working with the regulations that we have at
13	hand -- again, we do not make laws; we interpret them and

14	execute them.  But, this is an attempt to funnel new agents,
15	to funnel drugs that have not been properly studied to the
16	people who we think can study them, can give us the answers
17	that will lead to important information.
18	          Although I am presenting it, this work has been
19	done by many people.  Dianne has been actively involved with
20	it.  Steve Hirschfield has been actively involved with it,
21	as well as the entire pediatric team that Dianne oversees.
22	So, I am open for questions but really I would like to
23	deflect the entire questions not only to myself but Dianne
24	and Steve also since they have been active participants in
25	this program.  Thank  you.
		74
 1	          DR. CHESNEY:  Thank you very much, Dr. Pazdur.
 2	That was extremely clear and helpful, I believe, to all of

 3	us.  I am wondering, Dr. Weiner, would you like to respond
 4	first to Dr. Murphy's request or wait?  Okay.  Yes,
 5	questions for Dr. Pazdur?  Dr. Finklestein has the first
 6	one.
 7		DR. FINKLESTEIN:  I would like to make a comment,
 8	a comment that I also made at the February meeting and have
 9	made subsequently.  I am probably the senior pediatric
10	oncologist in this room, and for most of my career the FDA
11	was "we" and "they."  But, in February I concluded that it
12	is "we" and "we," and since then I have absolutely watched
13	what has happened at the FDA and I am convinced that it is
14	"we" and "we."  The tone that I hope we will adopt for the
15	rest of the meeting today will accept the fact that we
16	really are all on the same side of the fence.
17		Now, since the February meeting, in the spring,
18	with Greg Reaman, who is sitting right opposite me, who has
19	the same hairdo so you can recognize him --
20		[Laughter]

21		-- co-chaired a meeting, and in that meeting was a
22	group that came from the FDA, the NCI, PhARMA, the
23	cooperative groups and the public, and the pediatric
24	oncologists.  All the participating parties were in the same
25	room, with one goal in mind, that is, to advance the therapy
			75
 1	for children with cancer.  So, I am convinced that the FDA

 2	will not direct, but I am convinced that the FDA will work
 3	with us in advancing the care of children with cancer.
 4	Research is the standard of care.
 5		Now, my colleagues in pediatric oncology I know
 6	will absolutely agree with the next statement, we spend a
 7	lot of time in the multi-disciplinary approach to children
 8	with cancer.  This was alluded to by Malcolm.  So, consent
 9	forms are important to us.  All of us as psychologists,

10	social workers, psychiatrists, people who spend time with

11	our children, with the siblings, with the families, we
12	recognize that when a child is diagnosed with cancer we
13	change the family's life forever.
14	          So, I look at what we are doing today as just
15	another tool in working with this community which I

16	mentioned, which Greg co-chaired, to advance therapy with
17	cancer.  I don't think one aspect is going to direct the
18	other.  I think we will all work together.  So, I don't

19	consider FDAMA a threat.  I look forward to finding out, as
20	Rich Pazdur pointed out, how we can use the rule, the
21	exclusivity, the interpretation to help children with
22	cancer, and if you can't do it completely in the FDA, and I
23	don't think you can, we will do it through the NCI; we will
24	do it through the cooperative groups; we will do it through
25	the public.  I think working together we will get the job

		76
 1	done.  Thank you.
 2	          DR. CHESNEY:  Thank you very much.  Dr. Friedman?
 3	          DR. FRIEDMAN:  Richard, one question, for a drug

 4	that clearly is now in the Phase II or better stage for
 5	adults where a drug company has a clear indication that

 6	there is going to be a marketable agent that will produce
 7	financial gain, the plan you have outlined seems quite
 8	reasonable.  For a drug that is in very early stages of
 9	adult evaluation, Phase I potentially, where they are not

10	sure there will be any financial gain to the organization at
11	all, the real time where pediatric oncologists say, "gee,

12	we'd love to get this drug; it's in the lab, we'd like to
13	get access to it in the lab; we'd like to get access to it
14	in the clinic," there, where a company has less strong
15	conviction that the drug will ever produce financial gain
16	for them, I don't see that there is the same incentive for
17	them to expand to pediatrics with that and get an increase

18	in exclusivity which may never be of any meaning to them.
19	How do we deal with that issue?
20	          DR. PAZDUR:  I think that potentially is a problem
21	because, obviously, exclusivity has to be attached to a
22	patent, in a sense, or something that is in existence.  We
23	have been making efforts to basically promote this when we
24	meet with companies in all of our meetings, whether it be
25	end of Phase I meetings or IND meetings, to encourage them
		77
 1	to participate in this.
 2	          I would hope also that there may be some
 3	competition even within the cooperative groups -- not
 4	competition within the cooperative groups but if multiple
 5	agents are coming forth obviously there is a limited number
 6	of patients to be entered on these protocols, and perhaps
 7	this would provide an incentive for the companies to come to
 8	the pediatric groups earlier on in the course of the drug
 9	development process.
10	          DR. FRIEDMAN:  Let me follow it up with one more
11	question that may reflect my ignorance of the regulations,
12	but if you have a company with a reasonable portfolio of

13	agents that are out there that are being evaluated, some of
14	which are clearly being sold and yet there are clearly, in
15	the developmental side of that organization, drugs that we
16	are interested in accessing to pediatric oncology, why
17	cannot we use a carrot that says we will give you
18	exclusivity for one of your agents because we clearly see
19	the profit that will come to you from that but, in return,
20	we want to access for the pediatric oncology community

21	compounds A, B and C which may or may not ever make the
22	financial gain for your organization?  Why does it have to
23	be linked to the single drug we want in pediatrics?  Why not
24	give them a financial carrot, and the bigger the drug the
25	more one can ask from that organization?
			78
 1		DR. PAZDUR:  Well, we don't make laws.  That is
 2	one of the problems.
 3		DR. MURPHY:  Actually, just to address that
 4	question first, that was discussed.  There have been various
 5	mechanisms that have been discussed, and that is called the
 6	"wild card" exclusivity which a company would be able to
 7	apply to any of their products.  I can tell you that it has
 8	been discussed.  I can tell you that in looking at the
 9	economic impact of what we are doing already, it is very

10	costly, and that is without the wild card.  In other words,
11	the FDAMA activity, as it is right now and I can't say any
12	more than that, this is costing us, and it is one of the

13	things that will be discussed in the FDAMA assessment by
14	Congress -- how much is the cost to the taxpayer and to
15	society to develop these products for children?  I am a
16	pediatrician.  I think it is long overdue.  The Academy
17	thinks it is long overdue.  Many people who take care of

18	children think it is long overdue.  I just want to put forth
19	that we have been doing the math on this and this is an
20	expensive program and people are going to have to make a
21	cut.
22		So, I just want to say, first of all, that
23	alternative approaches have been discussed.  They are even
24	more expensive.  Now, that doesn't rule them out, and people
25	may look at that again in the re-authorization of the
			79
 1	legislation.  That may be looked at again.
 2		I know we have emphasized how often you can't
 3	extrapolate or where the diseases aren't the same, but where
 4	a product is in-house and the disease is the same and it is
 5	early on, you could use the rule if exclusivity were not
 6	going to be applicable for some reason.
 7		DR. CHESNEY:  I think Dr. Balis has a question.

 8		DR. BALIS:  In twenty years I have probably
 9	treated two patients with colon cancer and there are reports
10	of it occurring in kids.  So, if a company comes to the FDA
11	with an application for colon cancer you could theoretically
12	say that it should be studied in children since it occurs,
13	but that literally probably would take centuries to do.
14	What is the cut-off that you have in terms of incidence of
15	diseases to apply the rule?
16		DR. MURPHY:  We have two criteria for the rule.

17	One is a meaningful therapeutic benefit and the other is
18	substantial use.  You can qualify under either.  You do not
19	need both.  So, the substantial use is 50,000 population,
20	however, there are populations which do not meet that

21	substantial use but may meet the meaningful therapeutic
22	benefit.  In other words, it would provide a meaningful

23	therapeutic benefit to have the information that we need to
24	dose it and to know what the safety is for that population,
25	and then the rule would allow us to require those studies.
			80
 1		DR. HIRSCHFIELD:  We haven't come to that
 2	situation, and if we ever get a block-buster drug in colon
 3	cancer, of which there really none right now, then we
 4	potentially could face that.  We have looked at ball park
 5	ideas of several hundred cases which would sort of be a
 6	threshold.
 7		I would just like to reiterate something that
 8	Jerry Finklestein said to answer Henry Friedman's question,
 9	and that is the working together approach because we are
10	very excited about having colleagues who are pediatric
11	oncologists and industry, and many of them took time out of
12	their schedules to be here today with us in the audience,

13	and we think by having advocates in the companies, as well
14	as inquiries from the NCI, as well as inquiries from the

15	cooperative groups and the investigators, as well as
16	inquiries from the parents and the patient advocacy groups,
17	as well as receiving letters of invitation from us to
18	participate that we hope that that combination would be
19	sufficiently persuasive that these new drugs could be made
20	available.
21	          DR. PAZDUR:  The other point I want to mention is
22	I think we have to have some integrity and credibility here
23	in the application of these rules.  To try to extrapolate
24	and say that colorectal carcinoma or breast cancer or lung

25	cancer is a pediatric disease I think would produce a lot of
		81
 1	problems with our sponsors.  Okay?  And, although we might
 2	like to exert a heavy hand, there are situations that I
 3	think for the sake of continued really good faith effort in
 4	promoting this, we should look at this in a very objective
 5	fashion.
 6	          DR. CHESNEY:  Dr. Reynolds, did you have a
 7	question?
 8	          DR. REYNOLDS:  Yes, thank you.  Within the
 9	Children's Cancer Group, strategy group for neuroblastoma as
10	well as the new approaches to neuroblastoma therapy

11	consortium, as well as we think probably within the
12	Children's Oncology Group as this is formed, we have a
13	stated commitment to do development of agents based upon

14	good preclinical data, and we have relied for the most part
15	upon large numbers of cell lines available in vitro to
16	determine activity for most agents, and that has served us
17	well.  One of the frustrating components of this has been in
18	getting access to new agents as they are being developed

19	within the pharmaceutical companies, and I know there is
20	discussion of using this sort of preclinical modeling to
21	develop priority schemes within the Children's Oncology

22	Group beyond just neuroblastoma that would address some of

23	the questions such as Susan has addressed, and that is, what
24	is driving what we are going to do within the testing here.
25	Is it the need to test an agent for exclusivity or is it the
			82
 1	science?  And, since there are limited numbers of patients,
 2	good preclinical models are extremely important in
 3	developing the prioritization of doing Phase I studies.
 4		You mentioned facilitation with the FDA.  Can the
 5	FDA facilitate getting these agents early on into the
 6	laboratories of investigators studying pediatric cancer so

 7	we might see if they have some promise and warrant further
 8	testing in children rather than just adults?
 9		DR. HIRSCHFIELD:  A good point, an interesting
10	strategy.  Our grip is essentially when something is made
11	available for clinical use, and for the most part that is

12	where our responsibilities and our mission lie.  In terms of
13	making agents available for laboratory studies, we don't
14	have any regulatory authority.
15		DR. REYNOLDS:  Have you had problems obtaining

16	these agents?  Because my experience in the academic world
17	has usually been that companies have given the agents out
18	for preclinical studies.  We, for example, have wanted to
19	study any farnesyl transferase inhibitor in neuroblastoma
20	and I don't know of anyone who has been able to do such in
21	vitro, certainly not in my laboratory.
22		DR. PAZDUR:  Here, again, I would like to
23	reiterate that the decision of what drug should be studied
24	by a specific cooperative group is not an FDA decision.

25	Obviously, it is that group's decision and it should be made
			83
 1	on your scientific assessment, whether it be on preclinical
 2	assessments or on perceived clinical potential of the drug.
 3		DR. REYNOLDS:  True, but we are not getting access
 4	to these, nor is industry even returning phone calls or

 5	letters requesting access to these agents.  So, if there
 6	could be some facilitation through the cooperative group and
 7	the NCI by FDA for getting agents in for preclinical testing
 8	I think we would all benefit, including the companies.
 9		DR. PAZDUR:  We heard that, and we will make it a
10	point in our discussion with the companies when we meet with
11	them on preclinical matters.
12		DR. CHESNEY:  Dr. Spielberg?
13		DR. SPIELBERG:  I think we are all struggling with
14	a lot of issues here.  On the other hand, I think a
15	perspective that Dr. Finklestein put forth is absolutely
16	unique.  Probably in no other area of pediatric therapeutics
17	right now do we have the opportunity to make such changes as
18	we do here.  The presentations this morning had better

19	science than almost any other therapeutic area that this
20	group has dealt with but even more important is what Dr.
21	Finklestein emphasized.  We have here representatives from
22	the best pediatric clinical organization for doing
23	investigation anywhere in any therapeutic area.  There

24	really is a network.  Other groups talk about networks;
25	there really is a network.
			84
 1		Even more important, we have the cognate of COG if
 2	you will within industry of pediatric oncologists now within
 3	the industry who have been trained mostly from the same
 4	kinds of programs.  The issues of early access apply really
 5	throughout all therapeutic areas, but often there are no
 6	advocates within industry within whom the pediatricians who
 7	are taking care of the patients can actually interact.  Our
 8	best hope, I believe, for those early interactions and for

 9	solving the issues of exclusivity and coming up with other
10	novel ideas is the fact that we have real advocates within
11	the industry, coming from the same programs, dealing with

12	the same patients, trained under the same circumstances, who
13	recognize these issues.
14		Having spent 25 years on the other side in
15	pediatric clinical pharmacology, I had the same frustrations
16	in all sorts of different therapeutic areas of calling a

17	company blindly and ending up with no one to talk to, and
18	being turned down repeatedly.  The whole issue of early
19	access, of working out these programs, of trying to get
20	advocacy within companies is having, if you will, plants
21	within companies, and we have the unique opportunity here
22	because we have a large number of pediatric oncologists

23	within companies who can act as advocates, and many of whom
24	are here today and are active participants in that process.
25	In no other therapeutic area do we really have that same
			85
 1	kind of opportunity.
 2		So, the issues of early access is in knowing whom
 3	to call.  You know, it is the old ghost-buster story.  The

 4	issue here is that we have ghost busters now lined up in
 5	multiple different companies.  Is it always going to work?
 6	Of course not.  If it works with a couple of compounds that
 7	the COG needs to get into early evaluation and preclinical

 8	models, that is where it is going to happen.  It is going to
 9	come from personal contacts and interpersonal contacts.

10		If we need advocacy to solve the kinds of things
11	that Dr. Murphy was talking about, either modifications of
12	FDAMA or wild card approach because of the nature of things
13	-- for example, we are already doing very well with all of
14	the ancillary drugs that are used in oncology that keep

15	children alive, the antibiotics, the things that relieve
16	pain, the things that relieve nausea -- those all work

17	pretty well under FDAMA right now.  There may be a way of
18	saying, okay, if you are working on compounds that are  used
19	in oncology, somehow or another working out some mechanism

20	as those compounds get more benefit because you are also
21	working on a compound which is a very orphan drug that you

22	are introducing to actually attack the tumor -- there may be
23	creative ways of doing this, but the way that we are going
24	to do it is exactly what Dr. Finklestein described at the
25	beginning, the fact that there is incredible good will
		86
 1	within the agency right now, as well as pediatric
 2	oncologists within the agency, pediatric oncologists in
 3	industry and pediatric oncologists out there actually doing
 4	the studies and treating the kids.
 5	          So, I think while, indeed, the cup is still half

 6	empty and we have a long way to go, I feel it is more than
 7	half full because we have all these people here today, and

 8	all these people are listening and they are listening to Dr.
 9	Weiner's concerns; they are listening to the concerns of the
10	oncologists.  It is not going to be simple, but the bottom
11	line is if it is important and it needs to be done, it will
12	be done in the context of all these people working together.
13	          DR. CHESNEY:  Thank  you, Dr. Spielberg.  Dr.
14	Nelson?
15	          DR. NELSON:  In listening to this, I guess in the
16	form of a comment I am going to ask a question about FDAMA
17	and see if there is an angle on this early access that might
18	be viable.  My understanding of FDAMA is a company needs to
19	respond to a written request.  The written request is shaped
20	by the notion of what might be in the interests of pediatric
21	patients and in the public health.  It strikes me that
22	cooperation at the level of the formation of the written
23	request from the standpoint of preclinical modeling of what
24	drugs ought to be in the pipeline, and the like, that at the
25	written request level one could focus those to compounds
		87
 1	that the oncology community truly wants to use.  So, it

 2	would then be driven by science and by the priorities of COG
 3	within the formation of the written request.
 4		A couple of concerns though, since the motivation
 5	to use the rule instead of FDAMA is at potentially sunsets,
 6	unless it gets approved which is where I think some of the
 7	warnings about expense come in and the political process, if
 8	a written request is issued before it sun sets but, yet,
 9	there hasn't been a response I don't know what the situation
10	would be in terms of allowing that exclusivity to still
11	exist.  I am also not clear about the impact of the
12	exclusion of biologicals and how that is defined in terms of
13	some of the new agents that are trying to do antibody-
14	mediated sort of attacks at receptors and that sort of
15	thing, and whether that is a loophole in the application of
16	FDAMA.
17		DR. MURPHY:  Let me try to address first the
18	preclinical part.  FDAMA is very clear on that issue.  We
19	have to ask for clinical studies and they actually routinely
20	are pharmacokinetic studies.  Even though they are done in
21	human beings, they are not considered in that category but
22	for FDAMA they are because of the recognition that for
23	pediatric development dose-finding, extrapolation, all those
24	issues are relevant.  So, FDAMA requires us to ask for
25	clinical studies.
			88
 1		However, when we issue a written request, and we
 2	have done this, where we think there is critical
 3	information, preclinical information that needs to be
 4	developed, we have included it in the written request as an
 5	informative process that we will be looking for this, but it
 6	cannot be an element of meeting the terms of the written
 7	request.  Does that make any sense?
 8		DR. NELSON:  It makes sense, but I guess somehow
 9	you need to decide who to write that letter to and about
10	what if part of the process of cooperation is at that level,
11	not at the level of asking the company to do the clinical
12	studies but at the level of deciding which compound to focus
13	a written request to -- if that is where the cooperation
14	takes place.
15	          DR. MURPHY:  Right, that is what we are trying to
16	construct with this approach, that we work with the
17	cooperative groups in issuing written requests that are
18	targeting those priority products because of all the issues
19	that you have heard brought forth today.  That is a real
20	concern to us.  You know, we really want to maintain -- we
21	think our goal is a public health goal here and to maintain
22	that public health goal we need to have a cooperative
23	approach to developing the products for which we would issue
24	written requests, and that is what this structure is
25	supposed to assist in doing.
		89
 1	          DR. NELSON:  Right.  I guess just one brief
 2	question, in facilitating getting certain compounds into the
 3	preclinical testing -- I mean, I would think if you were a

 4	company with a certain compound, if you heard rumors that
 5	there was an interest in developing a written request on
 6	that compound and that a certain physician wants to do

 7	preclinical modeling, I think it would be in your best
 8	interest to send that compound to that person.  So, doesn't
 9	that begin to make some of these connections in the pre-
10	written request phase that are being asked for?
11	          DR. MURPHY:  Yes, it appears to make good sense.
12	One would hope it would work that way.  What we are trying
13	to say is that we have certain constraints within which we
14	have to work.  We wish to develop the science and have them
15	putting in these -- I won't use the word requests but the
16	recognition of certain preclinical areas that we think are

17	important and, again, doing that in this context, the
18	oncology context with the process that you have heard
19	outlined today.

20		The question you had about sunset, I try never to
21	answer this question because I am always saying something
22	incorrect legally, but my understanding is that if we have

23	issued a written request for a product that is on the market
24	prior to the sunset, they can bring in the studies after the
25	sunset and it would still be able to gain that exclusivity.
			90
 1		Now, I have been very open about this, that I am
 2	hoping Congress will not have this exclusivity sunset
 3	because I think it is the engine that is driving product
 4	development for children and also the science in many areas.
 5		DR. CHESNEY:  Dr. Boyett, do you have a question?
 6		DR. BOYETT:  Yes, I have a question for Richard.
 7	Throughout your presentation you alluded to the need to have
 8	well designed studies, and I think most of us agree that our
 9	clinical trials should be based on sound statistical science
10	with a design that specifically addresses the study
11	objective.  If your study comes from the cooperative groups,
12	I don't have real concern because I know the design at a

13	very high standard will address the study objective.  I
14	don't know how the FDA can provide assurance that these
15	studies will be well designed if they don't come through

16	such a mechanism because, as I understand it, the FDA is not
17	authorized to critique a study design.
18		DR. HIRSCHFIELD:  Yes, I will address that.  We
19	critique study designs all the time --
20		[Laughter]
21		-- the question maybe is do people listen to us?
22		[Laughter]
23		But when a study comes in, there are some
24	circumstances where we review the study design in detail.
25	For a new IND, study designs are reviewed in detail.  When
		91
 1	someone submits a study design which they say is for a
 2	pivotal study for registration, we review that in detail.
 3	There are a number of other protocols that fall in between
 4	where we do not typically send out our comments.  We look at
 5	them but, unless we are requested, we don't send out
 6	comments.
 7	          In terms of the pediatric written requests and
 8	pediatric studies in general, we look at the studies in
 9	great detail, and when we say great detail it means at least
10	-- at least two physicians reviewing the protocol plus at
11	least two statisticians reviewing the protocol and, if need
12	be, we also have biopharmaceutical consultation and toxicity
13	consultation.
14	          DR. BOYETT:  If I could just follow up, I would
15	hope that you would provide comments, especially for these
16	that are going to argue for exclusivity for their drug.  We
17	have had the experience in Memphis, just this past year, of
18	an investigator coming to us with a "FDA approved" trial for
19	our scientific review committee to approve, and the study
20	design was absolutely inadequate for addressing the study
21	question.
22	          DR. PAZDUR:  It is difficult to comment on a
23	specific example.  You know, we do not approve protocols; we
24	let them proceed, in a sense.  So, you know, this concept of
25	does the FDA approve a protocol -- no, technically they are
		92
 1	allowed to proceed and depending on what level of risk we
 2	are looking at, different protocols obviously undergo
 3	different levels of review.  Some are even exempt from FDA
 4	review if they are using commercially available drugs in

 5	safe doses, and recognized routes, without a commercial
 6	intent, or commercial intent on claim.  So, in a sense, it
 7	really depends on what the protocol is.
 8		I think in this situation where we are talking
 9	about pediatric oncology and the fact that these are being
10	done with a commercial intent by the sponsor in terms of
11	exclusivity, obtaining exclusivity, these would be looked at
12	quite closely.
13		DR. MURPHY:  Could I just say one more thing?  I
14	think that we are often accused of many dastardly deeds, but
15	one of the things in the process, as has been pointed out,
16	is that we allow a protocol to proceed, and we have a
17	mechanism called a "hold" mechanism.  We have very strict
18	guidance and regulations as to how we can put a protocol on
19	hold, and we have an entire activity surrounding a reporting
20	mechanism and when we put a protocol on hold.  I guess I can
21	say we could argue probably for a long time about how a
22	poorly designed protocol is a safety issue but, in general,
23	we cannot put a protocol on hold unless it is a safety issue
24	or clearly has to be put on hold for concerns that we can
25	articulate and can justify.  Having a design that we don't
			93
 1	agree with -- usually it is not within our power to put the
 2	protocol on hold unless it crosses a certain threshold.
 3	Basically, as I say, it is just totally clear that it will
 4	never be able to achieve the ends that it is intended to.
 5	One could argue that that is a safety issue but, in general,
 6	what I am trying to say is that the areas in which we can
 7	tell an investigator that they absolutely cannot proceed are
 8	limited compared to the number of protocols which are not
 9	designed the way we would like them to be designed, but may
10	still achieve the ends that researcher feels that they could
11	achieve.  So, there is a huge spectrum in there, as you can
12	imagine.
13		DR. PAZDUR:  Here, again, I think there is this

14	basic misconception, that is, we do not approve these
15	protocols.  This is not like NCIC that has a vested interest
16	in these protocols.  These are allowed basically to proceed
17	rather than a formal approval process.
18	          DR. SPIELBERG:  I would like to make one quick
19	comment though because I think it is important that people
20	understand the FDAMA process as opposed to most typical
21	protocols.  The written requests really provide industry a
22	great deal of specificity, down to the number of patients,
23	the endpoints to be evaluated, the duration of the trials,
24	in much greater specificity than is typical for the average
25	drug study where the sponsor says, "oh, I'd like to study X
		94
 1	indication," and then design a protocol which is then

 2	submitted to the agency for review.  In setting up the
 3	written request a great deal of specificity, including the
 4	indication, the precise number of patients, the precise
 5	nature of the study -- because at the end of the day,
 6	provision of exclusivity is dependent on the agency
 7	reviewing step by step the written request against the
 8	material.
 9	          So, in fact, the agency really has a great deal

10	more control over the nature of the studies done under FDAMA
11	than under typical studies, and one would certainly hope

12	that in areas where there is difficulty designing studies
13	the input comes from the subspecialists, etc. to make sure
14	that that negotiation which goes on with the FDA results in
15	a protocol that truly is going to get the information the
16	kids need and I think that process has worked extremely

17	well.
18	          DR. PAZDUR:  One of the other features, we meet
19	with sponsors on a continuous basis, going over these
20	protocols and for important protocols such as this that we

21	are looking for implementation in this program, we would
22	probably meet with the sponsors and go over them.
23		DR. MURPHY:  I guess one of the confusions here is
24	that maybe we are talking about two different activities
25	when we talk about the hold issue and we talk about the
			95
 1	general procedure.  What Steve is addressing is the written
 2	request process which is very different.  The process for
 3	drug development for children under FDAMA is very different
 4	than the routine process because FDA does have tremendous
 5	amount of authority in what they ask for in their written
 6	requests, and that is why it is very important that we have
 7	expert input and cooperative effort.
 8		I would also like to say that for any serious or
 9	life-threatening disease we will meet with the sponsors
10	early on in the development of the product.  Again, this is
11	not FDAMA; this is just in general but particularly when you
12	look at the Pediatric Rule.  There are many aspects of this
13	and it clearly tells us for all pediatric drug development
14	that we will meet with the sponsors and talk about their
15	pediatric plan for serious and life-threatening diseases at
16	the end of Phase I, and for other non-serious or life-
17	threatening diseases at the end of Phase II.  That is in our
18	regulations.
19		So, we are meeting with our sponsors.  But, again,
20	it comes back to what I said the first time, it is advising
21	but what we would want them to do, what we will do, and
22	where we will come out in the end are sometimes not always
23	the same.  However, under the rule, again, we can require
24	studies and we would work with the sponsor in developing
25	what those studies are, but that is a different process than
			96
 1	the exclusivity process.
 2		DR. HIRSCHFIELD:  And, our written request
 3	template says that the trial designs should have the input
 4	of pediatric oncologists, and all the studies should be at
 5	facilities which are specialized in the treatment of
 6	children with cancer.  So, that is a condition generically
 7	of the written request.
 8		DR. CHESNEY:  We don't have anybody scheduled for
 9	the open public hearing, and we have three people who have
10	been patiently waiting to ask their questions here, and we
11	want to give Dr. Weiner a chance also.  So, my thinking is
12	that we allow these three people to ask their questions, and
13	any comments from Dr. Weiner, and plan our break at 10:45.
14	Dr. Friedman?
15		DR. FRIEDMAN:  I think it was covered.
16		DR. CHESNEY:  Dr. Gorman?
17		DR. GORMAN:  I would like to make a comment and

18	then ask a question of Dr. Spielberg.  As an outsider, it
19	seems to me that both the Oncology Group and the Food and
20	Drug Administration have worked very hard to try to fine-

21	tune FDAMA and the Pediatric Rule to move children's studies
22	further on.  But one of the things I have learned sitting on
23	this committee is that the FDA is restricted because it
24	doesn't make laws; it only interprets laws that are
25	presently on the books.
			97
 1		There is also the question about early clinical
 2	access for people to drugs that are in development by
 3	pharmaceutical companies, and I would like to posit to you,
 4	before I ask the question of Dr. Spielberg, that you are
 5	still intervening in the process way too late, and this is

 6	not under the aegis of the Food and Drug Administration but
 7	may be something that the group that sits across the table
 8	from me would strive for.
 9		It strikes me the chemical moieties need to be
10	studied for pediatric cancers rather than being studied

11	strictly for adult cancers and then being adopted for
12	pediatric cancers, and my question to Dr. Spielberg is in
13	the development of new oncologic agents, are there panels in
14	the early testing of clinical moieties before clinical
15	trials are even considered, specifically designed for the

16	biology that we know about pediatric cancers?  Because this
17	is one of the few areas where we have enough biological
18	information to do early tests on those types of agents?
19	          DR. SPIELBERG:  I am really not the person to ask
20	in terms of the biology.  I think the generic question

21	though is in the screening processes that normally go on
22	within companies or, for that matter, at NCI, do we have
23	enough validated models preclinically that will suggest a

24	pediatric applicability of a given compound early enough so
25	that that compound -- for example, there may be a situation
		98
 1	where it doesn't work in any of the adult preclinical models
 2	but might give hits in the pediatric model.  You know, take
 3	the tumor type that is atypical for pediatrics and is there
 4	a unique pediatric disease?  The real question is how
 5	predictive are the models, and are they currently being
 6	included in the general screens, and I have to defer that to
 7	the oncologists.
 8	          DR. GORMAN:  I would like to just follow that up

 9	because I realize that is a very specific question to ask
10	somebody with very general knowledge, but there are three
11	programs, as far as I understand it, that now allow -- or
12	that our government has tried to make available to children
13	drugs.  One is the Pediatric Rule, the second is FDAMA and
14	the third is the orphan drug program.  All three were,
15	hopefully, designed to test or promote the development of

16	pharmaceutical agents in small populations, and one of those
17	should be tinkered with, in whatever legal way things get
18	tinkered with, to allow for us to reach back because in this
19	particular area there is enough biological -- I realize
20	there is a long way from testing chemical moieties until
21	they become clinical agents, but there needs to be a
22	reaching back far enough downstream that you are not left in
23	the position of using drugs that show promise for big
24	diseases and then have the development of agents
25	specifically for the biological of your diseases.
			99
 1		DR. SPIELBERG:  I would point out comfortably as
 2	well that FDAMA can be applied to orphan drugs so that if
 3	you do have an orphan -- if you have any kind of
 4	exclusivity, including orphan drug exclusivity, you can get
 5	an additional six months.
 6		DR. CHESNEY:  Dr. Smith, were you going to
 7	respond?
 8		DR. SMITH:  I was just going to echo Dr.
 9	Spielberg's comment that there is a real question about what
10	the validity of the preclinical screens are, both in the

11	adult models where they are applied by drug companies but
12	how effective they are, and in pediatric cancers as well.
13		We, at the NCI, do recognize this is a priority
14	area and researchers in the Children's Oncology Group
15	recognize this is a priority area, and we are working
16	together to try to development a pilot program that would
17	facilitate the screening of new agents, and to do it in a
18	rapid way so that the information is actually useful in

19	considering the prioritization of agents.  But, we have to
20	do this recognizing that the systems for the preclinical

21	screens as of this time aren't validated as to whether they
22	really are predictive, and what shows as promising in a
23	preclinical screen isn't truly validated as being an agent
24	that is going to work for a particular type of cancer.
25		DR. GORMAN:  Being relatively a newcomer to this,

			100
 1	with only 12 years of interest in this particular area, it
 2	strikes me that these same screens do predict for the
 3	pharmaceutical companies a pathway on which to go down,
 4	which agents show initial promise, and then more from there
 5	forward.  And, in the restructuring of these laws, perhaps a
 6	financial incentive for the companies that is meaningful
 7	would allow that process to develop much more rapidly.
 8		DR. SMITH:  And, we think as well that the use of
 9	NCI funds for researchers to study new molecular targets and
10	new agents is an appropriate avenue to pursue as well.
11		DR. CHESNEY:  Dr. Fink?
12		DR. FINK:  My comments were essentially the same
13	as Dr. Gorman's, and I think if NCI is already doing it,

14	obviously getting these preclinical screens into the hands
15	of the pharmaceutical industry is one of the answers to the
16	availability question, and it clearly falls outside, I
17	think, the Pediatric Rule of FDAMA because these are really
18	orphan diseases and the Pediatric Rule isn't going to apply
19	to most of them in terms of numbers.
20		DR. CHESNEY:  One more question, and then Dr.
21	Weiner and then our break.
22		DR. COHN:  Yes, I was just wondering in terms of
23	the Pediatric Rule, if someone could just clarify, if you

24	have a class of drugs that is not necessarily tumor specific
25	but pathway specific, for example, the anti-antigenic agents
			101
 1	which potentially could be used for adult cancer and
 2	pediatric cancer alike, does the Pediatric Rule apply to
 3	that classification of drugs?
 4		DR. HIRSCHFIELD:  Dr. Cohn, stay tuned for this

 5	afternoon.  That is going to be their topic of discussion.
 6		DR. CHESNEY:  Thank you, Dr. Hirschfield.  Dr.
 7	Weiner, any concluding comments?  Questions?

 8	          DR. WEINER:  Yes, just two comments to response to
 9	what Dr. Murphy had asked and also just by way of summary
10	from our perspective, and this is a remark that I made

11	actually in the meeting in February that Dr. Finklestein
12	referred to which is that from our perspective time is

13	really the issue.  In implementing FDAMA and the Rule, time
14	is really the question.  How long does it actually take to
15	Phase I and Phase II trials in kids, and what is the meaning
16	of that in terms of "incentivizing" the pharmaceutical
17	companies to do this in pediatrics?  Will it be worth it?
18	From our perspective, anything that really impedes the
19	progress and the efficiency of the systems involved in
20	evaluating agents and getting new information that is going
21	to be useful for treatment or kids is a bad idea.  That is
22	all we have got.
23	          The second point I really wanted to address had to
24	do with flexibility.  I think, you know, the conversation
25	today has yielded a lot of interesting suggestions about how
		102
 1	greater flexibility might be brought to bear with respect to
 2	FDAMA and with respect to the implementation of the
 3	Pediatric Rule, both formal in terms of the redesign of
 4	FDAMA specific provisions for cancer perhaps and, in
 5	addition, an informal mechanism such as that which was
 6	suggested by Dr. Spielberg and by others, picking up on the
 7	notion that, yes, there are informal contacts in industry

 8	and personal contacts that, hopefully, will be of benefit
 9	but there are also opportunities to bring FDA to the table,
10	as happened in February, so that we can come up with more
11	creative solutions to getting new agents, evaluating new

12	agents, as well as understanding agents that are already
13	approved and already in use in treatment for kids so that we
14	can have sufficient information about those as well.

15		DR. CHESNEY:  Thank you for your very thoughtful
16	comments, and I understand there is Valium outside for our
17	FDA colleagues who I think have stood up extremely well to
18	the challenges presented this morning.
19		I would like to reiterate what Dr. Finklestein
20	said, that I really believe this is a "we/we" situation and
21	not a "we/they" and, please, be back by 10:55 and we will
22	attempt to address the question that the FDA specifically
23	gave us.  Thank you.
24		[Brief recess]
25		          Open Public Hearing

			103
 1		DR. CHESNEY:  We are past the time for the open
 2	public hearing and nobody has signed up but if there is
 3	anybody here today that would like to make a comment at the
 4	microphone, this would be a good time to do so.  Yes?
 5		DR. REAMAN:  I would just like to make a comment

 6	because, as Dr. Finklestein referred to earlier, I was at
 7	this meeting in February where there was a great deal of

 8	discussion, and certainly the end result of that meeting was
 9	that this is a "we/we" situation and we are working together
10	very collaboratively.
11		Subsequent to that, in review of the guidance that
12	was put forth from the FDA there were some concerns as
13	related to flexibility to some of the interpretation, but I
14	must say from my perspective now, being responsible for
15	developmental therapeutics and sharing that responsibility
16	in the Children's Oncology Group, I see absolutely nothing
17	about the guidance which would limit the early access to new
18	agents for children with cancer, and I would really applaud
19	the FDA in everything that they have done to interpret and
20	to remove any obstacles from the Pediatric Rule and FDAMA in
21	ensuring this.  Thank you.
22		DR. CHESNEY:  Thank you, Dr. Reaman.  Any other

23	comments?  If not, we need then to go on to the question to
24	the committee, and I wondered if Dr. Hirschfield, Dr. Pazdur
25	or Dr. Murphy would like to read it or interpret it for us,
			104
 1	or do we take it as written?
 2		DR. HIRSCHFIELD:  I think you could take it as
 3	written.  I could just read it out loud for those who may
 4	not have a copy of the question:  Special characteristics of
 5	pediatric oncology necessitated a more general drug
 6	development plan to qualify for the FDAMA pediatric
 7	exclusivity incentive.  These characteristics are rarity of
 8	the diseases, life-threatening natural history of the
 9	diseases, biological differences between adult and pediatric
10	tumors, the existence of established cooperative groups, and
11	research protocols as the standard of care.  Are there other
12	areas of pediatrics that have similar characteristics that
13	may benefit from a similar approach?
14		               Discussion
15		DR. CHESNEY:  Thank you.  Comments from the
16	committee?  Yes?
17		DR. PRZEPIORKA:  The information that we have been
18	given so far yesterday and today indicates that extension of
19	exclusivity is for drugs and biologics, and I was wondering
20	if this is also true for devices, such as catheters or
21	transdermal delivery systems, or diagnostics for pediatric
22	diseases.
23		DR. MURPHY:  The rule includes biologics.  Now, if
24	you look at the list that we did publish under the FDAMA
25	requirement, it did include some biologics because we did
			105
 1	not look at whether something had a patent or exclusivity,
 2	and because biologics normally don't have patents -- that is
 3	why exclusivity is not usually including those.  So, I am
 4	just trying to recognize that there is a little bit of

 5	confusion about the fact that we did have some biologics on
 6	that list.  We were trying to look at products that we
 7	thought would have a public health benefit potentially if
 8	they were labeled so they were on the list.  But, again, as
 9	Dr. Pazdur said, you have to have something to attach it to
10	for exclusivity to work.  So, that is a problem in that most
11	biologics are not approved where they have that patent
12	mechanism.  So.  Devices -- no.  It does not apply to that
13	either.
14		DR. CHESNEY:  Other conditions which might qualify
15	as pediatric oncology has?  Dr. Fink?
16		DR. FINK:  Well, the two groups that I deal with,
17	cystic fibrosis, although there is a strong national
18	organization there, and the other would be the neuromuscular
19	disorders and, again, there is a strong voluntary health

20	agency that has somewhat taken leadership in those two
21	diseases, but they are similar in that they are life-

22	threatening; they are orphan diseases; and there are care
23	networks through the CF centers and the NMDA centers.
24		DR. CHESNEY:  Dr. Luban?
25		DR. LUBAN:  I would like to add to that group
			106
 1	sickle cell disease.  Now, while it might not be life-

 2	threatening it certainly is quite morbid and there is,
 3	through the sickle cell centers sponsored by NHLBI, a
 4	growing clinical trials network.

 5		DR. CHESNEY:  Maybe I could add one group.  I
 6	don't think we have any pediatric nephrologists in the room,
 7	but having lived with one for 30-plus years --
 8		[Laughter]
 9		-- who has devoted his career to trying to bring
10	rare pediatric diseases to the attention of Congress, and

11	their needs, I would just like to say that there are many
12	renal diseases that also fall into the same category as Dr.
13	Fink just mentioned.  They are relatively rare.  They have
14	very strong support groups, and I can't elaborate on them
15	but maybe somebody else in the room can but there is a very
16	elaborate nephrotic syndrome network of investigators that
17	would be similar to some of the pediatric oncology groups.
18	Yes, Dr. Luban?
19		DR. LUBAN:  Perhaps Dr. Hudak or Ward could

20	comment on the use of the neonatal networks for some
21	clinical trials, particularly in prematures.
22		DR. HUDAK:  Sure, the neonatal network is an NIH
23	sponsored group of study centers for which there is
24	competitive application by sites.  It is headed up under NIH
25	CD.  I think it has been in existence now for 15 years, and
			107
 1	the network I think is a good example of how cooperation
 2	between NIH and academic centers can produce some meaningful
 3	and important results, and it also illustrates, frankly,
 4	some of the perils of doing large, multi-center trials where
 5	there is a significant lag phase in terms of an idea gets
 6	developed and when it gets implemented, and what happens in
 7	the interim in the clinical centers.  But, this has led to
 8	some important information and clarification of therapies in
 9	neonatology, and that is a little bit different model than
10	the orphan type diseases because we are never at a dearth of
11	neonates, and it does target some of the important
12	morbidities that we see in premature babies.
13		DR. WARD:  I think the other area that is actively
14	involved in multicenter trials is that of the pediatric
15	pharmacology research units.  Dr. Kauffman wanted to comment
16	about it, but that has allowed also multicenter trials to

17	proceed in areas of very important aspects of pediatric
18	therapeutics, and to proceed fairly efficiently.
19		DR. CHESNEY:  Yes, Dr. Balis?

20		DR. BALIS:  The other disease I want to raise is
21	neurofibromatosis, which is a disease that shares a lot in
22	common with cancer and which many of the new agents that we
23	are developing that are molecularly targeted may have

24	application, but at this point there really is no other
25	standard therapy, other than surgery.
			108
 1		DR. CHESNEY:  Several other categories that have
 2	occurred to me are the immune deficiency diseases; chronic
 3	granulomatous disease, very small numbers of patients,
 4	inevitably fatal, and I don't know about their support group
 5	but certainly SCIDs and some of the other better defined
 6	genetic immunodeficiency diseases have very elaborate

 7	support groups and networks.  Then, the whole area of
 8	genetic and metabolic diseases, again, cystinosis falls in
 9	that category but probably other people here can think of
10	many more of those.  Dr. Danford?
11		DR. DANFORD:  I wish I could say that pediatric
12	cardiology and heart disease had things in common with the
13	research protocols and networks available in oncology but,
14	unfortunately, I can't.  There are scattered examples of
15	multicenter trials but, by no stretch of the imagination,

16	can we say the standard of care equals Phase III trials even
17	in cardiology conditions that are treated with medicines
18	rather than surgeries.
19		The one place where we could say that there might
20	be that kind of a situation would be in devices, and there
21	the interventional cardiologists do have a well-developed
22	nationwide network.  Unfortunately, we just heard that FDAMA
23	and the Pediatric Rule don't apply in those situations.
24		DR. CHESNEY:  Dr. Luban?
25		DR. LUBAN:  I would like to propose not a group
			109
 1	but, rather, a disease phenomenon that crosses groups, that

 2	is very, very common and requires a potential application of
 3	the rule, and that is in thrombosis, childhood thrombosis --
 4	very, very common; unfortunately, poorly treated.  At this
 5	point, no organized clinical trials, although there have
 6	been some moves through the hemophilia treatment centers to
 7	incorporate thrombosis trials in those groups.  And, with
 8	the advent of all of the new low molecular weight heparins,
 9	it is potentially an important avenue to explore.
10		DR. CHESNEY:  Dr. Fink, I wonder if you could

11	elaborate or tell us a little bit more about the cystic
12	fibrosis situation, which I thought was very analogous to
13	the oncology example.
14		DR. FINK:  Well, there are 125 centers that are
15	partially funded by the National CF Foundation that

16	participate in collaborative Phase I, Phase II and Phase III
17	trials, and recently the National Foundation has even gone a
18	step further and developed eight therapeutic development

19	network centers that take care of the Phase I and Phase II
20	trials and to use the entire network for the Phase III

21	trials, so that there is even a gradation, and centering
22	Phase I and Phase II trials in larger academic centers that
23	have a large population and heavy research support has led
24	to more efficient production of Phase I and Phase II trials,
25	and then the Phase III trials obviously, because of patient
			110
 1	needs, are spread to the wider network.  That has been a
 2	combined effort that really has both federal and private
 3	funding.
 4		DR. CHESNEY:  Dr. Luban, could you tell us more
 5	about the sickle cell networks?
 6		DR. LUBAN:  The National Hearth, Blood and Lung
 7	Institute has for years funded sickle cell centers which are
 8	a combination of both basic science as well as clinical
 9	research.  For many years the clinical research was very
10	single-institution directed, and it has just been within the
11	last three or four years that there has been more of an

12	attempt to bring those centers together and have them do
13	cooperative clinical investigations and the initiation now
14	of hydroxyurea trials.
15		My understanding from the Branch is that they

16	would like to do more and more clinical trials and, of
17	course, the infrastructure is all paid for already by NIH,
18	with nurse practitioners, data monitors, in a similar way
19	although clearly in a much lower scaled way than the cancer
20	cooperative groups.  Certainly, also from a biological

21	perspective, lots of animal models, SCID mouse particularly,
22	as well as pharmacologic manipulation so that as drugs can
23	be developed, and are being developed, there should be a
24	mechanism to do some translational clinical trials.
25		DR. CHESNEY:  Yes, Dr. O'Fallon?
			111
 1		DR. O'FALLON:  I believe there is an AIDS
 2	cooperative group for children.
 3		DR. CHESNEY:  Very active network of AIDS clinical
 4	treatment units, of which we have one at St. Jude, very
 5	actively involved in sharing data and comparing notes.  Yes,
 6	Dr. Fink?
 7		DR. FINK:  Yes, one of the things that occurred to
 8	me yesterday when we were talking about psychoactive drugs
 9	is that almost all of the diseases and groups we are talking
10	about share the issues of how do you cope at a family level
11	with chronic disease?  How do you administer chronic
12	medications, and what do you do with the adolescent with a
13	chronic disease?  And, yet, none of the groups probably have
14	the psychiatric expertise or maybe the number of patients to
15	take on that issue, and there clearly is a need across

16	pediatrics to try and understand family and individual

17	coping and growing up with a chronic medical disability.
18		DR. CHESNEY:  Thank you.  I think we heard about
19	autism yesterday which also very much falls into this

20	category of relatively rare disease with a bad need for new
21	drugs, new approaches.  Dr. Ward?
22		DR. WARD:  I would like to just provide something
23	of an overview.  I think we have just heard of multiple
24	areas in pediatric medicine and pediatric problems that need
25	additional therapeutic research.  I think FDAMA can work,
			112
 1	and is working in many of these.  And, from the February
 2	meeting, the FDA proposed mechanism by which trials at Phase
 3	I and Phase II level could qualify for exclusivity -- we
 4	heard it in its application to oncology drugs, but there are
 5	probably many other areas of therapeutics, from cystic
 6	fibrosis to cystinosis to other inborn errors of metabolism,
 7	that may benefit from that process.
 8		When it comes time for renewal, I have concerns
 9	about trying to create carve-outs for specific clinical

10	areas, especially if we have a process that can serve all
11	areas of pediatrics effectively, because if one area is
12	carved out and identified as unique many other areas will

13	feel they are also unique, and the potential effect could be
14	an unwinding of congressional support for renewal.  And, I
15	think we have to be very cautious in how we proceed over the
16	next 18 months as this comes up for a great deal of debate
17	and discussion.
18		DR. CHESNEY:  Thank you.  Any other comments?
19	Suggestions for other diseases which the FDA has asked for?
20	I guess, not having been at the February meeting but having
21	worked with our pediatric subcommittee for sometime, I would
22	also like to emphasize what Dr. Ward just said so
23	articulately.  I think many of us in the room have disabled
24	children or children with a limited life span, including
25	myself, and I think we would all like a carve-out, if you
		113
 1	will, but I think that it is important that we try in every
 2	possible way to support FDAMA, and I am very impressed at
 3	what the Oncology Group has done at the FDA -- Dr. Pazdur's
 4	presentation today -- to work with FDAMA, and I just would
 5	like to reiterate what Dr. Ward said, that we should all try
 6	at every level to support what has been a historic
 7	contribution to pediatric care.
 8	          DR. MURPHY:  I guess I want to second or third
 9	that because I think when you go to Congress you never know
10	what you are going to come out with at the end, folks.  So,
11	we have something that is working.  We are working on ways
12	to make it work better where we have identified problems.

13	If you tinker with it too much, you don't know that you are
14	going to get it at all, first of all, secondly, you don't
15	know what you are going to end up with.
16	          It is like a new child having certain infirmities
17	and we want to trade it in for another child, I would say
18	let us work with this child and support developing this

19	child, if you will, because it truly is a program in its
20	infancy.  Think about what the potential would be for moving
21	all these various fields forward, if we could ever get to

22	the point where  we actually had products that are already
23	out there that aren't labeled and get them studied, plus
24	then move these developmental fields forward in all these

25	areas of science -- we have an opportunity here, and I would
		114
 1	caution some restraint as we go forward and, instead of
 2	trying to fix every single problem use the tools we have
 3	been given and work with them and work to have FDAMA renewed
 4	very much in the format that it is -- not that FDA doesn't
 5	have its problems either with it, but we really believe that

 6	we are just now discovering how to work with this
 7	opportunity in the most positive way.  Thank you.
 8		DR. CHESNEY:  Dr. Spielberg:
 9		DR. SPIELBERG:  I would fourth that.  With the

10	perspective of having been in pediatric pharmacology for 25
11	years, this really is historic.  I think most of us who have
12	been in the field for a long period of time never would have
13	imagined that we would be in the position where we are today
14	where a lot of the past issues are no longer issues; where
15	drugs are being actively studied; where large numbers of
16	compounds which had been orphan for many, many years are now
17	being actively studied.
18		The renewal of the legislation really is crucial I
19	think not only to the issue of getting drugs studied, but
20	really also has tremendous impact on the overall activities
21	within pediatric departments around the country.  It has
22	stimulated a great deal of translational research.
23		If I can be critical of departments of pediatrics
24	because I was in them for many years, even when I was junior
25	faculty I was told there were two things you could do,
			115
 1	molecular biological or patient care, and that was it, and
 2	molecular biological was too difficult for clinicians and,
 3	after all, the molecular biologists didn't understand
 4	anything about patients so they should stay away.
 5		What this has done is revitalize the whole issue
 6	of translational research.  The old model which I was taught
 7	in the '60s in medical school of bench to bedside really
 8	does have validity, of getting science to the patients who
 9	need it, and this initiative has really reawakened that in a
10	remarkable way.  It is truly critical for renewal not only
11	for pharmacologic interventions but really for clinical
12	investigation in pediatrics in general.
13		And, there are certain things that have been done

14	around the sites independent of the FDAMA effort, and I
15	think that is another lesson that we can take.  If there are
16	specific issues, we can go outside the legislation to try to
17	fix certain things.  One example is that we have been
18	working on legislation to increase the number of pediatric
19	pharmacology trainees, you know, Ralph and I -- Bob is the
20	only one who doesn't share our hairdo -- but we all are
21	getting old and we recognize that so many years have gone by
22	without pediatric departments focusing on the need for
23	translational research that the next generation of
24	translational researchers isn't there.
25	          But that legislation, including some clever things
		116
 1	that Sen. Dodd's and DeWine's office came up with of debt
 2	forgiveness of those who go into pediatric investigation and
 3	stay in that field, along with additional support for the
 4	PPRU network to actually support the training slots that are
 5	needed, is really one aspect of things that we can work on
 6	independent of FDAMA, but even that initiative is truly

 7	dependent on FDAMA renewal otherwise we are going to be
 8	training people who won't have jobs in the long run. One of
 9	the neatest things about trying to train young people is
10	that they will have jobs, otherwise why spend all those
11	years?  And, FDAMA provides routes for pediatricians to be
12	involved in government, to be at FDA, to be at NIH.  It
13	provides routes for them to go into industry because
14	industry will be working on pediatric projects, and it will
15	obviously provide routes for their careers in academia so
16	that the studies can be carried out.
17	          So, you know, if you look at that piece of

18	legislation for trainees and then you look at FDAMA you say,
19	"aha, the two work together and they really do complement

20	each other."  Similarly, I think as time goes by, I think
21	Dianne is right, I mean we have had -- what? -- a year and a
22	half experience with this, barely two; ten drugs getting
23	labeled in the previous ten years for kids and eleven drugs
24	getting labeled in the last year.  I mean, that is a ten-
25	fold increase in the rate of activity.  And, obviously, from
		117
 1	all the compounds that are now being studied, all those
 2	things will lead into labels.  We have made mistakes and we
 3	have realized knowledge gaps.  Those knowledge gaps then can
 4	be turned into support for NIH funds to study those disease
 5	processes so that we can get outcome variables that we can
 6	study so that we can, in fact, get drugs properly labeled
 7	for kids.  It all kind of beings to work together.  But
 8	critical to the whole effort really is getting FDAMA renewed
 9	and keeping the process going.
10	          DR. CHESNEY:  If I could just make one more
11	comment, my husband, for those of you who don't know, is the
12	chairman of our department but if I had a dollar for every
13	time he has come back from a meeting at the NIH or Congress
14	and said, "I can't stand these internists; they forget that
15	children aren't just little adults and that we absolutely
16	need to focus on pediatric issues."  And, I think there have
17	been many positive outcomes of his work and many others, the
18	PPRUs is just an incredible idea.  Maybe, Ralph, you can
19	tell me sometime whose idea it was, but these centers that
20	are just devoted to studying drugs in children are just
21	revolutionary.  And, I think in so many ways FDAMA
22	represents this major new movement in support of children
23	that I would just add again to Dr. Spielberg's always
24	articulate comments that it is really critical that we try
25	to work within the system or we will be back where we were
		118
 1	when internists ran the show -- apologies to any internists
 2	in the room!  Any other comments?  Ralph?
 3		DR. KAUFFMAN:  I would just add briefly to Steve's
 4	comments, and that is we need to understand that renewal of
 5	FDAMA is not automatic.  There is very powerful opposition
 6	out there that will be doing everything possible to try to
 7	see that FDAMA is not renewed, and will be lobbying whoever
 8	is in Congress next session very aggressively to try to keep
 9	this legislation from being renewed.  So, it isn't going to
10	be automatic, and all of us are going to have to engage in a
11	concerted effort, those who have the welfare of children at
12	heart, to make sure that this gets done because it certainly
13	is not a sure thing.
14		DR. CHESNEY:  Thank you.  Dr. Ettinger?
15		MS. ETTINGER:  I just feel, from the unique
16	perspective of being at the bedside as a nurse, I can
17	reiterate what Susan had said.  It is really important that
18	we put concrete measures from bench to bedside because it is
19	our parents and it is the families who actually drive this
20	including parent support groups in all of these, they are

21	the ones who actually bring it forth and I think it is most
22	important that we continue that.
23		DR. CHESNEY:  Dr. Murphy, the last word.
24		DR. MURPHY:  I just want to thank you for your

25	thoughts and the fact that, as we move forward in each of
			119
 1	these areas, we will be bringing different issues to this
 2	committee, again usually supplemented with the
 3	subspecialists, as you saw yesterday with neuropharm., and
 4	actually they have been one of the more active participants
 5	in this last year and a half in trying to help us to develop
 6	priority setting in how we move forward in this area.  And,
 7	we will, as always, listen to what you have said as far as

 8	some of the areas that we may need to look at in our future
 9	written requests as we try to move the science and the

10	information that is available.  Because -- it a very good

11	point to end -- what are we trying to do?  People say why is
12	the label so important?  Because that is FDA's way of
13	providing the science and the information.  Now, we are
14	hoping to develop other mechanisms and being able to
15	transmit the information to the public in other ways besides
16	just the label, but for right now the label is our main say
17	of communicating to both the professional and, through some
18	of our package inserts and med. guides, to the patients and
19	the families.  And, that is the goal.  The goal is that you
20	will have the right information, meaning you will know how
21	you are dosing the child.  The mother and father have the

22	expectation that when their child receives that medicine it
23	will have been studied and we will know that it will work,
24	and we will know how to advise them as to how the adverse
25	effects are.  So, we are expanding this spectrum of the

		120
 1	preclinical all the way to not just the bedside in the
 2	hospital but the bedside at home in the middle of the night
 3	when you should be able to expect something as simple and

 4	common as your anti-pruritic to have the right dose.  So,
 5	thank you all very much.
 6	          DR. CHESNEY:  I want to thank all of our speakers
 7	today.  I want to thank Dr. Smith, Dr. Weiner, Dr. Pazdur,
 8	everybody who made contributions and comments this morning.
 9	I think this has been a very, very informative session for
10	those of us who are not oncologists.
11	          This meeting will reconvene at one o'clock.
12	Yesterday lunch was in the Plaza Cafe and there was room

13	reserved for the FDA; we are not sure if that is true today.
14	I think our executive secretary has an announcement.
15	          DR. TEMPLETON-SOMERS:  I just want to clarify this
16	afternoon's meeting because I think there might be some

17	confusion.  The pediatric subcommittee of oncology will
18	convene at one o'clock in the Chesapeake Suites to talk
19	about the extrapolation issue, and the pediatric
20	subcommittee of the anti-infective drugs stays in this room
21	and you will be meeting also at one o'clock.

22		DR. CHESNEY:  Thank you very much.
23		[Whereupon, at 11:34 a.m., the proceedings were
24	recessed]