1 DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
PEDIATRIC SUBCOMMITTEE
OF THE ANTI-INFECTIVE DRUGS ADVISORY COMMITTEE
			Monday, September 11, 2000

						8:00 a.m.
	Hyatt Regency Bethesda One Bethesda Metro Center 
Bethesda, Maryland

			2
PARTICIPANTS
P. Joan Chesney, M.D., Chairperson
Jayne E. Peterson, R.Ph., J.D., Executive Secretary
MEMBERS
	Judith O'Fallon, Ph.D.
	Keith Rodvold, Pharm.D. (Consumer Representative)
SGE CONSULTANTS
	David Danford, M.D. 

Robert Fink, M.D.
Norman C. Fost, M.D., M.P.H. 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

Jeffrey R. Botkin, M.D., M.P.H. (a.m.) Professor Francis Crawley (a.m.)
Susan Ellenberg, Ph.D. Ralph Kauffman M.D. 
Richard Malone, M.D. (p.m. session) Mark Riddle, M.D.
Neal Ryan, M.D. (p.m. session) Steven Spielberg, M.D., Ph.D. Robert Ward, M.D., FAAP, FCP 
Charles Weijer, M.D., Ph.D. (a.m. session) Benjamin Wilfond, M.D.
Peter Wolff, M.D. (a.m. session)
Dr. Barbara van Zwieten-Boot (a.m. session) Benedetto Vitiello, M.D. (p.m. session)
FDA 
	Russell Katz, M.D. (p.m. session)

Tom Laughren, M.D. (p.m. session) Dianne Murphy, M.D.
Rosemary Roberts, M.D. William J. Rodriguez, M.D. Robert Temple, M.D.

							3
C O N T E N T S
		Page No. MORNING SESSION - ETHICAL ISSUES 
Call to Order/Introductions: P. Joan Chesney, M.D.			 5
Conflict of Interest Statement: 
	Jayne E. Peterson, R.Ph. J.D.			 8
Welcome and Review of Meeting Agenda/Background

Information and Overview: Dianne Murphy, M.D.			10
Part 1: The Ethics of Placebo-Controlled Trials
in Children
Open Public Hearing				19
Overview of Placebo-Controlled Trial Design:
Benefits and Difficulties:  
	Robert Temple, M.D.			20
International Perspective on Pediatric
Placebo-Controlled Trials:
	Dr. Barbara van Zwieten-Boot			46
Questions from the Subcommittee			63
Ethical Concerns in Pediatric Placebo-Controlled
Trials:
	Charles Weijer, M.D., Ph.D.			72
Ethical Concerns in Pediatric Placebo-Controlled
Trials from the European Experience:
	Prof. Francis Crawley			90
Questions from the Subcommittee		100
Use of Data and Safety Monitoring Boards and
their Role in Pediatric Clinical Trials:		112
	Susan Ellenberg, Ph.D.
Questions from the Subcommittee		129
Subcommittee Discussion of Case Studies/
Introductory Remarks
	Dianne Murphy, M.D.		133
Example A: Pediatric Placebo-Controlled Add-On
Clinical Trial Design: Presentation of Example:
	Debra Birenbaum, M.D.		135
Example B: Pediatric Placebo-Controlled Trial
Design When There is No Approved Therapy
	Rosemary Roberts, M.D.		168

			4 C O N T E N T S (Continued)
					Page No. Example C: Pediatric Placebo-Controlled Clinical

Trial Design Including a Withdrawal Phase When There is Only One or Limited Effective Therapy 
Steven Hirschfield, M.D., Ph.D.		195
AFTERNOON SESSION - PEDIATRIC PSYCHOTROPIC
DRUG USE ISSUES 
	Part 2: A Proposed Approach to the Development 

of Psychotropic Drug Therapies for Pediatrics
Introduction
			Dianne Murphy, M.D.		225
Conflict of Interest Statement: 
			Jayne E. Peterson, R.Ph. J.D.		229
Open Public Hearing		232
Current Regulatory Issues in Pediatric
Psychopharmacology:
			Thomas Laughren, M.D.		232
Pediatric Psychopharmacology: A Clinical
Perspective:
			Richard Malone, M.D.		245
Pediatric Psychopharmacology: A Research
Perspective:
			Mark Riddle, M.D.		252
NIMH Perspective on Pediatric
Psychopharmacology:
			Benedetto Vitiello, M.D.		262
Subcommittee Discussion of Questions/Issues		288  

			5 1		         P R O C E E D I N G S
	2		    MORNING SESSION - ETHICAL ISSUES
	3		      Call to Order/Introductions
	4		DR. CHESNEY:  Good morning and welcome to what we
	5	look forward to be a very, very interesting two days for
	6	very different subjects.
	7		Just a couple of housekeeping issues.  The first

	8	one is when you turn on the microphone by pushing the green
	9	button, if you could please give your name before you ask
10	your question or make your comment, which makes it easy for
11	the person who is transcribing the information.
12		I would like to start by having everybody
13	introduce themselves and maybe we could start down at this
14	end with Dr. Rodriguez.
15		DR. RODRIGUEZ:  I am Bill Rodriguez.  I am
16	currently a pediatric science/director adviser at the CDER,
17	and hopefully trying to work in the pediatric initiatives.
18		DR. MURPHY:  I am Dianne Murphy.  I am the
19	Associate Director for Pediatrics at the Center for Drugs.
20		DR. ROBERTS:  Rosemary Roberts.  I am a member of
21	the pediatrics team.
22		DR. GELLER:  Barbara Geller.  I am a Professor of
23	Psychiatry at Washington University in St. Louis.
24		DR. LUBAN:  Naomi Luban.  I am a pediatric

25	hematologist/oncologist.  I have a primary interest in

				6 1	transfusion medicine, and I am Professor of Pathology and
	2	Pediatrics at George Washington practicing out of Children's
	3	Hospital.
	4		DR. SANTANA:  I am Victor Santana.  I am a
	5	pediatric oncologist from St. Jude's Children's Research
	6	Hospital in Memphis, Tennessee.
	7		DR. FOST:  Norm Fost, pediatrician, Director of
	8	the Medical Ethics Program and chair the IRB at the
	9	University of Wisconsin in Madison.
10		DR. RODVOLD:  Keith Rodvold, Professor of Pharmacy
11	Practice, Colleges of Pharmacy and Medicine, University of
12	Illinois at Chicago.
13		DR. HUDAK:  I am Mark Hudak.  I am a neonatologist
14	and Professor of Pediatrics, University of Florida at
15	Jacksonville.
16		DR. NELSON:  Robert Nelson, I am a pediatric
17	critical care physician at Children's Hospital,
18	Philadelphia, and I am the Director of their Research
19	Regulatory Affairs Office.
20		DR. CHESNEY:  Joan Chesney.  I am Professor of

21	Pediatrics at the University of Tennessee in Memphis, and
22	also in Academic Affairs at St. Jude.
23		MS. PETERSON:  I am Jayne Peterson.  I am the
24	Executive Secretary of the Pediatric Subcommittee for FDA.
25		DR. FINK:  Bob Fink, Professor of Pediatrics and

			7 1	Pediatric Pulmonology of Children's National Medical Center
	2	in Washington, D.C.
	3		DR. FUCHS:  Susan Fuchs, Associate Professor of
	4	Pediatrics, Associate Director of Pediatric Emergency
	5	Medicine at Children's Memorial Hospital in Chicago,
	6	Illinois.
	7		DR. GORMAN:  Richard Gorman, Clinical Professor of
	8	Pediatrics at the University of Maryland and in private
	9	practice in Maryland.
10		DR. DANFORD:  I am Dave Danford.  I am a pediatric
11	cardiologist at University of Nebraska Medical Center and
12	Creighton University in Omaha.
13		DR. O'FALLON:  Judith O'Fallon, Professor of
14	Biostatistics at the Mayo Clinic, group statistician for the
15	North Central Cancer Treatment Group.
16		DR. WOLFF:  Peter Wolff, Chair of The Children's
17	Hospital, the one in Boston, of the IRB.
18		DR. WILFOND:  Ben Wilfond.  I am a pediatric
19	pulmonologist at the National Human Genome Research
20	Institute, where I am also the Associate Chair of the IRB,
21	and also a member of the Bioethics Department.
22		DR. WARD:  I am Bob Ward, Professor of Pediatrics,
23	University of Utah, and a neonatologist, and I chair the
24	Committee on Drugs for the Academy of Pediatrics.
25		DR. SPIELBERG:  Steven Spielberg.  I am head of

			8 1	Pediatric Drug Development at Johnson & Johnson representing
	2	PhRMA.
	3		DR. KAUFFMAN:  Ralph Kauffman.  I am Professor of
	4	Pediatrics and Pharmacology at the University of Missouri at
	5	Kansas City, and Director of Medical Research at the
	6	Children's Hospital in Kansas City.
	7		DR. BOTKIN:  I am Jeff Botkin, Professor of
	8	Pediatrics and Medical Ethics at the University of Utah.
	9		DR. CHESNEY:  Thank you very much.
10		I would like to introduce Dianne Murphy who
11	everybody knows already, Associate Director of Pediatrics
12	for the Center for Drug Evaluation and Research.
13		I am sorry.  Jayne has to give the Conflict of
14	Interest Statement.  My apologies.
15		     Conflict of Interest Statement
16		MS. PETERSON:  The following announcement
17	addresses the issue of conflict of interest with regard to
18	this meeting and is made a part of the record to preclude
19	even the appearance of such at this meeting.  Based on the
20	submitted agenda for the meeting and all financial interests
21	reported by the subcommittee participants, it has been
22	determined that since the issues to be discussed by the
23	Subcommittee will not have a unique impact on any particular
24	firm or product but, rather, may have widespread
25	implications to all similar products, in accordance with 18

			9 1	USC 208B, general matters waivers have been granted to each
	2	special government employee participating in today's
	3	meeting.
	4		A copy of this waiver statement may be obtained by
	5	submitting a written request to the Agency's Freedom of
	6	Information Office, Room 12A30, of the Parklawn Building.
	7		With respect to FDA's invited guests and guest
	8	speakers, Dr. Ralph Kauffman, Dr. Steven Spielberg, and Dr.
	9	Robert Ward have reported interests which we believe should
10	be made public to allow the participants to objectively
11	evaluate their comments.
12		Dr. Kauffman would like to disclose that he has
13	grants with Bristol-Myers Squibb and is involved in research
14	for Bristol-Myers Squibb, Astra, Zeneca, Janssen, Merck,
15	R.W. Johnson, and Aventis, and is a scientific adviser for
16	Bristol-Myers Squibb, Johnson & Johnson, and for Purdue
17	Pharma.
18		Dr. Spielberg would like to disclose that he is an
19	employee of Johnson & Johnson.  Dr. Ward would like to

20	disclose that he owns stock in Ascent Pediatrics and
21	Viropharma.  He has grants with Wyeth-Ayerst, Novartis,
22	Ascent Pediatrics, Aventis Pharmaceuticals, and Sepracor,

23	and he receives consulting fees from Janssen Pharmaceutical
24	and is a scientific adviser for McNeil Consumer Products.
25		In the event that the discussions involve any

			10 1	other products or firms not already on the agenda, for which
	2	an FDA participant has a financial interest, the
	3	participants are aware of the need to exclude themselves
	4	from such involvement and their exclusion will be noted for
	5	the record.
	6		With respect to all other participants, we ask, in
	7	the interest of fairness, that they address any current or
	8	previous financial involvement with any firm whose products
	9	they may wish to comment upon.
10		Thank you.
11		DR. FOST:  Joan, I thought I had sent it in.  I am
12	a consultant to the PowderJect Vaccine Corporation.
13		MS. PETERSON:  Thank you.
14		DR. CHESNEY:  Any other additions?
15		[No response.]
16		DR. CHESNEY:  Dr. Dianne Murphy will give us our
17	mission for this first session.
18		 Welcome and Review of Meeting Agenda/

19		  Background Information and Overview
20		DR. MURPHY:  My tasks are three this morning,
21	first, to welcome you most sincerely.  We appreciate the

22	thoughtful comments that I know we will receive today, as we
23	did in November.
24		Secondly, is to go over how we hope the day will
25	progress, and, thirdly, is to provide an introduction to the

			11 1	ethical discussion that we will have this morning.
	2		[Slide.]
	3		During the morning and early afternoon, we will
	4	address the ethical issues attendant in the conduct of
	5	pediatric clinical trials, utilizing the placebo arm in the
	6	trial design.
	7		We are very fortunate to have, not only the
	8	majority of the ethicists who participated in last
	9	November's Advisory Committee meeting, which I will update
10	you on in a moment, but also to have additional expertise
11	with us today.
12		I would like to recognize Dr. Barbara van Zwieten-
13	Boot, who is the Efficacy Coordinator of the Medicines
14	Evaluation Board in the Netherlands and the Vice Chair of

15	the Efficacy Working Part of the Committee of Proprietary
16	Medicinal Products.
17		We would also like to recognize Dr. Charles

18	Weijer, who is a bioethicist and Assistant Professor of
19	Medicine at Dalhousie University, Halifax, Nova Scotia, and
20	Professor Francis Crawley, Chairman of the Ethics Working
21	Party, European Forum for Good Clinical Practice and a

22	member of the Ethics Working Group, Confederation of
23	European Specialists in Pediatrics.
24		We sincerely thank you for being here with us this
25	morning.

			12 1		I have already been asked if the examples that you
	2	have been sent are real cases, and the answer is yes.  As we
	3	did in November, we have tried to bring to you issues that

	4	the FDA is dealing with today, yesterday, and tomorrow, and
	5	we will speak a little bit more just before we go into the
	6	questions as to how we would like you to think about them.
	7		[Slide.]
	8		So, why are we here?  As of September, the FDA,
	9	under the Food and Drug Modernization Act, Section 111, has
10	been actively involved in issuing written requests for
11	products to be studied in children.
12		I wanted to provide you a quick overview as to

13	what that means.  That means that we have issued 157 written
14	requests that would involve 332 studies.  We anticipate
15	approximately 85 percent of these studies have or will be
16	conducted after discussing this with the various sponsors to
17	whom these written requests have been issued.
18		That means that at least 282 of these studies
19	should be conducted.  We know that of these studies that we
20	have asked for, 164 of those specify the number of children,
21	the remainder do not.  Of those 164, the minimum number of
22	children who would need to be enrolled in clinical trials to
23	complete these studies would be 20,000 children.
24		[Slide.]
25		So, that was really a variation upon the theme

			13 1	about why we were here in November.  I wanted to quickly

	2	bring the committee up to date as to the results of their
	3	discussion in November, so that we can use that as an
	4	introduction, if you will, to our process today.
	5		The question in November fundamentally was should
	6	children participate in clinical trials which will not
	7	provide a direct benefit to the child, or the other way it
	8	has been phrased is should normal volunteers participate in
	9	pediatric trials.
10		[Slide.]
11		This is, just so everyone will know, that we have
12	been busy since the last meeting.  The consensus statement
13	that was derived from the discussion, which I have three
14	slides on this, for a day-long discussion with wonderful
15	give and take, and controversy and thoughtfulness, and we
16	have managed to come down to what we think is a consensus
17	statement of what was said at that meeting, which is that,
18	in general, pediatric studies should be conducted in
19	subjects who may benefit from participation in the trial.
20		Usually, this implies the subject has or is
21	susceptible to the disease under study, and the Advisory
22	Committee utilized a broad definition of potential benefit,
23	for example, any child has the potential to benefit from a
24	treatment of otitis.

25		[Slide.]

			14 1		In general, children who can give assent should be
	2	enrolled in a study in preference to, or prior to, children
	3	who cannot give assent.  Careful consideration must be given
	4	to the importance of the potential benefit of the study.  In
	5	certain circumstances, the potential benefit that may be

	6	derived from studying children who cannot give assent may
	7	override the preference for enrolling assenting children
	8	first.
	9		[Slide.]
10		The third point which we felt was a pretty
11	universal consensus was that the FDA should adopt the
12	principles described in Subpart D, Additional Protections
13	for Children Involved as Subjects in Research.  The blue
14	part is where it is in the Federal Register.
15		This recommendation was also endorsed by the

16	American Academy of Pediatrics and PhRMA.  Note that the
17	Pediatric Ethics Working Group agreed that it is appropriate
18	for FDA to consider adoption of a similar statement, and a
19	committee has been established to address this issue.
20		[Slide.]
21		The group that is involved in this, just to give
22	you an idea of the breadth of the involvement at the agency,
23	involves somebody from Anti-Infectives where we always
24	classically, traditionally had a number of pediatric trials,
25	the Pediatric Team, the Office of the Chief Counsel, the

			15 1	Regulatory Policy Staff, individuals from Oncology Division,
	2	the Office of Regulatory Affairs, the Office of Science
	3	Coordination and Communication, somebody from our Devices
	4	Center and our Biologic Center, in addition to the Division
	5	of Special Investigations.
	6		[Slide.]
	7		At this point, this group is working to
	8	incorporate the principles of Health and Human Services'
	9	regulations into 45 CFR Part 46, Subpart D, and they are
10	diligently working to coordinate with HHS in the Office for
11	Human Research Protections to ensure a consistent
12	integration of standards at this point.
13		[Slide.]
14		Now, I thought of all the things I could say to
15	bring us to the issue of placebo-controlled trials.  I think
16	sometimes revisiting history and telling a story may be the
17	best way to bring us to our discussion this morning.
18		An example I am going to take is from a book by

19	Thomas Maeder on Adverse Reactions written in 1994.  The
20	first sentence in that book says, "The Study of
21	Chloramphenicol is the study of modern medicines."
22		When you read this book, the entire book is
23	basically about the story of chloramphenicol.  You could
24	list statements directly out of it, the majority of them,
25	and apply them to today.  Many things are very similar.

			16 1		This product was the wonder drug of its time with
	2	few side effects thought to be attendant to it.  As a matter
	3	of fact, that was one of its important characteristics.  It
	4	was one of the first oral broad-spectrum antibiotics, and
	5	was available to treat many diseases that did not have
	6	appropriate or a therapy as useful as far as administration
	7	- typhoid, typhus, and gram-negative and H. flu meningitis.
	8		At the time of its approval, the risk-benefit

	9	balance was very much on the side of the benefit of this
10	therapy.  After approval, it was associated with a rare but
11	fatal hemolytic adverse event, aplastic anemia.  Later, it
12	was shown to cause gray baby syndrome frequently resulting
13	in death in infants that were treated.
14		This was later shown to be due to the immaturity
15	of the liver and its inability to metabolize the drug, so
16	that blood levels reached basically toxic levels.  At the
17	time, this therapy, treatment of antibiotics including

18	chloramphenicol were a recommendation by the American
19	Academy of Pediatrics and other professional groups

20	including for the treatment of a premature infant who was
21	born after 24 hours of rupture of membranes because of the
22	high morbidity and mortality that was associated with that
23	group at that time.
24		[Slide.]
25		In an effort to try to define what was happening

			17 1	once cases began occurring, a trial was designed.  That
	2	trial was led by Dr. Hodgman and her colleagues at a
	3	university in the West, established a research protocol

	4	according to which, for one year, from March of 1958 to
	5	February of 1959, all premature infants delivered at the

	6	hospital 24 or more hours after rupture of membranes would
	7	be assigned to one of four experimental groups.  Remember,
	8	it was considered that this was a group at high risk for
	9	morbidity and mortality.

10		One group was to receive no antibiotics.  This was
11	not the standard of care.  The next group was to receive
12	intramuscular injections of chloramphenicol, the third group
13	was to receive procaine penicillin and streptomycin, and the
14	fourth group was to receive all three antibiotics.
15		The groups without chloramphenicol are Groups 1
16	and Groups 3.
17		[Slide.]
18		The experimental protocol was reviewed by the

19	hospital research committee.  The only objection at that
20	time was whether or not it was ethical to include a "not
21	treatment" group, which by prevailing standards would
22	subject the infants to increased risk.
23		[Slide.]

24		This is at the end of the study.  If you remember
25	now it is a year later, February 1959, 126 newborn infants

			18 1	were enrolled in the experiment, of which 52, or 41 percent,
	2	had died.  This was high.
	3		The death rates in Groups 1 and 3, those given
	4	either nothing or penicillin and streptomycin, were 19
	5	percent and 18 percent.  In the chloramphenicol group, 60
	6	percent died.  Among those given chloramphenicol and the
	7	other antibiotics, the death rate was 68 percent.
	8		[Slide.]
	9		Some people found the experiment ghostly."  This
10	is all quoted.  "Even in days when informed consent and
11	patients' rights were not issues they have become today, Dr.
12	Wideman of Alabama wrote that their study was one of the
13	most horrifying examples of professional misbehavior he had
14	ever encountered."

15		[Slide.]
16		"Dr. Hodgman 35 years later herself says that Dr.
17	Wideman is right.  We had a goal when we started; we were
18	going to study X number of babies.  But it was becoming
19	obvious that chloramphenicol wasn't good for these babies. 
20	We discussed stopping the study early, and the decision was
21	made that unless you have convincing evidence, nobody is
22	going to believe you."
23		This is one of the questions that we are going to
24	be asking you to address today, which is use of data and

25	safety monitoring boards or other mechanisms to ensure the

			19 1	safety of the children in these trials.
	2		[Slide.]
	3		In 1972, Dr. Hodgman was criticized by Senator

	4	Edward Kennedy for her human experimentation and compared
	5	her to the investigators in Tuskegee, Alabama, who had
	6	knowingly withheld treatment from 400 black men with
	7	syphilis.  At first, oddly enough, she was criticized for
	8	withholding needed drugs from the high-risk infants in the

	9	no treatment control arm, but after the Senator's staff got
10	the facts"--I am quoting--"she was criticized for
11	administering chloramphenicol to the two test groups."
12		I have gone through this because I do believe at
13	the end of the day that we will not have a consensus.  I

14	believe we are here for a discussion.
15		[Slide.]
16		Because I think it is still critical to realize
17	that unless you have convincing evidence, nobody is going to
18	believe you, how do we do that in a way that protects the
19	children who are enrolled in these trials?
20		Thank you.  I look forward to your discussion.
21	         Part 1:  The Ethics of Placebo-Controlled
22		      Clinical Trials in Children
23		          Open Public Hearing
24		DR. CHESNEY:  We don't have anybody who has
25	registered as wanting to comment, but this is time if there

			20 1	is anybody in the room who would like to make a comment
	2	concerning the issue of ethics of placebo-controlled

	3	clinical trials, please feel free to come up to the
	4	microphone.
	5		[No response.]
	6		DR. CHESNEY:  I guess we don't have anybody who
	7	does want to make a comment at this time, so we will go

	8	ahead and hear from Dr. Temple, who is Director of the
	9	Office of Medical Policy.  We were provided several articles
10	by Dr. Temple in our reading before this meeting, so we look
11	forward to hearing from him in person, an overview of
12	placebo-controlled trial design:  benefits and difficulties.
13	        Overview of Placebo-Controlled Trial Design:
14		       Benefits and Difficulties
15		[Slide.]
16		DR. TEMPLE:  I am going to talk today about the

17	use of placebos in clinical trials in general, that is,
18	issues not particularly related to pediatric studies and
19	what the problems are with alternative designs like active
20	controls, and then talk about some study design
21	modifications that are compatible with reaching a solid

22	conclusion, but that may make the trials more comfortable
23	when pediatric patients are involved or indeed when adults
24	are involved.
25		So, I will talk a little about the ethical issues

			21 1	in general, problems with active control non-inferiority
	2	studies, and some design modifications that may help.
	3		[Slide.]
	4		I just want to keep three different cases in mind
	5	regarding the use of placebos, one, where there is no
	6	available therapy at all, usually people don't object to a

	7	placebo control; when there is well-established effective
	8	therapy for the particular people involved in the study,

	9	that is when the problem arises, and that is the situation I
10	am going to discuss.
11		In adults at least, use of placebo or placebo with
12	an active control, that is, three-arm study, is generally
13	acceptable in symptomatic patients, but it is not acceptable
14	when denial or deferral of therapy leads to harm, like death
15	or irreversible morbidity.
16		Whether that same conclusion is equally applicable
17	to children where the consent process is different at least
18	needs to be discussed.  I am not going to discuss that, that
19	is for you, but it remains true for reasons I will explain,
20	that in many of these situations anyway, you still need a

21	placebo to have an informative study.
22		[Slide.]
23		But in that case, there may be study design
24	changes that will make the whole thing somewhat more
25	comfortable, but still lead to adequate data.

			22 1		Finally, a difficult problem and one that I won't
	2	address in detail is suppose there is well-established
	3	therapy in adults.  I mean we know antihypertensive therapy
	4	is good for adults, but not children, and the therapy is
	5	potentially life saving.
	6		When is it legitimate to test those outcomes in

	7	the new group in the face of the known adult benefit, that
	8	is, there may be very strong prior?  Again, I think that is
	9	a big problem, but I am not going to have that much to say
10	about it.
11		[Slide.]
12		The debate about placebo has hinged on the
13	following question:  When there is known effective therapy
14	for a condition, is it or when is it ethical to deny this
15	treatment to some patients in a clinical trial?
16		This question arises at least partly because of a
17	phrase in the Declaration of Helsinki, 1975 version, that
18	says in any medical study, every patient including those of
19	a control group, if there is one, should be assured of the
20	best proven diagnostic and therapeutic method.

21		Now, what exactly that meant has been considerably
22	debated, and you would have thought it should matter what
23	condition is being treated.
24		[Slide.]
25		Some people, notably Rothman and Michaels writing

			23 1	in about 1975 in The New England Journal contend that the

	2	Declaration has to be read literally and absolutely, and
	3	therefore, the condition being treated is irrelevant, and
	4	Dr. Rothman says this explicitly.
	5		So, he thinks there can't be placebo-controlled
	6	trials involved in this because we have a treatment in
	7	seasonal allergic rhinitis because there are lots of
	8	antihistamines, headache, because we have lots of drugs,
	9	insomnia, anxiety, outpatient depression, obsessive
10	compulsive disease.
11		Unfortunately, the phrasing in the Declaration

12	would bar any trial, even active comparisons, when there is
13	a known existing therapy because the people randomized to
14	the new drug aren't getting the best available therapy, so

15	it seems unlikely that they could have meant that literally.
16		What they said they meant when they added that

17	section is that they wanted physicians participating in
18	trials to be aware that there is a patient in there, and

19	that if they need therapy, they are supposed to get it.  It
20	is not clear that they meant that there shouldn't be any
21	more placebos, and they certainly didn't suggest that in any
22	of the commentary.

23		[Slide.]
24		A recently accepted ICH guideline called "E-10"
25	says essentially that patients can be asked to participate

			24 1	in placebo-controlled trials even if there is existing
	2	therapy when the risk of lack of treatment is only
	3	discomfort.
	4		Now, people will have their limits on how much
	5	discomfort feels good.  Patients in a trial obviously have
	6	to be free to leave it at any time without penalty, and the
	7	examples given in the document, it is actually beyond
	8	developing, it has now been accepted by all three regions in
	9	the ICH, generally, this applies to most psychiatric

10	conditions, such as outpatient depression, OCD, panic
11	disorder, anxiety, angina, and a large number of other
12	symptomatic conclusions where therapy is not known to
13	improve outcome.

14		[Slide.]
15		Just quickly, there are a lot of situations where
16	you can't use placebos, you can't deny people life-saving
17	therapy with thrombolytics, beta blockers, aspirin post-

18	infarction, ACE inhibitors in almost any situation involving
19	ventricular dysfunction, antibiotic prophylaxis in "dirty
20	surgery," and so on.

21		[Slide.]
22		Then, people get into arguments about whether
23	therapy is in fact morbidity preventing or life-saving. 
24	There is a current debate about the use of placebos in

25	trials in schizophrenia, whether you think a hypertension

			25 1	trial is okay probably depends on its duration.
	2		There has been criticism in placebo-controlled

	3	trials of the use of antiemetics in severely emetogenic
	4	cancer chemotherapy, probably because of fear that the
	5	therapy won't be delivered appropriately.

	6		You could argue about whether thrombolytics should
	7	be used after 12 hours.  There is clear evidence earlier,
	8	and whether aspirin is effective in primary prevention could
	9	be the subject of a long debate.
10		[Slide.]
11		The question is why are they needed.  It isn't
12	really placebos, it is really a trial that shows the
13	difference between treatments as opposed to a trial that
14	fails to show a difference or it's perfectly okay to beat an
15	active treatment, that's informative, or to show a dose
16	response, that's informative, too.
17		[Slide.]
18		The problems associated with trials designed to
19	show equivalence, that is, that the new therapy is not worse
20	than the previous therapy or not worse by some amount are

21	three.  One, there is a historical assumption, that is, of
22	assay sensitivity.  I will explain that further, but
23	basically, that is the assumption that the trial could have
24	distinguished effective from ineffective therapies.
25		Another problem is that there is some lack of

			26 1	incentive to doing a really good trial when the purpose of
	2	the trial is not to show a difference, and sometimes trials
	3	can get very large, but three is not the major problem
	4	usually.  It might be in the pediatric setting.
	5		[Slide.]
	6		These trials, the trials in which the goal was not
	7	to beat the control group, but to show that you weren't
	8	inferior to it, were once called equivalence trials.  They
	9	are now called non-inferiority trials because of increased
10	sophistication about these things.
11		The naive approach was you compare the new and the
12	control drug.  If there is no difference, you say, okay, the
13	new drug works.  The problem with that is that increase in
14	variance alone, such as making the study too small, will
15	create a success, so that is undesirable.
16		A more sophisticated design is the non-inferiority
17	design, which specifies as a null hypothesis the new drug is
18	inferior by some margin called M, and then test this
19	significantly.  If the 95 percent confidence interval for

20	the upper bound of the inferiority of the new trial is less
21	than M, that is, if it couldn't be more inferior than the
22	margin, then, the null hypothesis is rejected.

23		It should be noted that if the confidence interval
24	is very wide, if you made your study too small, the study
25	will not declare non-inferiority inappropriately, so that is

			27 1	good.  It solves the size variance problem, but it does not
	2	assure assay sensitivity.
	3		[Slide.]
	4		So, the fundamental question in either equivalence
	5	or non-inferiority trial is this:  Did the active control

	6	drug have an effect of the size expected in the trial that
	7	was carried out?  If it didn't, equivalence or non-
	8	inferiority, by the expected amount of that effect, is not
	9	meaningful.  The equivalent or non-inferior drug might have
10	no effect at all.

11		[Slide.]
12		Assay sensitivity is the ability of a specific
13	trial to show a difference of a specified size between

14	treatments, if there is one, and that can be affected by the
15	population you put into the trial.  Maybe these are non-

16	responders, for example.  By the quality of the study, for
17	example, if no one takes the drug or if the therapies are
18	mixed up, you are not likely to show a difference, and if
19	the study is too small, but that is solved by the non-
20	inferiority design.

21		[Slide.]
22		It is worth noting that in a trial intended to
23	show a difference between treatments, the assay sensitivity
24	problem takes care of itself, at least from a regulator's
25	point of view.  A successful trial did have assay

			28 1	sensitivity, a failed trial may or may not, but we don't
	2	approve the drug by mistake, so we are comfortable.  The
	3	therapy, of course, is not available, and that is a possible
	4	problem.
	5		Many sponsors now in the situations where assay
	6	sensitivity can't be assured include an active control as an
	7	internal standard.  Then, you can tell the difference
	8	between a failed study, that is, neither drug, control or
	9	the new drug, was superior to placebo and a failed drug. 
10	The control drug was superior, but the new drug was not.
11		[Slide.]
12		Remember, in the superiority trial that is
13	successful, you have assured yourself of assay sensitivity,
14	but in a non-inferiority trial, assay sensitivity is not
15	directly measured in the trial.  That is, the trial does not
16	itself show the study's ability to distinguish active from
17	inactive therapy, so you have to deduce the presence of
18	assay sensitivity, and you basically do that based on
19	historical experience showing something called sensitivity
20	to drug effects, which we define I think in a later slide as
21	historical evidence that, in general, good trials could
22	distinguish active from inactive drugs.
23		In addition to that, however, one has to look very
24	closely at the study quality and particularly, importantly,
25	you have to make sure that the current trial is very similar

			29 1	to the trials that did show assay sensitivity in the past, a
	2	problem because medicine marches on, and you may not be able
	3	to keep therapies the same.  Again, a three-arm trial is a
	4	really good thing.
	5		[Slide.]
	6		So, sensitivity to drug effect is a historically-
	7	based conclusion that properly designed trials with a
	8	specific active drug or perhaps a group of related drugs
	9	reliably show an effect of some defined size.
10		Generally, you look at all the placebo-controlled
11	trials that you know about and see that they were
12	successful.  Sensitivity to drug effects is an abstract
13	conclusion about a well-designed trial, assay sensitivity is
14	a conclusion about the specific trial.
15		[Slide.]
16		If well conducted and designed placebo-controlled
17	trials more than occasionally show no difference between the
18	active control and placebo, perhaps without some good
19	explanation, sensitivity to drug effects doesn't exist, and
20	one cannot conclude a new drug is effective from a non-
21	inferiority trial of similar design and conduct.
22		[Slide.]
23		Sensitivity to drug effects is, as I said, shown
24	by placebo-controlled trials, the situations in which it is
25	hard to show, that is, where trials regularly fail to beat

			30 1	placebo, are when the drug effects are small to variable and
	2	often when there is a substantial and variable improvement
	3	in the placebo group, that makes life difficult.
	4		[Slide.]
	5		Anyway, bottom line, if you can't be very sure
	6	that the positive control in the study would have beaten the
	7	placebo group had one been present, the fundamental
	8	assumption of the positive control or equivalence or non-
	9	inferiority study can't be made, and that design is not
10	usable.
11		[Slide.]
12		Just some examples of situations.  This is all

13	based on adult data, but it is equally true at least in
14	depression for children, current drugs lack sensitivity to
15	drug effect.  That is, good trials regularly don't show
16	anything, usually for reasons we don't understand.

17		That is true in depression.  It is true in
18	anxiety.  It is true in dementia.  It is true in symptomatic
19	congestive heart failure, perhaps surprising.  It is
20	definitely true in seasonal allergies.  GERD is notoriously
21	difficult to show anything on.
22		Most of the studies of post-infarction beta
23	blockade have failed to distinguish drug from placebo.  It
24	is possible that is a matter of size, but nowadays with
25	people getting aspirin and then all kinds of other stuff in

			31 1	addition, it is very unclear what the effect size would be. 
	2	Post-infarction aspirin is widely accepted as being useful,
	3	but as probably everybody knows, the largest trial of that
	4	intervention ever carried out in the United States failed to
	5	show anything, in fact, leans slightly the wrong way on
	6	survival.
	7		[Slide.]
	8		It isn't that the controls aren't effective.  We
	9	know antidepressants, antilytics, antihistamines, et cetera,
10	work.  They are better than placebo far more than the

11	predicted roughly 1 in 40.  It is just that you can't
12	exactly define conditions in which they will always work.
13		[Slide.]
14		Now, having established that there is sensitivity
15	to drug effects and that you would believe that a study

16	might be successful, you have to choose a non-inferiority
17	margin.  Remember, the whole point of a non-inferiority
18	trial is to declare that the new drug is no more than M
19	worse than the old drug, so that is the margin.

20		The margin can't possibly be any larger than the
21	smallest effect you are willing to presume the control drug
22	has in this study.  That is as big as it can be.  In fact,
23	if you then excluded that margin, you would be sure that the
24	new drug has any effect at all, that is, is better than
25	placebo.

			32 1		Usually, in active control trials, people want to
	2	know something more than that.  So, for example, in
	3	thrombolytic trials, the Center for Biologic Evaluation and
	4	Research concluded that at least 50 percent of the effect of
	5	the control thrombolytic ought to be preserved.  So, their
	6	margin was half of the effect size that they were pretty
	7	sure the control drug would have.  Anyway, that is plainly a
	8	clinical judgment.
	9		[Slide.]
10		As I said, the margin could be the entire effect
11	or it could be some smaller part.
12		[Slide.]
13		Just to illustrate how this is done, on this axis,
14	I am showing the difference between the control drug and the
15	test drug, so that going up means the control drug is
16	better.  You can't probably see them, but there are dotted
17	lines across M1, M2, and M0.  This slides needs more work,
18	but anyway, M1 here is the whole effect of the control drug
19	that you are quite sure from historical experience the
20	control drug would have.
21		M2 is half that, and M0 is supposed to go through
22	the zero line.  That means there is no difference between
23	the therapies.  If you weren't sure from historical
24	experience that the control drug reliably could be placebo,
25	you would have to use M0.  That means only superiority would

			33 1	be informative.
	2		Just a couple of examples.  In this case, and
	3	again this is the actual measured difference and this is the
	4	made-up confidence interval, in this case, the new drug is

	5	non-inferior to half of the 50 percent margin, so that is
	6	pretty good evidence that the new drug is effective.  It is
	7	definitely better than the M1.
	8		In case 2, the point estimate is a little bit
	9	higher, so that if the margin was the entire effect of the
10	control agent, it would be an effective agent, but if you
11	had to preserve at least 50 percent of the effect of the

12	control agent, this wouldn't.
13		The third case, the 95 percent confidence interval
14	is greater than the whole M1.  That means there is at least
15	some chance that this drug has no effect at all.
16		The fourth example shows superiority to the
17	control drug.
18		The fifth example shows the effect of the large

19	variance.  The point estimate actually favors the new drug,
20	but the confidence interval is outside of M1 because it's
21	too small a study.
22		[Slide.]
23		Anyway, you have heard this.  The assumption of
24	assay sensitivity is not necessarily true for all effective
25	drugs.  I am just going to illustrate with a couple of

			34 1	examples briefly.
	2		[Slide.]
	3		The first slide shows all six trials of a new
	4	antidepressant called nomefencine.  We were still hiding its
	5	name at the time this slide was made.  These are all three-
	6	arm studies.  They have the nomefencine, imipramine, and
	7	placebo, but I am not showing you placebo yet.
	8		You can see that some of the trials are fairly
	9	small.  These are the sample sizes here.  These are sort of
10	typical of the time in which they were done.  These trials
11	here are very tiny.  You wouldn't really expect much from
12	them.
13		What we are measuring here is change in HAM-D at
14	the end of four weeks, a fairly standard measure, and these
15	trials were analyzed using a common baseline for reasons I
16	won't get into.
17		What is important here is that the six trials show
18	absolutely no difference between the new drug and
19	imipramine.  They are almost within a point of each other. 
20	So, if you believed in equivalence trials, you would say,
21	well, this certainly shows it.
22		[Slide.]
23		The trouble is five out of the six trials had no
24	ability to detect anything, so that in Trial 1, placebo is
25	practically on top of the new drug and imipramine.  The same

			35 1	with the second trial.  The same with the third trial.  The
	2	placebo is actually slightly better.
	3		Only this tiny little trial with seven or eight
	4	people per group had assay sensitivity, had some ability to
	5	distinguish active drugs from inactive drugs, so the placebo
	6	hardly changed from baseline at all, and the new drugs
	7	worked like gangbusters.  The next two show nothing at all.

	8		So, five out of the six trials were uninformative. 
	9	It doesn't mean the drug works, it doesn't mean it doesn't
10	work, you just don't learn anything.
11		[Slide.]
12		I went back over three years of psychotropic drug
13	experience a couple of years ago.  Tom Laughren, who is
14	here, has done that more recently.  We get essentially the
15	same results.
16		This is the rate of studies of reasonable size--

17	you will see the sizes on here--that failed to distinguish
18	active drug from placebo.  In many cases, it is not that
19	they were near, you know, 0.07, it's that they didn't show
20	anything.
21		So, 1 out of 3, venlafaxine controlled release
22	failed.  Five out of 10 mirtazipine, 1 out of 1 trazadone.

23	Some of these were the control drugs.  Nefazadone, 3 out of
24	7 failed on nefazadone, actually, 3 out of 5 imipramine. 
25	All of the flow release trials of buproprion failed. 

			36 1	Probably the dose was a little low, but it was an effective
	2	dose.
	3		[Slide.]
	4		The same thing with antipsychotics, the same thing
	5	with OCD.
	6		[Slide.]
	7		Similar in panic.
	8		[Slide.]
	9		Just briefly, Milton Packer, Director of the

10	Center for Heart Failure Research at Columbia, but he is
11	also our advisory committee chairman on the Cardiorenal
12	Advisory Committee, looked at all the FDA reviews for

13	effectiveness in symptomatic heart failure.
14		What he found, four or five drugs, most of them
15	ACE inhibitors, was that exercise tolerance seemed to be
16	successful less than half the time.  That is usually the
17	hallmark.  Symptomatic improvement arguably was slightly
18	better, but not consistently.  Change in New York Heart

19	Association class was not too consistent.  Global looked in
20	some ways most promising, but these are all drugs that
21	unequivocally are effective in heart failure.  They improve
22	symptoms, they improve survival, but it is not so easy to

23	show it.  All of these trials were large in the neighborhood
24	of 100 or more per treatment arm.
25		[Slide.]

			37 1		Just one more point.  I won't dwell on this, but
	2	when you are showing to show a difference between two

	3	therapies, you have to be on best conceivable behavior
	4	because many of the kinds of errors you might make will
	5	interfere with the ability to show what you want to show
	6	because they will increase variance.
	7		Sloppiness can obscure differences.  Now, as I
	8	said, the non-inferiority design is a protection against

	9	certain kinds of sloppiness, like too small, but it doesn't
10	protect against others.
11		[Slide.]
12		So, even if sensitivity to drug effects exists for
13	a therapeutic class, you can still undermine the ability of
14	the trial to have shown a difference if there was one by
15	such factors as poor compliance.
16		[Slide.]
17		If nobody takes the drug, you can't see a
18	difference.  A population that tends to improve
19	spontaneously, this may be the problem in depression where
20	people are much better in the placebo group, or a population
21	that is unusually resistant, use of concomitant medication
22	that interferes with the test or that reduces the extent of
23	potential response, poor diagnostic criteria, that is,

24	patients don't have the actual disease, you can't show a
25	difference if they don't have it.  Insensitive measures of

			38 1	drug effect.  Poor quality of measurements, those might

	2	increase variance, it might not, it is hard to say, and
	3	mixing up the treatments, you might laugh, but that has
	4	happened.  That guarantees success in the trial.
	5		[Slide.]
	6		In general, these factors that I listed don't

	7	affect variance, so they don't make the confidence interval
	8	wide, but they can reduce or obliterate the active control

	9	versus test differences, that is, they are biased toward the
10	null, which leads to false conclusions of non-inferiority.
11		It is worth noting that some analytic approaches
12	that are conservative in a different showing trial, like
13	intent to treat, are not conservative in a non-inferiority
14	trial.
15		[Slide.]
16		So, the things you ask about a new trial are is
17	the design of this new trial similar to the trials that were
18	successful, is it the same patients, are they treated the

19	same way, has therapy evolved in such a way as to make the
20	effect smaller, that is, is there any new therapy that now
21	has been added, and is the endpoint being measured the one
22	in which the previous trials were successful.
23		[Slide.]
24		I think I will skip this.  The main point here is
25	that because we are weighing historical evidence as opposed

			39 1	to measuring assay sensitivity in the immediate trial, one
	2	has to make a conservative choice about the margin, and that
	3	often leads to relatively large studies.
	4		That is not too big a problem in the adult
	5	population, but it might be considered a problem in the
	6	pediatric population.
	7		[Slide.]
	8		Just sort of a final reminder.  The lack of a
	9	difference or non-inferiority by itself does not show
10	anything except non-inferiority.  For the non-inferiority

11	trial to also imply effectiveness, which isn't actually
12	measured in the trial, you need a critical additional piece
13	of unmeasured information that is assurance that the active
14	control actually had an effect of the defined size in that
15	study.
16		[Slide.]
17		It is worth mentioning that the assay sensitivity
18	question arises when the intent is to compare two drugs. 

19	Unless one of the therapies is superior, in which case it is
20	informative, if the objective is to say this is just as good
21	as that one, you have the same problems.
22		[Slide.]
23		Just briefly, and then I will spend a couple of

24	minutes on these.  Even if a placebo-controlled trial is
25	ethical in a particular situation in adults, it may be

			40 1	unpleasant for people.  They may not want to be in it.  The
	2	investigators may feel uncomfortable.
	3		So, it is worth thinking about study designs that
	4	are still ethically acceptable that might be more appealing
	5	than a simple drug versus placebo, things one can do.  This
	6	is really important to later in the day.
	7		The first situation is the add-on trial.  I will
	8	go through these quickly, and then I want to go to the
	9	proximate.  One is the add-on trial, and we will come back
10	to that.
11		[Slide.]
12		Beating the standard is always good, and doing a
13	dose response study is informative.  Sometimes you can carry
14	out a trial in a population that isn't known to benefit from
15	standard therapy or that has failed on it.  I will come back
16	to that.
17		[Slide.]
18		One can build early escape provisions into the
19	protocol, so that patients not doing well don't have
20	prolonged exposure to an ineffective therapy.  I will come
21	back to that, and you can do a randomized withdrawal study,
22	and I will come back to that.
23		Could we do the proximate ones now.
24		[Slide.]
25		In a lot of situations, when there is known

			41 1	effective therapy, the only trial you can carry out

	2	ethically is an add-on trial.  You can't leave ACE
	3	inhibitors out of a heart failure regimen anymore, they
	4	improve survival, so you can't leave them out, but if you
	5	have a new therapy, you can add it to the accepted therapy.
	6		That involves randomization to the standard drug
	7	plus the test drug or standard plus placebo, and you can

	8	introduce dose response elements into it, and this gives
	9	clear evidence of an effect, but unfortunately, no data on
10	monotherapy.  Still, you at least know something which is
11	better than knowing nothing.
12		This is absolutely standard now in antiepileptic
13	pediatric studies where it is generally felt that leaving
14	patients untreated is not acceptable.
15		[Slide.]
16		The design here is very simple.  They are on a
17	standard therapy for some period of time, or this could

18	either be because they are on it already or because you put
19	them on it in the lead-in period, and then you randomize to
20	the standard plus the drug, there could be several doses, or
21	standard versus placebo, and you show a difference between
22	these two, and then that works.
23		Sometimes you can actually take the standard

24	therapy away and observe what goes on then, and that is
25	sometimes done in antiepileptic drugs.

			42 1		[Slide.]
	2		It is sometimes possible to study non-responders
	3	to available therapy.  That avoids denying somebody anything
	4	that they could use.  It does give data on a different group
	5	that may be less responsive to the therapy if it is of the
	6	same pharmacologic class, or they may be non-responsive at
	7	all.
	8		Randomizing these patients to drug or placebo does
	9	give you information about whether the new drug works.  If
10	you really wanted to know whether the drug was superior or
11	superior in non-responders, then, you would need to
12	randomize back to the drug they failed on or the new drug
13	and show superiority.  The next slide shows that.
14		[Slide.]
15		An important element of design is studies that in
16	one way or another limit duration of exposure to an
17	ineffective treatment.  One general concept is early escape
18	or early advance.
19		Even if a placebo could be used in trials with
20	symptomatic therapies because no harm will come to people,
21	prolonged treatment with an ineffective agent may be
22	uncomfortable and you might find that particularly true in
23	children.
24		One thing that trials can do is introduce an early
25	escape or an early advance if it is a crossover study, that

			43 1	is, you move to the next therapy in which patients failing
	2	to improve to some defined extent or who worsen at some
	3	specified time or at any time, are considered completers or
	4	failures.  Their last value can then be carried forward for
	5	a conventional analysis or the ability to complete can
	6	actually be used as an efficacy endpoint.
	7		That was actually the design used to study
	8	vasospastic angina with nifedipine, the first approval for
	9	that claim.  Nobody particularly wanted people having
10	multiple episodes of vasospastic angina, so as soon as they
11	worsened, even for a day, they were considered failures.
12		[Slide.]
13		Unfortunately, early escape in a conventional
14	trial may leave too few patients treated for the duration of
15	interest, but you might not like the idea of a very long

16	placebo-controlled trial in children or in anybody else.
17		One remedy is the randomized withdrawal trial

18	proposed first by Amery in 1975 for angina trials.  This is
19	a situation in which people are on the therapy of interest
20	for a long period of time and are seeming to do well, and
21	are then randomly taken off the trial.
22		This allows long-term exposure without long-term
23	placebo, and this, too, can have early escape provisions. 
24	So, it gives information on long-term effects without long-
25	term placebo.  You have to worry about the possibility of

			44 1	withdrawal effects, narcotics or nitrates, or something like
	2	that.
	3		It is a trial that is enriched with responders. 

	4	Only people doing well and responding well are likely to be
	5	in the trial, so it might overestimate the effect in naive

	6	patients, but it does give you evidence about effectiveness.
	7		As I said, it can have early escape provisions,
	8	and if there is an existing open protocol, it eases
	9	recruitment.  In other words, if there is a large number of
10	people on this drug for one reason or another, and you want
11	to do a trial like this, and can convince people to be in
12	it, all the patients are there, you don't have to recruit
13	them over a long period of time.
14		So, the nifedipine trial that I described took
15	people who are already on therapy.  They were able to do the
16	trial in about three months, whereas, waiting for large
17	numbers of people with vasospastic angina to show up in your
18	office could take a very long time.
19		[Slide.]
20		The general design is people are on the drug and
21	they are randomized to either a single dose or several
22	different doses and to placebo.
23		[Slide.]
24		Another thing worth thinking about--and we do as
25	part of the Pediatric Rule--one might ask a different

			45 1	question.  Given adult data, it may not be necessary to
	2	carry out the same trials in children.  You have a strong
	3	prior, if you like, and as you know, we are actually allowed
	4	to believe the drug works the same way in children as in
	5	adults even if there is no evidence other than our own

	6	belief or your own belief, so that a simpler, shorter
	7	question might be better than that.
	8		Just as an example, in hypertension, the typical
	9	adult placebo-controlled trial, just to show that it lowers

10	blood pressure, would run four to 12 weeks, would a one-week
11	trial in children suffice perhaps with a randomized
12	withdrawal trial after a longer period?  After all, you are
13	fairly sure it is going to work.
14		In seasonal allergy trials, very large trials are
15	often needed because of variable pollen and possibly other
16	reasons, but we know that studies in Chambers, in which an
17	antigen is induced, are usually much smaller and much more
18	sensitive, would that be sufficient in the antihistamine
19	case?
20		Now, we have approved drugs without any studies at
21	all.
22		[Slide.]
23		Could one suffice for a drug intended for long-
24	term analgesic use in children even with a relatively small,
25	short study in adults given our knowledge that the drug has

			46 1	long-term effectiveness in adults?  All questions that need
	2	to be answered case by case.
	3		That's it.  On some other slides, which I won't
	4	show, I had some examples of trials that actually used some
	5	of these designs, but I think that is not the important
	6	question here, so I think I won't show them.
	7		Anyway, the active controlled trial is often
	8	uninformative, and that poses a real problem because it is

	9	not a good thing to approve a drug when it doesn't actually
10	work.  Our hope is that we can have studies that are
11	interpretable and that yet feel comfortable, and you will
12	discuss this much more I know.  Thanks.
13		DR. CHESNEY:  Our next speaker is Dr. Barbara van
14	Zwieten-Boot.
15		      International Perspective on
16		  Pediatric Placebo-Controlled Trials

17		DR. VAN ZWIETEN-BOOT:  Good morning.
18		[Slide.]
19		First, if you will give me two minutes, I will try
20	and show you where I come from because I understand by now
21	that Europe is somewhat difficult for most people that are
22	not really living there and, even if you do, you still don't
23	understand it.
24		[Slide.]
25		Apart from having patients and the doctors and the

			47 1	pharmaceutical industry, there are, in Europe, three other
	2	players in the field of licensing drugs.  The member states,
	3	which we, at the moment have fifteen, as you know, and two

	4	almost, Iceland and Norway; the Commission in Brussels who
	5	is a kind of civil servant to the Europe that doesn't exist
	6	at the moment, but we do have to have civil servants; and
	7	CPMP EMEA which is based in London and is the European
	8	licensing authority.
	9		For those products that follow the European route
10	or the central route, you have to go to London. If it is a
11	product that, for one reason or another, follows the

12	national route, you have to go to the member states.
13		So CPMP is the part where you go for a license and
14	they do the assessment, at least they are responsible for
15	the assessment.  CPMP consists of fifteen times two persons,
16	so every member state sends two persons.  But you sit there
17	as experts and not as representatives of your country.  And
18	there are two more, one from Norway and one from Iceland. 
19	And there is a chair which, at the moment, is Professor
20	Alexandre from France.
21		If you send in your license and your product
22	there, they will appoint two coordinators or a
23	rapporteur/co-rapporteur.  They are responsible for doing
24	the assessment.  Usually, they fall back on the member

25	states to supply the personnel to do that and it will be

			48 1	discussed here in London.  The EMEA is supportive, both for
	2	the legal support, logistics.  They support in the meetings,
	3	et cetera.
	4		CPMP has a group of working parties, ad hoc or
	5	standing working parties, and there is a group that is doing
	6	scientific advice which, to some extent, is the same as you
	7	do in phase II or phase III discussions with the industry.
	8		Working parties are also coming from the member
	9	states so you have fifteen official members and a chair, and
10	a vice-chair in some situations.  They are setting up the

11	policy documents.  The guidelines are coming from there. 
12	Using the guidelines, you then can make your assessment of
13	specific products.
14		That is where I come from.  I work in The
15	Netherlands.  I work for the Medicines Evaluation Board in
16	The Netherlands but I am also vice-chair of one of the
17	working parties, the Efficacy Working Party, and an expert
18	to CPMC, so part of my time, I will be in London.

19		In the working parties, we make European
20	guidelines and we are also involved in the international
21	guidelines, the ICH guidelines, that Dr. Temple just has
22	been talking about and two of them are actually in the

23	handout that the FDA has given to you; E-10, which is the
24	choice of control, and E-11, which is the pediatric
25	guideline.

			49 1		But all of this that we do here is we make
	2	guidelines.  CPMP has no opinion.  To make it a directive or
	3	to have a directive, you have to go to the Commission.  If

	4	the Commission draws up a directive, then the member states
	5	have to put that in law.  So, what we do is guidance and

	6	companies can follow it or not, although, if they don't,
	7	they have to come up with good justification.  It is in

	8	Brussels that you can have the law.  That is the difference
	9	between the two. 
10		Then, at the moment, they are working, for
11	instance, on the clinical-trial directive which tries to put
12	the GCP, good clinical-practice guideline, that we have made
13	for ICH in a legal framework because, at the moment, in
14	Europe, it is just a guideline.  But we want to have it in a
15	legal framework, so they are working on that.
16		At the same time, then, they try to regulate more
17	on the European level how to have clinical trials.  But one
18	of the things that you see there is that they are very

19	careful not to harmonize ethics because it is thought in
20	Europe that ethics belongs to the member states.  It is up
21	to the member state to see, in their domain, what is
22	ethical.
23		So there is no European harmonization or ethics
24	although there are a lot of discussions going on in Europe
25	about ethics.  And that is where Professor Crawley comes

				50 1	from.  But I am here.  I am working for the authorities.
	2		[Slide.]
	3		To show you that we have the same problems in
	4	Europe as you have here, this is from a recent publication
	5	in the British Medical Journal.  It was a kind of survey

	6	done in five pediatric clinics in Europe; Derby, which is
	7	the U.K.; Uppsala is Sweden; Marburg is Germany; Bergamo,
	8	Italy; Rotterdam is The Netherlands.
	9		They, for a certain time, followed the

10	prescriptions that were given and, not surprisingly and more
11	or less what you see, too, is that about 50 percent are
12	either unlicensed or off-label.  Seven, almost, were
13	unlicensed drug use so, apparently, there were experimental
14	drugs used, and about 39 were off-label use of drugs.
15		If you look into that publication, you will see

16	that the drugs that were prescribed and that were not off-
17	label for a huge number of prescriptions was parasitimals
18	which, and it is about two-thirds of the patients in these
19	clinics, but some of them were university clinics that
20	received unlicensed or off-label treatment.

21		So we have a problem here and we have realized it.
22		[Slide.]
23		So what are we doing?  In Europe, we are in a
24	somewhat different situation than you are because we have to
25	deal with various member states.  But what we have done up

			51 1	to now is we had a European guideline which was written, I
	2	think, in '89 and we have updated that in 1997, put more
	3	emphasis on the need to do these kinds of trials, when to do
	4	them, how to do them.  We have, somewhat--in this guideline,
	5	there was more emphasis on the need for clinical trials than
	6	you will see in E-11, to some extent.
	7		And we gave some guidance what to put into the
	8	SPC, which is your datasheet, if you have no trials done. 
	9	We, because the FDA had their own rules and Japan wanted to
10	have some rules of pediatrics, came up with a discussion in
11	E-11.  Dr. Spielberg is here and he knows much more about it
12	than I do.  And it is in your handout.  You can see what
13	kind of data were discussed there.
14		At the same time, in the EU, we address certain

15	therapeutic areas and we start up, now, to put in those
16	guidances there, where it is relevant, some comments on the
17	clinical trials in children. 
18		But it is curious to see how difficult it is to
19	get that starting.  It is not only industry that does not
20	want to do it, it is also we, ourselves, the assessors and
21	the authorities that have to switch and have to start

22	thinking that it is really necessary, if there is a
23	situation where we ask it yes or no.
24		And then, because this is our old guideline, there
25	is a discussion starting now in Brussels whether or not we

			52 1	need to have something like a directive put in law, maybe
	2	along the lines that the FDA has done here, or maybe
	3	somewhat different.  That has certainly not crystallized out
	4	at the moment, but we are discussing it.
	5		France has the presidency at the moment for the
	6	EU.  We switch presidents every six months.  France has put,
	7	as one of the things that they want to accomplish during the
	8	six months, that there will be some more emphasis on
	9	pediatric trials and they have circulated a memorandum to

10	that extent which is being discussed, I would say, in two
11	weeks time.
12		All of this, or most of this, is about new

13	chemical entities or a line extension to release new
14	products.  What we still have to address actually will be
15	very difficult but that is something that you probably have
16	seen here also is what to do with the products we have

17	already licensed, what kind of data do we need there, to
18	come up with evidence-based advice in the datasheet or SPC.
19		[Slide.]
20		So that is where we are.  What if you are going to
21	develop a drug, then?  The purpose of clinical development
22	in children, you may say that is self-evident.  But what I
23	would like to discuss with you, or maybe in the discussion
24	for this morning, is that if you read E-11, one of the

25	basics there is what kind of data do you need, when.  To

			53 1	what extent can you extrapolate or not?
	2		Is it always necessary, just like Dr. Temple just
	3	said, to have a full-blown program or not?  I think that is
	4	something that we should take in mind when you are
	5	discussing the need or not for placebo.
	6		In the case--and this is, more or less, coming
	7	from E-11--the disease is typical for children, the efficacy
	8	and safety have to be shown.  If it is a disease that is
	9	only in children, like Lennox-Gastaut, for instance, if you
10	want to go to the antiepileptics or ADRS in premature
11	children, then you need to show it just like you have in
12	development in adults.
13		Usually, you can't extrapolate for adults because
14	they don't have that disease.  So you need to have the whole
15	development plan.
16		If, however, you have a disease that is the same
17	in adults and children, the disease process and the outcome
18	is the same, then the focus of the clinical development
19	should not be the whole program but much more what is the
20	effective dose or dose regimen and what about safety.
21		The safety we are talking about here is, then, not
22	only the safety that you see in adults but also the specific
23	safety focusing on children like growth, CNS development,
24	learning, behavior and maybe the endocrinological process
25	when puberty starts--certainly, if you are talking about CNS

			54 1	products this afternoon.
	2		[Slide.]
	3		In E-11, you will see that in the case where the
	4	disease is the same for adults and children, some
	5	extrapolation from adults to children may be appropriate. 
	6	This, again, as Dr. Temple said, will be on a case-by-case
	7	basis but the considerations you could have are the
	8	following.
	9		Sometimes, it could be done on pharmacokinetic
10	data provided that relation between blood levels and
11	efficacy is known.  That is very difficult.  We know, to
12	some extent, which dose or which blood levels give an
13	effect.  But whether or not that is the optimal is something
14	different.  Dose-response data are usually very bad in a lot
15	of situations.
16		But there is a way out if you can show that, then
17	you have pharmacokinetic data, then you can extrapolate your
18	data.  You don't need to have, maybe, a clinical trial.
19		If you don't, you could try and fall back on
20	pharmacodynamic data or studies with a surrogate endpoint if
21	you know that this endpoint is relevant for efficacy.  So
22	maybe you could have tumor response instead of going all the
23	way down to the mortality rate if you know already that, for
24	that specific tumor, the drug is effective in adults.
25		Or you could do, for instance, in asthma, FVE1

			55 1	trials as we do with salbutamol, or albuterol, as you call

	2	it here, instead of doing your full-blown clinical trials
	3	and use that as an extrapolation provided that out of these
	4	data, you get your dose regimen data.
	5		If not, you have to do clinical studies.  But,
	6	again, if you already know the drug works in adults, then
	7	you might be sufficed to have only one trial instead of the
	8	usual program.  And, if that trial shows you what you
	9	expected, then you will assume that the rest will follow,
10	too.
11		But, whatever you do, you need to have adequate
12	safety data.  And that may be a problem if you only want to
13	have pharmacokinetic data.
14		[Slide.]
15		The point is, if you do pharmacokinetics studies,
16	of course, you have advantages.  Usually they are small-

17	scale trials and, therefore, you have fast results.  They
18	are somewhat larger than we have in the usual volunteer
19	studies in adults because you can't run the same trials. 

20	But you usually have data from various children together to
21	get your time curve.  It can be done.
22		But there are disadvantages that maybe you should
23	consider when you try to go that way instead of having a
24	placebo-controlled trial.  One, and that is certainly a
25	problem in Europe, is the fact that pharmacokinetic studies

			56 1	are usually done in a non-therapeutic setting. 
	2		We have addressed that point in the DSCP guideline
	3	for those of you who want to see it there, but this is an

	4	issue in Europe.  In my own country, in The Netherlands,
	5	there has been, I think, a twenty-year debate in Parliament
	6	on the law that would regulate clinical trials in humans. 
	7	This was one of the big issues; can you have a trial in
	8	volunteer children that are healthy or at least don't
	9	benefit from the drug they get.
10		In the end it was yes.  I know from my German

11	colleague who told me that it is not allowed in Germany.  So
12	it is not easy to go this way if you cannot do the trials
13	because you need separate studies.
14		Clinical studies, the large advantage, of course,
15	is that you get clinically meaningful results.  You can
16	interpret it and you can use it in the clinical practice. 
17	You have comparative safety data which makes it much easier
18	for us to understand what the safety problems are, and you
19	do it in a therapeutic setting.  For one reason or another,
20	that is easier to do than in a non-therapeutic trial.  You
21	shouldn't misunderstand it.  This is really a big problem

22	for us. 
23		The disadvantages, of course, are the large
24	numbers.  It is a slow process and a choice of comparator.
25		[Slide.]

			57 1		There we come, then, in the problem of the
	2	placebo.  This is from E-10 and it is more or less already

	3	discussed by Dr. Temple.  If there is no standard treatment
	4	available, you can do a placebo-controlled trial although,
	5	in some situations, you may choose for a no-treatment
	6	control which we see in oncology a lot because the scheme,
	7	the dose regimen, is so difficult that it is easier to have
	8	not a placebo but a non-treatment control.
	9		Sometimes, what we ask for is superiority over

10	best of care so everybody gets best of care and you are sure
11	that your drug is better than that.  There is always the
12	possibility of a dose response.  We show that a high
13	concentration or a high dose of the drug is better than the
14	lower dose but it may be discussed whether or not a low dose
15	has not the same ethical implications as the placebo does.
16		The other is that if standard treatment is
17	available, what are we going to do then.  That has just been
18	discussed by Dr. Temple.  You can try to do a non-
19	inferiority versus standard but then you need to know
20	something about what he called assay sensitivity, what in 11
21	is called historical evidence of sensitivity to drug effect
22	which means that you should be quite sure not only that the
23	standard works but that it works in clinical trials and is
24	always, or most of the time, different from placebo.

25		If you don't know that, you cannot set your

			58 1	margin.  If you cannot set the margin, you cannot do
	2	equivalence or non-inferiority trials because the results,
	3	you don't know what to do with them.  You can't interpret
	4	them.
	5		The problem here is in children that we just have
	6	said that most of the drugs are used off-label.  We know
	7	that they work, or we think that they work, or at least they
	8	are used and may be standard therapy.  But there may be a
	9	lack of good data to know what the effect size is.  If you
10	don't know the effect size, again, then you run into
11	troubles with setting your margin.
12		It may be that the margin is set in such a way
13	that you run into the placebo and, therefore, show that your
14	drug may be as effective as the active control but also
15	would have been as effective as placebo if placebo was used.
16		So there is a very big danger in doing that.  And
17	you can only do it if you have sufficient data to justify

18	it.  If that is impossible to do, and it might be in more
19	cases than we think, then we come to the superiority versus
20	the standard which we always will accept, all of us. 
21	Provided that there are no safety risks on the other side,
22	we will allow it.
23		If not, then we are back to placebo.  As Dr.
24	Temple already has said, there are a variety of possible
25	placebo-controlled designs which might help to resolve some

			59 1	of the ethical issues, at least make it more acceptable.
	2		The other note is that placebo control, some
	3	people seem to think that if you give a placebo, you don't

	4	do anything at all.  But that is not true.  Seeing the high
	5	placebo effect in a lot of trials that I got in, sometimes
	6	up to 60 to 70 percent, placebo might be a good drug.
	7		But it is not only that.  It is also the placebo
	8	control doesn't imply the use of rescue medication or

	9	palliative medication, depending on the situation, cannot be
10	considered.  Of course, you can give morphine in an oncology
11	trial.  So it is not that the patient is not treated.  He is
12	not treated for that specific area where he is ill.
13		[Slide.]
14		So where are we?  As far as I can see, certainly,
15	the disease is not the same as for adults.  Ethical and
16	methodological considerations are the same for adults and
17	children.  Even if efficacy is demonstrated in adults, if,
18	therefore, efficacy in children might be expected, you need
19	to some something about assay sensitivity or historical
20	evidence of sensitivity to drug effects. 
21		It is an awful sentence, but that is the way it
22	was defined in the E-10.  You need to know it because,
23	otherwise, you can't draw a conclusion from your trial in
24	the case that a clinical trial is considered necessary.  The
25	need for a placebo has to be justified but, also, the need

			60 1	for an active control.  Always, and it not only for
	2	children--it is also for adults, but, certainly in children,
	3	you have to justify your clinical-trial program.
	4		But if, on methodological grounds, it is said that
	5	you need a placebo and that it is the only way to come to a
	6	conclusion, then I would say that it would make the
	7	acceptance of the placebo higher.  There is no law against

	8	placebo use in therapeutic trials in the EU.  There is in
	9	some member states a law against non-therapeutic trials, in
10	general.
11		[Slide.]
12		I have picked up two examples, just to give some
13	flavor of what we are talking about.  This is from our own
14	database in The Netherlands.  Actually, we have, the last
15	ten years or so, accepted about seven new antiepileptic

16	drugs, three of which have no clinical data in children, but
17	we are running trials, at the moment, so I left them out,
18	which gives us four.
19		You can see that it sometimes takes a long time to
20	go through a process.  Here you see a drug that was licensed
21	for adults in 1991 and the children's studies came in	2000. 
22	We licensed it in 2000.  It took ten years to review the

23	evidence, and I can tell you the drug was used for a long
24	time.
25		What you also see is that most of the trials are

			61 1	done as an add-on.  There are very few monotherapy studies,
	2	only, in this case, we had the monotherapy study against
	3	phenytoin and, because of the results, we allowed that as a
	4	monotherapy claim.  But most of them are in the add-on
	5	situation which is a good situation to show an effect of the
	6	drug but doesn't help you much further if no further studies
	7	are done.
	8		What you also can see is that not only for typical
	9	seizure types, like Lennox-Gastaut, placebo-controlled
10	trials were done but also for the partial seizures with or
11	without generalization even though there is a discussion

12	whether or not the partial seizures you see in children are
13	the same as the partial seizures you see in adults.
14		One of the reasons for that probably is that if
15	you are in an add-on situation, you already have two or

16	three antiepileptics and you add your test drug,
17	pharmacokinetics will not help you because it has become
18	much too difficult to understand what you are doing and,
19	therefore, you get in your placebo-controlled trials.
20		Now, I realize, this is becoming controversial. 

21	This I picked.  I must say, this is a typical Dutch example. 
22	It is certainly not a European example, but it helped to
23	make a few points later.
24		Otitis media--this is a quote from the Association
25	or Society of General Practitioners in The Netherlands who

			62 1	make their own treatment algorithm, and they say that the
	2	treatment is symptomatic in all children.  That means you
	3	give parasitimal and anticongestants if you want, except for
	4	children less than six months old and children--you may
	5	start antibiotics if, after three days, the symptoms
	6	increase or the children are not improving.
	7		But for the usual situations, the GPs start with
	8	symptomatic treatment.  This is based on the placebo-
	9	controlled trial in 1981 from the Dutch GP centers and this
10	is a very large observational study where they found that
11	more than 90 percent of the children could do without
12	antibiotics and were improved after three days
13		This is from here, I would say, and would show
14	that there is a huge debate going on, at least at that time
15	and I got the impression this morning that it is still going
16	on.  The reason I gave this example, even I know it is
17	difficult to do here.
18		[Slide.]
19		It is because if there is one area where you could
20	maybe extrapolate on pharmacokinetics, it should be the
21	antibiotics because you know the bacteria it affects and you
22	know there is a relation between the dose or the blood
23	samples and the blood levels and on the effect, and my
24	colleagues in that field tell me you even can predict PK/PD.
25	However, if you do that, you have to know for sure that the

			63 1	same bacteria or the same strains are in the adults and the
	2	children, and in this case, apparently, that is not so.
	3		You also need to know that it is relevant to treat
	4	that group with antibiotics, and as I said, in this case,
	5	where 90 percent of the children apparently could do
	6	without, you have no assay sensitivity, and therefore, it
	7	might be difficult to do it without placebo.
	8		A third point I would like to make is that there

	9	was a huge willingness of parents and doctors for this kind
10	of trials.  The placebo was a reasonable large trial, and
11	the observational studies were almost 5,000 kids, so
12	apparently, if you tell them why we do it, we can do it.
13		[Slide.]
14		The conclusion, this is a quote actually from a
15	French document that is now circulating, because as I said,
16	they have taken initiative, and they said that the use of
17	placebo in children raises no more ethical problems than in
18	adults.  The use of the placebo, or in brackets, reference
19	product facilitates rigorous evaluation of the effects of a

20	product.  It is, in fact, the absence of the evaluation that
21	should be seen as unethical.
22		Thank you.
23		DR. CHESNEY:  Thank you very much.
24		We have 10 minutes now for the Committee to ask
25	questions of both Dr. Temple and Dr. van Zwieten-Boot.

				64 1		Yes, Dr. Nelson.
	2		    Questions from the Subcommittee
	3		DR. NELSON:  A question for Dr. Temple.  The
	4	threshold that you offer and in your slides for a placebo to
	5	be considered is when the withholding of the effect of
	6	treatment would not result in either death or irreversible
	7	morbidity.
	8		My question is whether you believe E-10 discussed
	9	that issue in the context of pediatrics, and if not, whether
10	it would be appropriate to tackle it in E-11.
11		DR. TEMPLE:  I don't think E-10 really did
12	consider it.  It presumed informed consent.  That was an

13	important part of its consideration.  Informed consent is
14	clearly a different animal in children.  So, I think E-11
15	probably does need to discuss it, but E-10, I don't believe
16	did.
17		DR. CHESNEY:  Yes.
18		DR. WARD:  For Dr. Temple.  You proposed using
19	crossover when there was a failure of effect, and how would
20	you handle that statistically, would you then use intention
21	to treat and leave the patient in the original assignment,

22	or would you consider that failure of the original treatment
23	to be an endpoint?
24		DR. TEMPLE:  Well, you can do either of those

25	things.  In the example I didn't show, in the nifedipine

			65 1	vasospastic angina, they count it as an endpoint, inability
	2	to complete the one-week trial, and you saw a difference in
	3	number who complete.
	4		You would also, however, carry the last
	5	observation forward and do a sort of conventional analysis
	6	if you allowed people to leave after a certain period of
	7	time.  I think either could work.  There is not so many
	8	illustrations as one might like.
	9		DR. CHESNEY:  Dr. Wolff.
10		DR. WOLFF:  This is a naive question to you for my
11	information.  If there is effective standard treatment, why
12	would one under any circumstance want to--given also the

13	limitations of the non-inferiority design--why would one
14	even engage in such studies other than to put new drug on
15	the market?
16		DR. TEMPLE:  Well, that is an important reason,
17	but there are reasons to have more than one example of a
18	particular drug.  I mean in the antibiotic area, for

19	example, each of the drug classes has its own toxicity, and
20	you might well want to know whether a drug with different or
21	less toxicity worked.
22		Just a classic example.  When there were only

23	sedating antihistamines around, you might want a non-
24	sedating antihistamine in children, so they don't sleep
25	through their classes.

			66 1		Many, many examples.  For example, the new
	2	antidepressants do not differ in effectiveness from the old
	3	antidepressants.  They differ markedly in the side effects
	4	and tolerability.  The same for the new atypical
	5	antipsychotics.
	6		There is often reason to have more than one
	7	treatment for something.
	8		DR. WOLFF:  But that goes into superiority,
	9	doesn't it?
10		DR. TEMPLE:  No, even if it's--well, it is
11	superior in tolerability, but the new antipsychotics and
12	antidepressants are not superior in effectiveness to the old
13	ones.
14		DR. CHESNEY:  Dr. Spielberg.
15		DR. SPIELBERG:  Just a brief comment on Dianne's
16	comments on chloramphenicol.  I think that story has to put
17	us in awe and make us remember just what we do not know at
18	any time about biology and medicine, but I think there are
19	several more messages in that story that need to be put into
20	this mix.
21		The first is what was going on at the time that

22	the clinical trial was going on.  In fact, chloramphenicol
23	was being rapidly introduced into therapy in nurseries all
24	around the country, particularly at university medical

25	centers, which thought they were smarter than the non-

			67 1	university centers, so that there was a tremendous amount of
	2	non-controlled use going on.
	3		In fact, one of the classic epidemiology studies,
	4	which was published just about the same time that the
	5	controlled trial came out, showed that at one university
	6	hospital, mortality had gone up dramatically compared to
	7	non-university hospitals in the same community as a result
	8	of the introduction of chloramphenicol.
	9		The second thing was the conventional wisdom was
10	pen-strep, and that study showed that, in fact, pen-strep
11	was no better than placebo, which made us rethink the entire
12	issue of how to manage babies with premature rupture of
13	membranes and how to begin approaching therapeutics in that
14	setting in a somewhat more rational way.
15		So, that study had a lot more richness in it than,
16	in fact, just that issue.  But if we fast forward, then, how
17	we would do that study today, which I think is what we need
18	to think about, 1960, in order to measure a chloramphenicol
19	level, you needed 25 ml of blood.  Well, you know, think
20	about the circulating volume in a baby.  You couldn't have
21	really done pharmacokinetics back then.
22		Today, we would have done a non-therapeutic single
23	dose pharmacokinetic study to figure out what the right dose
24	of chloramphenicol was in the first place, and then if we
25	engaged in a clinical trial--and we will talk about it later

			68 1	--we would have used data safety monitoring boards because
	2	we are starting off with unknown therapy in a very complex
	3	setting.  It would have been a very different kind of study.
	4		In fact, when I see that study sort of getting, if
	5	you will, bad press, to me, it is a paradigm of what could

	6	have been done in the 1960s, but also points out just how
	7	much progress we have made in trying to do these kinds of

	8	studies today, in fact, back then, I think with the ethical
	9	decisions, probably might have gone to a placebo-controlled
10	trial even in that setting.
11		Just one more anecdote.  I was involved in one
12	placebo-controlled trial, something that should have been
13	obvious and safe.  It was a study of Vitamin C in
14	cystinosis.  Somebody had shown in vitro quite clearly that
15	ascorbic acid decreased the cysteine content of fibroblasts
16	from these children.  Everybody said it's unethical to do a
17	placebo-controlled study because, after all, Vitamin C is
18	safe, we weren't going for megadoses of Vitamin C.
19		With the data safety monitoring board, with the
20	placebo-controlled study, the study was stopped because the
21	children on Vitamin C were going into renal failure faster
22	than those on placebo for reasons we don't understand, but
23	again that tells us we need to be in awe of biology and
24	medicine.
25		DR. CHESNEY:  Dr. Kauffman.

				69 1		DR. KAUFFMAN:  Just to follow up on Dr. Spielberg. 
	2	I have a question for Dr. Temple and then a comment.
	3		You emphasized throughout your talk the efficacy
	4	side of the coin and the importance of placebo or controlled
	5	studies for efficacy.  To what extent are placebo controls

	6	or some type of control important for safety evaluations?
	7		DR. TEMPLE:  To assess the rate of some event, you
	8	need either an active control whose rate you are pretty sure
	9	of, or once again, a placebo.  If you don't, the fact is

10	many of the so-called safety studies in pediatrics are just
11	open trials, and the only choice you have is to attribute
12	everything bad that happens to the drug, which may not be
13	the right conclusion.  It is hard to think of what the
14	alternative is.
15		Sometimes the desire is to show that a particular
16	drug lacks a side effect that another drug has.  In that
17	case, all of the same kinds of thinking applies.  That is a
18	study with a hypothesis is, as a general matter, failure to
19	show a difference is uninformative unless you know that the
20	control would have had that effect.
21		For example, if you wanted to show that Claritin
22	or something like that is non-sedating in children, you
23	really do need a sedating antihistamine to compare it with
24	and show a difference.  If nobody gets sedated, that just
25	might mean that that was not a sleepy population.  So, the

			70 1	same kind of thinking.
	2		DR. KAUFFMAN:  Or kids don't get sleepy.
	3		DR. TEMPLE:  Or kids don't get sleepy at all,
	4	right, so it may not be an advantage.  Once again, you need
	5	the positive control in that case, the drug that causes
	6	sedation serves as your placebo.  It's the internal
	7	standard.
	8		DR. KAUFFMAN:  I wanted to follow up on the

	9	widespread off-label use that Steve referred to in the
10	chloramphenicol study, because that has bothered me for a
11	long time and I am not alone, I don't think.

12		That is, it is fairly common in pediatric medicine
13	that a drug is adopted into widespread off-label use across
14	the pediatric age group, becomes accepted in the pediatric
15	practice community sort of as, quote, "the standard of
16	care," but it is off label, and then we come along and say
17	we need a study.
18		What are the ethical implications of taking an
19	accepted, non-FDA-approved, non-labeled, but accepted

20	treatment and then trying to enroll kids into a formal
21	placebo-controlled study or some other type of controlled
22	study to evaluate that drug after it has come into
23	widespread use?  There are just dozens of examples of that
24	in pediatric medicine.  It's a practical issue, too.
25		DR. TEMPLE:  And it is a formidable problem.  One

			71 1	possibility is the randomized withdrawal study.  For
	2	example, if you think drug whatever is an effective
	3	antidepressant, not that depression studies in children have
	4	been very successful for the most part, but if they did, you
	5	could take people who are being treated with whatever the
	6	antidepressant people think the standard is, and then
	7	randomized to a new antidepressant or placebo, with the

	8	early escape provision being that as soon as depression
	9	rears its head, the children would be out of the study, they
10	would escape.
11		That isn't exactly what you wanted to know as far
12	as the treatment of acute depression goes, but it would give
13	you some indication that the drug is active in that setting. 
14	Whether that is sufficiently more comfortable to allow
15	people to engage in that study is something that I am not
16	fit to answer, but people here probably can.
17		DR. CHESNEY:  I think we could take one more
18	burning question and then we need to move on.
19		Dr. Spielberg.
20		DR. SPIELBERG:  Just a good example of that
21	situation, Ralph, that sounds trivial, but it really had a

22	big effect on pediatric practice, was a placebo-controlled
23	study of what we were all doing back when in treating
24	otitis, which was to use pseudoephedrine and antihistamine
25	combinations.

			72 1		A placebo-controlled trial was done which showed
	2	that, in fact, those drugs really did not help, and that was
	3	tremendously important because in practical practice, we
	4	were always telling parents you have to go home and you have
	5	to give this drug plus the antibiotic.  There were
	6	therapeutic and compliance issues associated with that.
	7		The practice was dramatically changed overnight
	8	when those studies came out and people no longer were
	9	writing for those products.  So, even though it was standard
10	of care and everybody knows that, in fact, it turned out to
11	be wrong, and practice changed as a result of it.
12		DR. CHESNEY:  Thank you.  That reminds me of the
13	mist tents in cystic fibrosis.
14		I think we need to move on.  Our next speaker is
15	Dr. Charles Weijer, who is a bioethicist and Assistant

16	Professor of Medicine at Dalhousie University in Nova
17	Scotia, and he is going to talk about the ethical concerns
18	in pediatric placebo-controlled trials.
19	  Ethical Concerns in Pediatric Placebo-Controlled Trials
20		DR. WEIJER:  Thank you very much.
21		[Slide.]
22		I have been interested in the issue of the ethics
23	of placebo controls and the ethics of randomized controlled
24	trials for some time.  I trained at McGill University with
25	my mentor, Benjamin Freedman, whom some of you may know as

			73 1	really one of the founding figures in the ethics of
	2	randomized controlled trials.  So, some of the ideas and

	3	criticisms that I am going to talk about today are Benjie
	4	Freedman's work, and much of them represent work that we did
	5	in collaboration, and a small portion of it is my own.
	6		I feel a bit uncomfortable up here actually.  I
	7	was asked to give a talk on the ethics of placebo-controlled
	8	trials, and I see that Dr. Temple has already given us a
	9	lecture on the ethics of placebo-controlled trials.
10		Believing that there is value in diversity, and so
11	on, I think you will find that some of my views of the
12	ethics of clinical research are perhaps at variance with Dr.
13	Temple's views.
14		Let me set a broader framework here in terms of
15	how we actually think about the ethics of clinical research. 
16	One of the founding documents that we continue to rely on in
17	research ethics is a document produced in the late seventies
18	by the U.S. National Commission for the Protection of Human
19	Subjects of Biomedical and Behavioral Research.
20		Now, that pivotal commission in its Belmont Report
21	set out three ethical principles that guide the conduct of

22	research involving human subjects, and those principles are
23	respect for persons' beneficence and justice.  Respect for
24	persons requires that we respect the autonomous choices of
25	individuals.  An important corollary, particularly in the

			74 1	setting of pediatrics, is that it also requires that we
	2	protect those who are incapable of autonomous choice.
	3		Beneficence is typically expressed in terms of two
	4	complementary rules, first, do no harm, second, maximize
	5	potential benefits while minimizing harms, and the principle
	6	of justice, of course, refers to the fact that there needs
	7	to be an equitable distribution of the potential harms and
	8	benefits in clinical research.
	9		In the setting of pediatrics, I think a couple of
10	aspects of this ethical framework require further
11	exploration.  First, the fact that the principle of respect
12	for persons requires that we protect those who are incapable
13	of autonomous choice.
14		I think that protection shifts appropriately our
15	emphasis onto the principle of beneficence, in other words,
16	what are acceptable benefits and risks to which children in
17	research may be exposed.
18		Now, I have got a couple of overheads here before
19	I switch over to Power Point, and this I think reflects, I
20	hope, an evolving view internationally in the ethics of
21	research with regard to the specific guidance that
22	institutional review boards, local ethics committees are
23	given with regard to how is it exactly that they determine
24	in a particular study whether the risks and benefits in that
25	study are acceptable.

			75 1		Sometimes we talk about an acceptable risk-benefit
	2	ratio, other times we talk about an acceptable balance of
	3	potential benefits and risks.  We need to recognize, of
	4	course, the metaphorical nature of each of those phrases and
	5	what IRBs need is specific guidance as to how exactly they
	6	are supposed to determine that.
	7		What I want to present here is, in fact, work that
	8	I have done as a part of the World Health Organization,
	9	Council for International Organizations of Medical Sciences,
10	that is, CIOMS, Steering Committee revising their 1993
11	international guidelines, and also work that I have just
12	recently submitted to the U.S. National Bioethics Advisory
13	Commission on philosophical aspects of risk analysis.
14		What we see here is really a comprehensive and
15	systematic approach to the analysis of risks and benefits in
16	research.  It recognizes that many, many clinical studies

17	contain a mixture of procedures.  Some of those procedures
18	are administered with therapeutic intent, others are not
19	administered with therapeutic intent, that is, they are

20	administered solely to answer the scientific question at
21	stake.
22		The fundamental recognition of this ethical
23	approach is to say that the ethics of therapeutic procedures
24	need to be evaluated separately from the ethics of non-

25	therapeutic procedures.  Therapeutic procedures must pass

			76 1	the test of clinical equipoise.  This was the notion
	2	originated by Benjamin Freedman in a 1987 article in The New
	3	England Journal of Medicine that I think many recognize as
	4	setting the moral foundation for the modern randomized
	5	controlled trial.
	6		Freedman said that in order for a trial to proceed
	7	ethically, at the start of the study there must exist a
	8	state of genuine uncertainty in the community of expert
	9	practitioners as to the preferred treatment.
10		So, then, an IRB reviewing a study must review the
11	justification for the study, and may use things like a
12	literature review or consultation with impartial experts to
13	determine that, in fact, a state of clinical equipoise
14	exists.
15		Now, this, in fact, is crucial to the
16	determination of whether a placebo-controlled trial is
17	ethically permissible or not, and I am going to go on and
18	say a lot more about that.
19		Non-therapeutic procedures, on the other hand,
20	offer by definition no prospect of benefit to research
21	participants, and therefore, any appeal to a so-called risk-
22	benefit calculus is inappropriate.  There are no benefits to
23	trial participants, period.
24		So, we need to use a different moral calculus. 

25	First off, risks must be minimized, so, for example, if one

			77 1	could piggyback a procedure on something that is being done
	2	for therapeutic purposes, you need do that, and after one
	3	has done that, the risks must be reasonable in relation to
	4	the knowledge to be gained.
	5		That fundamentally involves an assessment of the
	6	study's value and requires not only input from relevant
	7	experts, and so on, but also, in fact, requires the input of
	8	community representatives on institutional review boards,
	9	because ultimately, the benefit here is to the community or
10	to our society at large.
11		Thus, with regard to the evaluation of non-
12	therapeutic procedures, we are not talking about a risk-

13	benefit calculus, rather, we are talking about a risk-
14	knowledge calculus.
15		Now, that framework holds for all clinical
16	research.  It gets a little more complicated with children
17	because, as I said, additional protections must be invoked
18	because children are a vulnerable population.
19		[Slide.]
20		A lot of this is the same, and I want to just

21	point out a couple of differences.  The first difference,
22	the first protection is that you can't do a study involving
23	children unless, in fact, the institutional review board is
24	convinced that the study hypothesis requires the inclusion
25	of members of a vulnerable population, and, of course, in

			78 1	the context of today, that is children.
	2		One might add refinements to this, as I have
	3	noticed that this very committee has, with regard to the
	4	inclusion of older children who perhaps may be either
	5	capable of consent or at least capable of assent versus the
	6	inclusion of younger children who are incapable of either.

	7		The second major protection actually applies only
	8	to non-therapeutic procedures, and that is, that the risks
	9	posed by non-therapeutic procedures can be no more than a
10	minor increase above minimal risk.
11		There is a lot of misunderstanding about minimal
12	risk and for good reason.  Part of it is that the National
13	Commission itself was sort of confused about what the
14	concept should mean, but I think it has become quite clear
15	that the minimal risk is only sensibly applied to non-
16	therapeutic procedures.
17		So, then, this "no more than a minor increase
18	above minimal risk" threshold means that a study may only
19	proceed if there is no more than a minor increase above the
20	risks of daily life for the study population in question.
21		As I have said, this only applies to non-

22	therapeutic procedures.  I can't say that enough.  The whole
23	confusion in this country over proper standards for
24	emergency research emanated from a failure to recognize that
25	very simple point.  Fundamentally, it is a qualitative

			79 1	judgment made by the institutional review board, the IRB

	2	acting in loco parentis, acting as the scrupulous parent
	3	would act in making such a decision.
	4		I am now going to switch over to the Power Point.
	5		[Slide.]
	6		When we are talking about the permissibility of
	7	placebo controls, fundamentally, we are looking at a
	8	question that has troubled ethicists for probably a couple
	9	of decades now.  That is, that we believe that physicians
10	owe their patients certain duties.  One of them is the duty
11	to care, a duty to provide effective treatment to their
12	patient.
13		Many physicians and ethicists in the eighties
14	became very concerned as to whether it would be permissible
15	at all for responsible clinicians to enroll their patients
16	in randomized controlled trials, in other words, trials in
17	which patients would receive one treatment or another, or
18	one treatment and even placebo, as a matter of chance. 

19	"How," many asked, "could the ethical physician ever allow
20	her patient to be allowed to be randomized to treatment?"
21		Well, there were a lot of attempts at answering
22	that question, and I think there was only one good answer,
23	and the answer I think is a very clever one, and it is, of
24	course, clinical equipoise, and you see the definition

25	there, I have already mentioned it, but let me tell you what

			80 1	I think is actually really important and innovative about
	2	it.
	3		Clinical equipoise actually recognizes that under
	4	certain circumstances, treatments within a randomized
	5	controlled trial can be potentially consistent with the

	6	standard of care to which clinicians are held in their
	7	practice.
	8		Now those conditions are when there is a state of
	9	honest professional disagreement among expert clinicians as
10	to the preferred treatment.  So, then, equipoise recognizes
11	that experimental treatments or other treatments within a
12	randomized controlled trial may be consistent with the
13	standard of care and therefore, and importantly, consistent
14	with the physician's duty to her patient, and that is the
15	reason why, under these constraints, doctors may ethically
16	offer trial enrollment to their patients.
17		[Slide.]
18		Essentially, when one thinks about the choice of
19	control treatment, this has implications for when one can
20	permissibly use a placebo control.  Let me give you just

21	sort of a summary view of this.
22		Essentially, equipoise holds that for first
23	generation treatments, in other words, when there is no
24	available therapy, one ought to, in fact, use a placebo

25	control, but for second generation treatments, certainly

			81 1	after placebo-controlled trials have demonstrated a

	2	treatment to be effective for a particular patient
	3	population, for second generation treatment, the comparator
	4	must be an active control.
	5		Now, Benjie Freedman, when sort of working out

	6	logically the implications of this, said there were five
	7	circumstances in which one may use ethically a placebo
	8	control.  First off is there is no standard therapy.  Second
	9	off, a standard therapy is no better than placebo.  Third, a
10	rather theoretical category, the standard therapy is
11	placebo, not too common.
12		Importantly, if there is doubt regarding the net
13	therapeutic advantage of standard therapy, now I don't know
14	the exact circumstances of the chloramphenicol trial, but it
15	seems to me that it is conceivable that the chloramphenicol
16	trial, in fact, was perhaps done because there was rising
17	doubt as to whether chloramphenicol was safe and effective. 
18	So, that is an example of that important condition.
19		Finally, when standard treatment is unavailable

20	due to cost or short supply.  This obviously touches on the
21	HIV trials in Africa and Thailand, that whole debate, and I
22	pray that we are not going to get into that here.
23		One other thing I might mention is that the

24	question of no standard therapy also might apply to
25	circumstances where no treatment is a part of standard

			82 1	therapy, and so, for example, the otitis media study that we
	2	heard about where a substantial proportion of clinicians, in
	3	fact, would not advocate the use of antibiotics under
	4	certain circumstances might be a case in which we could do a
	5	placebo-controlled trial.
	6		Now, Dr. Temple, in his lecture--and I do have to
	7	respond to this because Dr. Temple does like to talk about
	8	ethics, which is a good thing--but he comes up with a
	9	standard that he claims is well accepted.
10		It may be believed by many, but it is surely
11	without any moral foundation, and that standard is that it
12	is okay to do a placebo-controlled trial unless you are
13	going to kill someone or disable them permanently.
14		Well, that seems to me to be problematic.  Recall
15	now that all of this comes from the physician's duty to her
16	patient, the physician's duty of care to her patient.  For
17	Dr. Temple and others who believe this standard to actually
18	provide a moral justification, to actually say that this is
19	a philosophically sound notion would have to begin by
20	arguing that, in fact, a physician's duty of care for her
21	patient is only limited to circumstances in which the
22	patient might die or be permanently disabled.
23		Now, if that troubles you, if you think that maybe
24	that would be a bad thing for the practice of medicine,

25	then, it follows as a matter of pure logic that you must

			83 1	also be troubled by the standard that Dr. Temple has put
	2	forward.
	3		[Slide.]
	4		Let me add a couple of additional cases to Benjie
	5	Freedman's list.  I think they are implicit, but let me just
	6	make them explicit.
	7		I think it is similarly unproblematic to do trials
	8	on patients who are, in fact, refractory to standard
	9	treatment or standard second-line treatment or standard

10	third-line treatment, what have you, and the reason is, is
11	because for refractory patients, there is by definition no
12	standard of care, right?  So, it actually falls under the
13	first of the five of Freedman's conditions.
14		[Slide.]
15		Another important example is that it is perfectly
16	permissible to use a placebo control in add-on studies. 

17	Why?  Because everybody gets the standard therapy, nobody is
18	being deprived of any needed medical treatment, and so, in
19	fact, it is permissible when everybody gets standard
20	therapy, to do a comparison of the experimental treatment
21	versus placebo.
22		[Slide.]
23		Now, this is an example of why people like me
24	should never be given programs like Power Point, you know,
25	because then we try and put graphs in and numbers.  This is,

			84 1	as I am sure you will agree, completely incomprehensible.
	2		What I wanted to talk about for a few minutes here
	3	--and please ignore this slide--are what I think are some

	4	advantages of active control equivalent studies, because
	5	until about 1996 or so, when Benjie Freedman and myself
	6	published a two-part paper in the Journal of Law and

	7	Medicine and Ethics, in the fall '96 issue actually, really
	8	people were talking about placebo controls and their
	9	miraculous advantages as if the only alternative was to do
10	bad research, to do sloppy research, to do unfortunate
11	things like take a standard superiority trial, and if there
12	is no difference between the two treatments, fallaciously
13	conclude that they are equivalent.
14		Well, of course, that is bad science, and really
15	nobody has seriously suggested otherwise.  What we
16	suggested, however, is that there are, in fact, rigorous

17	trial designs called an active control equivalence study out
18	of respect for the originators of the trial design, and
19	that, in fact, in circumstances, many circumstances in the
20	regulation of drugs, it seems to address the questions that
21	we want to get to.
22		Ultimately, a placebo control is only going to
23	provide us with information as to whether a new treatment is
24	better than nothing.  Well, it seems to me that in our
25	society, a society of rising costs, the multiplication of

			85 1	me-too drugs, and so on, that, in fact, perhaps we might
	2	want to know whether the new treatment is as good as what we
	3	are using now.
	4		I think there are some real advantages of this
	5	trial design, the so-called active control equivalence
	6	study.  Dr. Temple has described it to you quite accurately
	7	I think, and really what it asks is, is there strong
	8	evidence that this new treatment is no worse than a certain
	9	percentage, no more than a certain percentage worse than the
10	current treatment.  So, is it no more than, say, 10 percent
11	worse than, and if we have strong evidence of that, then, we
12	will conclude that the treatments are equivalent.
13		If one actually wanted to do an active control

14	superiority study, the studies would need to be huge for
15	sure.  Here, I have one example, you know, assuming certain
16	placebo effects, standard drug effects, new drug effects,
17	and so on, and you can see that the active control study
18	would, in fact, be something like 14 times larger than the
19	placebo-controlled study.
20		But, in fact, an active control equivalence study
21	surely is larger than a placebo-controlled study, perhaps
22	one and a half times as large, two and a half times as

23	large.  It depends very much how you define equivalence.
24		But the point is, is that sample size requirements
25	are actually intermediate between the placebo control and

			86 1	the active control superiority study, and I think that
	2	largely makes it feasible.
	3		So, that is the point of this slide.  There is

	4	only one word that this slide should actually have on it,
	5	and it should just say "feasible."  I will change that.
	6		[Slide.]
	7		I think there are scientific and clinical
	8	advantages to active control equivalence studies.  I think
	9	that so-called Ace studies ask questions that are actually

10	clinically relevant.  Now, the FDA, under the 1962 Kefauver-
11	Harris Act, as I understand it, is actually only able to
12	require that new drugs have some effect.
13		So, in fact, the actions of the FDA may be
14	somewhat limited by the provisions of that Act.  Well, that
15	isn't necessarily what clinicians want to know, and that
16	isn't necessarily what patients want to know.  It seems to
17	me that the standard, is this treatment better than nothing,
18	is inadequate.  Better than nothing is just not good enough.
19		An Ace study asks I think the question that

20	clinicians and patients want to know, that is, is this
21	treatment as good as or better than what we are currently
22	using.
23		[Slide.]
24		There are other scientific advantages.  We talked
25	earlier about the use of Claritin, non-sedating

				87 1	antihistamines.  Well, you know, in fact, an active control
	2	equivalence study helps us ask exactly that question.  We

	3	could say are they roughly equivalent, and furthermore, a
	4	superiority question, does it have less side effects.  So,
	5	there is the possibility of incorporating multiple
	6	hypotheses into this trial design.
	7		[Slide.]
	8		Well, I think there are regulatory advantages,
	9	too.  I think we have to worry about the fact that a
10	regulatory agency may approve a drug that is superior to
11	placebo, but, in fact, that does not rule out the
12	possibility that the drug is substantially inferior to
13	standard treatment, and it seems to me if the purpose of a

14	regulatory agency is to protect the public in some way, that
15	we need evidence that new treatments are, in fact, at least
16	equivalent to old treatments.
17		There is also the issue of cost, why is it that
18	new drugs never seem to be cheaper than the old ones.  Well,
19	as you are discovering here in the United States, and as we
20	are discovering in Canada, in fact, we can't afford

21	everything, and some concerns about the cost of new
22	treatments need to be incorporated into studies.
23		This was noted by Henry and Hill in the BMJ a few
24	years ago, who said many new drugs are expensive, and in

25	some countries, drug budgets are growing faster than other

			88 1	health care sectors.  The key questions are:  how much
	2	better are the new drugs than the old ones, how much more
	3	does it cost to obtain additional benefits, and does the
	4	extra cost represent value for the money.
	5		Well, I think those are important questions, and I
	6	think, as a society, we need to address them.
	7		[Slide.]
	8		There are also ethical and legal advantages.  I

	9	have said a lot about this, but let me put it yet another
10	way, an advantage of an active control equivalence study is
11	that patients are not knowingly given inferior treatment,
12	and that fundamentally is what is at stake.
13		That is what the Declaration of Helsinki--you
14	noticed I haven't mentioned that document--but that is what
15	it really means in that sort of confused wording of Article
16	2.3, is that the medical care of patients ought not be
17	disadvantaged by trial participation.
18		That is what it means.  I have avoided appealing
19	to it.  I think it has been a mistake in the debate to

20	appeal to it too much because it's a badly written document,
21	but as I have tried to argue, research ethics and everything
22	that we have been doing in research ethics for the last 30
23	years, in fact, argues to the same conclusion.
24		I think doctors, institutions, institutional
25	review boards, and who knows, maybe even regulators, ought

			89 1	to be worried about the liability of enrolling patients in
	2	placebo-controlled trials when effective standard treatment
	3	exists.
	4		As I have said, doctors owe a duty of care to
	5	their patients, and an investigator's chief concern ought to
	6	be the health and well-being of her patient, not her own
	7	career, not, you know, sort of the consulting fees that she
	8	gets from the drug company, not making the FDA happy, but
	9	the health and well-being of her patient.
10		Providing a placebo when standard effective care
11	exists may, in fact, be negligent practice and may be the
12	basis of a lawsuit.
13		[Slide.]
14		So, what we have tried to get here are a couple of
15	questions - placebo-controlled trials, are they ethical, are
16	they necessary?  I think the answer we have gotten to is
17	sort of a qualified no to both questions.  Surely, placebo-
18	controlled trials may be accepted in carefully defined
19	circumstances.
20		I have talked about add-on treatments, treatment-
21	resistant patients, where there isn't a standard of care,
22	and so on, but I think the active control equivalence study
23	design is underutilized, and I have tried to outline how, in
24	fact, there are some scientific, clinical, regulatory,
25	ethical, and legal advantages to that design.

			90 1		Thank you.
	2		DR. CHESNEY:  Thank you very much, Dr. Weijer.
	3		Our next speaker is Professor Francis Crawley, who
	4	is Chairman of the Ethics Working Party for the European
	5	Forum for Good Clinical Practice, and a member of the Ethics
	6	Working Group for the Confederation of European Specialists
	7	in Pediatrics.
	8		He is going to be speaking to us about ethical

	9	concerns in pediatric placebo-controlled trials from the
10	European perspective.
11	      Ethical Concerns in Pediatric Placebo-Controlled
12		  Trials from the European Experience

13		PROF. CRAWLEY:  Thank you, Madam Chair.
14		Ladies and gentlemen, it is really a great
15	privilege and an honor for me to have a few minutes to
16	address you on the European experience with respect to
17	pediatric controlled trials.

18		I want to thank Drs. Jayne Peterson and Elaine
19	Esber for helping to facilitate my presence here and also

20	for helping me to understand the conversation that you have
21	been having as a committee, the ongoing conversation you
22	have been having with respect to the ethics and the science
23	of clinical trials in the pediatric population.
24		I also think that I should thank Dr. Robert Temple
25	for, although we haven't communicated on this particular

			91 1	meeting, he has been very helpful to me personally in
	2	understanding the relationships between the U.S. and Europe
	3	and in a wider sense, as well, through much of his
	4	participation in the discussion.
	5		I think it really is a great honor to be here to
	6	be able to speak to this committee.  What you people in this
	7	committee will decide will affect not only children in the
	8	United States, but it will affect directly children in
	9	Europe, and I can tell you from my experience with the WHO
10	and UN-AIDS and CIOMS, it will affect children directly in
11	the world at large.  Your openness to have persons such as
12	myself and Dr. van Zwieten-Boot to be able to come and talk
13	about our experience will help this.
14		I think also there will be a reciprocal
15	relationship, as well, and that is the way in which we
16	decide in Europe to conduct clinical trials in the pediatric
17	population will also affect to some extent the way pediatric
18	trials are carried out in the United States.
19		Dr. van Zwieten-Boot presented you with what I

20	think is an excellent map of the regulatory framework for
21	clinical trials in Europe, a very complex and difficult

22	mapping.  As she pointed out, I am somewhat outside of that
23	map, and the map I wanted to introduce you to, just in a
24	wider sense perhaps, another map of Europe, has to do
25	perhaps with health and the situation of health in Europe.

			92 1		I want to point out to you that it was not until

	2	1992 that the European Union received a mandate in public
	3	health, that mandate described in the Treaty of Maastricht,
	4	and it is reiterated and described somewhat differently in
	5	the Treaty of Amsterdam.
	6		This is a limited, very limited area for the
	7	European Union to act in the area of health.  Most of the

	8	actions in the area of public health are reserved for the
	9	member states, and that affects clinical trials directly,
10	and I think Dr. van Zwieten-Boot showed that quite well
11	here.
12		[Slide.]
13		Also, Europe is not only the 15 member states to
14	the European Union, as you all know.  There are 41 member
15	states of the Council of Europe, and all of these member
16	states feel themselves to be European, and are, from a

17	European's point of view, European.
18		So, Europe is a wide concept and a complex and
19	difficult concept.  Within the concept of Europe, there is a
20	wide expression of different feelings about culture and how
21	culture influences decisions that are made in the important
22	areas of our lives, and one area, of course, is health.
23		I can tell you on Saturday I attended a meeting in
24	Belgium of specialists in radiation where there were
25	speakers who came from England to present a particular point

			93 1	of view on managing radiation practice, and one could feel a
	2	strong difference between a U.K. approach and a Belgian
	3	approach to rather simple matters in care and common
	4	practice.
	5		As. Dr. van Zwieten-Boot pointed out, at the
	6	European level, one is very hesitant to talk about ethics

	7	outside of cultural context.  There are good reasons for
	8	that.  But nevertheless, both within the regulatory
	9	framework, as Dr. van Zwieten-Boot pointed out, and also

10	outside of that framework, there is a wide discussion today
11	going on now, an increasing discussion on the role of
12	clinical trials in pediatric medicine, and that is what I
13	want to look at with you.
14		I have given you some handouts, but I have also,
15	in the presentation itself, I have reduced the number of

16	slides I will speak to, and I will try to speak most
17	directly now to the issue of the placebo-controlled trial in
18	pediatrics.
19		[Slide.]
20		This slide you don't have in your collection.  It
21	is the only slide you don't have.  I have tried to summarize
22	somehow by using some concepts here.  I think that the
23	pediatrician's concern in practice, the physician's concern
24	in practice has to do with the duty of care and the standard
25	of care, and decisions based on these two ethical and

			94 1	deontological requirements.
	2		The duty of care is clearly an ethical
	3	requirement, indeed, it is a requirement we all have in all
	4	areas of our life, but it is also requirement specific with
	5	respect to health that the physician has, and that is
	6	expressed in the Physician's Oath.
	7		The standard of care is an expression, in a
	8	certain sense, of a generalizable way of caring for patients
	9	in particular circumstances, and this standard of care is
10	usually put forward by the profession itself, and is a
11	deontological standard.
12		Both the duty of care and the standard of care are
13	generalizable concepts that speak to a generalized

14	population, but the physician or the pediatrician is
15	concerned in an ethical sense in the first place with the
16	person who is standing in front of him or her, and that

17	means you are concerned with an individual in treatment, and
18	here, we can speak of the bonus pater familias here, the

19	responsibility the physician has to decide in a specific
20	circumstance using generalizable concepts and generalized
21	background from the duty of care and the standard of care.
22		[Slide.]

23		Ronald Kurz, Professor Kurz from the University of
24	Graz in Austria is the Chairman of the Confederation of

25	European Specialists in Pediatrics, the Working Party on

			95 1	Ethics.  He was formerly, until this year, he was also
	2	President of CESP.
	3		He recently expressed that, "It is in the interest
	4	of children to evaluate medicinal products with
	5	scientifically proven methods.  A precondition is minimizing
	6	distress and risk due to studies."
	7		I think that what we can say in a generalizable
	8	sense today for the European experience would be the
	9	following two things:  One, there is a need to examine
10	clinical trials in pediatrics.  There is a need to do them. 
11	I think there is a greater awareness of a need for it, of
12	the deficiency in pediatric medicine without having those
13	trials, and a concern with how to carry them out.  That is
14	one thing to say.
15		A second thing to say, as Professor Kurz here
16	indicates quite clearly, is I find in the European
17	discussion, I think in almost any country I go to within the
18	terms here, is that there is a strong interest in protecting
19	the child, but not only protecting the child, but in finding
20	out what the interests and the concerns of the trial are,

21	and allowing those interests and concerns to be articulated
22	within the circumstances of treatment, which in a clinical
23	trial sense would be in the circumstances of
24	experimentation.
25		That is an interest to assure that the voice of

			96 1	the child is heard, and that at any age.
	2		[Slide.]
	3		Professor Peter De Deyn from the University of
	4	Antwerpen recently wrote that, "Properly controlled
	5	randomized controlled trials form the only scientifically
	6	valid tools."
	7		In his writing here, he reflects a very strong

	8	European position, and I think an international position
	9	today, since 1948 with the British Medical Association, the
10	British Medical Journal, the expression of the randomized
11	controlled trial as the founding or as the way of
12	justifying, giving us evidence for one treatment versus
13	another treatment.
14		[Slide.]
15		He goes further, Professor De Deyn, he insists,
16	and I quote, "It is ethically justified that the optimal,
17	and therefore often placebo-controlled and ethically
18	founded, randomized controlled trial meets the duties of
19	benefiting society and increasing knowledge"--and then here
20	I think somewhat less sophisticated than Dr. Temple--"and
21	without jeopardizing the well-being of the experimental
22	subjects."
23		[Slide.]
24		The justification for randomization is scientific
25	equipoise or equipoise in general, and we can look at this

			97 1	as both scientific equipoise and personal equipoise, and we
	2	can take this back to the earliest writings on randomized
	3	controlled trials in 1948 in the BMJ.
	4		[Slide.]
	5		Scientific equipoise insists that the medical
	6	community is genuinely uncertain as to which treatment is
	7	best.
	8		[Slide.]
	9		Personal equipoise, that the patient
10	himself/herself is in a situation, as well, of uncertainty
11	as to which treatment is best.  Sometimes personal equipoise
12	also refers to the physician's own uncertainty, the
13	investigator's own uncertainty here.
14		But also I think it is very important--and in
15	terms of pediatric trials, this idea of personal equipoise
16	is very important--because the justification for the
17	invitation to the patient is not only a scientific
18	justification here, but it is also a justification in the
19	motivation for the patient to consent.
20		Of course, in the pediatric population, this
21	becomes more complex.
22		[Slide.]
23		Drs. Wagner and Herrmann, they are both
24	philosophers, trained in philosophy, Ph.D.'s in Philosophy. 
25	Dr. Wagner works for Solvay Pharmaceuticals in Germany.  Dr.

			98 1	Herrmann is a Professor of Bioethics at the University of
	2	Berlin.
	3		In a recent article, they are wrote that, "Benefit
	4	and risk are ethical commodities determined normatively on

	5	the basis of empirically proven preparation characteristics
	6	occurring with a certain probability."
	7		I have lifted this out of context.  I think it
	8	speaks for itself out of context.  In context, there is no
	9	undertone here, there is no problematic with this.  For me,
10	there is a problematic here.  I think what they are saying
11	is quite true.  Benefits and risks are commodities that we
12	are using in ethics in order to justify randomized

13	controlled trials.  We are using our weighing and assessment
14	of benefit-risk as normative ethical tools for justifying
15	randomized controlled trials.  They are commodities.
16		[Slide.]
17		Again, there seems to be no awareness I think in
18	the article of what is being said here.  "For the management
19	of uncertainty, ethical principles are important decision-
20	/action-guiding tools."
21		If the randomized controlled trial is the Golden
22	Rule, then, it is uncertainty that becomes the problematic
23	for ethics in science, and here, both from an industry point
24	of view, if you want, and from an academic point of view, it
25	is the management of uncertainty that forms our key interest

			99 1	in the design and carrying out of randomized controlled
	2	trials.
	3		[Slide.]
	4		So, a question.
	5		[Slide.]
	6		Are placebos and controls ever justified in
	7	pediatric research?  The answer is clearly yes.  Both are
	8	permissible in some circumstances.  Where their use is

	9	justified in adults, the same may be true in children,
10	subject to consent.

11		[Slide.]
12		Are placebos and controls ever justified in
13	pediatric research?  The answer is clearly no.  New

14	treatments should always be tested against old and there is
15	no case for withholding established treatments from children
16	even if the evidence for efficacy is thin.  Furthermore,
17	placebos mean deception and controls signify uncertainty of
18	a kind--uncertainty again--of a kind to which children
19	should not be exposed.  This was published by Professor Tim
20	Chambers from Ireland just recently this year.  This is the
21	seventh question of the seven questions.
22		[Slide.]
23		Conclusion.  Pediatric placebo-controlled trials
24	can only be justified when the design, enrollment, and
25	conduct of such trials are such that they are in the best

				100 1	interest of the child-participant with a view towards
	2	his/her health and a concern with his/her dignity.
	3		Thank you very much.
	4		DR. CHESNEY:  Thank you, Dr. Crawley, for
	5	clarifying the seventh question of the seven questions.  I

	6	think with the permission of the Executive Secretary, that
	7	we will take a 10-minute break now and then come back with
	8	questions before we hear from Dr. Ellenberg.
	9		If you could be sure to be back in 10 minutes,
10	please, we will proceed.
11		[Break.]
12		DR. CHESNEY:  The questions that we are being
13	asked to address, which are in the handout that was on the

14	table this morning, are slightly modified from the ones that
15	we received at home, so please be sure to use the ones that
16	are in the forms that were on the table.
17		Now we have 10 minutes for questions from the
18	subcommittee for Drs. Weijer and Dr. Crawley.
19		Yes, Dr. Danford.
20		    Questions from the Subcommittee
21		DR. DANFORD:  I would like to ask Dr. Weijer in
22	particular about two potential criticisms I see with the
23	concept of clinical equipoise that he cites as a principle
24	on which the ethical clinical investigation is based.
25		It seems to me that this might be a somewhat murky

			101 1	standard and a somewhat inappropriate one, murky in that it
	2	doesn't really give us a threshold to go by of what

	3	represents actual genuine clinical uncertainty, and
	4	inappropriate in that we have numerous examples where the
	5	standard of care and the opinion of experts hasn't really
	6	stood up to the harsh light of scientific scrutiny.
	7		Could he address those two issues and see if he
	8	can support the concept of clinical equipoise a little bit
	9	better?
10		DR. CHESNEY:  Dr. Weijer, did you hear the
11	question?
12		DR. DANFORD:  I can ask it more briefly.  Is

13	clinical equipoise too murky a concept for actual use in
14	that we don't have a threshold to tell us what represents
15	genuine uncertainty, and is it too inappropriate a standard

16	in that the standard of care and the opinions of experts are
17	so often wrong when they are held up in the harsh light of
18	scientific research?
19		DR. WEIJER:  Thanks for that question.  Hopefully,
20	all the other banquet rooms will hear my answer, too.  It's
21	only just.
22		[Laughter.]
23		DR. WEIJER:  No, I don't think--I think
24	historically, one needs to recognize where the concept of

25	clinical equipoise comes from, and I think that is why I

			102 1	brought us back to the question which people seem to forget,
	2	and it was a burning question 20 years ago.  The question
	3	is, can an ethical physician ever offer trial enrollment to
	4	a patient under her care.
	5		I think the innovation of equipoise is to
	6	recognize that experimental treatments or other treatment
	7	arms within a randomized controlled trial may be consistent
	8	with standard of care, and therefore, offering trial
	9	enrollment may be consistent with the ethical and legal
10	duties of the physician.
11		Clinical equipoise is certainly no more murky than
12	the notion of standard of care, which is the legal and

13	ethical norm that governs the practice of physicians.  I
14	don't believe it suffers from any fault or any more
15	murkiness than the notion of standard of care.  Standard of
16	care with perhaps its flaws successfully governs the

17	practice of physicians, so therefore, I think clinical
18	equipoise with its certain amount of murkiness admittedly is
19	an adequate standard for clinical research.
20		Fundamentally, you know, you might ask, well, what
21	is genuine uncertainty, and there being all kinds of really
22	silly studies published, you know, saying what percentage of
23	physicians, is it 50 percent have to think this new
24	treatment is a good idea, or 49, or what have you, and I
25	think that fundamentally misconstrues the question.

			103 1		What it is in an ethical standard meant to guide
	2	the deliberations of IRBs, and the point of the matter is,
	3	is that they need to take reasonable steps to assure that a
	4	state of clinical equipoise exists, and that often involves
	5	looking at the study justification, consulting with experts,
	6	looking at the literature.  In practice, it is a concept
	7	that I, many other ethicists, and many IRBs utilize, and I
	8	think successfully so.
	9		DR. CHESNEY:  Dr. Fost.
10		DR. FOST:  Well, I don't think the problem is that
11	it is murky, I just think it's the wrong standard.  That is,
12	the assumption that the community standard, that the
13	standard of practice or the community equipoise, as you call
14	it, is safe or effective is just wrong in the absence of
15	science.
16		The examples are too numerous to count, and the

17	number of children who have been killed and harmed by that
18	assumption is in the hundreds of thousands.  Let me just
19	mention a handful from your own city.
20		Dr. Usher from Montreal for 10 or 15 years had

21	every newborn in North America with hyaline membrane disease
22	with RDS being treated with concentrated solutions of
23	bicarbonate to correct the respiratory acidosis.  This was
24	standard practice.  It was universal practice.
25		Jerry O'Dell was the sole person screaming in the

		104 1	wilderness that this made no physiologic sense, that his
	2	studies in mice showed that it made no sense, but it wasn't
	3	until his disciple, Mike Simmons, did the randomized
	4	placebo-controlled trial showing that it was causing more
	5	harm than help, that these concentrated solutions were
	6	shrinking the brain and causing intracranial bleeding, and
	7	was one of the major causes of brain damage in newborns, and
	8	it is no longer done today.  Nobody does it.  But for 10 or
	9	15 years, it was, and untold thousands of children were
10	killed and harmed by it.
11	          Oxygen, the unregulated use of oxygen for nearly
12	half a century, it was standard of care, and the assumption,
13	it must be safe, you know, it's everywhere, and the notion
14	that oxygen had a dose response curve and that there was a
15	right dose to use and a wrong dose just didn't occur to
16	anybody, again until a single person began showing, Arnold
17	Pace, that it could be harmful.
18	          The whole basis of genetic screening and newborn
19	screening programs in North America, now in the world, the
20	PKU study, it was just assumed that everybody with a high

21	phenylalanine had PKU and had to be on a restricted diet. 
22	It was the standard of practice throughout the country, it
23	wasn't just the standard, it was mandated by law.  What

24	could make something more the standard?  It just didn't
25	occur to anybody for a decade that phenylalanine restriction

			105 1	could make you retarded, and second, that a high blood
	2	phenylalanine didn't mean that you were at risk for PKU.  In
	3	fact, 90 percent of children in retrospect were not at risk.
	4		Exchange transfusion for minimally elevated
	5	bilirubin in normal newborns.  I could identify studies that
	6	cumulatively have killed hundreds of thousands of children
	7	based on an assumption that the community standard was the
	8	right standard.
	9		So, it seems to me a better standard is individual
10	equipoise, that is, the investigator, himself or herself,

11	has to have reason to doubt.  The notion that the American
12	Academy of Pediatrics says this is a great treatment is, to
13	me, not sufficient.
14		The question is whether there is any science
15	behind it, and the investigator must persuade somebody that
16	there is not any science behind it and that it is worth
17	studying.
18		The second point I just wanted to disagree with
19	you on is this notion, your statement--if I have it right--
20	that the hypothesis must require using a vulnerable
21	population.  That seems to me wrong also, that is, for
22	children who have life-threatening illnesses, such as
23	cancer, for which there is no other effective treatment.
24		The hypothesis that a new chemotherapeutic
25	requires study in children is not true.  It is just that it

				106 1	may very well be in the interests of children to be in such
	2	a study.  Rabies would be another example.  If there were an
	3	effective anti-rabies drug, the hypothesis of showing that
	4	this agent is effective against rabies wouldn't require
	5	studying it in children, but if you had a child with rabies,
	6	you would surely want him or her to be in the study if there
	7	was appropriate animal work, and so on.
	8		Thank you.
	9		DR. WEIJER:  May I respond?
10		DR. CHESNEY:  Yes.
11		DR. WEIJER:  Thank you.
12		DR. CHESNEY:  I was going to ask you how much it
13	was worth to you.
14		DR. WEIJER:  Well, with respect, Dr. Fost, I think
15	listening to your comments, one would have to wonder why
16	anyone goes to a doctor.  You make it sound as if every
17	standard treatment is not only ineffective, but harmful, and
18	surely that is unlikely to be the case.
19		I think you have misread my talk on a number of
20	levels, and I am only going to have time to address a few of
21	them.  Most importantly, I am not from Montreal, I am from
22	Halifax, the proud home of Dalhousie University, and am no
23	longer at McGill.  My university requires me to point that
24	out.
25		Second of all, I am not advocating for a concept

			107 1	which you call "community equipoise."  That is a confused

	2	notion coined by John Lantos and Jason Karlowisch in the
	3	literature.  It is not one that is widely advocated.  I

	4	think I was rather clear in advocating for a notion called
	5	"clinical equipoise," advocated by Benjamin Freedman in The
	6	New England Journal in 1987.
	7		I think you also misunderstand the fact that I am

	8	not arguing against good science.  I think medicine is where
	9	it's at today fundamentally because it's undergoing a shift
10	from an art based largely on idiosyncratic ideas and case
11	stories to one that is based on a foundation of good
12	science.  I wholeheartedly support that.
13		Clinical equipoise, in fact, is the ethical notion
14	that allows randomized controlled trials to go forward in
15	medicine.
16		The examples you raised, I think are really
17	unproblematic for clinical equipoise.  You speak of them as
18	if, you know, science couldn't go forward somehow if we
19	believed in this notion of clinical equipoise.  As I think I
20	showed quite clearly in my list, there are numerous
21	circumstances.  Science can always go forward.  The question
22	is, is how is it best to go forward ethically and
23	scientifically.
24		A placebo-controlled trial, as I said quite
25	clearly, is indicated when there is a growing doubt as to

			108 1	the efficacy of an existing treatment, and therefore,
	2	clinical equipoise would have supported the trials you
	3	pointed to with regard to the treatment of RDS in neonates,
	4	the treatment of hyperoxygenation, and so on.
	5		So, Dr. Fost, those trials would have gone forward
	6	under the notion of clinical equipoise.
	7		I guess there is so much more I would like to
	8	respond to, but just let me say one last thing, that with
	9	regard to my requirement that the study hypothesis requires
10	the inclusion of the vulnerable population, again, you
11	misconstrue me.
12		The study hypothesis, for example, in a
13	chemotherapy trial involving children is not is this
14	chemotherapy agent in the abstract effective and therefore
15	we could just test it in adults, but rather, is it effective
16	in the treatment of this particular childhood cancer, and
17	that, of course, would be sufficient, you know, ceteris
18	paribus, to justify the inclusion of children in that study.
19		I am sure we will have more to say to one another
20	later.
21		DR. CHESNEY:  Thank you.
22		One more question.  Dr. Nelson has been indicating
23	he had one for some time now, and then we will move on.
24		DR. NELSON:  Charles, you may want to stay at the
25	mike because I am interested in your reaction to this

			109 1	interpretation, moving in a slightly different direction.
	2		I find myself compelled and have learned a lot in
	3	reading about the issue of assay sensitivity and the need
	4	for an internal control within a trial to be able to
	5	determine that.
	6		My question is this.  If one of the conditions
	7	under which you need such an internal trial is where there
	8	is a diverse population of variable response, there is sort
	9	of difficulty in predicting whether a population would
10	respond to treatment that is proven effective.  Let's limit
11	it to those circumstances.
12		Could one bring that down to the specific patient-
13	clinician encounter where one would then be uncertain if
14	that individual before you would have a spontaneous
15	resolution, would respond to the drug or wouldn't, not to

16	where the uncertainty in that clinical encounter could be a
17	justification for recommending to that patient consistent

18	with one's obligation that you enroll in a trial that has an
19	internal standard even in the presence of a proven effective
20	agent?
21		DR. WEIJER:  Thanks for that question.  It
22	reminded me that there was something else I wanted to say to
23	Dr. Fost.
24		This notion of individual equipoise, I think more
25	properly referred to as "Peto's uncertainty principle," is

			110 1	an idea that a lot of people find appealing.  Certainly if
	2	you are British, I believe you are bound to swear allegiance
	3	to it.  Certainly in North America, it is a notion that is
	4	beginning to take hold.
	5		Basically, it says, you know, it is ethical for a
	6	trial to proceed so long as the individual doctor is
	7	uncertain in her own mind as to the preferred treatment for
	8	a particular patient, essentially your question I take it.
	9		It is I think a deeply problematic notion, and in
10	the next couple of week I have got an article coming out in
11	the British Medical Journal actually criticizing the notion
12	of the uncertainty principle in favor of clinical equipoise.
13		The problem with just resting everything on the

14	uncertainty of the individual clinician is multiple.  First
15	off, and I think most fundamentally, it fails to recognize
16	that the norms to which we hold clinicians are not
17	individual norms, but rather community norms.
18		They are governed by the norm of the standard of
19	practice of the community of expert clinicians.  There are
20	good reasons why we don't allow individual doctors to be

21	guided by whatever beliefs happen to be in their head simply
22	because doctors, just like everyone else, can hold crazy

23	beliefs or incompetent beliefs, and the sort of standard
24	that the uncertainty principle articulates would offer no
25	grounds upon which to find those actions problematic.

			111 1		The second problem with that kind of thinking is
	2	that it doesn't allow randomized controlled trials to be
	3	conducted in a very important circumstance, namely, where
	4	everybody is certain.
	5		Now, that may sound curious to you, but, in fact,
	6	there are all kinds of circumstances where everybody is sure
	7	they know what to do.  They just all disagree with one
	8	another.
	9		Take, for example, a trial, a very important trial
10	in the early seventies, NSABP BL-6, the conservative breast
11	management versus mastectomy trial, which it essentially
12	addressed the question of, for the treatment of early breast
13	cancer, do we need to engage in fairly radical surgery or

14	can we use breast-conserving surgery followed by radiation
15	therapy.
16		Well, surgeons are a pretty certain lot overall,
17	and in fact, there were such strong feelings in these two
18	camps that the trial had a tremendous amount of difficulty
19	getting off the ground.  Well, according to this notion of
20	individual uncertainty, individual equipoise as we have

21	heard it called, or I think more properly Peto's uncertainty
22	principle, those important trials, when there are
23	essentially two entrenched camps each advocating their own
24	treatment, could not ethically proceed.
25		Of course, according to clinical equipoise, which

			112 1	recognizes community disagreement, those important trials
	2	would be allowed to go forward.
	3		DR. CHESNEY:  Thank you very much.  Interesting
	4	point.
	5		Dr. Susan Ellenberg will speak with us next.  She
	6	is the Director of the Office of Biostatistics and
	7	Epidemiology for the FDA, and she is going to address a very
	8	important issue, which is are data safety monitoring boards
	9	necessary for every pediatric trial or under what
10	circumstances might they be useful.
11	     Use of Data and Safety Monitoring Boards and their
12		   Role in Pediatric Clinical Trials
13		[Slide.]
14		DR. ELLENBERG:  I thought we should start with a
15	definition.  A data monitoring committee--this is my
16	definition, other people may have different definitions,
17	pretty straightforward--is a group of experts that reviews
18	the ongoing conduct of a clinical trial to ensure continuing
19	patient safety as well as the continuing validity and
20	scientific merit of the trial.
21		[Slide.]
22		These committees go by a variety of names.  I am
23	using the phrase data monitoring committee because that has
24	been the phrase adopted in the International Conference of
25	Harmonization documents.  You will frequently hear these

			113 1	called data and safety monitoring boards.
	2		I think you can take as many as you want from
	3	Column A and one from Column B and one from Column C, and
	4	you will probably find some committee somewhere that has
	5	been called by that name.  So, I didn't want anybody to be
	6	confused as to whether a data monitoring committee is
	7	something different from what they are used to having it
	8	called.
	9		[Slide.]
10		Why do we need to do interim monitoring of trial
11	data?  I am not sure if I need to even address this question
12	given the chloramphenicol example that was presented
13	earlier, but there are a number of reasons actually that go
14	beyond that.
15		First, we want to identify rapidly any safety

16	problem, and that is important for interim monitoring
17	whether or not there is a data monitoring committee.  You
18	have got to watch and make sure there is nothing unexpected
19	that was happening that would make you reconsider whether
20	the trial should continue.
21		You need to look at the data to identify any

22	logistical problems with trial conduct that you might be
23	able to correct, and therefore, have a better quality trial
24	by the time you get finished - is the accrual inadequate, is
25	there undesirable distribution of baseline characteristics. 

			114 1	Maybe something was wrong with the randomization program. 

	2	Are there too many dropouts and too much noncompliance, and
	3	some intervention may be needed to make the trial
	4	worthwhile.
	5		We want to evaluate the continued feasibility of
	6	the trial as presently designed.  If some of these problems
	7	can't really be fixed, it may not be worth continuing the

	8	trial, and perhaps we should go on to something else, and
	9	finally, and what gets the most press, to determine whether
10	the trial objectives have already been met and the trial may
11	be terminated early.  That is, the results are sufficiently
12	definitive that we don't need to go on to the end.
13		[Slide.]
14		Why data monitoring committees?  Because
15	everything that I have said doesn't mean that you need to

16	have some kind of external committee.  The people who are
17	doing the trial could pay attention to all those things.

18		A data monitoring committee I think is needed for
19	two main reasons.  One, to ensure that there will be regular
20	and systematic interim monitoring.  We all know in our
21	practice of our daily lives that there are certain things

22	that we know that we should be doing, but we put them off,
23	we don't pay as much attention to it as perhaps we should.
24		When you have a committee that is meeting on a
25	regular basis, those data are going to be looked at, and

			115 1	they are going to be assessed, and that is important.
	2		Secondly, to provide an objective and a
	3	statistically valid assessment of the interim data.  This is
	4	probably the major motivation for developing data monitoring
	5	committees in the first place.
	6		[Slide.]
	7		I am going to say a little bit about statistically
	8	valid because there are some complications here.  Assurance
	9	of ongoing patient safety requires regular review and
10	assessment of the accumulating data, but if we continue to
11	do statistical tests each time we look at the data, we will
12	increase our false positive rate.
13		If we define our statistical criteria, so that
14	there is only 1 chance in 20 that we would have a result
15	this extreme, if there were really no difference, and if you
16	do that test 5 or 10 or 20 times during the course of the
17	trial, the chance is much higher than 5 percent that you
18	will eventually see that p less than 0.05, and you will have
19	totally misled yourself as to the strength of the evidence.
20		So, once that was recognized, I think in the
21	sixties and seventies there started to be publications about
22	this, recognize that the strategy of just watch the data as
23	it goes along and stop as soon as the p is less than 0.05 is
24	inadequate.
25		[Slide.]

			116 1		The most common approach used in clinical trials

	2	is something called group sequential testing.  Instead of
	3	looking at the data as it comes in, you agree that you are
	4	going to look at it every 6 months, every 3 months, every

	5	year, whatever seems appropriate to the trial, the analyses
	6	are performed at pre-specified intervals and a statistical
	7	plan, a statistical monitoring plan is developed that
	8	provides boundaries showing what p-values might be required
	9	for early termination.
10		That would be consistent with having an overall
11	false positive rate as low as the one we want, and those p-
12	values usually vary with time.  That is, you need a much

13	stronger strength of evidence to stop early in the study,
14	and as you get close to the end of the study, the p-values
15	are more closer to the nominal 0.05, but the overall Type 1
16	error for the study is controlled at 0.05, and there are
17	actually numerous ways to do this that I am not going to get
18	into.
19		[Slide.]
20		No matter how fancy a statistical procedure you
21	have, you can never get away from the need for judgment.  It
22	is not a question of pushing a button and seeing whether you
23	are across the statistical boundaries.  These considerations
24	alone are inadequate for monitoring.
25		The algorithms that are developed, which I think

			117 1	have been very, very useful in clinical trials, cannot
	2	account for all possible developments, and the exercise of
	3	clinical judgment is essential to the monitoring practice.
	4		For one thing, your p-value is usually based on a
	5	single outcome variable, your primary outcome variable. 
	6	There is a balancing of safety and efficacy outcomes that is
	7	absolutely essential.  If you are across the boundary for

	8	efficacy, but some unexpected safety problem has arisen,
	9	that has to be balanced against the emerging efficacy
10	outcomes.  It may not be so clear that the study should be
11	stopped yet.
12		There needs to be consideration of unexpected

13	outcomes, as well as consideration of new information
14	external to the trial.  Another related trial finishes

15	somewhere else and has been published, and that may have an
16	impact on whether or not this study should be continued.
17		[Slide.]
18		Just a brief history of the data monitoring
19	committees in the U.S.  They have traditionally been used
20	primarily for trials with mortality or major morbidity
21	endpoints.  In those trials, there is an ethical imperative
22	to monitor efficacy, as well as safety.  In fact, you can't
23	even distinguish efficacy and safety if you have a major
24	endpoint because if there is inferiority with regard to the
25	efficacy endpoint, it is a safety concern.

			118 1		Also, in these kinds of trials, the objectivity is
	2	seen as extremely important.  It becomes much more difficult
	3	when you are looking at mortality outcomes or other very
	4	serious outcomes.
	5		There is just a tendency to not want to let things
	6	get too much out of hand and having to balance that with
	7	wanting to make sure that you have a scientific result that
	8	people can believe and that will be persuasive becomes
	9	difficult.  So, it is good to have an objective view, people
10	who aren't formally involved in the trial.
11		Data monitoring committees have been components of
12	many NIH-sponsored trials since at least the early 1960s. 
13	In fact, in the U.S., that is where data monitoring
14	committees got started.  They were rarely used in industry
15	trials prior to 1990, I think because for the most part,
16	industry trials didn't focus on mortality and major
17	endpoints early, but with the increasing number of industry-
18	sponsored trials with major endpoints, there is an
19	increasing interest in use of data monitoring committees in
20	other than government-sponsored trials.
21		[Slide.]
22		So, on to the important question of what trials

23	need data monitoring committees.  One answer is not all
24	trials needs data monitoring committees.  I think that we

25	would get ourselves into a situation of doing more harm than

			119 1	good if we required all trials to have data monitoring
	2	committees, but some trials would clearly benefit.
	3		[Slide.]
	4		Trials that might be stopped early for efficacy. 
	5	Generally, it is very good to have a data monitoring
	6	committee, and for the most part, these are trials where the
	7	treatment is aimed at reducing mortality or morbidity.
	8		If you are looking at a treatment to relieve a
	9	relatively mild symptom, even if you had a super blockbuster
10	effect early on, you would probably want to continue the

11	trial at the end because you would want to have a full
12	safety database with a comparison to the placebo.
13		You would want to understand everything about
14	possible safety concerns because what this treatment does

15	may be useful, but it is not that critical to people's basic
16	health.  So, that is when you need a committee to look at
17	those efficacy results and the stopping boundaries
18	carefully.
19		So, in these kinds of trials, there is an ethical
20	requirement to terminate a clearly inferior treatment, which
21	there would not be necessarily in a less serious situation,
22	and there is a need to ensure that the kind of statistically
23	valid approach that I mentioned before is used for decisions
24	about early termination or we want to control the false
25	positive rate.

			120 1		[Slide.]
	2		We might sometimes want to stop a trial early for
	3	lack of efficacy, and an example might be a treatment aimed
	4	at controlling symptoms of a chronic disease where you need
	5	long-term observation.  People are going to be treated for a
	6	long time.  The endpoint might not be mortality or
	7	irreversible morbidity, but it might be something that has a
	8	strong relationship to quality of life.
	9		When it becomes clear that the new treatment is

10	clearly inferior in some way, you might want to terminate
11	the trial, and so that the trial participants could revert
12	to a standard treatment.
13		Now, here, the false positive issue is not
14	relevant.  You are not going to make a decision that a new
15	treatment is effective or that you are going to possibly
16	prove an ineffective treatment.  What is at issue is the
17	power, whether you are going to stop too early and perhaps
18	not identify a potentially effective treatment.
19		[Slide.]
20		Some trials other than these that raise special
21	safety or ethical concerns sometimes might benefit from a

22	data monitoring committee.  Trials of novel and potentially
23	dangerous therapies.  We have all been very aware of the
24	recent issues in gene therapy, and there have been calls for
25	data monitoring committees for early stage Phase I gene

			121 1	therapy trials.
	2		Xenotransplantation is another area that has been
	3	very controversial, using animal tissue transplanted into
	4	humans with possibilities of transmission of infections, and
	5	so you might want to have an outside objective committee
	6	looking carefully at the safety data from such trials.
	7		I can tell you from personal experience that all
	8	of the Phase I, the initial Phase I HIV vaccine trials all
	9	had data monitoring committees.  They were also randomized
10	and placebo controlled.  Special issues arising, you may
11	want an outside committee.
12		Trials with informed consent waived.  This is the
13	only type of trial that the FDA requires have an independent
14	data monitoring committee.  Trials of a new treatment in an
15	emergency situation, the patient is unconscious or otherwise
16	unable to provide consent, and there is no proxy, no family
17	member or legally authorized representative readily
18	available, and there is a provision in our regulations that
19	such studies can be carried out without a patient's consent,
20	and these studies have lots of extra protections required
21	for them including an independent data monitoring committee.
22		[Slide.]
23		There are certainly some special issues in
24	pediatric studies that may increase the desire or usefulness
25	of a data monitoring committee.  You have got a vulnerable

			122 1	population obviously.  Consent is always by proxy, and with
	2	assent needed for children over a certain age.  We are
	3	always more concerned about issues in vulnerable
	4	populations.
	5		Long-term effects are especially important in
	6	pediatric studies, issues of physical growth and cognitive
	7	development, so there are a lot of things that we are
	8	concerned about, safety of treatments, and a variety of

	9	things that we want to watch and perhaps might want an
10	independent committee not vested in the trial to be looking
11	at those and helping with those decisions.
12		A possibly relevant issue is that products
13	investigated in children may be available if they are
14	already approved for use in adults, so the issue of when do
15	you stop the study and make a treatment available to people
16	who want to use it isn't quite the same as it often is in

17	adult studies, because these, for better or for worse, these
18	treatments are available to be used in children off label. 
19	So, that is a little bit of a different situation.
20		Finally, I don't think that there can be any
21	argument that there is an extra emotional component in
22	treating sick children, and it is often useful to have again
23	a separate, independent committee helping to make objective
24	judgments.
25		As has been pointed out, there might be a tendency

			123 1	to want to stop a study if one treatment looks somewhat
	2	better than the other, perhaps before it is definitive, and
	3	it is not going to help children if there is ineffective
	4	treatments on the market, and so those judgments can be very
	5	difficult.
	6		[Slide.]
	7		Now, I am going to talk a little bit about the
	8	nuts and bolts of data monitoring committees.  What kind of
	9	people do you have on data monitoring committees?  This is a
10	list of sorts of people that were mentioned in NIH trial
11	data monitoring committees at a conference that I
12	participated in some years ago - clinical medicine and the
13	appropriate specialty or specialties related to the trial,
14	biostatistics and biomedical ethics were the three areas of
15	expertise most commonly mentioned although in trials you
16	would sometimes find people expert in the basic
17	science/pharmacology, epidemiology, clinical trial
18	methodology, law, and increasingly patient advocates or

19	community representatives instead of, or in addition to,
20	somebody with special expertise in biomedical ethics.
21		The size of data monitoring committees, however,
22	may be as small as three, so you obviously aren't going to
23	have necessarily all of those expertise on every trial.
24		[Slide.]
25		I would like to say a little bit about an

			124 1	independent data monitoring committee.  It's a phrase that I
	2	have used.  An independent data monitoring committee--and
	3	again this is my own definition--is one in which no member
	4	has either any personal basis for preferring the outcome to
	5	be in one or the other direction.
	6		When I say "personal basis," I mean a personal
	7	gain.  Obviously, everybody would like to have a new
	8	treatment be developed that is going to be better to treat
	9	children, so in that sense, everybody may have a preference,
10	but I am talking about a personal preference, and I will go
11	on to that in the next slide, or any ability to influence
12	the trial conduct in a role other than that of DMC member,
13	that is, that you wouldn't want the knowledge of the
14	accumulating data to influence how the trial was carried
15	out.
16		[Slide.]
17		So, the types of conflicts of interest that could
18	lead people to have personal preferences, one, clearly
19	financial involvement either with the product being studied
20	or with a competing product, patient involvement, those
21	entering patients on the study, treating study patients or
22	evaluating patient outcomes could be influenced, perhaps not
23	consciously, but could be influenced if they know which
24	treatment is which, and that would be particularly the case
25	for studies that are unblinded.

			125 1		There is also the issue of intellectual
	2	involvement, the person, somebody who prepared the protocol
	3	or who was involved in earlier development of the product,

	4	somebody whose intellectual standing in the community may
	5	stand to be greatly enhanced if this turns out to be a big

	6	blockbuster product, that may reduce somebody's objectivity.
	7		I think regulatory involvement is an issue here,
	8	as well.  I think those of us who wear regulatory hats and
	9	have to make decisions later on may not want to be involved
10	in making other kinds of decisions during the course of the
11	trial.
12		[Slide.]
13		Interim results of clinical trials monitored by
14	committees should be held confidential.  I think that is the
15	way this mostly works.  The knowledge of interim data could
16	affect the trial conduct, and that is the bottom line
17	reason.  It could affect how patients are entered, how many
18	or what kind.  It could affect how patients are cared for

19	and whether or not they are encouraged to stay on the
20	protocol or not.
21		It could affect how patients are assessed, that
22	is, those evaluating the outcomes, and it could certainly
23	affect an action that a sponsor might take to decide on

24	their own that the study should continue or to be stopped,
25	and having an independent committee being the only group

			126 1	that is looking at the interim results improves the ability
	2	to maintain this confidentiality and therefore protects the
	3	integrity of the trial.
	4		[Slide.]
	5		Data monitoring committees have been given a
	6	variety of responsibilities.  I think it is important to
	7	recognize that what data monitoring committees do has only
	8	recently been widely on the table.  A colleague of mine,
	9	Janet Wittes, wrote what has been a widely cited paper
10	called, "Behind Closed Doors," about data monitoring
11	committees.
12		They have different approaches and different
13	structures have been developed at a lot of different places,
14	and so they don't all run the same way, and I think we are
15	in very much of a learning stage about data monitoring
16	committees and how they work, and perhaps how they should
17	work.
18		Almost all data monitoring committees are involved
19	in evaluating the accumulating data with regard to efficacy
20	and safety.  That's the bread and butter.  They may
21	recommend termination or continuation of the study or they
22	may recommend other study modifications either to improve
23	the conduct of the trial or to improve safety.  For example,
24	they may feel that the dose level needs to be reduced. 
25	There is a concern about the level of toxicity that is being

			127 1	observed.
	2		Some data monitoring committees are asked to
	3	review and approve the study protocol.  They are asked to
	4	play a larger role in assessing study conduct, and they may
	5	recommend additional analyses if the analyses that the
	6	statistical center presents to them, they feel they are not
	7	getting all the information that they need to make their
	8	decisions.
	9		[Slide.]
10		Regulatory status.  As I mentioned, there is only
11	one mention of data monitoring committees regulations in the
12	U.S., and that is that they are required for the emergency
13	research studies in which informed consent has been waived.
14		They are mentioned in several guidance documents. 
15	The ones that have been developed by the International
16	Committees for Conduct of Clinical Trials, the Good Clinical
17	Practices.  The E-6 guideline mentions that use of data
18	monitoring committees.  E-9 guidelines, statistical
19	principles for clinical trials goes into a little more
20	detail, not a whole lot, about data monitoring committees.
21		[Slide.]
22		I will just read to you the brief statement in the
23	E-6.  The sponsor may consider establishing an independent
24	data monitoring committee to assess the progress of a
25	clinical trial including the safety data and the critical

			128 1	efficacy endpoints at intervals, and to recommend to the
	2	sponsor whether to continue, modify, or stop a trial.
	3		The independent data monitoring committee should
	4	have written operating procedures and maintain records of
	5	all its meetings, and that is all that is stated.  So, there
	6	hasn't been a lot of guidance from the regulatory standpoint
	7	anyway about operation of data monitoring committees.
	8		[Slide.]
	9		I would just like to conclude with a mention of
10	the Office of Inspector General Report on Institutional

11	Review Boards that came out in June of 1998.  Despite the
12	fact that it was focusing on IRBs, there were a couple of
13	recommendations about data monitoring committees.
14		One was that data monitoring committees be
15	required for trials under NIH, OPRR, and FDA purview that
16	meet specified conditions.  It didn't say what those should
17	be.  It said we should figure that out.  We need to define

18	those conditions, and we all should specify requirements for
19	data monitoring committee composition.
20		The second recommendation was that data monitoring
21	committees should have primary responsibility for reviewing
22	and evaluating the adverse experiences occurring in trials,
23	and that these assessments, along with summary data, could
24	be shared with institutional review boards.
25		Now, there is a working group at FDA that has been

			129 1	looking at these recommendations.  I should update this.  We
	2	are not considering development of a guidance document.  We
	3	are developing a guidance document, but it is a difficult
	4	task because, as I said, there isn't a consistent worldwide
	5	view of those these committees should operate and especially
	6	what is the best way for data monitoring committees to
	7	interface with IRBs, but we are working on this, and hope to
	8	have some guidance shortly, which I am sure will be
	9	controversial.
10		Thank you.
11		DR. CHESNEY:  Thank you, Dr. Ellenberg.
12		Any questions for Dr. Ellenberg?  Yes, Dr. Fost.
13		    Questions from the Subcommittee
14		DR. FOST:  Susan, could you say a little bit more
15	on this issue?  You have written about it elsewhere, I know,
16	but your own view on the role of the monitoring committee
17	prior to the formulation of the study, the study design, and
18	stopping points.
19		As you pointed out elsewhere, it is very difficult
20	to be a member of one of these things and be ethically
21	responsible when you are in stark disagreement with the
22	design or with the consent form or with the stopping rules. 
23	But when you are ask, as a condition for being on these
24	things, to be involved in that, the sponsor or the

25	investigator says it slows everything down, you are

			130 1	micromanaging something that we have spent two years
	2	developing with a lot of experts, we don't need your help on
	3	that, that is not why we are asking you, but that you are

	4	being asked to serve over a project that you sort of feel
	5	uncomfortable about.
	6		DR. ELLENBERG:  I think you are exactly right,
	7	and, you know, I don't need to repeat what you have said,

	8	but my own feeling is that if you can't, if you are asked to
	9	be a member of data monitoring committee, and the protocol
10	is one especially with regard to what the monitoring
11	guidelines are and what would be the conditions under which
12	one might stop the study, and so on, and so forth, if you do
13	not feel that that is appropriate, and is going to give
14	either a valid answer or is going to adequately protect the
15	safety of the people on the trial, those are the two reasons
16	for the committee, then, I don't see how one can serve on
17	such a committee.
18		I think the only solution is to not be on the
19	committee.
20		DR. FOST:  It is not a trivial point about the
21	name of the thing then.  If you believe that the committee,
22	or whatever you call it, should play some role prior to the
23	initiation of the study, then, get the word data out of

24	there.  I think it should just be called a monitoring
25	committee or an oversight committee, because if your

			131 1	recommendation leads to them being called data anything,
	2	somebody will say--they usually do--look, we are a data
	3	monitoring committee, we are not a design committee, we are
	4	not a consent committee.
	5		DR. ELLENBERG:  I will tell you what happens when
	6	you just say monitoring committee.  People get that confused
	7	with site monitoring and other kinds of monitoring.  Some
	8	people say monitoring, some people say auditing.  No matter
	9	what you do, there are going to be some people who are going
10	to figure out a way to interpret it in a way that you don't
11	want.
12		So, I am not so worried about the words, but I
13	think that in most cases, the data monitoring committee does
14	get a chance to get a look at the protocol beforehand.  I
15	agree with you that there is often reluctance, but, you
16	know, it is the same with IRBs.  An IRB looks at the
17	protocol, and they can decide--and people get irritated with
18	them, too--but, you know, when you have oversight, you are
19	going to irritate people.
20		DR. CHESNEY:  Dr. Nelson.
21		DR. NELSON:  The question relates around the issue
22	of objectivity and the sharing of data from monitoring
23	committees to IRBs and to participants.  My understanding of
24	one of the reasons data monitoring committees were formed
25	initially was to prevent investigators from looking at trend

			132 1	data and deciding to walk with their feet and abandon
	2	various trials.
	3		The question I have is the extent to which
	4	investigators, clinicians and participants would want to

	5	know probability data about which arm they are in that is
	6	not reaching a so-called objective p equals less than 0.05,
	7	which is just a statistical definition of objectivity.

	8		How does that square with IRB's obligation to
	9	report results or information that affects the participants
10	willingness to participate?  So, for example, if I am in an
11	arm that has a 95 percent probability of reaching p equals
12	less than 0.05, the study may not stop, but I might consider
13	that relevant to my willingness to continue.
14		DR. ELLENBERG:  Well, what you are raising is sort
15	of a fundamental conundrum of randomized trials and one that
16	many people have wrung their hands over for many years, and
17	some folks have written that it is actually unethical to
18	keep all these results confidential, and the results should
19	always be out and available, and people should be able to

20	make these decisions.
21		I think it is recognized that if that were the
22	case, we would never be able to complete clinical trials,
23	and I think that, you know, I can see that Dr. Fost is

24	raising his hand, and he is much more familiar with the
25	bioethics literature than I have, but I think that there is

			133 1	a better answer to that than I would be able to give, so,
	2	Norman.
	3		DR. FOST:  Just quickly.  I think the solution to
	4	that, Skip, is the consent form--they haven't to date--and
	5	they need to say there will be analysis of this data during
	6	the trial that will not be available to the investigator or
	7	to you.  It may show significance, and we are simply not
	8	going to tell you that.  If you don't like that, then, don't
	9	be in the study, but a condition of being in this study is
10	we are going to withhold data unless an independent
11	committee says it's time to stop.
12		DR. CHESNEY:  Thank you.
13		I am sorry we have to move on because we are
14	behind and we have to start the session this afternoon at 3
15	o'clock because it's a totally separate session, and we have
16	new speakers coming in.
17		Our deadline now is that we have to break for
18	lunch at 12:15, so, Dr. Murphy is going to give us general
19	comments about the case studies, and then Dr. Birenbaum will
20	give us Example A, and we will have 15 minutes or so to
21	discuss that first question.
22		Subcommittee Discussion of Case Studies
23		          Introductory Remarks
24		DR. MURPHY:  For the committee, I wanted you to

25	please note that the questions are slightly different from

			134 1	the ones that were mailed to you.  We have eliminated the
	2	example that was not a real life case, so the ones that are
	3	on the table are the ones that we will be discussing today.
	4		We have put before you three levels of cases or
	5	examples of trials that we thought were progressing from the
	6	least controversial to the more controversial, and we will
	7	stop at the end of each set of examples and present
	8	questions to you.
	9		The medical officers who were involved and working
10	in selecting the examples and developing the questions will
11	present them to you.  We have tried, in response to the
12	committee's requests last time, to provide more details, and
13	yet develop some commonality amongst the cases that we are
14	not talking about so specific that we can't apply some
15	broader principles to these.
16		We reviewed quite a binderful of cases in trying
17	to develop the commonalities in the case and then have them
18	be slightly different, so that we could pose or focus the

19	questions for you.
20		We look forward to your discussion.  The
21	categories are the add-on studies, which is a drug or
22	placebo are added to an established therapy on which the
23	patient has relapses or less than optimal control of
24	disease.
25		What we are calling the classical placebo-

			135 1	controlled trial, basically, that is a placebo-controlled
	2	trial where there is no approved pediatric therapy. 
	3	Approved adult therapies may have failed in prior pediatric
	4	studies.  That will be the second category.
	5		The third category of trials will be withdrawal
	6	trials, which will be randomized withdrawal studies possibly
	7	with early escape features that decrease the duration of
	8	exposure to a therapy that is ineffective for a given
	9	patient.
10		Dr. Birenbaum, if you would come on up and present
11	the first set of examples.
12	       Example A: Pediatric Placebo-Controlled Add-on
13		         Clinical Trial Design
14		[Slide.]
15		DR. BIRENBAUM:  As Dr. Murphy said, the placebo-
16	controlled add-on trial design examples for discussion today
17	are actually taken from pediatric studies submitted to the
18	agency for review.  We have tried to provide enough detail
19	in the description of these studies for the committee to

20	focus its subsequent discussion and the questions that
21	follow are to provide an opportunity for the committee to
22	comment on both the ethical issues specific to each study,
23	as well as the trial design in general.
24		In our first example, asthma, children with the
25	condition were stable but with less than optimal control of

			136 1	signs, symptoms, and/or exacerbations.
	2		After fulfilling the enrollment criteria, patients
	3	received standard of care plus study drug or standard of
	4	care plus placebo.  Standard of care included continued
	5	maintenance of prior pharmacologic therapies, such as short-
	6	acting beta agonists and additional asthma controller
	7	medications.
	8		Specific trial design elements in this study
	9	included several hundred 2- to 5-year-old children with a
10	history of asthma who were enrolled at multiple centers.  A
11	two-week, single-blind standard of care plus placebo run-in
12	period, which assessed randomization eligibility and patient
13	compliance.
14		A 12-week, double-blind randomized active
15	treatment period in which patients received either study
16	drug plus standard of care or placebo for standard of care. 
17	The protocol further specified a 36-week open label
18	extension period to determine safety and tolerability, an

19	action plan for worsening symptoms in individual patients.
20		Criteria for individual patient discontinuation

21	from treatment, and a blinded interim analysis that assessed
22	and compared adverse events and exacerbation frequency of

23	asthma.  I should point out this was not a data monitoring
24	board.
25		Safety measurements included adverse event and

			137 1	asthma exacerbation monitoring, physical exam, vital signs,
	2	routine labs, and twice daily peak flow monitoring.  The
	3	efficacy parameters included daytime and nighttime asthma
	4	symptoms.
	5		[Slide.]
	6		In our second example, seizures, children with the
	7	condition are stable, but have less than optimal control of
	8	the seizure events.  After fulfilling enrollment criteria,

	9	the patients were randomized to receive either standard of
10	care plus study drug or standard of care plus placebo.
11		They will have continued maintenance of ongoing
12	pharmacologic therapies, and additional child designed
13	elements in this study included or will include 50, 3- to
14	12-year-old children with partial seizures, a 6-week
15	baseline period with patients on standard of care to assess
16	randomization eligibility and compliance, followed by a 12-
17	week double-blind, randomized placebo-controlled trial in
18	which patients received either study drug plus standard of
19	care or placebo plus standard of care.
20		The protocol further provides criteria for

21	individual patient discontinuation from treatment and
22	standard measures of clinical and laboratory safety

23	parameters.  The primary efficacy parameter in this study is
24	a reduction in frequency of partial seizures.
25		These two trials are examples of studies in which

			138 1	the Food and Drug Administration is comfortable using this

	2	clinical trial design.  It is less clear whether trials of
	3	this design necessarily warrant use of a data safety
	4	monitoring board or data monitoring committee.
	5		Further, differences in the clinical implications
	6	of disease exacerbations may be different across the

	7	spectrum of medical illnesses, for example, an asthma
	8	exacerbation versus a seizure event.
	9		We ask that you consider these issues in your
10	discussion of the following questions:
11		[Slide.]
12		Is there a situation, population, disease or
13	condition where this type of placebo-controlled study would
14	not be appropriate?
15		DR. CHESNEY:  Why don't you read through all three
16	questions and then we will allot a certain amount of time
17	for each one.
18		[Slide.]
19		DR. BIRENBAUM:  What role, if any, does a data
20	safety monitoring board play, is it necessary for the
21	ethical conduct for each of these trials?  Does having
22	stopping rules for individual patients affect this decision?
23		[Slide.]
24		What are the differences in level of morbidity or
25	discomfort in children that would recommend use of a data

				139 1	safety monitoring board?
	2		DR. CHESNEY:  Thank you very much.
	3		So, our first question:  Is there a situation,
	4	population, disease or condition where this type of add-on
	5	placebo-controlled study would not be appropriate?
	6		Yes.
	7		DR. WILFOND:  Well, I think the question would
	8	focus on why is it the case that optimal therapy isn't

	9	working, in other words, is it because they have been
10	receiving a range of therapies, are people perhaps not
11	having access to standard therapy or the best therapy. 

12	Perhaps they live in an area where they don't get access to
13	good medical care.
14		I think that would be a reason where I think we
15	might be very concerned about offering a clinical trial
16	rather than the ideal therapy.  It strikes me that one
17	solution would be to have a list of standardized approach
18	saying what treatments a person ought to be on before it is
19	concluded that they have not responded to optimal therapy.
20		DR. CHESNEY:  Thank you.
21		DR. WOLFF:  I wasn't sure whether the discussion
22	should be limited to these questions.  There are some prior
23	questions which I don't understand.

24		Why is safety and efficacy measured after the fact
25	instead of before?  In fact, in all four of these, it

			140 1	somehow comes in the middle, and there is no prior Phase I
	2	or Phase II.
	3		Another question is why does this protocol specify
	4	several hundred children instead of a specified number, so
	5	you could do some estimation.  Maybe these are not relevant
	6	to your question, but they would certain be of concern to
	7	anybody who does an IRB review of these.
	8		DR. CHESNEY:  Dr. Murphy, do you want to comment?
	9		DR. MURPHY:  I think that again, the level of
10	specificity could get us down to a very individual case, and
11	we were making the assumptions that in this situation, you
12	would have nothing in the Phase I or II trials that would
13	modify your behavior in response to this question.  So, if
14	it is not there, we didn't put it there because we made that
15	assumption.
16		Secondly, we did round the numbers.  We tried to
17	take actual cases again because you would have made these

18	statistical assessments on whatever you thought the
19	difference would be, and so we didn't want to get into
20	making that difference.  We thought we would prefer the
21	discussion to focus more on if there were a class or if

22	there were some broad category of safety or some other issue
23	besides the calculation of the difference.
24		DR. WOLFF:  But this first one in particular, both
25	of them actually, specify that the safety and efficacy will

			141 1	be done in the course of the study.  Am I misunderstanding?
	2		DR. MURPHY:  Basically, the conduct of the trial
	3	is to look at the performance of this therapy for both its
	4	safety and its efficacy.  You have set the trial up to look
	5	at that issue.
	6		DR. TEMPLE:  Maybe the question has to do with the
	7	definitions of what the trials of various phases do.  It is
	8	common to describe Phase I studies as assessing safety. 
	9	Well, that is sort of true, but they assess the safety of a
10	single dose, which is not the full-bore assessment of safety

11	that you are looking for.  So, they do get you a little bit. 
12	They tell you that it is tolerated and nothing terrible
13	happens.
14		What a Phase II study means in this context is a

15	little hard to say.  The first controlled trial studying
16	effectiveness is either a Phase II or a Phase III study, it
17	is sort of a matter of definition.
18		Whether this kind of trial should precede the sort
19	of exposure safety trial that is common in pediatric
20	settings could be debated.  This gives you a better quality
21	of information than just exposing a couple hundred people,
22	but you are not going to carry out a very long-term placebo-
23	controlled trial, so you don't really have too much choice.
24		Sometimes an active control trial if there was

25	something you could study can get you safety, but I think

				142 1	the thinking is this would be a relatively early trial
	2	before you know a great deal.  Of course, you know
	3	everything in adults, which is relevant.
	4		DR. WOLFF:  I will shut up in a minute, but is the
	5	idea to save some time?
	6		DR. TEMPLE:  You mean by studying safety and
	7	effectiveness at the same time?
	8		DR. WOLFF:  Yes.
	9		DR. TEMPLE:  Well, see, I would say you always do
10	that in a placebo-controlled trial.  You are looking for the
11	rate of--depending on its size--you are looking at the rate
12	of relatively common adverse events, and you have a control
13	to see any difference between, even in an add-on study, too,
14	the difference between the group that gets the new drug and
15	the group that doesn't on safety endpoints are presumably

16	side effects that are due to the drug.
17		You learn that, and you also learn whether it
18	works.  I mean you always do that.
19		DR. MURPHY:  I guess we would say that you
20	shouldn't put any product into a child where you are not
21	going to assess the safety aspects of it.
22		DR. CHESNEY:  Dr. Gorman had a question.
23		DR. GORMAN:  In response to Question 1, it seems
24	to me that--and the discussions on the IRB on which I sit--
25	always deals with the placebo controls and the amount of

				143 1	safety for escaping people from studies with acute
	2	exacerbation of their diseases, and both asthma and seizures
	3	present good examples of those where the exacerbations can
	4	be immediately life-threatening or very rapidly life-
	5	threatening.
	6		In these kinds of situations, placebo-controlled
	7	studies would be acceptable to our IRB as long as that
	8	safety was a little bit more aggressively assured than in
	9	this protocol where it says that AE's will be monitored, but
10	no escaping is allowed or it is not discussed very
11	dramatically in this protocol.
12		DR. MURPHY:  Thank you.  So, what you are saying
13	is that basically, you just need clearly defined escape
14	rules for the individual patient.
15		DR. GORMAN:  Correct.
16		DR. CHESNEY:  Dr. Nelson had a question.
17		DR. NELSON:  It is actually on the open label
18	extension portion of the asthma example.  In other
19	conditions, particularly some areas such as depression and
20	psychological problems in a situation where there may be a
21	possibility of a positive response to placebos or a
22	spontaneous remission, our committees occasionally struggle
23	with the fact that you could have someone on the initial
24	randomized trial that is on the placebo arm doing just fine,
25	and then is exposed to the drug unnecessarily.

			144 1		We have tried to suggest, sometimes successfully,
	2	sometimes not, having the second phase not be just an open
	3	label, but to continue the blind and allow for perhaps
	4	crossover.  If I recall, in reading, I think it was E-10
	5	that might have even been the suggested model.
	6		So, there are circumstances where the second open
	7	label phase presents some problems to those who are doing
	8	just fine on placebo.
	9		DR. CHESNEY:  Dr. Temple.
10		DR. TEMPLE:  You could also, if you wanted to
11	learn more about long-term effectiveness or maintenance, use
12	both the responders on drug and conceivably the responders
13	on placebo, enter them into a trial in which they are
14	treated for a period and then randomly withdrawn with the
15	potential for early stopping as soon as exacerbation occurs.
16		One of the things you always want to know is
17	whether you have persistent effects.  On the whole, nobody
18	is prepared to do a six- or eight-month placebo-controlled
19	trial in these settings.  So, the randomized withdrawal with
20	a standard for stopping therapy and crossing them over is
21	perhaps one way to get at that.
22		There is also usually debate about how long to
23	treat people, so it helps answer that question.
24		DR. MURPHY:  Let me ask you.  Dr. Temple just made
25	a statement that nobody would do a six- to eight-month.  Are

			145 1	you suggesting, then, in the extension trial, that it would
	2	be appropriate to continue?
	3		Certainly, the children, if you had clear stopping
	4	rules, would have been discontinued that you would prefer
	5	then that we have a randomized long-term extension as a
	6	possible alternative approach?
	7		DR. NELSON:  I guess the devil is in the details

	8	of what particular situation you are studying.  My reaction
	9	to this particular protocol we reviewed last week was it

10	wasn't clear to me why they didn't just design a six-month
11	trial instead of do a six-week trial with a six-month
12	extension.
13		As long as you are clear about who has responded
14	well and have clear evidence of that, and have clear ways to
15	respond to those who have responded poorly or are having

16	difficulties, we were unclear why you couldn't just simply
17	maintain the blind if indeed someone was doing just fine,
18	and not start giving them a drug that they don't need if
19	they are on placebo.

20		DR. CHESNEY:  Dr. Murphy, some guidance.  Shall we
21	go on to Question 2 given only 10 minutes left?
22		DR. MURPHY:  Two hands to your right.  We would
23	like to hear their comments.
24		DR. CHESNEY:  So, we will stick with Question	1.
25		Dr. Fink.

			146 1		DR. FINK:  Yes, I have a question.  In this study,
	2	particularly with asthma, what happens when the standard of
	3	care involves the majority of study drugs?  Many of us would
	4	define an inhaled steroid as a standard of care for asthma,
	5	at least moderate or severe, and yet, the majority of the
	6	studies are of inhaled steroids of various manufacturers, so
	7	that they usually exclude the use of an inhaled steroid to
	8	go into the placebo-controlled trial.
	9		So, the exclusion criteria often take you out of
10	the standard of care criteria.
11		DR. MURPHY:  I think we try to get at that later
12	on with the withdrawal, you have a population where the

13	standard of care already is the steroid.  What you are
14	saying is that--and that is what we were trying to get at,
15	what level of exacerbation--you are saying that one would
16	say any child who is having exacerbations could not go into
17	this trial because they would first need to go on to an
18	inhaled steroid?
19		DR. FINK:  Yes, the standard of care would say

20	that that is actually the appropriate treatment, but then
21	the study prohibits you from participating if you are
22	already on the inhaled steroid.
23		DR. TEMPLE:  If this is a case where you could
24	conclude that an active control non-inferiority trial to

25	added steroid was persuasive, and perhaps with steroids you

			147 1	could, that might work and you might be able to do that kind
	2	of trial.
	3		If it is a not so dramatically effective drug
	4	where you couldn't with any honesty assert that there is
	5	assay sensitivity, then that trial wouldn't be informative
	6	anymore and you would have to either abandon hope and forget
	7	about it or do the sort of thing that Dianne mentioned, we
	8	talked about later, do a randomized withdrawal trial,
	9	watching very closely for exacerbation, and you would have
10	to decide whether you are comfortable with that design.
11		DR. FINK:  Then, it would seem that it would lead
12	to potentially the conclusion to your first question, that
13	this type of study design would be inappropriate for any
14	population where the standard of care included a drug of the
15	class under study.
16		DR. TEMPLE:  Actually, the definition of this case
17	was where that hadn't been true.  You are right, that is a
18	very good question, but this case ducked that question.

19		DR. FUCHS:  Hopefully answering one situation,
20	then, I guess people would probably have problems with this
21	study is if you are using IM as the method of delivery.  I
22	mean if you had to give a kid, not necessarily asthma, but
23	seizures, you were all assuming it's either inhaler or by
24	mouth.  I think a lot of people would have problems if you
25	are going to be telling someone they are getting a couple

					148 1	shots a day, and it could be a placebo.
	2		DR. MURPHY:  So, you are saying where--again,
	3	trying to address the situation it would be unacceptable--

	4	where you have a standard of care that is less invasive and
	5	less distressful than the product which is more distressful
	6	to the child, is that your statement?
	7		DR. FUCHS:  That is how I would foresee it, and I
	8	would think that a lot of parents would see it that way,
	9	too.
10		DR. TEMPLE:  I thought you were addressing the

11	question of whether you should give an injection placebo.
12		DR. FUCHS:  Well, that, too.  I mean if you have a
13	standard of care that is not an injection, obviously, and

14	then you add another medicine, but the placebo is going to
15	have to be the same method of delivery that your new
16	medicine is, I think you would have a lot of problems with
17	that.  It could be the same for an I.V. medicine, too, you
18	are just sort of taking it at a different phase.
19		DR. TEMPLE:  You wouldn't object to one in which
20	there was no treatment, though.
21		DR. FUCHS:  No.
22		DR. TEMPLE:  And then the question would be
23	whether that is a credible study without a blind.
24		DR. CHESNEY:  Dr. Wilfond.
25		DR. WILFOND:  I have another issue related to the

			149 1	issue of optimal control, which is not the question raised

	2	before, regarding the cause of the optimal control, but the
	3	concern that particularly in studies in pediatrics, you

	4	would at least potentially worry that the motivation of
	5	parents to enroll their child in the study was precisely
	6	because of the lack of optimal control, and I am just
	7	raising that as a question.  This creates a tension that

	8	perhaps the motivation for participation would be based upon
	9	that concern, and you ought to at least make sure that there
10	are ways of at least providing clear alternatives to the
11	study in that regard.
12		DR. CHESNEY:  Dr. Botkin.
13		DR. BOTKIN:  I think this discussion highlights

14	some of the difficulty about defining the standard of care,
15	and I would say the issue is a little bit broader than what
16	Dr. Fink had raised, and I would point to the antiseizure
17	medication example and say if a patient were to enter the
18	study with poorly controlled seizures on one seizure

19	medication, is that person receiving the standard of care or
20	not.
21		I would contend that by one definition, you might
22	say that indeed they have since you are attempting to
23	control those seizures.  By another definition, you would
24	say they hadn't since they hadn't progressed through what is
25	a typical sequence of events, which is either increasing the

			150 1	dose or adding additional agents, et cetera.
	2		So, I think there is a risk with this type of
	3	justification, that patients who are inadequately treated
	4	are defined as being on the standard of care, and then
	5	justifying their inclusion in an add-on protocol.
	6		DR. MURPHY:  I would say that your point is well
	7	taken and we clearly would say that for this trial design,
	8	called an add-on trial design, the standard of care would be
	9	that which is acceptable in the community at that time.
10		The usual approach is that if a child is having
11	seizures and they are not controlled with one
12	anticonvulsant, that they would receive another one before
13	they would be considered in any sort of control.  Then, that
14	would be two therapies that would be considered the standard
15	of care.
16		Again, we didn't want to say two versus three for
17	a specific disease, but try to get to the fact that there

18	would be a defined standard of care.
19		DR. CHESNEY:  Dr. Temple.

20		DR. TEMPLE:  It is not uncommon in these trials to
21	observe people on the supposed standard of care during the
22	lead-in period.  If they then fall below the level of
23	control that was considered necessary for the trial, then,
24	they wouldn't enter it.  So, it gives you an opportunity to
25	check for poor compliance and obtaining the optimal level,

			151 1	and things like that.
	2		I guess it seems worth noting that most of the
	3	drugs for epilepsy are not exactly pleasant, and have their
	4	own problems, so that you can imagine that people would
	5	decide on a standard of care that wasn't necessarily optimal
	6	seizure, but was some balance of seizure control and ability
	7	to tolerate it.  But a lead-in period is the norm for these
	8	types of trials.  Just take our word for it.
	9		That is how they enter the screen, but then they
10	would be looked at further usually.  Dr. Katz is here and

11	can tell me if I am right about that.  There is often an
12	observed lead-in period on whatever the supposed optimal
13	standard control is.

14		DR. MURPHY:  And that is why you see that in both
15	of these.
16		DR. CHESNEY:  Dr. O'Fallon.
17		DR. O'FALLON:  No one has mentioned the fact that
18	one of the limitations of this study design is that actually
19	the question it is answering is whether this new therapy is
20	effective in conjunction with the standard, whatever you

21	choose it to be, and that really doesn't answer one of the
22	questions you have been wanting, which is, is it effective,
23	by itself even.
24		So that is a design limitation.  It may be one

25	that has to be accepted at the beginning, but we have all

			152 1	seen therapies in which the timing and the order in which
	2	the therapies were delivered, two things can be effective
	3	when given one way, but not in the other way, and there are
	4	all those other issues that will never be sorted out with
	5	this particular design.
	6		DR. CHESNEY:  Dr. Ward.
	7		DR. WARD:  I just wondered if you would consider
	8	labeling this then for poorly controlled seizures as opposed
	9	to for seizures, because you have a very selected population
10	to start with in which you are testing.
11		DR. CHESNEY:  Dr. Kauffman.
12		DR. KAUFFMAN:  I was going to make a related
13	point, and that is it seems to me that one of the
14	limitations of this approach is, particularly with the
15	seizure example, is we intentionally selected a refractory
16	group of patients, so there is a high probability of showing
17	non-efficacy where the drug may really be efficacious in
18	another setting or subpopulation.
19		DR. TEMPLE:  All those last comments are
20	absolutely right.  The problem is that it is not easy to

21	evaluate drugs in this setting.  One proposal is, oh, just
22	compare it with dilantin, but if you don't know what the
23	seizure rate in the absence of therapy would be, you don't
24	have any evidence that you have got any activity at all. 
25	You just don't know unless you let the person escape from

			153 1	therapy.
	2		So, this is a compromise, not an entirely
	3	satisfying one, that gets you at least some information on
	4	whether it works when you add it to the other therapy. 
	5	Furthermore, you could say, well, that is the most important
	6	problem anyway, people who aren't being well treated by
	7	available therapy, that is the biggest problem.
	8		How to get monotherapy is not well known.  There
	9	are some careful withdrawal designs--Barbara van Zwieten can
10	talk about those--and they are actually mentioned in the E-
11	10 document, but how happy everybody is with those could be
12	debated.
13		As long as it is considered bad to allow people to
14	have more seizures than they otherwise would, and there is a
15	pretty good case for that, this is a very thorny problem.
16		DR. CHESNEY:  Dr. Hudak.
17		DR. HUDAK:  I think one of the problems with this
18	particular study design, too, that hasn't been explicitly
19	recognized is the fact that this is, as Judith said, a test
20	of standard versus standard plus new.
21		One has to realize that in that setting, depending
22	what the agents are and what the biology is, there is always
23	the potential that the standard plus new is worse than the
24	standard, when, in fact, the standard versus new might show
25	the new better than the standard when you are looking at

			154 1	either safety or efficacy.
	2		So, one has to step back and consider those issues
	3	in these trial designs, too.
	4		DR. MURPHY:  The other answer is that yes, we
	5	would be labeling it as Dr. Temple alluded to.  We would not
	6	be labeling it for monotherapy, it would be labeled for
	7	adjunctive therapy.
	8		DR. TEMPLE:  There is one more problem that I
	9	should mention that you haven't yet.  You can't really work
10	up a drug that is similar pharmacologically to the drug you
11	have already got this way, and that means that if it has a
12	better side effect profile, you can't really discover it

13	this way.
14		We see this on--just to divert for a second--in
15	heart failure, the current therapies have to be given, you
16	have to give everybody a diuretic, you have to give
17	everybody an ACE inhibitor.  Now you have to give them a
18	beta blocker and pretty soon you will have to give them

19	Aldactone.
20		So, all of the trials are add-on trials, but if
21	somebody has a new ACE inhibitor, you can't study it that
22	way unless you can come to the conclusion that an

23	equivalence trial would be informative, which is a different
24	question.
25		DR. CHESNEY:  One last question, Dr. Spielberg, or

			155 1	comment.
	2		DR. SPIELBERG:  I think all these comments are
	3	really right on the mark.  The issue, though, in almost any
	4	drug development program is that it is iterative, and you
	5	get certain information from one trial that will lead to the
	6	next design for the next trial where you are confident that
	7	the drug in fact works and is tolerated reasonably well in a
	8	population.  It is sufficient to go from a more severe
	9	population into a less severely affected population with a
10	different trial design.  It may be a comparative best model
11	therapy.
12		But the issues again are really iterative ones and
13	I suppose the question that Dianne is asking here is if this
14	is an appropriate acceptable design to initiate a program
15	for compounds like this.
16		DR. CHESNEY:  I think we have to break now for
17	lunch for just half an hour, please.
18		[Luncheon recess taken from 12:20 p.m. to 1:10
19	p.m.]
20		DR. CHESNEY:  I think we are ready to begin.
21		Just two housekeeping issues before we start.  The
22	first one is that we do have to start our break at 2:45

23	because of the new topic to be discussed at 3 o'clock and
24	new speakers.  In order to do that, with Dr. Murphy's help,
25	we have prioritized the remaining questions, so we will not

				156 1	be doing all of them.  Several of them can easily be handled
	2	together.
	3		I think as the other examples are presented, you
	4	will see which questions we have decided to address and
	5	which ones we won't, and we will only address one more
	6	question for Example A, and that is the second one.
	7		What role, if any, does a data safety monitoring
	8	board play, is it necessary for the ethical conduct for each
	9	of these trials?  Does having stopping rules for the
10	individual patient affect this decision?
11		Comments?  Yes, Dr. Ward.
12		DR. WARD:  Because the second therapy may alter

13	the effectiveness of what is viewed as standard of care
14	through either induction of its metabolism or inhibition of
15	its metabolism, the previous level of control of the
16	particular clinical symptoms may change dramatically, and
17	having ongoing monitoring of that I think protects the
18	patient in both of these clinical situations.
19		Even though I think we have chosen clinical
20	situations, clinical conditions that we view as not life-
21	threatening, they certainly can end up being almost life-

22	threatening or leading at least to hospitalization.  I think
23	that needs to be detected in a timely fashion.
24		DR. CHESNEY:  Dr. Fink.
25		DR. FINK:  If we take these examples where both

			157 1	studies are only 12 weeks in duration, I don't think it is
	2	practical to have a data safety monitoring board.  By the
	3	time you actually could look at much data, the study will be
	4	terminated.
	5		So, I think that where trials are under probably
	6	six months' duration, use of a monitoring committee probably
	7	isn't that practical.
	8		DR. CHESNEY:  Dr. Ellenberg, do you want to make
	9	any comment about that?
10		DR. ELLENBERG:  I think part of it depends on--it
11	may be only a 12 week course, but if it is going to take
12	several years for the study to be completed, you might want
13	to have somebody watching.
14		I think what I want to say most is that this kind
15	of trial obviously needs careful clinical monitoring.  The
16	question about whether it needs a separate, independent

17	group monitoring, looking over the shoulder of the people
18	conducting the study is another issue.  I don't think there
19	is any question that it has to have monitoring, and a trial
20	like that may, in fact, benefit from data monitoring
21	committee, but you would need to tease out what are the

22	special things about it that would require the separate,
23	independent committee as opposed to having the usual people
24	who are monitoring trials just taking care of it internally.
25		DR. CHESNEY:  Dr. O'Fallon, do you want to comment

			158 1	or did she say everything?
	2		DR. O'FALLON:  We do want to keep the length of
	3	time that the patients are on the study separate from the
	4	length of time it takes to do the study.  That was my major
	5	reaction to what you have, but that other business up there
	6	about stopping rules for the patient and again the stopping
	7	rules from the study are two very distinct things, and I
	8	think we have got to keep them separate.
	9		DR. CHESNEY:  Dr. Fink.
10		DR. FINK:  The other issue I think that comes up,
11	and I think it could pose a risk with a data safety
12	monitoring committee, at least with asthma there is a marked
13	seasonality to it, and if you take the wintertime and you
14	look at a new therapy, it is going to look highly
15	ineffective or potentially worse than standard treatment
16	because of the increased asthma exacerbations that occur
17	every winter.  So, seasonality is also going to play a role,
18	at least in some of these disorders.
19		DR. MURPHY:  So, what I have heard thus far is
20	that in these two trials, which we have described for you
21	and which we would have clear escape or stopping rules for
22	the individual patient, and understanding that it is going
23	to take longer than 12 weeks, but for this situation I heard
24	one opinion that because this could affect the efficacy of
25	your standard of care that you should have a DSMB, and the

			159 1	other was that we do not need a DSMB.
	2		Is that what you are saying or not?  Again, what
	3	Susan said was what we are trying to point out.  We would
	4	have very clear stopping rules for individuals in these
	5	trials.
	6		DR. CHESNEY:  Dr. Wilfond.
	7		DR. WILFOND:  What occurs to me is that I wonder
	8	if even with the stopping rules, if it was a case that
	9	suddenly almost every patient was being stopped very
10	quickly, would that be the sort of information that would be
11	a factor in a decision to continue the trial.  If that was
12	the case, that might be the role that a DSMB might play.
13		DR. MURPHY:  So, there may be a role in these
14	types of trials, particularly if you knew that there might
15	be an issue with interactions or that that was a problem, or
16	there is any other particular reason to think that there may
17	be a worsening of the standard of care therapy particularly.
18		DR. FOST:  Joan, there is a confusion here between
19	escape guidelines and stopping rules.  Any study like this
20	would have escape guidelines or rescue guidelines is the

21	word where any individual patient could stop on his or her
22	own account, or their parents, or their doctor.  Stopping
23	guidelines have to do with an overall trend in the trial
24	which shows that the drug is either toxic or unsafe or is
25	not likely to produce a meaningful result.

				160 1		Whether it is meaningful to have a DSMB for that
	2	reason depends on more information than I can glean from
	3	this, like how long the trial is going to continue and Dr.
	4	Fink's point about whether there is enough time to
	5	intervene.
	6		DR. MURPHY:  So, length of the trial.
	7		DR. CHESNEY:  Dr. Gorman.
	8		DR. GORMAN:  But even in a 6- to 12-week trial,
	9	enrollment could take place over several years, and the
10	data, well, that is correct, for the individual patient it
11	wouldn't make much difference, but for the trial management,
12	and I guess what we all need reassurance about as we are

13	sitting here trying to discuss this data safety monitoring
14	board is how frequently the data is monitored in regards to
15	how significant we think the effects will be, and I don't
16	think we have enough data to really make that decision, and
17	we all are on the side of caution or mostly all are.
18		DR. CHESNEY:  Dr. Wolff.

19		DR. WOLFF:  I think especially in the second case,
20	where you really don't have a homogeneous group of partial
21	seizures, and some of them are on any kind of medication

22	where the addition may cause very serious effects, I don't
23	see why there should be a question about a DSMB.
24		DR. CHESNEY:  Dr. Spielberg.
25		DR. SPIELBERG:  The other practical thing,

			161 1	addressing what Dr. Ward brought up with respect to drug-

	2	drug interactions, in these kinds of trials, particularly
	3	with the anticonvulsants, many of which are inducers and
	4	inhibitors of drug metabolism, in addition to an external
	5	safety monitoring board, it is often helpful having an

	6	unblinded physician who is keeping track of drug levels of
	7	the other drugs.
	8		In many of the trials we did in my academic years,
	9	in fact, we had to have somebody who was responsible for
10	juggling the other medications to prevent other medications
11	from getting into toxic ranges when a new drug was added on.
12		To the extent that you have to do that will be

13	dependent on adult studies showing whether, in fact, these
14	drugs are inducers or inhibitors, but if they are and they
15	are likely to lead to drug-drug interactions, it is very
16	important to have an unblinded member of the investigative
17	team doing the adjustments of the other drugs.
18		DR. CHESNEY:  Are you implying that there would

19	need to be a DSMB for them to share that information or how
20	does that relate to the DSMB?
21		DR. SPIELBERG:  Not necessarily.  It is usually a
22	real clinical trial role, but it is another level of making
23	sure of the safety of each individual subject in the study
24	and making sure that none of those patients end up with
25	unacceptable levels of the other drugs, either high or low,

			162 1	because obviously, going down could exacerbate seizures,
	2	going up could lead to side effects.

	3		DR. CHESNEY:  Dr. O'Fallon.
	4		DR. O'FALLON:  I think the DSMB, its major value
	5	is with respect to the conduct of the study, and it does
	6	help the study team in the sense that they provide the
	7	objective look at the data.  The study team can get pretty
	8	carried away or very much involved in a study, and that's
	9	okay, but then it helps to have the DSMB that is there to
10	help to keep things in perspective.

11		Given that pediatric patients are so rare, I would
12	think that almost every study of this magnitude that is done
13	would end up being a bellwether study of some sort, and I

14	think that we should consider that having to--well, the
15	DSMB's ought to be part of the normal way of doing business
16	in the pediatric research of these bellwether issues.
17		DR. CHESNEY:  Dr. Kauffman.
18		DR. KAUFFMAN:  I wanted to ask Dr. Murphy would
19	these monitoring committees be required for a sponsor to

20	appoint or would the FDA appoint them?
21		The reason I am asking is we have run over the
22	last few years in the Pediatric Pharmacology Research Unit

23	Network, repeatedly run into situations where a company was
24	reluctant to place their studies within the network because
25	they did not want to subject their proprietary information

			163 1	to another overview group even accepting confidentiality. 
	2	They just did not want to extend the exposure of their
	3	proprietary information.
	4		DR. MURPHY:  We would not be requiring them. 
	5	There is not a regulation that says that we would require
	6	them.  The reason we are having this discussion is that when
	7	we are designing trials, which we all frequently do, we ford
	8	the safety or efficacy issues, whatever they are, we may
	9	recommend to the company that they would be well served by
10	having such a monitoring process in place, and we are trying
11	to define the parameters in which our experts would also
12	think that.
13		As far as their proprietary information, I think
14	that the DSMB should be constructed, so that you would have
15	people who would know that that is the type of information
16	that they do not--let me back up.
17		People who would talk about what they discuss at a
18	DSMB shouldn't be on a DSMB.  I think, Susan, can you say it
19	another way?  Because it is more than their proprietary

20	information that they can get out.  If you were releasing
21	information about the conduct of trials to the public, it
22	can have tremendous impact in a number of ways.

23		DR. ELLENBERG:  I think that is very correct.  One
24	of the issues, of course, is that up to this point there has
25	been a relatively small number of trials that have had data

			164 1	monitoring committees, and the people who serve on them are
	2	people who often have had that experience before and have
	3	some of this understanding.
	4		That is one of the dangers of moving to a
	5	situation where suddenly there is 20 times as many data
	6	monitoring committees as we ever had, and perhaps not having
	7	all people who totally understand that.
	8		I did want to comment, though, that another side
	9	of this confidentiality issue that we have dealt with is not
10	so much that the companies don't want other people to see

11	the data, but when you have an independent data monitoring
12	committee, it is generally the case of the company itself
13	does not have access to the interim data, because the
14	recommendations for what should happen are then made by the
15	data monitoring committee to the company, and that, in my
16	experience, has caused much of the resistance of companies
17	to establish them because they don't want to give up access
18	themselves to the interim data.
19		DR. CHESNEY:  Dr. Danford.
20		DR. DANFORD:  I am inclined to agree that a DSMB
21	would be very important for these studies, but I am nagged
22	by one comment that Dr. Ellenberg made in her presentation

23	to us earlier.  She said that data monitoring boards are not
24	always a good thing, and then she didn't say the reasons or
25	the precise circumstances where they are not a good thing,

			165 1	and I am wondering what she was thinking and whether it
	2	applies to either of these cases.
	3		DR. ELLENBERG:  I think it relates to what I was
	4	just saying.  There are clearly some disadvantages to have a
	5	data monitoring committee.  They add an extra layer of
	6	complexity to a trial.  They add expense.  They are
	7	complicated to develop and make sure that everybody is
	8	getting the information they need and when.
	9		So, there is an extra layer of complexity that you
10	can understand that people who are doing a trial don't
11	necessarily want to have unless it is necessary.  My concern
12	now is if there are vastly more data monitoring committees
13	put into place than we have had, there may not be enough

14	people with the level of understanding of clinical trials. 
15	It is not just the clinical experience, it's understanding
16	of clinical trials and how to interpret them, and all of

17	that.
18		You don't want people advising you that know less
19	about it than you do.  So, a bad data monitoring committee
20	is worse than no data monitoring committee.  That is my
21	concern.
22		DR. CHESNEY:  I think that is a real concern.  I
23	was just asked to be chair of a DSMB, and I don't know
24	anything about this particular drug or this protocol.  It is
25	going to take a lot of time on all of our parts, we are

			166 1	inexperienced, and I am not sure that it is going to add
	2	much to anything.
	3		But I wonder, Dr. Kauffman and Dr. Spielberg, if
	4	you could comment again on this issue, Dr. Kauffman
	5	particularly, since you do so many of these studies and you
	6	haven't had DSMB's presumably for most of them, under what
	7	circumstances do you think that we should absolutely
	8	recommend that there should be one?
	9		DR. KAUFFMAN:  I think, in general, where they
10	would be of most value and be feasible or practical would be
11	in the large Phase III studies that are going to be spread
12	across multiple investigators and institutions, and ongoing
13	for a prolonged period of time with a wide range of kids

14	involved over a period of time, particularly for chronic
15	conditions.
16		That is where I think they would have the most
17	value.  We do a fair number of short-term pharmacokinetic
18	Phase I/II studies now, too, and for those, as Dr. Fink
19	pointed out, they are frequently opened and done and

20	finished and closed out before you could ever even convene a
21	data safety monitoring committee, and to delay those four to
22	six months to get them up and going, and so forth, I think
23	would put such a blockade in this whole thing that it would
24	just be counterproductive.
25		The other issue that was raised I think is very

			167 1	important to think about, and that is, with the number of
	2	pediatric studies, the increase in the number of pediatric
	3	studies that we have seen and probably will continue in the
	4	coming years, to have a data monitoring safety committee for
	5	the majority of those, there aren't going to be enough
	6	people with enough time to do this.
	7		It is just going to not be feasible to do it, so
	8	we are going to have to be selective and do it where it has
	9	the greatest impact on children's health, where there is the
10	greatest potential risk, the larger studies, the greatest

11	exposure to the pediatric population, I think that is where
12	they have their greatest value.
13		DR. SPIELBERG:  I would really agree with Ralph,
14	and two other points.  I think any situation where
15	internally you are really concerned about early stopping

16	either from a safety or an efficacy point of view, a drug
17	for a life-threatening condition where you want to be able
18	to make that drug more broadly available, as rapidly as
19	possible, with all the appropriate stopping rules put in
20	there, as well as where you are concerned about toxicity.
21		On the toxicity side, what Ralph said though is
22	also a concern.  Of the people listed on those committees,
23	one thing left out is anybody really knowledgeable about

24	pediatric AE's, and pediatric side effects of drugs and the
25	ability to detect them and the ability to understand them is

				168 1	really something of a specialty, and there are very few
	2	folks around who really can help out with those kinds of
	3	things.  But if you are really concerned about side effect
	4	issues, you have to have clinical toxicology involved.
	5		DR. CHESNEY:  Dr. Murphy, do you think you have
	6	enough information that we should go on?
	7		DR. MURPHY:  Yes, I do, and I appreciate it
	8	because I think the issues that we hope would be brought out
	9	were, which is it would be very difficult to have the
10	adequate type of DSMB that you would want for every single
11	pediatric study.  I think that we are trying to define the
12	parameters, and we think that they definitely should be or
13	one should at least consider the discussion that they should
14	be utilized.  So, thank you.
15		DR. CHESNEY:  We will move on to Example B, and
16	Dr. Rosemary Roberts is going to present that to us.  She
17	will tell us what questions we will address instead of all
18	three.
19	    Example B: Pediatric Placebo-Controlled Trial Design
20		   When There is No Approved Therapy
21		DR. ROBERTS:  Good afternoon.  All of the
22	committee members and the invited speakers have in their
23	packet, attached to the back of their agenda, the examples,
24	and it might help if you just follow through and look at
25	that while I read to you the essential elements of the case.

			169 1		[Slide.]
	2		For Example B, there are pediatric placebo-

	3	controlled trials where there is no approved therapy. 
	4	Unlike the other examples from A and those that you will
	5	hear from C today, this is not a pediatric study that has
	6	been submitted to the agency for review.
	7		Instead, this outline is taken from the written
	8	request template that the Division of Neuropharm has
	9	developed and is up on the web, so I am just going to go

10	through the essential elements of the trial design that we
11	are requesting.
12		Now, the assumptions for depression are that the
13	patients have a chronic disease or condition that requires
14	long term therapy.  There is approved therapy in adults for
15	the condition, however, there is no approved therapy in the
16	pediatric population.
17		The trial design elements.  Age range, it will
18	involve children ages 7 to 11, and adolescents ages 12 to 17
19	with equal representation and a reasonable distribution
20	across both sexes.
21		We are requesting two randomized, double-blind,

22	parallel group, placebo-controlled acute treatment trials
23	with a duration of 6 to 8 weeks.
24		One of the trials should be a fixed dose study
25	including two or more fixed doses of the study drug as well

			170 1	as placebo.
	2		It is also recommended that there be a relapse

	3	prevention trial that would involve the randomization of
	4	responders from the acute treatment trials to continue on

	5	either study drug or placebo, with follow-up observation for
	6	relapse for 6 months or more.
	7		The request also includes pharmacokinetic
	8	assessments that should be made in the relevant age groups
	9	and be able to adequately characterize the pharmacokinetics
10	in those age groups.
11		The criteria for enrollment should include a valid
12	and reliable diagnostic method for recruiting children and
13	adolescents with major depressive disorder.
14		The study evaluations are to include a scale

15	specific to pediatric depression and sensitive to the
16	effects of drug treatment of pediatric depression, for

17	example, the Children's Depression Ratings Scale-Revised,
18	and a global measure, such as the Clinical Global
19	Impression.
20		The study endpoints should be change from baseline
21	to a single primary endpoint using the symptom rating scale
22	chosen for the trial.
23		Routine safety assessments should be included.

24		In this example, there is no approved therapy in
25	the pediatric population, but approved treatment for the

			171 1	condition in adults is available.  Further, it is believed
	2	that the efficacy in adults demonstrated in adequate and
	3	well-controlled trials cannot be extrapolated to the
	4	pediatric population.
	5		For approval in the pediatric population, the FDA
	6	is requesting that efficacy be shown in two adequate and
	7	well-controlled trials of the placebo control design.  For

	8	psychotropic drugs there is a concern that pharmacotherapy
	9	may have effects on cognitive development.  We ask that you
10	consider these issues in your discussion of the following
11	question.
12		We are going to focus on Question No. 2. 
13	Recognizing there is a concern that psychotropic therapies
14	may affect long-term cognitive development, what ethical

15	issues arise when only information from short-term
16	therapeutic trials is available?
17		DR. MURPHY:  I would like to focus that even a
18	little more, or expand it.  What we are really getting at
19	here is the question of duration of the studies.  The
20	information you have at the end of a study, which will be

21	measured in months, in which you will be treating children,
22	and what do we do about the long term, not just cognitive,
23	but long-term studies.
24		DR. CHESNEY:  Dr. Nelson.
25		DR. NELSON:  I guess starting with a question,

				172 1	what kind of control group would you propose to use for such
	2	a long-term study?  I mean it would be worthwhile doing it,
	3	but I can't imagine you would want to have a 16-year placebo
	4	control.
	5		DR. MURPHY:  Well, that is the issue.  What we are
	6	placing on the table is the fact that we do not know how one
	7	would have a controlled study in this situation, and what is
	8	the level of acceptability of having short-term data knowing
	9	that these products may be used on and off over the lifetime
10	of the child, and when one does not have a way in which we
11	feel we can design a controlled trial at this point.
12		DR. NELSON:  I guess some information is better
13	than none.  Are we basically then trying to come up with a
14	way to gather information in the absence of a control, or is
15	there some way it could be controlled?  I mean you have got
16	the control guru to your left.
17		DR. TEMPLE:  Well, it's a really hard problem. 

18	You sort of either accept population norms or do something
19	like that, or you try to dream up a design.  I have one I
20	would throw out for comment.
21		It is probably not known how long you really need
22	to treat people.  One could compare two approaches to
23	treatment, one in which you kept people on until a year had
24	elapsed, which is probably not incompatible with some
25	treatment, another in which you kept people on only for two

			173 1	months after they had recovered and waited.
	2		Now, both of those, I think would have to be
	3	considered within the scope of what standard therapy is, but
	4	comparing them might give you some idea about long-term
	5	effects, and you don't know the answer to which is better
	6	yet, so there might be some designs one could work on.
	7		I don't believe a study like I described has ever
	8	been done, but it doesn't seem impossible.
	9		DR. NELSON:  I guess as a pediatrician, I have
10	never thought of one year as a long time when you are
11	looking at cognitive development.
12		DR. TEMPLE:  No.  At one year you stop the therapy
13	and then if they recur, you treat again.  The other is at
14	two months you stop the therapy and if it recurs, you treat
15	again.  The assumption would be that you would have--well, I
16	don't even know this--but you might have considerably more

17	treatment and maybe a happier kid with the one-year therapy. 
18	The other, the shorter therapy might leave more episodes of
19	depression, but might leave growth and development
20	unimpeded.  So, you might make the case that that is an
21	interesting trial.
22		DR. CHESNEY:  Could I ask a question?  Can you do
23	an adequate analysis of cognitive state in a child that is

24	depressed?  In other words, could you have a baseline that
25	you could compare to a year later?

				174 1		DR. MURPHY:  I think what we are bringing out here
	2	are all the problems with this, is that you long-term-wise
	3	don't know what the normal outcome would be, and you may
	4	have a baseline that is actually worse, and so you are going
	5	to have an outcome in the long term that is better, and
	6	unless you have a control group that you didn't treat, which
	7	we don't think you could do, if you had made the diagnosis,
	8	the appropriate diagnosis, unless you have some other
	9	historical information, that would be very difficult, so we
10	continue to hear the discussion because we are struggling
11	with this issue.
12		DR. TEMPLE:  But you might test cognitive function
13	at a time when they weren't overly depressed.  That
14	certainly seems like a good thought.
15		DR. CHESNEY:  I think Dr. Gorman was first.
16		DR. GORMAN:  To go back to one of Dr. Nelson's

17	previous points, the randomized withdrawal in studies like
18	this presents some problems for our IRBs and may actually

19	present an opportunity to answer your question at least on a
20	moderately long-term basis if you use 6 months.
21		Rather than re-randomizing the responders in the
22	acute phase of the study, knowing that some of the
23	responders will be on placebo, continue to follow them
24	without re-randomization in the follow-on course.  Then, you
25	can look at their cognitive skills in the active drug versus

			175 1	the placebo in only the responders.
	2		DR. CHESNEY:  Dr. Spielberg.
	3		DR. SPIELBERG:  Just stepping back a little bit to
	4	the nature of the controls, because the first question that
	5	Dr. Roberts raised was that of non-approved therapy as a
	6	potential comparator rather than placebo, one of the things
	7	that we are going to face ubiquitously in pediatric studies
	8	that Dr. Temple didn't even address is that if you have non-
	9	approved therapies, you often don't have formulations.
10		If you don't have formulations, then, in order to
11	do a controlled study of a non-approved therapy versus your
12	new drug, not only don't you have a basis for doing it
13	because the first drug is non-approved, but you also may not
14	have a formulation that fits, which often leads into a
15	double-dummy design, because you can't bind the
16	formulations.  They have different colors, they have
17	different flavors, they may be bid, they may be tid, they

18	may be qd.  So, you end up with a very complex study design
19	which often runs into major compliance problems, and in a
20	situation with depression and such, you are going to be

21	facing it even worse.
22		The other issue, though, is that--and we have
23	faced this several times--is if there is no approved

24	therapy, you can't even do a best available therapy
25	approach.

			176 1		You could fall back and say, well, what is
	2	community standard, but then you have to ask what is the
	3	scientific basis of that community standard, and typically,
	4	that will not meet FDA standards because the drug isn't
	5	labeled in the first place.
	6		So, you are sort of chased around looking for a
	7	good comparator that is (a) non-approved, and (b) non-
	8	formulated, which makes from an FDA point of view a non-
	9	doable study, but also from a pragmatic point of view a non-
10	doable study because you don't have the matched formulations
11	available for a comparator.  You can't keep the study
12	blinded.
13		DR. MURPHY:  Steven, this disease, we are talking
14	about depression, you may not need a different formulation
15	because of the age population.
16		DR. SPIELBERG:  Although if you look at kids down
17	to 7, fewer than 30 percent will be able to take pills
18	depending on the size of the pill, and even at 11, only half
19	the kids will be able to swallow pills, and if you look at
20	those pills that are on the market in the OTC venue, which
21	is the key to looking at what children can and can't take,
22	the OTC preparations available for the 7- to 11-year olds

23	are very, very tiny.
24		Very few of our Rx pharmaceuticals meet those
25	criteria for friendliness for use, so that really does

					177 1	become a problem, and compliance in depression obviously is
	2	a major issue, and if the kid has trouble swallowing it the
	3	first time, he is not going to take it the second time.
	4		DR. MURPHY:  Right.  I am just saying it doesn't

	5	make it an impossible study because you may be able to find
	6	those kids who can take the preparation that you have.
	7		DR. CHESNEY:  Dr. Wolff.
	8		DR. WOLFF:  One of the concerns you raised was

	9	about whatever you mean by cognitive development and its
10	long-term effects, is that--
11		DR. MURPHY:  I really was expanding the question. 
12	It's just the long-term effects, cognitive being one of
13	them, because these are CNS therapies.
14		DR. WOLFF:  What I meant was that probably means
15	something to do with the brain with these pills.  At what

16	point do you then make a determination that it does or does
17	not have an adverse effect on cognitive function?  Isn't

18	that one of the problems?  It may not be in a year, it may
19	not be in two years.
20		DR. MURPHY:  That is the question, how does one
21	determine that if this may not occur during the immediate
22	therapy that you can define the adverse event during the
23	trial, or is that simply something we have to accept.

24		DR. WOLFF:  What I wondered was whether cognitive
25	development really means cognitive development or you have

			178 1	some hints about other, more objective, you know, other than
	2	psychological tests.
	3		DR. TEMPLE:  The suggestion of following people
	4	who do well on either drug or placebo has some problem with
	5	it.  The population that does well on placebo might be
	6	cognitively different from the ones who need a drug to get
	7	better, so that the loss to follow-up might what
	8	statisticians call informative, I think I am using it right,
	9	and you might be misled by that.  It's not a randomized
10	trial anymore.  So, it's treacherous.  You might choose to
11	do that anyway, but it could be misinforming.
12		DR. CHESNEY:  Dr. Wilfond.
13		DR. WILFOND:  It certainly does strike me that one
14	of the approaches that people have taken is following people
15	for a long period of time as the natural history studies,

16	epidemiologists do this all the time, and while they don't
17	have the advantages of a long-term control trial with
18	accurate data collection in a prospective study they can
19	still get lots of information that will accumulate over

20	years, so that does strike me as one approach that could be
21	used more commonly than it currently is.
22		DR. TEMPLE:  I think people are encouraged to try,
23	but subtle differences in epidemiologic studies are
24	treacherous.  If there were a controlled way to do it, then,
25	you would really know.

			179 1		DR. FINK:  If we look at the experience with
	2	asthma where there has been some data collection, there are
	3	two problems I see arising in even attempting to do this. 

	4	One, in adults who were asthmatic as children, less than 30
	5	percent recall a history of childhood asthma at age 30 even
	6	though they were hospitalized and on multiple medications.
	7		Secondly, we have an epidemiologic study that
	8	shows that there is an increased risk of glaucoma and
	9	cataracts at age 65 with a five-year exposure to inhaled
10	steroids within a lifetime, and yet everyone feels that the
11	new inhaled steroids are safer.
12		Are we going to demand 65-year studies of new
13	inhaled steroids to try and see whether they have a lesser
14	risk of glaucoma?
15		So, I think it is laudable, but anything short of
16	a national database that records all participation in
17	clinical trials and treatment with prescription drugs and
18	over-the-counter treatment is going to come up short of

19	answering the question.
20		DR. CHESNEY:  Dr. Gorman.
21		DR. GORMAN:  I wanted to follow up on my
22	colleague's down the table question.  What did you mean by
23	cognitive?  I immediately narrowed that down to intellectual
24	function, but is it also personality development?  I mean
25	not in terms of their major disease, but in other

				180 1	personality development.  Do people who are on Prozac not
	2	become captains of their football team?
	3		DR. MURPHY:  We were limiting it, maybe
	4	improperly, to learning, intellectual abilities, not to all
	5	other possible behavioral or personality adverse event
	6	potential, but to long-term learning and intellectual
	7	development.
	8		DR. GORMAN:  Meaning just the intellectual
	9	functions.
10		DR. MURPHY:  Yes.
11		DR. TEMPLE:  There are certainly other questions
12	that might arise.  You might wonder about sexual
13	development, for example, to pick a possibility for that
14	class of drugs.
15		DR. GORMAN:  More concerned about sexual behavior
16	perhaps than even sexual development.
17		DR. TEMPLE:  Yes, that is probably what I meant.
18		DR. CHESNEY:  Dr. Nelson.
19		DR. NELSON:  I think from the discussion, most of
20	us probably feel that it obviously is ethical to try and get
21	this information.  That is the way the question was phrased
22	in the first place, but if you thought that at best you
23	could get some sort of long-term registry kind of data, is
24	there any leverage one has in asking for it particularly

25	after a drug is approved?

			181 1		Effectively, you are talking about a long-term,
	2	postmarketing registry of individuals on the drug to be able
	3	to get a hint of whether there is anything going on or not
	4	regardless of how hard that might be to conclude, but is
	5	there any way that you can ask for that and have it stick?
	6		DR. MURPHY:  Let me not go to that last question
	7	first.  I think that the issues are on a registry,
	8	particularly people use the word national database, there
	9	would be issues of confidentiality that would be of concern.
10		I think also when we look at some of the very
11	limited long-term trials in pediatrics that we are trying to
12	take to undertake in other areas, the endpoint measurement,
13	these other fields where you have a much more concrete

14	endpoint is extremely difficult, and I think we are very
15	concerned about what endpoint you would be measuring unless
16	you--I mean somebody was telling the story about SATs or,
17	you know, and we don't know what that would be.

18		So, I think we have at least two major issues just
19	from a very pragmatic perspective, which would be the

20	confidentiality issues and the lack of certainty of the
21	endpoint measurement in this type of long-term trial.
22		DR. CHESNEY:  Dr. Luban.

23		DR. LUBAN:  The one thing that I wouldn't totally
24	put out of the picture is limited registry data on selected
25	cases, selected drugs, and selected patient populations.  I

				182 1	will give for an example the hemophilia population where
	2	certainly registering of those patients in serial follow-up,
	3	much of which has been paid for by the pharmaceutical
	4	industry, has provided a vast amount of information, very,
	5	very valuable, and very necessary not only for adverse
	6	events, but also for tasks of daily living, school
	7	attendance, and whatnot.
	8		DR. CHESNEY:  Dr. Danford.
	9		DR. DANFORD:  Not only does the length of follow-
10	up present a problem here but also the breadth of diagnoses
11	that you might be considering.  So often, children diagnosed
12	with depression don't have that as their sole diagnosis, but
13	there are other behavioral and psychiatric diagnoses that
14	can accompany depression, each of which may have an impact
15	on intellectual development.
16		So, I would imagine not only a very long study,
17	but a very large sample group to allow for those confounding
18	influences.
19		DR. CHESNEY:  Dr. Roberts and Dr. Murphy, would

20	you like to move on to Question 1, and if so, could either
21	of you maybe rephrase that or give us a few more specifics,
22	or would you like to continue on Question 2?
23		DR. MURPHY:  I think it would be helpful on
24	Question 1 to just focus in on the actual example in which
25	we have issued written requests.  As we said, we have no

			183 1	approved therapy in children.  We feel that we do have a
	2	history of failed therapies, products approved in adults,
	3	but failed in children, and that we feel that it is
	4	important to be able to answer whether the therapy is
	5	effective in children.
	6		We are asking for two trials, and this type of
	7	trial we feel is appropriate for this situation.  Is there a
	8	situation in which you have a chronic disease that you would
	9	not feel that this is appropriate?
10		We heard some of that this morning, and I guess
11	this would be your opportunity to say where you do not think
12	this would be an appropriate trial.

13		DR. CHESNEY:  Dr. Ward.
14		DR. WARD:  Dianne, I guess I would think that
15	children with bipolar disorder at significant risk for

16	suicide would not be one that you would want to randomize to
17	a placebo necessarily as opposed to all the difficulties
18	that were described this morning about equivalence, that
19	they probably warrant active treatment.
20		DR. MURPHY:  So, you are saying the approved
21	therapy in adults should be taken and basically extrapolated
22	to children?
23		DR. WARD:  Yes, because we actually have some
24	therapeutic guidelines about monitoring, for example, if we
25	would use lithium or if we used valproic acid for bipolar,

				184 1	and those have defined therapeutic ranges.
	2		As a neonatologist, I will confess to being well

	3	out of my level of clinical practice here, but I do think
	4	that those particular children would be at risk for
	5	deleterious effects on their health by not being actively
	6	treated.
	7		DR. CHESNEY:  Dr. Botkin.
	8		DR. BOTKIN:  I just had a question of
	9	clarification.  What is meant by approved, does that mean
10	FDA approved or does that mean approved by the community of

11	physicians either here or perhaps in other areas like Europe
12	or Asia that might have considerable experience with
13	particular agents?
14		DR. MURPHY:  In this scenario, we are speaking to
15	approved meaning FDA approved for use in children meaning it
16	has been studied in children.
17		DR. BOTKIN:  Well, that certainly raises the
18	possibility of whether you may need to have a third arm in
19	those circumstances where the medical community is widely

20	using an agent that, for whatever reason, is believed to be
21	effective, that may need to be included as part of the
22	clinical trial.
23		DR. CHESNEY:  Dr. Geller.
24		DR. GELLER:  Bipolar is my bailiwick.  I think
25	that everything everybody has said about looking at

			185 1	depression and bipolar is true.  It is very complicated. 
	2	But the major problem has been that the drugs that are
	3	effective in adults don't seem to work in kids.
	4		Some of it may be because the kids present more
	5	like severe adults, and they are very comorbid and there may
	6	be all kinds of diagnostic reasons.  So, you really get into
	7	a problem is you want to do add-on studies of what you would
	8	consider a standard therapy.
	9		I think this has been one of the reasons that has
10	kept the research from going on is people don't want to give
11	them placebo because they are suicidal and so sick, but if
12	you don't, you can wind up doing things you don't mean to.
13		For example, there is rather good data now,
14	valproate in teenage girls is elevating testerone levels and
15	producing later cysts of the ovaries.  The reason the data
16	came about was looking at it in children who were female and
17	epileptic, but it is already in very widespread use in
18	bipolar girls who are teenagers.
19		So, I think that that has to be weighed against
20	what you are losing if you have a placebo arm, and I think a
21	very good argument can be made that you would want to
22	hospitalize the children and study them where you can look
23	at them, which has been a terrible problem in child
24	psychiatry because all the inpatient units are closed.
25		I work at Barnes Hospital at Wash U.  Barnes has

			186 1	closed its inpatient child and adolescent psychiatry unit,
	2	something that would have been unthinkable, and it is
	3	impossible to have them on placebo on an outpatient basis in
	4	good conscience unless you are essentially hospitalizing
	5	them at home, which can be done, but at an expense now that
	6	with all parents at work now, there is not even one parent
	7	who is at home to do it.
	8		We used to be able to do studies like that, and
	9	one parent would be at home, but now almost every family has
10	two working parents.  So, I think there is a succession of
11	things that are needed, and one is there has to be some
12	financing for inpatient research for children who have
13	severe depressions and severe bipolar disorder.
14		Then, you can have placebo arms, and then you can
15	find out what works in this age group, and that then can be
16	a prelude to the longer term studies.
17		Just one final point.  The question was can you
18	look at cognition in children who are bipolar and depressed,
19	and the answer is it is very difficult because most of them,
20	even if they are otherwise brilliant during episodes, which
21	tend to be very chronic in kids, they are failing in school,
22	they are not functioning at all, so any improvement, whether
23	it is related to drug or not, is going to make it look as if
24	they are functioning cognitively better.
25		So, it is really going to be hard to decide what

			187 1	you are going to use as baseline to compare long-term
	2	follow-up to.  It may make more sense to use the baseline
	3	the first time you see them with 50 percent improvement or
	4	something as the baseline for later follow-up.
	5		DR. CHESNEY:  I think Dr. Spielberg was next and
	6	then Dr. Fost.
	7		DR. SPIELBERG:  I think Dr. Geller really
	8	summarized our quandary very effectively.  There is one
	9	additional confounder, and that is total numbers of patients
10	available even if we had the units available to hospitalize
11	them and to do the studies.
12		The number of children is very small.  As we have
13	recognized in pediatrics in the past, the requirement for
14	two, well-controlled studies has often acted as a
15	disincentive.  We have been told we really do have some real
16	problems extrapolating efficacy from adults here, so we do
17	have to come up with pediatric study designs, but remember
18	the number of drugs out there, the number of classes of

19	drugs out there, the number of new therapeutic classes
20	coming down the pike, and then the number of children
21	available to study even if we had the units available.
22		We are going to have to come up with some new

23	paradigms, and I think we are probably going to have to come
24	up with some new paradigms rather urgently of how to
25	evaluate these drugs in the smallest numbers of children

			188 1	possible, in the shortest duration of time, so that
	2	eventually, we can get to the point of doing comparative
	3	studies among different agents, and see which agents do and
	4	don't work.  We are going to run out of patients very
	5	quickly.
	6		DR. CHESNEY:  Dr. Fost.
	7		DR. FOST:  I was going to say that the issue is
	8	not doing the placebo-controlled trial, but monitoring, that
	9	is, it would be okay to do it as long as children are
10	radically monitored until Dr. Geller said it would be
11	unconscionable to do this in an ambulatory setting, but then
12	you also said that you thought the adult drugs were largely
13	ineffective, so I am a little confused.
14		Why is it unconscionable if there aren't any
15	effective treatments out there?
16		DR. GELLER:  That is an excellent argument that as
17	you can imagine, many people make to their IRBs all the
18	time.  The problem is that nowadays with families having
19	both working parents, it is very hard to find somebody who
20	can monitor a suicidal child on an outpatient basis.
21		If you had the child on no treatment, it would
22	probably be impossible to get families to agree to be in the
23	study.
24		DR. FOST:  What treatment would you use?
25		DR. GELLER:  What people are using clinically you

					189 1	mean?
	2		DR. FOST:  Treatments of no known efficacy is what
	3	you are advocating?
	4		DR. GELLER:  I am not advocating that we use
	5	treatments that have no efficacy.  What is being used
	6	clinically is people are just purely extrapolating from
	7	adults.
	8		DR. FOST:  But I thought you said that that seems
	9	not to be working.
10		DR. GELLER:  If you look at the naturalistic data,
11	our naturalistic data at the end of six months was that only
12	15 children out of a sample of 93 had recovered, and this is
13	very, very different from adult data on bipolar where you

14	get much, much higher rates of recovery.  Only half the
15	sample were receiving appropriate drugs, the disease is
16	under-recognized.
17		Naturalistic, they were followed by their own
18	practitioners, but even those who were followed by

19	practitioners giving them adult drugs, in adequate doses for
20	an adequate period of time, they still were not responding
21	and recovering.
22		DR. FOST:  Well, it sounds to me like you are

23	describing a situation where there is no known effective
24	treatment.
25		DR. GELLER:  That is essentially the case for the

			190 1	kids, which is why I think you need placebo arms if you are
	2	going to make comparisons, but I think if you are going to

	3	do that in a way that is going to be, as we are talking
	4	about, in an efficacious way, that you are going to need
	5	some inpatient units where suicidal kids who aren't on
	6	medication can be, so that parents and the community will
	7	accept it as a reasonable study.
	8		I think we are essentially in agreement and
	9	talking about just some logistic concerns for this
10	population.

11		DR. MURPHY:  I am going to try to summarize that
12	conversation.  What I have, I think I heard here, is that
13	for depression, where we have known studies with products

14	that are approved in adults do not work in children, we need
15	to do placebo-controlled trials because otherwise we will
16	never know or we will continue to experiment on our children
17	without ever having an answer; that we have real problems

18	when we get into various other diagnostic entities in this
19	area, and we have to find a way to study them in the

20	placebo-controlled trials in a safe way, so that the
21	children are not at any more risk or hopefully would be at
22	much less risk than just trying a drug hoping--because they
23	will be in the outpatient--hoping it works, and it may not.
24		Is that a fair summary?

25		DR. CHESNEY:  Dr. Temple.

			191 1		DR. TEMPLE:  At least in the bipolar setting where
	2	people are using drugs like valproate and lithium, you
	3	probably could do an add-on study even though you don't know
	4	those work of some more conventional antidepressant against
	5	a placebo.  That still leaves the problem of leaving them
	6	outside the hospital, a problem I have no solution to.
	7		The other possibility is if those drugs really
	8	work so poorly, an effective agent might well be able to
	9	beat them, so another possibility is being better than the
10	putative active control.
11		DR. FOST:  Joan, the issue of leaving them outside
12	the hospital seems to me analogous to the AZT trial
13	argument, that is, no one is going to be worse off.  Out of
14	the hospital is where they are anyway, so nobody is going to
15	be worse off.  So, half the kids in the trial might be
16	better off, the other half will be exactly where they were 
17	before.  You are not introducing any element of harm by
18	doing such a trial.
19		DR. CHESNEY:  Dr. Geller.
20		DR. GELLER:  I think intellectually I have full
21	agreement with what you are saying 1000 percent.  I think
22	this is more an issue of the logistics and how you are going
23	to do the studies with a relatively small population
24	compared to the number of adult bipolars in a way that will
25	give you answers in a reasonable amount of time, and this

			192 1	requires having families who will agree to have their kids
	2	in the study.  I think then you get into other kinds of
	3	issues of where the kids are safe, and so on.
	4		DR. CHESNEY:  Two more comments.  Dr. Nelson has

	5	been patiently waiting and Dr. Gorman.  Then, we probably
	6	need to go on to Example C.
	7		DR. NELSON:  I just want to keep the question

	8	about the purpose of the relapse prevention trial on the
	9	table, because I certainly haven't been convinced that there
10	is a need for that, and it would bother me if you had a
11	responder, given all this discussion of the lack of any
12	evidence that anything works, and than randomize them back
13	to placebo.
14		So, if I was reviewing that as an IRB, I would ask
15	the investigator to give me a good scientific justification,
16	put a lot of safety mechanisms in place, and nothing I have
17	heard so far convinces me that that is necessary.
18		DR. CHESNEY:  Dr. Gorman.
19		DR. GORMAN:  I want to go back to Question 2,
20	which was the cognitive development issue.  Depression
21	remains, at least in my clinical practice, a severe enough
22	disease that I would want effective therapy to be available
23	and approved even with that holding over my head for a long-
24	term concern, just like for cancer chemotherapy, it's a

25	disease that has severe morbidity and mortality, and even

			193 1	though I know radiating their brains will decrease their
	2	long-term cognitive ability, I still would like to have that
	3	treatment modality available to me today for their survival.
	4		DR. CHESNEY:  Dr. van Zwieten.
	5		DR. VAN ZWIETEN-BOOT:  One of the questions was
	6	about two placebo-controlled trials, but I got the
	7	impression that during the trial, you put together children
	8	and adolescents, and that is something that we have been
	9	discussing in Europe, whether or not that is suitable
10	certainly for depression.
11		First of all, the way the disease or disorder is
12	expressed may be totally different.  The course of the

13	disease may be different.  The endpoints, at least the
14	scales that you use, may be different.  Even if they have
15	the same side effects, they may be felt different by

16	adolescents and children.  Sexual dysfunction is not
17	something you will see in the younger children, but it

18	certainly may affect adolescents that are just coming into
19	puberty a lot more, and the other way around for other side
20	effects.
21		Anxiety or what we see hyperactivity may be much
22	more important for the younger children, and therefore, we
23	tend to say that you should do separate trials, at least

24	analyze them separately, but that means that you have to
25	power them in such a way that you better can do separate

			194 1	trials.  Did you consider that?
	2		DR. MURPHY:  We always consider whether we should
	3	do the older age group first and then go down to the younger
	4	age group.  I think the approach is that we would have the
	5	appropriate diagnostic tools and assessment tools that would
	6	be age appropriate.
	7		Tom, do you have any other response to that?
	8		DR. LAUGHREN:  It is actually a little bit murky
	9	what the specific requirements are.  Basically, where we
10	have ended up is that we want at least one trial that
11	essentially stratifies to both strata, but would probably
12	accept replication in one or the other for the second trial
13	as sort of a compromise, you know, given how difficult it is
14	to do these studies and the fact that some of these trials
15	were already started at the time that we were negotiating
16	with the companies.
17		But given the history of completely negative
18	outcomes in the older class of antidepressants, we did feel
19	that it would be very hazardous to extrapolate from the
20	adult data.  So, that is the basis of our requiring
21	replication in the younger population.
22		DR. MURPHY:  So, I think that what we are saying
23	is that if you did do a study in the older, you would still
24	need to do the study in the younger.
25		DR. CHESNEY:  I think we probably should move on. 

			195 1	We have only got 35 minutes to do Example C, which is the

	2	withdrawal phase.  Dr. Hirschfield is going to present the
	3	two different types of patients for Example C and tell us
	4	which questions we are to address.
	5	      Example C: Pediatric Placebo-Controlled Clinical

	6	       Trial Design Including a Withdrawal Phase When
	7	       There is Only One or Limited Effective Therapy
	8		DR. HIRSCHFIELD:  Good afternoon.

	9		We have been hearing all day since the early hours
10	about the withdrawal study design, so we would like to
11	present two examples and then move the discussion to focus
12	on Question 1 and then 3 following.
13		The first example is an asthma study.  The
14	patients are considered stable, but they continue to have

15	intermittent exacerbation on their current therapy whatever
16	it may be, whatever combination of drugs might be required
17	to maintain that level of control.
18		There would be standardization of care using a
19	specified inhaled corticosteroid during the run-in phase of
20	the trial, and we would say the length of the run-in phase
21	would be adequate to establish whatever parameters might be
22	needed.
23		That would be followed then by randomization to
24	either an active control, the study drug or placebo during
25	the withdrawal phase.  So, there are three arms, and each

			196 1	one would get at least their standard of care plus then the
	2	active control, the study drug, or placebo.
	3		There are specifics which for the sake of brevity
	4	I may skip over in reading through the sheet on this trial
	5	design, but we could answer any questions for clarification
	6	that might be needed.
	7		We will move to the second example, which would be
	8	the hypertension example.
	9		This condition is considered chronic, which would
10	require long-term therapy.  The patients have mild to
11	moderate hypertension.  The mild to moderate is defined by
12	the age-adjusted criteria for blood pressure.
13		We are looking in this particular study design at
14	children who are in early to mid puberty, so we will say 12
15	to 16 years old, males and females.  They have their mild to
16	moderate hypertension controlled by medication relatively

17	stable, so now they have a run-in period which we thought
18	would be a fairly lengthy run-in period of anywhere from 3
19	to 6 months, so that they are stabilized through the range
20	of their activities.
21		They receive this study drug for that period of
22	time.  They have their blood pressure measured at the same
23	time daily.  Then, they are randomized, and they will be

24	randomized to receive the study drug at the same dose or the
25	study drug at a somewhat reduced dose or at a very reduced

			197 1	dose, zero, so they are getting placebo at that time.
	2		They will continue to have their blood pressure
	3	monitored, and in this trial and in the asthma example, on
	4	an individual patient basis.  There are prospectively
	5	defined, explicit criteria for escape, for rescue therapy,
	6	or whatever else would be discussed in the protocol, and the
	7	patient would then be discontinued from the study when these
	8	criteria were met.
	9		Of course, it goes without saying, but I will say
10	it anyway, that safety is included as part of the
11	assessments.
12		So, now we come to the question specifically.  In
13	these two examples, we are asking about the applicability of
14	a withdrawal study design to learn about both efficacy and
15	toxicity over a relatively extended time period.
16		Both examples have a lead-in time when all
17	patients receive the same therapy after which they are
18	randomized, so that some patients continue to receive active
19	therapy while others receive placebo.
20		An important element of these examples is the
21	presence of well-defined conditions or rules for
22	discontinuation of the patient from the study and treatment
23	with active therapy.
24		Our first question is:  Do these examples
25	represent an acceptable level of risk for pediatric patients

			198 1	in a clinical trial?
	2		DR. CHESNEY:  Thank you.
	3		Dr. Nelson.
	4		DR. NELSON:  I feel a little differently about
	5	either one of these trials.  I know that we have turned down
	6	as an IRB a trial that involved a placebo group for children
	7	that we thought were on steroids and would have been then
	8	taken off steroids in asthma.
	9		I think the reason why I might feel differently is
10	certainly seeing the short-term risks of both morbidity and
11	mortality related to asthma, and the variability in standard
12	of care and access to care that occurs within certain
13	populations, that the risks of asthma--and this may just
14	show my bias working in an intensive care unit--strike me as
15	much different than the risk of hypertension, which might be
16	off medication for a certain period of time where there may
17	not be any short-term risk as opposed to long-term risk. 
18	That bias may just reflect my clinical practice, so I am
19	happy to be corrected on that second point.  I think that is
20	why I feel very differently about these two trials and the
21	placebo group in particular.
22		I wouldn't be very happy with the placebo group in
23	the asthma.  They are certainly not on standard of care.  It
24	is a very different example than the other one, and I don't
25	think you can put safety mechanisms in place to prevent that

			199 1	frankly.
	2		DR. CHESNEY:  Dr. Fink.
	3		DR. FINK:  I guess I would take the other approach
	4	to the asthma trial.  It would concern me, but I think it

	5	would be ethical and doable as long as the parameters for
	6	failing were set adequately, and that is, if you monitored
	7	pulmonary function or peak flow so that you had early

	8	indication of failure and did not wait for emergency room or
	9	hospital admission as your endpoint of failure.
10		Peak flow, if done properly, is probably every bit
11	as accurate as blood pressure in hypertension, and peak flow
12	would give you an early indication of failed therapy, so you
13	could set it high enough to prevent exacerbations that were
14	clinically significant, but it might, with the natural
15	variation in asthma, lead to a lot of treatment failures in
16	that placebo group, which would be just fine.
17		DR. NELSON:  I think rationally, you could design
18	it that way.  The real world would be that it would be that
19	it would be potentially done in situations where children
20	didn't have that easy access.
21		What worries me the most about a lot of these
22	studies in terms of my own bias is having non-pediatric IRBs
23	approving them, and then these kinds of studies being done
24	in situations where the basic framework of health care is
25	not well established where children are getting care because

				200 1	they lack adequate access, and where frankly, I don't think
	2	the people doing them are going to have the systems in place
	3	just for general care that can do it safely.
	4		Certainly, you can design it, and some groups
	5	could carry it out safely, I agree.
	6		DR. FOST:  Skip, would you be comfortable--it
	7	sounds to me again like a monitoring problem, not a design
	8	problem.  That is, if it were restricted to populations or
	9	individuals in which there were assurances that monitoring
10	was adequate.
11		DR. NELSON:  I would admit it's an open question. 
12	I would be very nervous about it, but it would be open for
13	discussion, but the difficulty is that studies like these,
14	once approved, are not restricted to those circumstances.
15		DR. FOST:  But that could be a condition.  The IRB
16	would require it, and you could monitor it through periodic
17	review.
18		DR. FINK:  Since we are getting to asthma trials,
19	this raises an issue I would like to I guess bring back to
20	the FDA.  To date, FDA has required manufacturers to provide
21	products or label them only for sale in the same format they
22	are used within a controlled clinical trial, and at least

23	for all of these discussions of inhaled medications, one of
24	the primary problems is what is the adherence or compliance
25	with taking the drug, and there are devices, computerized

			201 1	devices that can be used with the standard canisters, that
	2	have not been used in these clinical trials because the
	3	manufacturers don't want to be burdened with having then to
	4	provide those for clinical use.
	5		Has the FDA considered allowing a controlled
	6	clinical trial to use compliance monitors that would not be
	7	part of the package labeling or be required for sale?
	8		DR. TEMPLE:  There are trials that are conducted

	9	with certain kinds of compliance monitors, SMART bottles,
10	and things like that, that are definitely not part of the
11	approved labeling.  They are just designed to optimize the
12	available study.

13		Were the things that you were describing ways that
14	alter the delivery, though?
15		DR. FINK:  Well, that argument comes up that, for
16	the metered dose inhalers, if you use one of the devices
17	that has a potentially different pore size, it could alter
18	drug delivery although it is probably a small effect
19	compared to the adherence or compliance monitoring you get
20	from it, and some of the manufacturers are trying to develop
21	compliance devices that get around that issue.
22		DR. TEMPLE:  Those are worrisome.  As you
23	obviously know, the use of spacers with a lot of metered

24	dose inhalers is widespread and by no means all of those
25	have actually been tested with any particular product.  I

			202 1	would say we find that troublesome, but don't quite know
	2	what to do about it.
	3		Where a spacer or something like is recommended
	4	for use with a particular product, we do ask that it be

	5	studied with that product.  It's a thorny problem.  Pore
	6	size and things like that affect delivery and every aspect
	7	of the effectiveness of the treatment, or at least that is
	8	what our pulmonary people certainly believe.
	9		It would be difficult for us to label it for use
10	in a completely different way from the way it was studied. 
11	Maybe that is something that bears more discussion.
12		DR. MURPHY:  We are trying to ask in our written
13	request that the products are studied in the way that they
14	are going to be used.  We are looking at that and trying to
15	make sure that those various devices that will be used by
16	children are looked at.

17		DR. FINK:  It seems like there is an over-emphasis
18	on the devices, though because if you were going to
19	logically take that stance, then, a metered dose inhaler

20	that was shown to be effective in a controlled clinical
21	trial should have in its package labeling that this
22	medication has been shown to be effective when there is
23	every two-week follow-up medical care and review of proper
24	inhaler technique, because I would maintain that although
25	there are some delivery differences based on pore size,

			203 1	compliance and use of the device and how often you re-
	2	educate the patient are much bigger issues, and yet your
	3	package labeling doesn't say that they have to be seen every
	4	two weeks like they were in the controlled clinical trial
	5	even though you are harder on the devices.
	6		DR. MURPHY:  But the point of many of our labels
	7	are to describe the situation under which the trial was
	8	conducted, so that you understand that those are the
	9	circumstances in which this was proven to be efficacious and
10	safe, knowing that every step beyond that, that you take,
11	you impact it, because we can't possibly study every
12	variation that may exist out there, and certainly we don't
13	want to impact or try to modify the physician's ability to
14	do what the think is best.
15		So, that is why the label had in it how the trials
16	were conducted.
17		DR. TEMPLE:  But you are actually making a point
18	that has been made by a lot of people in a slightly wording,
19	that perhaps we should be studying what they call the
20	effectiveness of drugs, that is, outside of the confines of
21	a very rigid trial, and we have not regularly asked for
22	that.
23		One of the reasons it is difficult is that as soon
24	as you introduce a control, especially a placebo control,

25	nobody believes it is a naturalistic setting anymore, so it

			204 1	is not easy to study true effectiveness except
	2	epidemiologically and for the effect sizes that are seen
	3	here, epidemiologic studies and studies in HMOs are not very
	4	good.  Now, maybe for something hugely effective like a
	5	steroid, maybe that would work, I don't know.
	6		We have generally not asked for trials of that

	7	kind, but I would say there is growing interest in seeing
	8	whether less monitoring and things like that leads to a
	9	major compromise in effectiveness.
10		But it is certainly true, what is in the labeling
11	is trials done the way trials are done, very frequent
12	monitoring.  I mean the hypertension trial, people will be
13	monitored every two weeks.  No one thinks that is what you
14	should do in practice.
15		DR. CHESNEY:  Dr. Kauffman.
16		DR. KAUFFMAN:  I wanted to come back for a moment
17	to the hypertensive illustration, because that has been a
18	major problem for us in the PPRU.
19		With respect to 12- to 16-year-olds with mild to
20	moderate hypertension--and I assume although it is not
21	stated this would be individuals who have no apparent end
22	organ involvement at this stage of their life, they are

23	essentially healthy kids--I think I could live with this
24	study protocol very easily and agree that this is an
25	acceptable level of risk, particularly since most of these

				205 1	people are capable of participating in the consent process. 
	2	They are old enough to understand a lot of the risks.
	3		The real problems here are not the theoretical
	4	ethical considerations, the way you have laid it out, it's
	5	the practical considerations and it has to do with how do we
	6	standardize blood pressure monitoring, and that is a major
	7	problem we have struggled with.
	8		Blood pressure in this population is very labile,
	9	and it is hard to establish that they have mild to moderate
10	hypertension over a prolonged period of time, particularly
11	months, consistently.  We are supposed to treat them with,
12	quote "diet," and nonmedical means in this diagnostic
13	category.  It never works because they don't do it, but that
14	is what we are supposed to do.
15		It is hard to keep these kids coming back for this
16	frequent a follow-up.  There are just a lot of very
17	practical issues that get in the way of doing what sounds
18	very good theoretically, but really ends up bringing ethical
19	considerations to bear because of our inability to
20	consistently do the ideal.
21		DR. CHESNEY:  Thank you.
22		Dr. Gorman.
23		DR. GORMAN:  I guess to follow up on Dr.
24	Kauffman's comment, the placebo arm in this group would have
25	to have diet and exercise, and even though it is

			206 1	problematic, as he brings up, it is also shown to be
	2	effective when it is performed.
	3		So, a true placebo, by "placebo" in this
	4	particular case, I hope he means pharmacological placebo,
	5	not care.
	6		DR. CHESNEY:  Dr. O'Fallon.
	7		DR. O'FALLON:  This particular design struck me as
	8	the best from a point of view of evaluating the effect of a
	9	given agent of the three that we have looked at today.  This
10	one seemed to give you the best information about the actual
11	performance of a therapy.
12		But what troubles me about this one and the last
13	one, which is what I was going to say, is the endpoint
14	measurement seems to be such an issue.  I thought, because I
15	have not a physician, I thought that you would know when
16	they failed, that that was a fairly clear thing, a doctor
17	taking care of that patient would know when they wanted to
18	stop that therapy.
19		That would be absolutely essential somehow or this
20	wouldn't work.
21		DR. MURPHY:  I think what you were hearing is that
22	there are different levels of failure, and what is important
23	is where you set that level of failure, and when we heard

24	that failure where you end up in the intensive care unit is
25	not acceptable.

			207 1		Failure where you have a change in your peak flow
	2	might be, and that we would need--also, what I heard is we
	3	would need some sort of other external monitoring to make
	4	sure that we didn't have so many of these in one arm that it
	5	was unethical to continue the study.
	6		DR. O'FALLON:  Those measurements, though, we were
	7	hearing about how highly variable the blood pressure
	8	measurements were.  Definition of failure at the endpoint. 
	9	He was worried about going in on the front end, I was more
10	worried about coming out on the back end, when would the
11	doctor pull the plug on the therapy, because they were
12	convinced that the patient had failed.
13		DR. MURPHY:  Actually, one of the questions we
14	eliminated was this sort of getting at some of these issues,
15	which is a very long lead-in, so that you would get
16	hopefully beyond some of the issues of is it real or not,

17	that it is sustained, but not to the point where you felt
18	that you could not intervene, that you would have the

19	alternative approach of the intervention being diet and
20	exercise, all the things we love to talk about and know are
21	so hard to do.
22		DR. KAUFFMAN:  There are technical ways to do this
23	now.  For example, continuous monitoring at home, and so
24	forth, that are getting us to where we need to be here, so I
25	think we can get around some of these.

			208 1		It is hard to enroll in these because people don't
	2	want to do all this stuff.  They know what works.
	3		DR. CHESNEY:  Dr. Crawley has had his hand up, and
	4	then Dr. Temple, and then I think we should probably go to
	5	Question	3.
	6		Dr. Crawley.
	7		DR. CRAWLEY:  I just had a more general question
	8	in a certain sense.  When I look at the question that is
	9	presented to us here, do these examples represent acceptable
10	level of risks for the patient, I think we all here in the
11	room have the children in mind as being in our best
12	interest, but what I am hearing in the discussion of the

13	case studies today is largely with regard to the design of
14	these trials, so that they are in the best interest of the
15	patients.
16		But what I am missing myself, and I was just

17	wondering how the committee planned to address that, is
18	really the voice of those patients, the presence of the
19	patients, of the children, and I know it is not a simple

20	question or an easy task, but I was wondering how they could
21	be integrated into the discussion.
22		What I see largely around the table are top-level
23	professors in Pediatrics who have the best interest of the
24	patients in mind, but in the discussion on what is
25	acceptable for the patient and what is of the interest for

			209 1	the patient, I think it is not only the design of the study
	2	itself that is of interest, but also that communication and
	3	that dialogue with the patient that is of importance.
	4		Thank you.
	5		DR. CHESNEY:  Could I just ask Dr. Kauffman to
	6	comment on that because it is my impression that these PPRUs
	7	are to some degree addressing that issue, is that correct?
	8		DR. KAUFFMAN:  I am not sure what you mean.  At
	9	our place, we did a retrospective survey several years ago,
10	our coordinators did, to try to glean from 60, 70 kids who
11	had participated in clinical trials what their perception of
12	it was, and these were kids 5 to 16 years of age, and
13	overall, they reported back that it was a positive
14	experience, they would do it again if they were given the
15	opportunity.  Over 95 percent of them said that.
16		I think Dr. Nelson has much better perspective

17	data that we do on this.  He may not want to talk about it
18	at this point, but I think he is doing one of the things
19	that needs to be done to try to get at this issue, how do

20	kids feel about this experience and what is their perception
21	of taking risks or getting benefits from being in a study.
22		DR. NELSON:  What Ralph is referring to are some
23	focus groups that I have been doing, which is hard to
24	summarize.  I think every child is going to be different,
25	and I think part of the challenge is being able to construct

			210 1	a trial to allow them to demonstrate that difference ranging
	2	from kids that wouldn't want to come close to this kind of a
	3	study to others that I recall.  I did a focus group at
	4	Ralph's place, and one 9-year-old, who gave an analysis of

	5	placebo-controlled study and talked about the two arms and
	6	said I would be happy to participate.  I mean I am sitting
	7	there, jaw hit the table.

	8		So, there is a lot of variability, and I am trying
	9	somehow to design things in a way that would allow them to
10	do that, but the other caveat is, you know, that voice I
11	think needs to be set within the context the parental
12	obligation to protect, as well.
13		The relationship between the parent and the child,
14	and the parent being able to feel that that voice is within
15	the framework of the ability of the parent to protect the

16	child from risks that they wouldn't otherwise want that
17	child to be under.
18		It is kind of where I have my doubts about the
19	asthma, and I am less doubtful about the blood pressure.  I
20	think knowing the reality of how most asthma care is
21	delivered in many parts of the country, which is poorly,

22	that is partly what bothers me, just about the framework
23	within which this kind of study would impact in terms of the
24	parents' access to health care.
25		DR. CHESNEY:  Dr. Santana and then Dr. Temple, and

			211 1	then we need to go on.
	2		DR. SANTANA:  I guess what I heard our colleague
	3	from across the ocean say is something completely different. 
	4	What I think he was challenging us to think is that these
	5	studies may be okay to do, but we need to think of parallel
	6	studies that go with these to give us a really better
	7	understanding of what kids know that they are getting into
	8	and that they have a true comprehension of what these trials
	9	are asking them to do.
10		In a study that somebody at St. Jude did, looking
11	at Phase I trials, and end-of-life situations in kids with

12	cancer and whether the kids truly understood what a Phase I
13	trial was and if they had their choice, what was their
14	choice, and you would be very surprised about the type of
15	responses that this person who was doing the research got.
16		It's that most of the kids did understand what a
17	Phase I trial was, and they made the right decision when

18	they wanted to participate.
19		So, I think the challenge is that we don't have to
20	resolve the issue here today, but that some of these very
21	controversial studies should have parallel studies that help
22	us get a better understanding of what the kids are truly

23	understanding, and they really know what they are getting
24	into.
25		DR. CHESNEY:  Dr. Nelson wanted to make a final

			212 1	comment.
	2		DR. NELSON:  Yes, I begged for one last comment. 
	3	One of my concerns in this arena with the threshold about
	4	placebos is particularly if you are looking at certain
	5	endpoints that rely on symptom reporting, which within a

	6	trial is the extent to which children report differently,
	7	and I don't think we have really any information about how

	8	endpoints that rely, not on sign recognition, but on symptom
	9	reporting, how that would be impacted differently in a
10	pediatric as opposed to an adult trial.
11		So, that is one question that causes me to worry
12	about the death or irreversible morbidity sort of threshold
13	in placebo criteria.
14		DR. CHESNEY:  Dr. Temple.
15		DR. TEMPLE:  I don't have anything about the
16	rather interesting discussion that just took place.  I just
17	wanted to observe that if managing to follow kids because of
18	the complexity of their lives is difficult, these kinds of
19	designs to some extent minimize the period of intense
20	follow.  You can monitor relatively infrequently during the
21	lead-in period and much more intensively even for a matter
22	of days, for example, in a hypertension trial to see whether
23	they have escaped.
24		DR. CHESNEY:  I think our last question before the
25	break is No. 3.  What role, if any, does a DSMB play, is it

			213 1	necessary for the ethical conduct for each of these trials
	2	to have a data safety monitoring board?
	3		Dr. Fink.
	4		DR. FINK:  I would like to raise an issue here,

	5	and I don't know what the number is, but I think one issue
	6	that should be looked at carefully is that a data safety
	7	monitoring board may be much more important in the typical
	8	multicenter trial where each individual center may only
	9	enroll 8 to 10 patients, because in that kind of setting--
10	and it is very common in the asthma trials--no individual
11	center has a good feel for the side effects, adverse
12	reactions, or problems that are occurring in the overall
13	trial, and as the trials get spread over more and more

14	centers, as is commonly done, the ability of someone to have
15	oversight of the entire trial is really lost.
16		I don't know if the magic number is 10 or 20, but
17	at some certain number of centers involved in a trial, an

18	oversight board I think becomes probably more advisable.
19		DR. MURPHY:  In pediatrics, this problem is
20	magnified, the fact that we have small numbers frequently
21	and need large numbers of centers.
22		DR. CHESNEY:  I think that emphasizes the point
23	Dr. Kauffman made also, they are probably most important in
24	the larger multicenter.
25		Other comments?  Yes.

			214 1		DR. FINK:  The one other concern I have with this
	2	discussion of what is ethical, we are evolving into fairly

	3	sophisticated study designs, and at least in some diseases,
	4	like asthma, I think we have already seen that it has the

	5	effect that it tends to exclude minority populations from
	6	participation in controlled clinical trials, and I don't

	7	know if that is something the data safety monitoring board
	8	should be taking on, but somehow we need to ensure that
	9	minority populations are adequately represented, because the
10	typical asthma trial that is performed today is 80 percent
11	suburban white participants even though the vast majority of
12	asthma and the burden of it falls on inner city blacks and
13	hispanics.
14		DR. CHESNEY:  Why is that?
15		DR. MURPHY:  I think we actually did address the
16	issue of adequate enrollment of minority populations in the
17	asthma trial.  Maybe we didn't put it in here.
18		DR. CHESNEY:  This is ignorance on my part.  Why
19	are the minority populations not being included?  Is it for
20	compliance or unwillingness to participate?
21		DR. FINK:  Some of it I think is difficulty in

22	getting informed consent.  As a clinical researcher, the
23	other thing you look at is your study coordinators want

24	patients where it is easy to collect the data and they will
25	keep their visits on time, and they make data collection, so

			215 1	that you tend to choose your best study subjects as the
	2	first ones you enroll.
	3		DR. CHESNEY:  Any other comments about data
	4	safety, monitoring boards in the setting of the withdrawal
	5	phase?
	6		Dr. O'Fallon.
	7		DR. O'FALLON:  The comments that have just been
	8	made now about what a DMC could do, I see all that
	9	responsibility as being the part of the statistical center
10	and the study team.  I don't know how you define a study

11	team for this sort of an asthma trial.  I do know a fair
12	amount about it in cancer.
13		You know the study team is a group of people who
14	are actually running that study, and they are the ones that
15	are responsible for the information that is coming out of
16	the unfolding data.

17		A DSMB in a certain sense overlooks the conduct of
18	the whole trial.  I think you should have a study team in

19	place that would be looking--and a data center--that would
20	be looking at the adverse events and that sort of thing.
21		DR. CHESNEY:  Dr. Gorman.

22		DR. GORMAN:  I am still struggling for words in my
23	non-ethical capacity to explain why withdrawal studies are
24	so difficult for us, and when we randomize going forward,
25	there is an equal chance you will get benefit or detriment. 

			216 1	Of course, you don't know.  But in withdrawal studies, you
	2	are taking people who are on adequate therapy, no matter
	3	what it is, and you are taking them off of it, and I think
	4	that is a different ethical condition to be in.
	5		I think that is why the IRBs that we have all sat
	6	on have had some difficulty withdrawing people from studies
	7	because in this case, you have people on appropriate
	8	therapy, and you take them off, and that is what makes these
	9	kinds of studies a little bit more difficult than
10	randomizing people prospectively because you are taking
11	people off of appropriate therapy, or therapy where they are
12	well maintained.
13		DR. CHESNEY:  Dr. Fink.
14		DR. FINK:  I think Dr. O'Fallon brought up an
15	interesting point.  Some of that probably depends on the
16	funding source.  The majority of asthma clinical trials are
17	industry sponsored, and as a result, there is no study group
18	except for the company itself, and to the extent at which
19	you trust them, and I don't entirely trust them.
20		I mean I have been asked to participate in
21	industry-sponsored trials where it is clear the company was
22	spreading the trial over multiple centers, so that every
23	center was underpowered to detect a difference of effect, so
24	that only the company would know whether their drug was

25	effective or not, but no one participating in the trial

			217 1	would ever have access to that data, and it is a very nice
	2	way for a pharmaceutical company to do a direct comparative
	3	trial at no risk because no single center has enough
	4	patients in the trial to look at efficacy.
	5		DR. FOST:  Let me help Dr. Gorman with his
	6	discomfort about withdrawal.  The reason you feel
	7	uncomfortable is because you think you now have the patient
	8	on something that is effective, and if you know that, it
	9	would be wrong.  The reason you are doing the withdrawal is
10	to find out, and until you do the withdrawal, you don't know
11	whether you have helped the patient or not.
12		DR. GORMAN:  Agreeing with that intellectually. 
13	Clinically, it becomes much more difficult because you have
14	put them on something somewhat randomly, you have randomized
15	them at the beginning, and then you have an effect.
16		DR. FOST:  You don't know that yet.
17		DR. WILFOND:  Now, I think I can help you out
18	because my point was also about that issue.  What strikes me
19	is that there are different populations that might be
20	willing to participate in any of these trials, and I think
21	those are people who, for whatever reason, are unhappy with
22	their current care, who are desperate for better treatment.
23		I think those are the people who are at the
24	greatest risk of being in a trial, whether it's an add-on or
25	withdrawal study, because their expectations are much

			218 1	greater in terms of therapeutic benefit.
	2		On the other hand, people who are doing well often
	3	will raise questions amongst themselves or their parents

	4	about when is it time to stop this therapy, and it seems
	5	that people in that situation are ideal candidates for
	6	trials where treatment is withdrawn, because in that case
	7	the options are either withdraw outside of a trial and be

	8	monitored by your physician or enroll in a trial where there
	9	is a 50 percent chance of withdrawing, or perhaps being a
10	drug that may be helpful, or you will find out.
11		I think that one of the things that hasn't been

12	done is there hasn't been a greater emphasis on trying to
13	encourage patients who are doing well to be in studies.

14		DR. CHESNEY:  Dr. Danford and then Dr. Temple, and
15	then we will let Dr. Temple and Dr. Murphy decide whether we
16	have answered all their concerns.
17		DR. DANFORD:  One last word of reassurance for Dr.
18	Gorman would be the reminder that drugs do have risks and
19	adverse effects, that you would be taking away the potential
20	for those risks and adverse effects in half of your patients
21	as you withdraw.
22		DR. TEMPLE:  The trials have somewhat different

23	purposes.  If patients are put onto a lead-in with a drug,
24	and appear to respond, you really don't know whether they
25	responded to the drug or not.  If they are part of a

			219 1	randomized trial, then, you might know.
	2		So, you really are--I guess Dr. Fost said--you are
	3	just finding out whether it is really working for them at
	4	the end of it.
	5		The other use of these trials is to take a drug
	6	that you are quite sure works in the short term, and examine
	7	whether it continues to work for the long term.  That, I
	8	guess, is a little different because then you are fairly
	9	sure you are giving the person something that is effective,
10	but as someone said, you want to find out whether it
11	continues to work, you want to see what the consequences of
12	withdrawing it are, because drugs do get withdrawn, so there
13	are things of interest to the patients even in that setting.
14		In the first case, you really don't know that it
15	worked, it just sort of looked like it did, you don't really
16	know.
17		DR. CHESNEY:  Dr. Murphy.
18		DR. MURPHY:  I think what I heard from this last
19	bit of discussion was that in the withdrawal trials, if we
20	can define the population that would be involved in a

21	withdrawal trial, so that the population is either at
22	minimal risk because you are going to be able to define
23	early enough what the failure rate is or early in the

24	disease, and those are actually two different things, may
25	involve two different processes.

			220 1		Dr. Gorman, to get at your issue, certainly, in

	2	asthma where you have a life-long disease where you would
	3	like to have people come off of certain therapies after a
	4	while, if there is a way to define that population in the
	5	trial, that that might make it a more acceptable trial
	6	approach.  Is that--no?
	7		DR. GORMAN:  I don't have any ethical difficulty
	8	with the study design.  I think why it makes it more

	9	difficult, I know it is the myth that you are doing
10	something good for your patient because you did something
11	and they got better, but they are the ones who are now doing
12	well, and you are asking them to withdraw.
13		Now, for asthma and for several other disease

14	states where they are intermittent with exacerbations and
15	calming down periods, I think a withdrawal study not only
16	makes sense intellectually, but is required to prove the
17	efficacy of these agents.

18		But the difficulty, the intrinsic difficulty is I
19	am doing something good, and you are making me stop it makes
20	it hard for institutional review boards, as well as
21	individual clinicians, to enroll people in these kinds of
22	studies, because the people are doing well, you want to
23	continue to have them do well.
24		DR. MURPHY:  We tried not to bring you anything
25	too easy to answer today.  I think that was quite clear in a

			221 1	number of the questions.
	2		DR. CHESNEY:  I think Dr. Fost had one more
	3	comment and then we will probably take our break.
	4		Dr. Fost.
	5		DR. FOST:  Just two brief ones.  That
	6	psychological problem is the same as doing a prospective
	7	trial when there is a standard therapy out there that has
	8	never been shown to be effective.  That is, you have people
	9	who are getting treated for something, and you think it must
10	be good because everybody is doing it, and yet you don't
11	really know.
12		But, Dianne, I would just hope one of the take-

13	home points of both these examples, the add-ons with the
14	placebo group, and the take-aways with people who you think
15	are having an effect, is that adequate monitoring is what
16	makes these trials ethically acceptable, and absent that,
17	they wouldn't be, either one of them, if there is some
18	possibility of serious harm coming to somebody.
19		So, the IRB needs to assure that selection of

20	patients will be under circumstances in which they can be
21	monitored properly.
22		DR. MURPHY:  I think you saw that in our questions
23	that that is one of the areas that we wanted to help bring
24	forth in the discussion.  We think that if we are going to
25	be able to do what is necessary, which is to find out if

			222 1	these products do work in children, and are safe, that we
	2	need to have a way.
	3		Clearly, today, you have told us, and some things
	4	we don't have a way yet to do it, which are some of the
	5	long-term studies, but that we will have to go with the
	6	information that we are able to develop at the present time,
	7	and maybe in the future we will be able to come back to you
	8	with additional knowledge that we would be able to move in a
	9	new design because of additional knowledge, but for right

10	now, for long-term studies, we will have to basically deal
11	with what we know in our controlled short-term studies, and
12	that we will also address the issues of levels of risk in

13	both of these, both for the patient monitoring and the trial
14	monitoring.
15		Yet, to address Susan's concern, I think it is
16	clearly not possible to have every pediatric trial involved
17	with the DSMB, nor probably necessary.
18		DR. CHESNEY:  Dianne, could I just make one
19	comment?  I am really troubled by Dr. Fink's example and I
20	wonder if you wouldn't develop some kind of recommendations
21	for the pharmaceutical firms, that if it was a situation

22	where there were multiple centers, and no one center was
23	going to recruit many children, that a DSMB is strongly
24	recommended or required.
25		DR. MURPHY:  I think we heard that message that

			223 1	multicenter trials, let's take away motivation, multicenter
	2	trials that are trials that we ought to look at considering
	3	DSMBs, particularly in pediatrics where, as we have talked

	4	today, we frequently have the problem of small populations.
	5		As far as nobody is going it come to us and say,
	6	gee, we think we need a multicenter trial because that way
	7	we can sort of keep any lack of efficacy quiet.  Usually,

	8	the reasons that are given are that it is difficult, and I
	9	mean we know this from adult trials, too, I mean this isn't
10	a pediatric problem, that it is often difficult to get the
11	numbers that you need in one place, and that is why we have
12	multicenter trials, and that is the usual reason that we are
13	given.
14		DR. CHESNEY:  Dr. O'Fallon, last before the break.
15		DR. O'FALLON:  We haven't even done anything with
16	the value of multistage designs or spending functions and

17	all that.  We mentioned them and then dropped it, but I
18	think such study designs are necessary no matter which of
19	the designs you are going with, because they do have the

20	ability to minimize the number of patients that are spent in
21	getting an answer.  They have the ability, they don't always
22	work, but they have the potential.
23		DR. MURPHY:  I think for those of us around in a
24	couple of years, it would be very helpful to bring forward
25	some of these trial designs that have failed in pediatrics

			224 1	and some that have succeeded, so that we can look if some of
	2	the issues that you are bringing up have played into--
	3	rather, they were appropriately monitored and stopped or not
	4	stopped when they should have been.
	5		DR. CHESNEY:  Let me thank all the speakers from

	6	this morning and particularly our international visitors,
	7	and we can take a 10-minute break now.  We need to be back

	8	here at 3 o'clock, maybe an 8-minute break, for a discussion
	9	of psychotropic drug use.
10		[Break.]

			225 1		           AFTERNOON SESSION
	2		 Pediatric Psychotropic Drug Use Issues
	3	     Part 2:  A Proposed Approach to the Development of
	4	         Psychotropic Drug Therapies for Pediatrics
	5		DR. CHESNEY:  This afternoon's session is a
	6	discussion of pediatric psychotropic drug use issues.  As I
	7	think you will hear from Dr. Murphy, there are a number of
	8	meetings scheduled over the next month or two to discuss
	9	this issue, and I think we are going to learn a great deal
10	about what will be discussed at the upcoming meetings, and I
11	think Dr. Murphy is going to lead off.
12		              Introduction
13		DR. MURPHY:  We knew you would just be invigorated
14	at this time of day.  We hope to do two things this
15	afternoon.  One, is to give you an update on what has been
16	going on in this field, which is the drug development for
17	psychotropic therapies, and secondly, is to have you comment
18	to us.  We realize this is a very short time, and we could
19	use at least a day or two on this topic, but I will tell you
20	what other avenues may be available to do that.
21		But we are moving forward now, and as we move
22	forward, we want to tell you about our plans, and we wanted
23	you to give us some comments as to a really sort of global
24	perspective as have we forgotten anything that we should be
25	thinking about or are we pretty much on target here, and

			226 1	that is very crude way of stating the questions which you
	2	will hear in more elegant form in a minute.
	3		If you weren't aware, this is an area of interest
	4	to the White House, and precipitated by some articles about
	5	the use of psychotropic therapies in preschool children, and
	6	there has been an initiative to bring this area forward for
	7	development as far as trying to define are children being
	8	undertreated, overtreated, appropriately treated,
	9	inappropriately treated with psychotropic therapies.
10		There will be next week a meeting sponsored by the
11	Surgeon General and FDA to address a broader issue, which is
12	the access to proper diagnosis, proper therapy, and, in
13	addition, FDA will be there to talk about the concerns that
14	we have, Tom Laughren will be presenting, in therapeutic
15	interventions when you don't know how to make the diagnosis,
16	and you don't know how to measure the endpoint.  So, that is
17	Tom's goal at the Surgeon General's meeting.
18		Because of the aspects I just mentioned, there is
19	a difficulty in making sure that we have the proper
20	diagnosis or that we have the proper way of measuring a
21	response to a therapy, there will be a research meeting
22	which NIMH and FDA are sponsoring in early October, and we
23	have plans to look at a number of these very questions, such
24	as are the diseases the same, are they not, what are we
25	missing in the way of fundamental knowledge in some of these

			227 1	areas or fundamental tools for diagnosing and measuring
	2	response to therapy.
	3		At this point, I will turn the meeting over to the
	4	people who know a lot more about this topic.  Thank you very
	5	much.
	6		DR. CHESNEY:  Jayne Peterson, our Executive
	7	Secretary, who you might also notice is a lawyer, tells me
	8	that we have to go through introducing ourselves again and
	9	following which she will read the Conflict of Interest
10	Statement.
11		So, if we could start, Dr. Rodriguez.
12		DR. RODRIGUEZ:  Bill Rodriguez.  I am with the
13	Food and Drug Administration.  I have the title of Pediatric
14	Science Consultant Director.  Thank you.
15		DR. MURPHY:  Dr. Dianne Murphy, Associate Director
16	for Pediatrics at the Center for Drugs.
17		DR. LAUGHREN:  Tom Laughren, team leader for
18	Psychopharmacology at FDA.
19		DR. KATZ:  Russ Katz, Director, Division of
20	Neuropharm, FDA.
21		DR. GELLER:  Barbara Geller, Professor of
22	Psychiatry, Washington University in St. Louis.
23		DR. LUBAN:  Naomi Luban, pediatric
24	hematologist/oncologist, Children's Hospital and GW
25	University.

				228 1		DR. SANTANA:  Victor Santana, pediatric
	2	oncologist, St. Jude's Children Research Hospital, Memphis,
	3	Tennessee.
	4		DR. FOST:  Norm Fost, pediatrician, Director of
	5	the Medical Ethics Program and chair the IRB at the
	6	University of Wisconsin at Madison.
	7		DR. RODVOLD:  Keith Rodvold, Professor of Pharmacy
	8	Practice, Colleges of Pharmacy and Medicine, University of
	9	Illinois at Chicago.
10		DR. HUDAK:  Mark Hudak, neonatologist, Professor
11	of Pediatrics, University of Florida at Jacksonville.

12		DR. NELSON:  Skip Nelson.  I am a pediatric
13	critical care physician and chair of the IRB at the
14	Children's Hospital of Philadelphia.

15		DR. CHESNEY:  Joan Chesney, Pediatric Infectious
16	Disease, in the Department of Pediatrics at the University
17	of Tennessee in Memphis and Academic Programs at St. Jude.
18		MS. PETERSON:  Jayne Peterson, Executive Secretary
19	of the Pediatric Subcommittee with FDA.
20		DR. FINK:  Bob Fink, pediatric pulmonologist at
21	Children's Hospital, Washington, D.C.
22		DR. FUCHS:  Susan Fuchs, pediatric emergency
23	medicine physician, Children's Memorial Hospital, Chicago,
24	Illinois.
25		DR. GORMAN:  Richard Gorman, general pediatrician

			229 1	in private practice in suburban Maryland.
	2		DR. DANFORD:  David Danford, Professor of
	3	Pediatrics in the Department of Cardiology Joint Division,
	4	University of Nebraska Medical Center.
	5		DR. O'FALLON:  Judith O'Fallon, Professor of
	6	Biostatistics, Mayo Clinic, and also group statistician for
	7	the North Central Cancer Treatment Group.
	8		DR. RYAN:  Neal Ryan, child psychiatrist,
	9	Professor of Psychiatry at the University of Pittsburgh.

10		DR. MALONE:  Richard Malone, Associate Professor
11	of Psychiatry at MCP-Hahneman University.
12		DR. WARD:  Bob Ward, neonatologist, Professor of
13	Pediatrics, University of Utah, and chair the American
14	Academy of Pediatric's Committee on Drugs.
15		DR. SPIELBERG:  Steven Spielberg, head of
16	Pediatric Drug Development, Johnson & Johnson, representing
17	PhRMA.
18		DR. CHESNEY:  Thank you.
19		Now, Jayne will read the Conflict of Interest
20	Statement.
21		     Conflict of Interest Statement
22		MS. PETERSON:  The following announcement
23	addresses the issue of conflict of interest with regard to
24	this meeting and is made a part of the record to preclude
25	even the appearance of such at this meeting.  Based on the

			230 1	submitted agenda for the meeting and all financial interests
	2	reported by the committee participants, it has been
	3	determined that since the issues to be discussed by the
	4	Subcommittee will not have a unique impact on any particular
	5	firm or product but, rather, have widespread implications to
	6	all similar products, in accordance with 18 USC 208B,
	7	general matters waivers have been granted to each special
	8	government employee participating in today's meeting.
	9		A copy of this waiver statement may be obtained by
10	submitting a written request to the Agency's Freedom of

11	Information Office, Room 12A30, of the Parklawn Building.
12		With respect to FDA's invited guests and guest
13	speakers, Dr. Ralph Kauffman, Dr. Mark Riddle, Dr. Neal
14	Ryan, Dr. Steven Spielberg, and Dr. Robert Ward have

15	reported interests which we believe should be made public to
16	allow the participants to objectively evaluate their
17	comments.
18		Dr. Kauffman would like to disclose that he has
19	grants with Bristol-Myers Squibb and is involved in research
20	for Bristol-Myers Squibb, Astra, Zeneca, Janssen, Merck,

21	R.W. Johnson, and Aventis, and is a scientific adviser for
22	the Bristol-Myers Squibb, Johnson & Johnson, and Purdue
23	Pharma.
24		Dr. Riddle would like to disclose that he is a
25	researcher through contracts with Lilly Research

			231 1	Laboratories, Smith Kline Beecham, Quintiles Pacific, and

	2	Pfizer, receives consulting fees from Excerpta Medica and
	3	Janssen, and is a scientific adviser to Shire
	4	Pharmaceutical.
	5		Dr. Ryan would like to disclose that he has
	6	contracts with Smith Kline Beecham and Wyeth-Ayerst, and is
	7	a scientific adviser to Wyeth-Ayerst, Smith Kline Beecham,
	8	Pfizer, and Eli Lilly.

	9		Dr. Spielberg would like to disclose that he is an
10	employee of Johnson & Johnson.  Dr. Ward would like to

11	disclose that he owns stock in Ascent Pediatrics and
12	Viropharma.  He has grants with Wyeth-Ayerst, Novartis,
13	Ascent Pediatrics, Aventis Pharmaceuticals, and Sepracor,

14	and he receives consulting fees from Janssen Pharmaceutical
15	and is a scientific adviser for McNeil Consumer Products.
16		In the event that the discussions involve any

17	other products or firms not already on the agenda, for which
18	an FDA participant has a financial interest, the
19	participants are aware of the need to exclude themselves
20	from such involvement and their exclusion will be noted for
21	the record.
22		With respect to all other participants, we ask, in
23	the interest of fairness, that they address any current or
24	previous financial involvement with any firm whose products
25	they may wish to comment upon.

				232 1		Thank you.
	2		DR. CHESNEY:  Thank you, Jayne.
	3		          Open Public Hearing
	4		DR. CHESNEY:  We don't have anybody formally
	5	signed up to participate in the open public hearing, but
	6	this is an opportunity if there is anybody who would like to
	7	come to the microphone to make any comments.
	8		[No response.]
	9		DR. CHESNEY:  I think we will proceed then.  Our
10	first speaker is Dr. Tom Laughren from the FDA, who is the
11	team leader for Psychiatric Drug Products in the Division of
12	Neuropharmacological Drug Products.  He is going to speak to
13	us about current regulatory issues in pediatric
14	psychopharmacology.
15	 Current Regulatory Issues in Pediatric Psychopharmacology
16		DR. LAUGHREN:  Thank you.
17		[Slide.]
18		As Dianne mentioned, the goal of this afternoon's
19	session is twofold.  We are going to try and update you on
20	certain events that have been happening in the area of
21	pediatric psychopharmacology.  I am going to talk about this
22	area from a regulatory perspective, and we will have other
23	speakers to talk about it from the standpoint of research

24	clinical, and then Dr. Vitiello from NIMH is going to talk
25	about it from their perspective.

			233 1		Secondly, we would like to get some feedback from
	2	the committee on certain questions that, if we can address

	3	them, would help us to move this process forward.
	4		[Slide.]
	5		These are the topics that I want to talk about
	6	this afternoon.  First, what I am going to do is very
	7	briefly review what approved indications there are in this
	8	area of pediatric psychopharmacology.  It is a fairly short
	9	list.

10		Secondly, I am going to very briefly give you some
11	background on several initiatives at FDA that have helped us
12	to move this process forward, and then I am going to talk
13	about in particular two initiatives, the Pediatric Rule and
14	FDAMA, and I am going to briefly review what has been
15	happening under each of those initiatives.
16		Finally, I am going to present the questions that
17	we would like some feedback on.
18		[Slide.]
19		This is the list of currently approved indications
20	in pediatric psychopharm.  As you can see, it is a short

21	list.  We have three drugs that are specifically approved
22	for pediatric OCD.  The ADHD drugs, of course, have been

23	approved for a long time.  That is probably the best studied
24	area in pediatric psychopharm.  Halopericol and Pimozide are
25	two drugs approved for Tourette's.  Lithium is approved down

			234 1	to I believe age 12 in mania.  Imipramine is approved for

	2	bedwetting.  Doxepin, another tricyclic, and this is very
	3	old labeling, is approved for something called
	4	psychoneurosis.  This predated the present group by many
	5	years.
	6		Finally, two antipsychotics, haloperidol and
	7	chlorpromazine, are approved for a variety of behavioral
	8	problems, everything ranging from agitation and aggression
	9	to hyperactivity.  Again, these approvals occurred a very
10	long time ago.
11		In any case, obviously, many of the disorders
12	which are currently being treated in this area do not have
13	approvals.
14		[Slide.]
15		Now, just a brief background on some of the
16	initiatives that have occurred in recent years.  Actually,
17	this goes back about 20 years with the 1979 Pediatric Rule,

18	which established the Pediatric Use Section in labeling, and
19	then the 1994 Pediatric Rule, the 1998 Pediatric Rule, and
20	then the 1997 FDA Modernization Act.
21		All of these initiatives were intended to
22	stimulate research in pediatric indications generally.  I am
23	going to focus mostly on the last two, the 1998 Pediatric
24	Rule and the FDA Modernization Act.
25		[Slide.]

			235 1		Just briefly, the Pediatric Rule allows FDA to
	2	require pediatric studies under certain conditions.  There
	3	are actually two parts of it, one part that refers to new
	4	drugs, and by that is meant not only new chemical entities,
	5	but also new indications for already approved drugs, new
	6	dosage forms, new dosing regimens, and new routes of
	7	administration.
	8		The critical element for invoking this rule is
	9	that there is some pending application or an application is
10	being considered for submission, and that allows us to have
11	discussions with the company and require that they do
12	studies in a pediatric population if it is felt to benefit
13	the population.
14		There is another part of that rule referring to
15	marketed drugs, which theoretically, would allow us to
16	require studies even though there is not a pending
17	application.  That part of the rule has not been invoked to
18	my understanding.  So, the focus has been almost entirely on
19	situations where an application is actually pending.
20		[Slide.]
21		Now, the other initiative actually occurred under
22	this 1997 FDA Modernization Act.  This again applies to both
23	new and marketed drugs.  Unlike the Pediatric Rule, which

24	allows us to require studies, this is voluntary, and this
25	encourages pediatric studies again when it is determined

			236 1	that information from those studies would produce health
	2	benefits.  It is not limited to approved indications.  As I
	3	pointed out, it is voluntary.
	4		The critical part of this law is that it allows
	5	for additional exclusivity to be given for doing those
	6	studies, and this additional exclusivity is applied to
	7	whatever existing exclusivity a drug may have or to whatever
	8	existing patent protection it might have, so this is a major
	9	financial incentive, and has resulted in a lot of activity
10	in pediatrics generally.
11		[Slide.]
12		So, the bottom line is that FDA wants and can
13	require pediatric studies for certain indications where
14	there is deemed to be a need.  The sponsors have a financial
15	incentive under FDAMA to conduct pediatric studies, and so
16	it behooves us to try and identify those indications where
17	there would be a benefit from doing pediatric studies and,
18	in addition, to work out the details of whatever might be
19	needed to conduct those development programs.
20		[Slide.]
21		What I want to do next is to talk about what some
22	of the results have been of these initiatives.  Under FDAMA,
23	we have issued written requests for three different

24	indications, and these are the indications - major
25	depressive disorder, obsessive compulsive disorder, and one

			237 1	for generalized anxiety disorder.
	2		Up until now there has been a total of nine
	3	written requests issued for these three different
	4	indications under FDAMA.
	5		[Slide.]
	6		In addition to FDAMA, we have invoked the
	7	Pediatric Rule in the following situations.  Again, the
	8	situation that occurs here is that a company is coming in
	9	with an application.  In most cases, it is a supplement for
10	a new indication in adults, and it is our judgment that
11	there is a need to look at pediatric populations.  So, under
12	the Pediatric Rule, we have required companies to do studies
13	in these four different areas - posttraumatic stress
14	disorder, social anxiety disorder, mania, and premenstrual
15	dysphoric disorder.  Obviously, the latter refers to
16	adolescents.
17		[Slide.]
18		Now, there was one situation which actually we

19	brought to this committee last November, and that was the
20	question of whether or not, under FDAMA, we should issue a
21	written request for a company that was developing a
22	hypnotic, and the question was whether or not we should

23	issue a written request to encourage the company to do
24	pediatric studies with what is the usual claim for insomnia
25	in adults.

			238 1		It was discussed with this committee, and the
	2	consensus was that that would not be a good idea, so we did
	3	not issue a written request.  Alternatively, the committee

	4	recommended that there may be one area that would benefit
	5	from further discussion and work, and that was the area of
	6	sleep phase deregulation in patients either in neonatal
	7	intensive care units or in pediatric intensive care units,
	8	an idea that had not developed to the point of justifying a
	9	written request, but something that ought to be explored.
10		[Slide.]
11		Now, there are several other areas where there is
12	active consideration of either invoking the Pediatric Rule

13	or issuing written requests, and these are the indications -
14	schizophrenia, panic disorder, this entity known as conduct
15	disorder, and then the question of ADHD in children less
16	than 6.
17		This becomes an issue because, as you may well be
18	aware, methylphenidate, which is, of course, approved for
19	the ADHD, the current labeling indicates that it should not
20	be given to children less than 6, and, of course, as you
21	well know, there is a fair amount of use of methylphenidate
22	and other stimulants in younger children.
23		So, the question is should FDA be asking companies
24	to study new formulations of these products in younger
25	children.

			239 1		[Slide.]
	2		Now, in terms of the written requests that we have
	3	already issued, these are the age cut-offs that we have
	4	established quite arbitrarily, you know, based on our
	5	discussions with various experts in the field.  For major
	6	depressive disorder and OCD, we have cut it off at 7 years,
	7	for GAD, at 6.
	8		[Slide.]
	9		The question, of course, is what is the
10	appropriate age cut-off for these various indications of
11	interest in pediatric psychopharmacology.
12		[Slide.]
13		Now, I want to turn briefly to a paper that I

14	believe was in your package.  This was a paper that was
15	published by Dr. Zito and her colleagues at the University
16	of Maryland back in February.  What it looks at is the
17	prevalence of use of various psychotropic drugs in

18	preschoolers that she was defining as age 2 to 4.
19		Basically the way this slide works is that we are
20	talking per 1,000.  So, if you think of a cohort of 1,000
21	patients, 4.1 out of that 1,000 in '91--she looked at
22	several databases, this is from the Midwestern Medicaid
23	database, and I am just giving you part of her data just to
24	make a couple of points--so, we are looking at '91 to '95,
25	and as you can see, the use of stimulants increased from

			240 1	about 3-fold during that period of time, so that here, in
	2	'95, roughly 1 out of 100 preschoolers in that population
	3	were being prescribed a stimulant.
	4		For antidepressants--and this includes both
	5	tricyclics and SSRIs--the use increased a little over 2-
	6	fold, from 1.4 to 3.2.  Clonidine use increased dramatically
	7	from 0.1 up to 2.3, and the neuroleptics, although the use
	8	didn't change, it's 0.7 to 0.9, you still have roughly 1 out
	9	of 1,000 preschoolers in that cohort who are getting an
10	antipsychotic.
11		[Slide.]
12		I think her data raised a number of questions. 

13	The most obvious one is what are the clinical entities that
14	are being treated in that population of 2- to 4-year-olds

15	and sort of a corollary to that, assuming that the stimulant
16	use is for ADHD, a question might be is ADHD a meaningful
17	diagnosis in these patients aged 2 to 4.
18		Another question that comes up, and this comes up
19	in part with my discussions with various experts in this
20	field, I have the impression that a lot of the use of other
21	psychotropics in preschoolers is not focused specifically on
22	diagnostic entities, but is focused more on certain
23	behaviors, and so that is one question is how much of this
24	use does represent the treatment of nonspecific symptoms

25	rather than specific diagnostic entities.  Then, a general

			241 1	question is, is the absolute use and the increase in use of
	2	these drugs in this population justified.
	3		[Slide.]
	4		Now, I want to turn briefly to this question of
	5	focusing on nonspecific symptoms rather than specific
	6	diagnostic entities, and the question is would nonspecific

	7	symptoms, such as, for example, agitation or aggression, be
	8	considered acceptable targets for drug development programs
	9	in the pediatric population.
10		[Slide.]
11		Now, there is a precedent in FDA for approving

12	drugs for nonspecific symptoms.  Most of our approvals are
13	for specific entities, such as, for example, something like
14	pneumococcal pneumonia, rheumatoid arthritis, but obviously,
15	we have approved drugs for nonspecific symptoms that cut
16	across diagnosis, things like pain and fever.  So, there is
17	a precedent for doing that.
18		[Slide.]
19		Now, what I would like to do in this slide is to
20	run through sort of the thought process that we go through
21	when we are considering whether or not to even entertain the
22	idea of looking at a nonspecific symptom as a target for an
23	indication.
24		In general, we would like to have a universal

25	definition for that symptom, in other words, whatever

			242 1	diagnostic entity it is associated with, it should be
	2	defined in the same way, it should be measured in the same
	3	way.  There should be some commonly accepted way of
	4	assessing and measuring that symptom.
	5		Ideally, you would have a pathophysiologic
	6	understanding of that symptom.  Again, from whatever context
	7	it arises, you would like that nonspecific part of it to
	8	have some understanding of it, again, so you can be
	9	confident that you are talking about the same thing from
10	disease to disease.
11		It should be equally responsive to treatment
12	regardless of the context in which it is occurring, and, in
13	general, if we were going to consider approving a
14	nonspecific claim, we would like it to be supported in
15	several different disease models.  For example, if you are
16	going to approve an analgesic, you would look at it in
17	several different pain models.
18		[Slide.]
19		Now, I am not going to spend a lot of time talking
20	about safety.  There was a good bit of discussion early on,
21	on some of the problems of assessing safety in this younger
22	population.  Obviously, one is concerned about pediatric

23	patients because of the fact that they are growing and
24	developing, and are perceived as being more vulnerable to
25	the effects of drugs.

			243 1		There are not a lot of good preclinical models for
	2	predicting possible subtle developmental effects, nor are
	3	there even good clinical methods for assessing subtle
	4	developmental effects.  We had again some discussion of that
	5	earlier.  As you get into the preschool population, there is
	6	obviously the additional problem of even having difficulty
	7	because these younger patients don't verbalize very well, so
	8	it is very difficult to get at adverse effects in much
	9	younger patients.

10		[Slide.]
11		As Dianne mentioned, there is a lot of activity
12	going on in the near term, in terms of looking at pediatric
13	psychopharmacology.  There is this conference, the Surgeon
14	General's Conference next Monday, which is going to look

15	more broadly at children's mental health.  Part of that will
16	focus on pediatric psychopharm.
17		NIMH is holding a workshop the following Monday on
18	the problems in looking at long-term safety of psychotropics
19	in children, and again there was some discussion of the
20	problems in doing that earlier in this meeting.
21		On October 2nd and 3rd, we are holding a joint
22	workshop with NIMH again to focus on the psychopharmacology
23	of very young children, preschoolers.
24		Then, the American Academy of Child and Adolescent
25	Psychiatry is having a workshop at its annual meeting later

			244 1	in October.  This is sort of a follow-on to the NIMH/FDA

	2	meeting, and the focus of this meeting is going to be to
	3	look at practical aspects of doing studies in preschoolers,
	4	you know, very practical things like how to make kids even

	5	comfortable participating in a clinical trial.  So, there is
	6	a lot going on in the near term.
	7		[Slide.]
	8		These are the questions that we would like to have
	9	you think about.  What additional psychiatric indications in
10	the pediatric age group would benefit from psychotropic
11	development programs?  In particular, what should be the
12	lower age limit that we should be looking at in considering
13	these?
14		Again, in particular, what psychiatric diagnoses
15	exist in the preschool population that would merit further
16	work in terms of drug development programs?
17		Again, this question about whether or not
18	nonspecific symptoms, such as agitation or aggression, would
19	be targets that should be look at in drug development
20	programs.
21		I think I will stop there.  Thanks.
22		DR. CHESNEY:  Thank you.  Our next speaker is Dr.
23	Richard Malone from the Eastern Pennsylvania Psychiatric
24	Institute in Philadelphia.  He will be speaking to us about
25	pediatric psychopharmacology: a clinical perspective.

			245 1	    Pediatric Psychopharmacology: A Clinical Perspective
	2		DR. MALONE:  I would like to thank the committee
	3	for this opportunity to speak today.  Most of my comments
	4	will really be directed towards preschoolers, and I think a
	5	lot of Dr. Laughren's were directed towards all children and
	6	adolescents.
	7		[Slide.]
	8		My first slide is similar to one of Dr.
	9	Laughren's.  The prescription of psychotropic medications to
10	children has always been somewhat controversial, at least

11	from a societal point of view, and I think this includes
12	both labeled and non-labeled usage, as well as some other
13	usages like polypharmacy.
14		Dr. Zito's recent publication highlights some of
15	the controversy that exists about prescribing medication in
16	preschoolers.  As was said previously, she had found in her
17	study that usage had increased between 1991 and 1995 for
18	stimulants, antidepressants, and clonidine.
19		Secondly, she found that the rate of neuroleptic

20	use was somewhat stable over that period of time.  I do know
21	that we had another dataset that I looked at partly with Dr.
22	Zito, where we found actually that the usage of the atypical
23	antipsychotics had increased during that period of time, but
24	I am not sure how that was related to this dataset.
25		Thirdly, she found that the less well established

			246 1	agents increased at the greatest rate.  I think all of these
	2	findings point towards the fact that we need--because most
	3	of this usage was off label--it points towards the fact that
	4	we need more well designed, preferably placebo-controlled
	5	studies to look at this usage.
	6		Another comment I would like to make about her

	7	findings is that the fact that the less well-established
	8	agents increased at the greatest rate, I think to some
	9	degree shows us what promotion of medications can do that
10	you can get newer medicines prescribed easily, and it also
11	shows the willingness of clinicians to use even less well-
12	established agents in their daily practice.
13		[Slide.]
14		Again these are the rates of prescription.  The
15	highest rate of prescription was for methylphenidate at	1.2
16	percent, and the other rates were all under 1 percent.
17		It is hard really to know what these medications
18	were being used for, because the report did not include
19	diagnoses, and I don't think there is a way that they can
20	tie diagnoses in with drug use in her report.  I think that
21	Dr. Laughren was right that many usages are probably

22	nonspecific although in my experience, I think most
23	preschoolers who end up on medication have some form of
24	hyperactivity than other comorbid conditions or symptoms

25	including aggression and also severe developmental disorders

			247 1	at times.  So one I guess, if you had to guess, would think
	2	that many of these children might have a diagnosis of ADH.

	3		In any case, I think we do need more
	4	psychoepidemiologic studies to try to figure out what
	5	exactly people are doing, studies that are designed to let
	6	you know what medications are being used and what they are
	7	being used for.
	8		[Slide.]
	9		Now, I think the main concern about using
10	psychotropic medication in young children is really the

11	safety issues.  Young children's brains are still developing
12	and we don't know how these drugs interact with the way
13	their brain will develop.
14		Secondly, many of these children will end up on
15	medication for a long-term period, and we don't know the
16	long-term effects of most of these drugs.
17		[Slide.]
18		I think in young children there are several things
19	to keep in mind.  Past studies have shown that in a number
20	of cases, young children have more serious side effects with
21	medication.
22		The first medicine I have up here is lithium.  In
23	1972, Campbell published an article about the use of lithium
24	in a group of young children, and they were being treated
25	mainly for aggressive behavior, but even in a small group of

			248 1	children, there were a number of serious side effects.  For
	2	instance, some neurologic side effects like dysarthria.  EKG
	3	changes, various forms of heart block were found in a number
	4	of these children.
	5		In another dataset, looking at lithium, actually
	6	in a somewhat older age group, it was found that the rate of
	7	side effects actually increased with decreasing age, again
	8	pointing out that younger children may have more side
	9	effects.
10		In the case of clomipramine, clomipramine had been
11	an agent, and had been studied in a group of children and
12	young adults with autism.  It had been found to be a fairly
13	effective agent in that particular study.
14		This study by Sanchez, et al., was a study in
15	young children, preschoolers, and what they found was that
16	they really didn't have any efficacy, but again they had a
17	number of serious side effects including things like urinary
18	retention and severe behavioral toxicity with the agent.

19		In both of these drugs, the side effects were
20	found at therapeutic dosages, so it wasn't really just a
21	matter of having high dosages of the drug causing side
22	effects.
23		[Slide.]
24		The other point about young children that was

25	partly shown in the clomipramine study is that behavioral

			249 1	toxicity with psychotropic medication may be greater in
	2	younger children than it is in other age groups.
	3		Haloperidol is probably one of the most critically
	4	studied treatments in autism, but if you look at the studies
	5	of haloperidol in autism, there are a number of behavioral
	6	side effects in some children including increased
	7	irritability.
	8		Actually, in the developmentally disordered age

	9	group, apart from these studies, it just seems clinically
10	that the rate of behavioral and other side effects seems to
11	be increased with other agents besides haloperidol and
12	clomipramine.
13		[Slide.]
14		In order to evaluate the side effects in young

15	children carefully, I think it will be necessary to have
16	placebo-controlled studies.  In many well-designed studies
17	of children using psychotropic medication, a significant

18	number of children have side effects on placebo, so without
19	a placebo control, it is going to be hard to estimate what
20	the actual side effect profile would be with active drug.
21		[Slide.]
22		I think another thing to keep in mind clinically
23	when designing studies of psychotropic medications in young
24	children, is that careful baseline assessments will be

25	needed and preferably at least two baseline assessment.

			250 1		When you are talking about young children, they

	2	may react very differently the first time they come into a
	3	new setting, so you would want more than one baseline
	4	rating.  Secondly, you are often separating young children
	5	from their mother or parent, again a new experience, and so
	6	their behavior may chance after one or two ratings just
	7	based on getting used to the setting.
	8		There are a number of assessments that are
	9	available for efficacy studies, and I am more familiar with
10	the assessments for studies in autism, but there are a
11	number of assessments that have been used in studies over
12	the years for efficacy, as well as safety.
13		[Slide.]
14		As has been said, there are very few medications
15	that are labeled for young children.  In fact, I think, by
16	and large, it is only amphetamine and haloperidol that is
17	labeled for children as young as 3 years old.  Most other
18	medications are labeled as not recommended for use. 
19	Therefore, it is pretty apparent that we do need careful,
20	well-designed studies with controls, and we do need to have
21	also adequate sample sizes to look at the safety and
22	efficacy of these medications.
23		Another point I would like to make is that these
24	studies should be done by investigators who are experienced
25	with the population.  I think this point had been made

			251 1	earlier that it is more difficult to assess young children
	2	for efficacy and safety.  Young children don't know how to
	3	present their complaints, and I think people who are used to
	4	rating even older children and adolescents don't always have
	5	the experience of rating young children for side effects.
	6		[Slide.]
	7		I was asked a little bit to comment on what
	8	disorders I might consider for studying in young children. 
	9	These are a list of the disorders from the DSM IV with their
10	prevalence rates.  Many of these disorders are not present
11	in young children particularly, but I think what you would 
12	want to consider in treating a young child with medication
13	is that they would have a serious disorder if you are
14	thinking of designing studies that has its own onset in
15	early childhood, and I think in this list that the disorders
16	that would come to mind are pervasive developmental disorder
17	or autism, a disorder that often has severe behavioral
18	symptoms and early onset.
19		I think many of the young children who end up
20	being put on medications do have forms of mental
21	retardation, but mental retardation alone is not an
22	indication for medication, and in treating children with
23	mental retardation, it is generally behavioral symptoms that
24	people are looking at.  However, most of those children also
25	do have comorbid ADH, I think.

			252 1		I think partly because the medications seem to be
	2	used probably most frequently in ADH and young children, it
	3	does call for study of that practice, particularly for the

	4	safety of that practice.
	5		I think the other concern I would like to raise
	6	about doing pharmacologic studies children, young children

	7	age 2 to 4, is we have to be careful that--I don't know how
	8	to say this--kind of the research industry doesn't start
	9	using young children as a commodity, that we have to be very
10	careful what we do with young children in studies.
11		Secondly, I think there has been a lot of concern
12	about the use of psychotropics in young children as
13	evidenced by everything that surrounded Dr. Zito's article,
14	and I would think one concern you might have is if you begin
15	labeling medications as appropriate for use in very young

16	children, you might have this unintended effect of actually
17	increasing the usage of medications in young children.

18		Those are the remarks I would like to make.
19		DR. CHESNEY:  Thank you, Dr. Malone.
20		Dr. Mark Riddle from Johns Hopkins Medical
21	Institution is going to speak to us about pediatric
22	psychopharmacology: a research perspective.

23	    Pediatric Psychopharmacology: A Research Perspective
24		[Slide.]
25		DR. RIDDLE:  I appreciate this opportunity to

			253 1	present to the committee.
	2		[Slide.]
	3		I am going to focus on 3- to 5-year-olds.  Now,
	4	why 3- to 5-year-olds, and perhaps before that, why this
	5	breakdown.  I don't think the breakdown I have here by ages
	6	fits necessarily the various age categories that the FDA
	7	uses.  I think it is fairly close.
	8		I have chosen it for a couple of reasons.  I think
	9	in terms of clinical experience, the lowest that I am aware
10	of most colleagues going in terms of age for prescribing
11	psychotropics is about 3.  If you look at Dr. Zito's data,
12	which was for 2- to 4-year-olds, there were very few 2-year-
13	olds in that sample.  So, for clinical reasons and looking
14	at her data, and also I think for developmental reasons in
15	terms of being able to have any chance of assessing a child,
16	I have chosen 3 to 5.
17		Now, why 5 is the upper limit?  I think because

18	many studies to date have gone to age 6 in kids, sometimes
19	7, but somewhere around 6 is what traditionally has been
20	considered school age.  It is also the age down to which
21	many assessment instruments that are used in clinical

22	research have been studies and validated, but this again is
23	perhaps my parochial approach to this, but 3- to 5-year-
24	olds.
25		[Slide.]

			254 1		What about current ways of classifying or trying
	2	to come up with a diagnosis that one might study?  Dr.
	3	Malone just talked about DSM, and I think offered an
	4	extensive list of potential diagnoses there, and I think you
	5	are all familiar with the DSM.
	6		The other diagnostic sort of published diagnostic
	7	booklet that is available is one called "Diagnostic
	8	Classification 0 to 3," and it was published in 1994 by the
	9	National Center for Clinical Infant Programs.  It
10	unfortunately focuses primarily on younger kids, and I don't
11	think it is perhaps at this point useful for the 3- to 5-
12	year-old group, but it is something that is out there, and I
13	think there is a group with expertise in thinking about
14	diagnoses in quite young kids.
15		So, I think what most clinicians are left with,

16	and perhaps researchers, too, is SOYP, and I don't mean to
17	be cute, but it is sort of seat of your pants. 
18	Unfortunately, I think that is kind of where the field is
19	right now diagnostically with 3- to 5-year-olds.
20		[Slide.]
21		What about current clinical practice?  I think
22	that although some of it is focused on the disorders that
23	Dr. Malone listed, again, my impression--and this is not
24	based on, I don't think there is any really good data
25	particularly in this country--there is some European data,

			255 1	sedation prn, and many of the drugs on the list that Dr.
	2	Zito had worked quite well as sedatives except for the
	3	stimulants;  sedation ongoing, and behavioral
	4	disorganization, and the neuroleptics and the stimulants for
	5	that sort of broad category.
	6		Now, this may be a bit of a cynical view, but I
	7	think part of the reason we really need research is I think
	8	this is what is going on currently, in part because there is
	9	not much out there to guide a clinician's practice.
10		[Slide.]
11		I am going to focus on what I think are, quote,
12	"indications" for the under 6-year-old group.  My colleagues
13	and I published a paper in 1998 where I think we used the
14	1997 package inserts.  We went through all the psychotropics
15	in the PDR looking for anything that appeared to be an
16	indication.
17		Dr. Laughren, I think I agree with you almost
18	completely, maybe I have got something that is not quite
19	right here, but I think that we have, not methylphenidate or
20	Ritalin, but the amphetamine salts, marketed in this country
21	now as Adderall, or dextroamphetamine are approved down to
22	age 3, no data that I am aware of to support this other than
23	we will talk about this in a bit, a few small studies.
24		I don't know if these were "grandfathered" in or
25	whatever, but I don't think there is any support for this.

			256 1		[Slide.]
	2		Then, we have the neuroleptics.  Again, I am not
	3	aware of any data to support this.  What are described as
	4	severe behavior problems or short-term HA hyperactivity down
	5	to age 1 for chlorpromazine--that is thorazine, the original
	6	and quite sedating neuroleptic--and haloperidol, again

	7	exactly the same descriptors, behavioral problems and
	8	hyperactivity short term, but there is no age listed in the
	9	package insert.  For haloperidol, for some reason it says
10	should only be used after a non-neuroleptic has been tried.

11		I listed thioridazine, and I don't know if this is
12	correct.  This is Mellaril.  I think it was there in '97. 
13	It is not in the '98 PDR, and there is now a "black box"
14	because of concerns about Q-T prolongation, so perhaps it is
15	not going to be used much, but at least chlorpromazine and
16	haloperidol may help with that disorganization and are quite
17	good sedatives.
18		[Slide.]
19		Dr. Laughren, this is the one I am most concerned
20	about, and I may be misreading this.  If you look at the
21	package insert, it lists three indications for diazepam
22	(Valium):  anxiety, muscle spasm, and adjunct
23	anticonvulsant.  Later, without saying which indication this
24	is for, it just says "indicated in use down to age 6
25	months."  Again, perhaps that is just for anticonvulsant

			257 1	use, but you wouldn't know that by reading the package
	2	insert.
	3		[Slide.]
	4		Other commonly used drugs, three of which weren't
	5	part of Dr. Zito's study, but I think are used fairly
	6	commonly in this age group, are diphenhydramine and

	7	hydroxyzine, again terrific sedatives, clonidine and
	8	phenobarbital.  Not much good data on this, but I think this
	9	is where the prescribing is.
10		[Slide.]
11		Now, what symptoms or disorders may be medication
12	responsive?  I don't think anyone has a good answer to that. 
13	I wish I could give you a research perspective, but I don't
14	think that currently there is much in the way of solid
15	believable data, because it is an area that just hasn't been
16	studied much.
17		I think the only area where we do have some small
18	controlled studies are for hyperactivity, impulsivity, and

19	distractibility, the core features of ADHD.
20		I have listed a couple of others here that I think
21	we see in 3- to 5-year-olds, symptoms or problems that we
22	see, that I think may be medication responsive.  These don't
23	fit so neatly with your DSM diagnoses, but aggression, that
24	Dr. Laughren mentioned, behavioral disorganization, I had

25	this in the slide, out of the slide, in the slide, out of

			258 1	the slide, I am not sure, but I think we see a fair number
	2	of kids, if you go into a therapeutic nursery, and talk to
	3	the teachers, and the youngsters are having a lot of
	4	difficulty with, several youngsters, sometimes, it's, well,
	5	this looks like ADHD to me, but other times he is just so
	6	disorganized, he is all over the place.  Is this psychotic,
	7	pre-psychotic, quasi-psychotic, what is it?
	8		I think the neuroleptics are used a lot for this. 
	9	Also, Dr. Malone mentioned autism, pervasive developmental
10	disorders, mental retardation.  Well, obviously, any of
11	these can occur in youngsters with any of those diagnoses,
12	and I think particularly amongst those with developmental
13	disabilities, this behavioral disorganization may be
14	something that is ill defined, but is treated a fair amount
15	with low-dose neuroleptics.
16		Then, I think in some youngsters there is fairly
17	severe anxiety that one can tease out, and it perhaps may be
18	responsive to medication, and in some, mood lability.
19		I don't think this is a definitive list.  I don't
20	think this is one that the research community would
21	necessarily agree upon.  It is sort of my best first pass.
22		[Slide.]
23		What about controlled psychotropic data to support
24	any of this?  I mentioned before, for ADHD, there are

25	several studies of methylphenidate (small n), results

			259 1	suggestive of the medication being more helpful than placebo
	2	for impulsivity, distractibility, hyperactivity, and that is
	3	all that I am aware of in the 3 to 5 population for any
	4	"psychiatric" problem.
	5		By the way, I have all these slides on a one-page
	6	handout.
	7		[Slide.]
	8		Now, can symptom severity be assessed in 3- to 5-
	9	year-olds?  Again, I will give you my take on that.  Here, I
10	have broken it down into three groups, what I would call
11	"external" symptoms, in other words, symptoms that we could
12	assess by looking at the child, not asking questions, not
13	asking for tell me about your internal distress, but let me
14	observe, watch, and I can assess it - activity,
15	distractibility, impulsivity.
16		I don't think this study has been mentioned, but
17	the NIMH has just funded a six-site study to compare placebo
18	and methylphenidate in preschoolers with ADHD.  There is
19	going to be a 12-week psychosocial treatment that will
20	precede the medication to try to not study kids that respond
21	to psychosocial treatment.
22		For that study, parent report, teacher report, and
23	then a simulated classroom observation are going to be the
24	primary measures.  I put a question mark next to the
25	simulated classroom.  There is, I think, enough experience

			260 1	and enough data to indicate that for older youngsters, the

	2	school age kids, the 6- to 12-year-olds, that a simulated
	3	classroom can work quite well for obtaining excellent
	4	observational data.
	5		There isn't much in the way of data in 3- to 5-
	6	year-olds, and we are going to be learning as we go here in
	7	part, in this study.
	8		[Slide.]
	9		The behavioral disorganization I have listed here
10	as both external and internal.  One can observe this again
11	in the home or the therapeutic nursery, and with some
12	articulate, say, 4- or 5-year-olds, you may be able to tell
13	from their speech something about thought disorganization. 
14	That is not always so easy to do.
15		Again, parent report, teacher report, and here,
16	expert clinician assessment, and I have a question mark
17	because I don't think this has been adequately studied.
18		[Slide.]
19		Finally, anxiety or mood difficulties, internal
20	symptoms primarily, and here, parent report, I think that
21	that may work reasonably well for some aspects of anxiety,
22	clinging, avoiding, difficulty separating, separation
23	anxiety, et cetera, so for some things, I think that is the
24	case, or fears, unrealistic fears.
25		For other symptoms, you know, do you feel

			261 1	depressed?  Huh?  I mean we don't expect 3- to 5-year-olds
	2	to be able to answer that question so well.  Or are you
	3	anxious today?  That sort of ability to be self-observant
	4	and to be able to report obviously is not very far along in
	5	terms of maturation.
	6		So, that is why again I have the question mark

	7	next to expert clinician assessment, can we do it, and it
	8	hasn't been done I don't think enough yet to say that we
	9	have the research instruments.
10		[Slide.]
11		Recommendations.  Again, this is a little cute,
12	but I thought with preschoolers, it's Stop, Look, Listen,
13	and then if it's everything is okay, go.
14		So, what I have with Stop, and I guess it's not
15	really stop, but I am concerned about the unsupported

16	indications.  Maybe I am just being a bit fussy, but I don't
17	think it's a service to preschool kids or clinicians to have
18	any of these "indications" in the package inserts since
19	there is no data to support them.
20		Look at the PATS experience, the Preschool ADHD
21	Treatment Study.  I hope that we will learn something from
22	this study over the next few years.  The study is just about
23	to start.  I think enrollment will start over the next
24	month, and will continue for a couple of years.
25		I think that this is going to be a learning

			262 1	experience for all of us.  There are six sites involved, and
	2	hopefully, we will gain some useful information, not only
	3	about is methylphenidate effective, but what are we doing
	4	right and what aren't we doing right in terms of conducting
	5	treatment studies in kids this age.
	6		Listen to more expert opinions.  Well, clearly,
	7	the agenda for the next couple of months, that Dr. Laughren
	8	had suggested that you all are doing that, which I think is
	9	terrific, and then finally, Go for more research. 
10	Obviously, anyone I think interested in young kids and these
11	disorders would push for that since the prescribing is
12	happening, the treatment is happening, and it is based on
13	almost no data.
14		Thank you.
15		DR. CHESNEY:  Thank you very much, Dr. Riddle.

16		Now, Dr. Vitiello, who is Chief of CATPIRB, DISR
17	at the NIMH, is going to review the NIMH perspective on
18	pediatric psychopharmacology.
19	      NIMH Perspective on Pediatric Psychopharmacology

20		DR. VITIELLO:  I am with the Trial Treatment
21	Branch at the NIMH.  That is the acronym, but it is much
22	more complicated.

23		[Slide.]
24		Just a few comments from our perspective. 
25	Historically, NIMH has played a major role in the

			263 1	development of any research in pediatric psychopharmacology,
	2	pediatric psychopharmacology in general, meaning in subjects
	3	under age 18.
	4		Actually, until very recently, NIMH has been the

	5	only source, the main and only source of support for most
	6	pediatric psychopharmacology, so that all the studies on

	7	stimulants, on tricylics, for instance, a little bit there
	8	has been done on clonidine, has been done under the support
	9	of NIMH.
10		Only recently, thanks to new legislation and new
11	rules that have been introduced in the last three or four
12	years, the industry has become interested in this, and we

13	are seeing actually a change, and we are already redirecting
14	our efforts, so we don't plan to do as much placebo control,
15	short-term studies just to show efficacy and safety on the
16	short term or pharmacokinetics studies as we have done in
17	the past, because we know that the industry will be probably
18	interested in doing that, and we will focus our attention on
19	other questions that are relevant to the clinicians, such as
20	what is the long-term effects of treatments, long-term
21	safety, or how does pharmacological treatment compare to a
22	psychotherapeutic treatment, or is there additive advantage
23	in combining pharmacological and psychotherapeutic
24	treatment.
25		So, these are all questions that we are moving to

			264 1	address, or the issue of comorbidity that typically is not
	2	addressed in the typical industry-supported studies.
	3		Anyway, since the theme of this meeting is mainly
	4	on very young children, preschoolers, I have to say very
	5	clearly that the study that Dr. Riddle mentioned, which is
	6	the preschoolers with attention deficit disorder treatment
	7	study, the PATS, that is starting now, is the only and first
	8	study that we have in our portfolio that we have started so
	9	far.
10		We haven't had any opportunity to study any

11	psychotropics in preschool age previously.  We have
12	preventive intervention, we have psychotherapeutic

13	intervention, but not pharmacological intervention.  Even in
14	the studies with autism, typically, the age of our protocol
15	start at about 5, because for that, the instruments, the

16	assessments, and the outcome measures have not just proven
17	to be sensitive enough to detect treatment effects.

18		But all said, which is the very essential
19	communication about preschoolers, I mean this is a new area
20	for us, and we are looking very much forward to the October
21	2nd meeting to get some directions in this are.  I want to
22	give you a perspective of what the psychopharmacology
23	program is at NIMH.

24		[Slide.]
25		The main research question that we have, that

			265 1	relates to treatment, relates to all the aspects that the

	2	clinician would like to know about the treatment, that is
	3	not limited to is it better that placebo, but how does it

	4	compare with other treatment, and is it safe, and for which
	5	patient it is indicated, and what are the moderators of
	6	treatment, and so forth.
	7		Our mission, of course, is not to register drugs
	8	or to get an indication.  Our researchers' primary goal is
	9	to answer a clinical dilemma that practitioners are

10	currently struggling with.  Each time that there is a
11	clinical dilemma, and there is a methodology for addressing
12	that dilemma, we are interested in the clinical trial.  So,
13	that has been really our policy.
14		[Slide.]
15		The branch where I operate addresses treatment and
16	preventive intervention in general, and I think this is a
17	very good thing, because we don't see psychopharmacology as
18	something isolated, but something that is to be integrated
19	into other treatments or preventive interventions that are
20	available for children and for families.
21		As you can see, roughly half of the budget in '99
22	was devoted to treatment, and the remaining 45 percent is to
23	preventive intervention.
24		[Slide.]
25		If we look at the pie of treatment, you will see

			266 1	that psychopharm, pure psychopharm meaning to test only

	2	treatment that relate to psychopharm, the percentage is
	3	about one-third.  One-third of the budget for treatment

	4	goes--I am sorry--a little less than one-third or one-fourth
	5	actually goes to psychopharm, one-third goes to psychosocial
	6	treatment, which is psychotherapy, and a larger portion that
	7	actually is growing in 2000 will be much bigger, goes to
	8	combined treatment.
	9		Combined treatment is a category that includes
10	clinical trials that compare either psychosocial to a

11	pharmacological intervention, or they compare combined
12	treatment, psychosocial plus pharmacotherapy compared to a
13	control, whatever it is.  It could be the single treatment
14	in isolation, or a placebo, or something else.
15		So, basically, we are moving into looking at,

16	comparing the effects of different treatment modalities.
17		[Slide.]
18		Granted that a substantial amount of money,
19	millions go to prevention, and we look here at treatment. 
20	Again, this is what the pie in the previous slides basically
21	summarized, that psychopharm is not the area where we put
22	most of the money, and this is not really done a priori,
23	this basically reflects the applications that are sent to us
24	from university and researchers, that seems to be more
25	interested in studying the combined treatment and

			267 1	psychosocial treatment than straight psychopharmacological
	2	studies.
	3		[Slide.]
	4		If we look at the indication, the clinical
	5	entities that get funding for treatment studies, you see

	6	that depression, this is 8 million per year that goes to
	7	support clinical trials in depression, followed by anxiety,
	8	attention deficit disorder, and autism.
	9		[Slide.]
10		One of the initiatives that was launched about

11	four years ago has been the network of a research unit on
12	pediatric psychopharmacology in order to provide a
13	structure, an infrastructure where clinical trials in
14	pediatrics could be conducted on children with mental health
15	disorders, that could be used either by NIMH, by industry,
16	or by private foundations.
17		[Slide.]
18		This is a network of research that are devoted to
19	multi-site clinical trials in children.
20		[Slide.]
21		The units are based at academic research settings,
22	and the main focus is to study the efficacy and safety of

23	psychotropics that are commonly used in the community, but
24	without adequate data.
25		[Slide.]

			268 1		Again, it was established about four years ago
	2	through competitive contracts with NIMH.
	3		[Slide.]
	4		At the moment, there are seven RUPPs.  Some of

	5	them have subcontracts, like Columbia has subcontract to
	6	NYU, Ohio State to Kennedy Krieger.
	7		[Slide.]
	8		There are experts in child psychiatry,
	9	psychopharmacology, pediatrics, clinical trial design
10	methods experts.

11		[Slide.]
12		There is a data management center that is
13	separate.
14		[Slide.]
15		And there is a statistician also that provides
16	support, and it is available for industry, for NIH, for any
17	private foundation who wants to support these studies.
18		[Slide.]
19		What NIMH does with this RUPPs is to support the
20	basic infrastructure, and then protocols that are of public
21	importance, not funded or unlikely to be funded through
22	grant mechanism, and not sponsored by industry.
23		[Slide.]
24		This is an example of multi-site protocols.  The
25	first one is a double-blind study comparing flavoxamine and

			269 1	placebo in children with anxiety disorder.  It is a study
	2	that was completed, and it has been submitted for
	3	publication.  It was the first double-blind study of an SSRI
	4	in children with anxiety disorder out of their OCD.
	5		This protocol is in progress now, has randomized
	6	about 75 subjects, is to study risperidone for children with
	7	autism and behavioral disturbances, such as aggression,
	8	agitation, and then there is also a study on SSRI for
	9	children who are depressed and also suffer from bipolar
10	disorder.
11		These are just examples of some studies.
12		[Slide.]
13		Another example of a study, the treatment of
14	adolescents with depression study.
15		[Slide.]
16		The study basically compares the effectiveness of
17	different treatment arms and different modalities.  One

18	treatment arm is fluoxetine, which is the medication-only
19	study, treatment arm.  Then, we have CBT, COMB (?) therapy,
20	which is a specific psychotherapy for depression, a
21	combination of the two, so patients randomized to COMB

22	receive both, and then placebo only.  So, this study
23	basically will inform about the relative efficacy of

24	modalities like pharmacotherapy and psychotherapy, and the
25	potential value of combining the two treatments together.

			270 1		[Slide.]
	2		The projected sample size is 432.  The study has
	3	just started.  We have randomized about 30 subjects at the
	4	moment.  It is a parallel group design.
	5		[Slide.]
	6		Different stages.  There is an acute treatment,
	7	consolidation, maintenance, and one year open follow-up.  It
	8	is set up to answer multiple questions at different stages.
	9		[Slide.]
10		These are recently funded studies through grants
11	that are either starting now or will be starting in the next
12	few months.  Just to give you an idea of what is in the
13	pipeline basically.
14		One is a study to evaluate the value of continuing
15	antidepressants in adolescents who have improved, were
16	treated because of depression and have improved on the
17	antidepressant.  Basically, it is aimed to answer a
18	question:  after six months of treatment of adolescent major
19	depression, is it a good idea to discontinue treatment or
20	you run the risk of increasing the relapse rate?
21		This study is run at the University of Texas,
22	Dallas, and the PI, Graham Amsley, will address that
23	question.  The study has started, but I don't know how many
24	patients have been enrolled so far.
25		So, basically, it is stabilization for six months

			271 1	and then randomization either to placebo or to continuing
	2	medication.  The medication in question is fluoxetine
	3	(Prozac).
	4		Another study is the treatment of SSRI-resistant
	5	depression in adolescents.  Now, there are couple of
	6	studies, one, NIMH supported, the other industry supported,
	7	who basically have shown that SSRI, such as fluoxetine or
	8	paroxetine, are better than placebo in the short term,
	9	however, there is still about 40 percent of adolescents who
10	do not respond well to this medication, so the resistance to
11	SSRI is very common.
12		So, the question is what to do with adolescents

13	who do not respond to a first trial with an SSRI, is it
14	worthwhile to give a second trial of another SSRI, or is it
15	worthwhile to switch to a different entity, which in this
16	case will be venlafaxine, or is it worthwhile to combine

17	pharmacotherapy with psychotherapy.
18		So, there are different treatment arms in this
19	study that will test this hypothesis.  The sample size is
20	going to be about 400.
21		[Slide.]
22		Another study that is starting is a straight
23	placebo-controlled efficacy trial of valproic acid or
24	lithium in youths with bipolar disorder, bipolar type 1. 
25	This would be the first--actually, Dr. Geller has already

			272 1	done one placebo-controlled study, but this would be the
	2	first multi-site study that will test in a placebo control
	3	fashion the efficacy of mood stabilizers in youths.
	4		[Slide.]
	5		The last one is the study that Dr. Riddle has
	6	mentioned, which is an efficacy and safety of Ritalin in
	7	preschoolers with attention deficit disorder.
	8		[Slide.]
	9		I can just give you the basics about this study. 
10	Basically, there will be two groups of patients, age 3 to 5,
11	which is the preschoolers, and the group 6 to 8, to contrast
12	the ages.  The preschoolers will be 198, the sample size,
13	and 66 will be the school age.
14		There will be a period of screening and evaluation
15	to make sure the diagnosis is correct, that there is no
16	spontaneous improvement, that behavioral intervention alone
17	that will be delivered during this period will not already
18	trigger improvement, so that a pharmacological trial will
19	not be justified.
20		It is to make sure really that these children
21	really deserve a trial of medication.  You know, we want to
22	be very careful that we don't expose children who can be
23	managed in other ways to medication.
24		There will be an open titration to explore a whole
25	range of doses to make sure that the doses are tolerated

			273 1	well, and there will be a placebo-controlled trial to see if
	2	methylphenidate is indeed better than placebo and is well

	3	tolerated in a controlled fashion, an open maintenance for
	4	patients who improve, and then a blinded discontinuation
	5	event of these 12 months to see if continuing treatment is
	6	appropriate and still is associated with improvement.
	7		[Slide.]
	8		Some areas where still we don't have enough
	9	research--I am not talking about preschoolers here, young
10	children--I am talking about across the board, you know,
11	areas where we need basically new protocols and new ideas,
12	basically psychosis and schizophrenia in particular, still
13	bipolar because it is under-represented in our portfolio,
14	depression in prepubertal children--we get very little

15	really under age 12, there is only one-half of a controlled
16	study on kids with major depression who are in prepubertal
17	age--autism, and conditions with comorbidity.
18		Also, we are encouraging researchers to look at
19	safety issues.  I think that particularly for preschoolers
20	this is of paramount importance.  All the questions that we

21	receive basically from the lay public and practitioners that
22	relate to young children have to do more with safety than

23	with efficacy, and the basic question that goes in their
24	mind is this basically - is it a good idea to expose for a
25	prolonged period of time a child whose brain is going

			274 1	through dramatic changes, to an agent who we know is
	2	psychotropic.
	3		That is a very good question to ask, a very
	4	difficult question to answer, but in some way, it is not
	5	specific to psychopharmacology, it is not specific to mental
	6	health, because a lot of drugs that are used in pediatrics
	7	are steroids, other drugs that are used for known CNS, known
	8	mental health reasons have an effect on the brain, and so in
	9	some way, that question can be asked to any entity that is
10	administered to children at a young age.
11		So, that is my comment about safety.  The other

12	comment about efficacy, when we go to very young children,
13	that occurred to me during the presentation by Dr. Malone
14	and Dr. Mark Riddle, that it is good to focus on symptoms,
15	but since we don't know very much what the predictive value
16	of symptoms are, not always we know the predictive value of

17	symptoms at this age, probably we are better off if we focus
18	really on impairment, on functional impairment.
19		You know, the child is aggressive or agitated or
20	moves around and doesn't pay attention, it is not quite as
21	important as the fact that because of these symptoms, he is
22	not able to attend the preschool, is not able to play with
23	other children, has no friends, is delayed in his
24	interpersonal and social skills development, and so any
25	treatment modality that we are testing in some way, we want

			275 1	that is effective not only in reducing the symptoms, but in
	2	improving the functional outcome that should be impaired at
	3	the very beginning for the child to participate into a
	4	study.
	5		So, these are the kind of ideas that I think will
	6	be part of the October 2nd meeting to which very much we are
	7	looking forward to.
	8		Thank you.
	9		DR. CHESNEY:  Thank you very much.
10		Are there questions of the subcommittee members or
11	any of the other speakers for the speakers before we go on
12	to the questions the FDA has given us?
13		DR. SPIELBERG:  A couple of questions about
14	biology which we really haven't dealt with much today.  We
15	are talking about sort of prevalence of symptoms in
16	children, often very ill defined.
17		You know, if you assume that the adult population,
18	X percentage of adults have schizophrenia, and then some
19	percentage of those have a series of different genes
20	associated although we are far from understanding all of

21	those, you have to assume that that same percentage of
22	children, in fact, have those genes present, but that the
23	diseases are not manifested at least as they are in the
24	standard adult DSM classifications of the disease.

25		The issue of prevention came up, and I know there

			276 1	is discussions about, you know, could you, in fact, prevent
	2	the first psychotic break by a pharmacologic intervention,

	3	these kinds of things.
	4		To deal with any of those things, I think we are
	5	going to need a heck of a lot more biology superimposed on
	6	those kids, you know, what is autism.  I don't know what

	7	autism is.  It is a series of symptoms like schizophrenia
	8	right now is a series of symptoms that we work on.
	9		As the biology is beginning to creep in, I think
10	that is going to help us immensely because, after all, the
11	drugs are directed against biologic targets.  We are
12	spending all of our time cloning receptors that supposedly
13	are associated with either symptom reduction or hopefully
14	getting at the etiology of the diseases, and yet, we know
15	that those genes that are represented in adult diseases are

16	present in kids not yet manifest, but maybe manifest in ways
17	that we are ignorant of actually being able to pick up at
18	that point.
19		Maybe we should be using more drug, maybe we
20	should be using less drug, maybe we should be using
21	different drugs that we are currently using in
22	classifications of kids, and I hope that at the discussion
23	we have, we can, in fact, get some much more broad insight
24	into biology, because if we are to make any judgments about
25	whether a drug should or shouldn't be used, it is going to

			277 1	be understanding the underpinnings of the behavior for which
	2	these drugs are being used in kids.
	3		DR. CHESNEY:  As usual, you articulate it much
	4	better than I ever could, but I wondered about genetics of
	5	some of these diseases.  For example, is a bipolar
	6	depression in a 3- to 5-year-old--and I was talking to Dr.
	7	Geller about this--the same as non-bipolar depression in a
	8	3- to 5-year-old, and would they respond differently, and if
	9	we had a wrongly selected group of children, would we not

10	show efficacy when it was there, and I am not even knowing
11	exactly how to word the issue, but, Dr. Riddle, maybe you
12	could comment on what we are trying to say.

13		DR. RIDDLE:  Well, I think as you have articulated
14	it, and as you know for most of our psychiatric diagnoses,
15	we rely on phenomenology.  Unfortunately, we have very
16	little more than that to go on.
17		For some of the disorders, we are beginning to

18	have some pathophysiology, although it is still somewhat
19	primitive, but I think that is moving along.
20		Also, for some of the disorders, we have family
21	studies that point to familiality and maybe segregation
22	analyses that might point to a particular mode of
23	transmission, but at this point we don't have much in the
24	way of identified genes.  I think that you know that

25		This is very anecdotal, but if I think about

			278 1	bipolar disorder, I have treated two youngsters under age 6,
	2	and in both of those youngsters, one of the parents had
	3	fairly severe bipolar disorder, and the other one had fairly
	4	severe recurrent major depressions.
	5		One of the questions--again, this is anecdotal--
	6	that that raises, are the youngsters with earlier onset just
	7	having more genetic loading, at least for some of the

	8	disorders.  One could think about that for depression,
	9	bipolar disorder, some types of anxiety, et cetera.
10		But to come back to where I started, I think even
11	for the school age kids and the adolescents, it is mostly
12	phenomenology.
13		DR. CHESNEY:  If I could ask one more question. 

14	Dr. Vitiello, you said right at the end that maybe we should
15	be focusing on functional impairment, and I guess maybe that
16	is all we have, but it reminds me of treating fever without
17	figuring out what causes the fever, and maybe that is what
18	we have to do at this point in time.
19		DR. VITIELLO:  Well, I don't know about fever, but
20	basically, what I was going to invite researchers not to
21	limit their attention to symptoms, but to go above and
22	beyond that, not to ignore symptoms, but to link symptoms to
23	functional impairment.
24		After all, for fever, we have--just to go back to
25	that example that you brought up--we have a threshold to

			279 1	define what fever is.  For issues such as aggression,
	2	agitation, hyperactivity, inattention, we don't really have
	3	a clear-cut threshold particularly for preschoolers.
	4		For school age, maybe there are some norms, but
	5	still are norms.  You know, there is not that clear cut-off
	6	that you have with a situation like fever.  So, I think it

	7	is essential to focus on what is the impairment of a child,
	8	and to expect that whatever treatment we deem effective,
	9	that impairment is reversed.
10		I wouldn't be satisfied just if the symptoms

11	disappeared if I don't have proof that the child will be
12	better off.
13		DR. CHESNEY:  Thank you.
14		Dr. Riddle.
15		DR. RIDDLE:  Just to follow that up, in the
16	anxiety study that Dr. Vitiello had mentioned, that was just
17	completed, for that study the primary outcome variable

18	included a combination of what we might consider the
19	symptoms, how much internal distress was the youngster

20	experiencing from the anxiety, and also how much were the
21	physical symptoms of anxiety bothering the youngster, so
22	what we would think of classically as symptoms.
23		But it also included how much problem was the

24	anxiety causing in terms of avoiding things, activities, et
25	cetera, how much problem was it causing in school, and how

			280 1	much problem was it causing at home and other settings.
	2		So, I think our studies, at least with the older
	3	youngsters, are beginning to include impairment in the
	4	assessments, although in a fairly primitive way.
	5		DR. CHESNEY:  Yes.
	6		DR. RYAN:  I wanted to just sort of reemphasize I
	7	think what Dr. Laughren put on the table for us, because I

	8	thought that organized at least my thinking well when you
	9	talked about the pluses and minuses of targeting symptoms
10	rather than syndromes.

11		I think impairment sort of fits in there where, as
12	I understood what he was saying, the main ideas were that
13	the symptom had to be in common across a range of disorders,
14	not simply a proxy for the disorder, and that hopefully it
15	is targeted by the treatment in all of the disorders, not
16	simply in one, and that, God willing, you have some idea on
17	the mechanism that it targets.  I think that everybody
18	including Dr. Laughren, would flex on that one a little bit.
19		I have to say that I was less clear where the
20	impairment fit in, because impairment, obviously, I think in
21	psychiatry, we have learned to use impairment as a threshold
22	criteria to say that the syndrome is significant enough that
23	you want to treat the stupid thing, you know, that it is not
24	simply deminimus or trivial or something and will get better
25	easily, but I don't see mechanisms where I would say you are

			281 1	particularly targeting impairment rather than using the
	2	impairment as a threshold.
	3		Similarly, you are possibly accepting the sleep
	4	disturbance, it was less clear to me if there were even
	5	other symptoms right now, that my particular choice of
	6	guesses would be that the symptom is ready to target, and it
	7	is a little tougher to know on the aggression one.  I think
	8	that is the interesting one, or at least one of the
	9	interesting ones that you put on the table.
10		DR. CHESNEY:  Dr. Gorman.
11		DR. GORMAN:  I would like to ask any member of the
12	panel that just presented, in the PATS study that several of
13	you mentioned, how are you comfortable that you are
14	enrolling people with ADHD, and then why can't that
15	methodology be generalized to other disorders.
16		DR. VITIELLO:  Mark, it is your call.  You are one
17	of the PIs, so I think it is appropriate that you address
18	it.
19		DR. RIDDLE:  That is a very good question, and it
20	is a question that I think every group that has looked at
21	this protocol has raised.  There clearly is no gold
22	standard, and the critique we often hear is, well, we expect
23	3- and 4- and 5-year-olds to be active, they are fairly
24	impulsive, and we don't expect them to stay sort of focused
25	and sit in the chair doing spelling problems for 45 minutes.

				282 1		So, the sort of "boys will be boys" argument is
	2	one that is throw up at us again and again.  Now, how to
	3	deal with it, what we have tried to do is to use an
	4	instrument that was normed, so that we could say, look, here
	5	is what the population of kids this age look like, here are
	6	the sorts of scores they get.
	7		To get into our study, the kids are going to have
	8	to be out here with the score.  Another is to rely some on
	9	expert experience, and that is always a bit scary, but I
10	think we have to do that.
11		The other is to have clear impairment and
12	agreement across settings, settings like home, school, et
13	cetera, and we don't know how to do it any better than that,
14	and I think that a tough critic would still say, you know,
15	that is kind of weak, but that is the best we have.
16		DR. GORMAN:  I guess being a sort of wishy-washy
17	critic, I assume you are talking about some sort of Connor
18	derivative for the scoring system you are using.
19		DR. RIDDLE:  Right, something of that nature, a
20	parent and teacher report, although, as I said, we are going
21	to use the simulated classroom.
22		DR. GORMAN:  I guess the question I am asking then
23	is that I think is, compared to some of the other
24	methodologies I have seen in the mental health area, very

25	rigorous.  Is not a similar program underway to create a

			283 1	criteria for autism, for instance, where this much language
	2	disability, this much behavioral disability, not functioning
	3	in settings at home and at school, why is that methodology
	4	so hard to generalize in the mental health field?
	5		DR. RIDDLE:  Ben, do you want to do the autism
	6	one?
	7		DR. VITIELLO:  It seems to me that the problem
	8	with autism is not the diagnosis, because you can make a
	9	diagnosis at age 2 with good validity, and so forth, is that
10	we don't really know enough about the pathogenesis of the
11	disorder to come up with a rational drug development
12	program, and so far there hasn't been, as far as I know, any
13	good candidates that is worthwhile testing in clinical
14	trials.
15		There have been clinical trials, of course, but

16	without very strong rationale for doing that, so that is
17	really the reason why we don't see more pharmacological
18	development in clinical trials in this age.
19		DR. CHESNEY:  Dr. Geller.
20		DR. GELLER:  Just going back to the question of
21	why it can't be generalized, Keith Connor developed the
22	scale for hyperactivity many decades ago, and although it
23	has been tweaked, it has really never been bettered or

24	surpassed or anything used instead of it, it works just
25	fine, because hyperactivity is extremely easy to measure. 

			284 1	You can measure it reliably.
	2		The question of threshold of what is impairment is
	3	very important because I think in one of the recent
	4	epidemiological studies, 63 percent of children who had
	5	skipped a grade were on Ritalin because, in that particular
	6	school setting, they were considered hyperactive, so
	7	threshold is really very crucial also.
	8		When it gets to illnesses like autism and mood
	9	disorders, we don't have a Connor scale that pinpoints it
10	reliably and in an easy 10-item way.  There are very
11	reliable and valid scales used in various kinds of research
12	studies, but nothing that has the simplicity and ease of use
13	and brevity of the Connor's.
14		DR. GORMAN:  I guess I am still struggling.  If I
15	took five mental health professionals and put them in a room
16	to examine one child sequentially, and the child had autism,
17	whatever that is, would they all make the same diagnosis,
18	and if so, would they use the same criteria?  And if they
19	used the same criteria, why aren't you comfortable telling
20	me that is the gold standard?
21		DR. GELLER:  If you did it and had five
22	clinicians, I think you might come up with five different
23	diagnoses.  One would see just the hyperactive component and
24	have the child on Ritalin, one would see the psychosis, and
25	one would see the language and send the children for LD.

			285 1		Like many large universities with a referral
	2	center, and when we get the charts of kids referred to us,
	3	that is usually what it looks like depending on the
	4	professional they were seeing, that is the diagnosis they
	5	have gotten.
	6		I think it will help to keep in mind what I
	7	frequently say to parents when I am doing an informing
	8	interview, which is I start by telling them psychiatry is
	9	500 years behind other medical specialties, and it goes back
10	to all these comments about biology.
11		We don't have an x-ray, biological peripheral
12	marker, a genetic marker or any other kind of method except
13	phenomenology, we can interview, and if you are interviewing
14	for something relatively straightforward like hyperactivity,
15	you can get a lot of agreement.  It is not so easy to
16	interview for which language impairment.  It's because the
17	child is bipolar, which is because they have a loose
18	association and they are schizophrenic, which is because
19	they have congenital aphasia, and which is because they have
20	the autistic impairment.
21		I think until we have more biology--I think that
22	comment is really very, very key--we are going to continue
23	to have difficulties developing interview scales that are

24	any better than the ones we have with the exception in the
25	preschool realm there is newer work.

				286 1		John Looby (?) at my facility and other
	2	investigators around the country are looking for methods of
	3	looking at mood disorders in children, but I think nothing
	4	will be a big enough gain until we have more of the biology.
	5		DR. RIDDLE:  I think I would generally agree with
	6	Dr. Geller, but I think if you had sort of five clinicians--
	7	there may be a lot of disagreement--I think if you had five
	8	clinicians that worked with kids with developmental
	9	disabilities, or who were researchers in the autism area,
10	there would be quite high agreement, and I think that most
11	of them now doing research would use one instrument and
12	actually could come to a diagnosis that everyone would say
13	yeah fairly independently.
14		But if you go out into the community at large, no,
15	but I think that the research for some of these disorders
16	can be done based on the phenomenology, I guess that is the
17	point I want to make.  I don't want to come away from this
18	with too much negativity.
19		DR. GORMAN:  I guess I feel that, you know, a lot
20	of symptoms, well, tuberculosis perhaps, we spent 300 years
21	trying to figure out was a single disease, with syphilis
22	perhaps an equal number of times, but at some point you have
23	to define a diagnosis before you can move forward, and I
24	think if that is the holding up point, then, in terms of
25	starting research programs into either psychopharmacology or

			287 1	psychotherapy or any other combined modality that you
	2	choose, then, you should become rapidly more comfortable
	3	with a diagnostic entity even if it's very exclusive.
	4		If you want to use the Connor scale and say that

	5	you have to be over the 90th percentile to be ADD, you are
	6	going to exclude a lot of children who have ADD, but you
	7	still have a diagnosis.
	8		I am guess I am curious as to why that hasn't
	9	progressed more rapidly.
10		DR. MALONE:  I work in autism, and I think what
11	Dr. Riddle said is true, if you get experienced clinicians,
12	and you put five of them in the room, that you would have
13	high agreement on the diagnosis, and there are a number of
14	instrument that are used in autism that are fairly reliable
15	for rating symptoms and making diagnoses.
16		I have had the same experience, for instance, in
17	asthma.  My son has asthma.  I think we had to go to about
18	three doctors before we got any diagnosis.  I could ask the
19	same question, you know, what is this asthma thing, but I

20	think it really depends on the experience of the clinicians.
21		DR. CHESNEY:  Yes.
22		DR. RYAN:  I want to sneak up on the question in a
23	different way or I want to combine two of them, which is
24	that if these disorders, which is looking like a lot of them
25	are, are complex genetic disorders, probably with a bunch of

			288 1	genes, you know, the 8 to 15, not the 3 or 4, and they are

	2	genes all of small effect, you know, heritability under 2,
	3	and they are distributed frequently in the population, you
	4	just have to have an infelicitous combination of them that
	5	adds up and gives you, you know, maybe like a hypertension
	6	equivalent.  I think it explains a lot of the complexity,
	7	but there certainly are biologic findings.
	8		There is not a biologic finding that is
	9	diagnostic.  Well, there certainly are psychological

10	symptoms.  Again, it is harder to make a test that says yes,
11	you have got it, or no, you don't, because they are
12	probably--probably many of them complex sort of additive

13	disorders there.  That is what you are trying to study.
14		DR. CHESNEY:  Actually, one very positive thing
15	that occurs to me is that by doing well controlled and
16	rigorous studies, we may be able to sort some of this out. 
17	There may be populations of children that respond
18	dramatically and others that don't, and because they are in
19	very well supervised trials, we can maybe sort some of that
20	out.
21	        Subcommittee Discussion of Questions/Issues

22		DR. CHESNEY:  Maybe we should go on to the
23	questions.  Dr. Murphy, do you want to elaborate on these at
24	all or should we just go at them as written?
25		DR. MURPHY:  You are having such a great

			289 1	discussion, just go at them.
	2		DR. CHESNEY:  Well, the first one, what additional
	3	psychiatric indications in the pediatric age group would
	4	benefit from psychotropic development programs, and what
	5	ages should be included?
	6		By "additional," do you mean other than everything
	7	we have discussed here?
	8		DR. LAUGHREN:  Let me paraphrase the question a
	9	little bit.  Basically, what I am asking is how are we doing
10	in terms of our application of the Pediatric Rule and FDAMA
11	in terms of where we have been either encouraging or
12	requiring studies.  You saw the list.  Is that about right
13	or are there areas that we have been ignoring that we should
14	be looking at, have we gone too far in some areas, and in
15	particular, what about the age cut-offs, is that about right
16	for the disorders that we have targeted or should we be
17	looking at different age ranges?
18		DR. CHESNEY:  Can we include our speakers having
19	suggestions, so it is not just the subcommittee?  So, if any
20	of the speakers have suggestions, please go ahead and
21	volunteer.
22		Dr. Riddle.
23		DR. RIDDLE:  I don't know if you have the
24	authority to do this, but I am concerned that some negative
25	studies may not be published, that the company is required

				290 1	to do the study, does it, there is no effect, they have
	2	gotten their six months' exclusivity, done deal, and we
	3	really need that negative data out there.  I don't know what
	4	the deal is on that.
	5		DR. MURPHY:  The deal is that if they have
	6	negative results and we think it is a relevant, real
	7	negative result, it will go in the label.  That is the point
	8	of exclusivity, it clearly says that when we asked for the
	9	studies, that even if they are negative, and particularly if
10	there is a safety issue or an adverse event, that
11	information will become available in the label.
12		DR. RIDDLE:  Just one other comment or question. 
13	The difference between ages 6 and 7, I am not sure I
14	understand what that is about.
15		DR. LAUGHREN:  It is purely arbitrary.  It is
16	based on discussions we had at the time with various people
17	in the field about where we thought we ought to cut it, but
18	that is a question for you, again, in regard to the younger
19	populations, it sounds to me from what you are saying that
20	there is not much rationale for going much below those ages
21	in terms of these diagnostic entities.
22		DR. RIDDLE:  Yes, I would agree.  I think down to
23	6 or 7 generally, for the disorders that you have looked at
24	or are planning to look at, I think we can make a diagnosis,
25	can get a reasonable assessment, and kids may benefit from

			291 1	the medicine, 6 or 7, who knows.
	2		Below that, maybe--maybe for ADHD, I think that is
	3	what I would say, maybe, and perhaps we need to see what
	4	happens with this NIMH study first.
	5		DR. LAUGHREN:  I am glad you offer that because
	6	that was going to be my next question, because we do have
	7	the authority at this point under the Pediatric Rule as new
	8	formulations of methylphenidate and other stimulants come
	9	along to require companies to go below that age, but if the
10	feeling is that we ought to wait and see, that is fine, too.
11		DR. RIDDLE:  One more here and I will stop.  It
12	does seem to me that you are between the rock and the hard
13	spot, that the field that may not be mature enough to permit
14	the studies, on the one hand, on the other hand, there is so
15	much willy-nilly or a fair amount of willy-nilly prescribing
16	going on that it is painful to sit and wait, and not have
17	data.
18		DR. MURPHY:  One of the things that we can do
19	under the rule is we can defer studies.  We have an option
20	of not waiving them.  However, we are then in the quandary
21	of to defer studies, we have to come up with the best

22	estimate of when we think we are going to ask for those
23	studies to be done, and sometimes that is very clear, you

24	are waiting for additional data either in an older age group
25	or in an adult or some other process that is more delineated

			292 1	than what we have here.
	2		I think what Tom was saying is we could--was your
	3	comment that we should say until we get more information
	4	from the ongoing study, we should defer.  We could come up
	5	with some estimates of what that would be, any further
	6	studies in the younger age group.
	7		DR. RIDDLE:  Ben, maybe you can help me on this,
	8	but if we took ADHD, for example, I would think that in

	9	three years, the data collection for at least the acute
10	phase of that study will be complete and we will know
11	something about was the study reasonable successful at
12	recruitment assessment measuring change.

13		If the answer is yes, we are having some longer
14	acting preparations coming on the market for both
15	methylphenidate and amphetamine, and I think that they are
16	going to be very attractive because of their convenience.
17		The study that NIMH is funding is short-acting
18	methylphenidate.  It's a place to start.  I don't know,

19	three years is a very long time, but something like that, it
20	seems to me, would not be unreasonable.
21		DR. CHESNEY:  Dr. Nelson.
22		DR. NELSON:  This is not an area I know much

23	about, but I guess the question is, is there any dose
24	response data at least in older children where you can make
25	a diagnostic classification with any kind of certainty to

			293 1	where at least you could get, in those children whose
	2	clinicians have decided to use the drug, at least some basic
	3	pharmacokinetic data to find out that you are at least not
	4	overdosing them even if the indication is unclear?
	5		DR. RIDDLE:  Again, a very good question, and
	6	there hasn't been much dose response data generated
	7	recently, but there was quite a bit a number of years ago,
	8	and kids vary quite a bit as to what dose they may need, and
	9	where the field is, is start low, gradually move the dose up
10	until you have kind of reached maximal efficacy and/or run
11	into side effects that are problematic, and then back off a
12	bit.
13		I think it is not that primitive because nobody
14	has taken a look and tried to establish a good dose response
15	curve.  I think that the individual variability is so great
16	that it's a wash.
17		Does that get at your question?
18		DR. NELSON:  I guess it is unclear to me if it is
19	the right time to just give up doing it, or if you just need
20	more data to find out if it works.
21		DR. CHESNEY:  Dr. Spielberg.
22		DR. SPIELBERG:  In fact, Skip, I am not so much

23	worried about overdosing as I am underdosing.  I would bet
24	that in a lot of the failed trials, given the more rapid
25	clearance of almost every chemical substance on earth in

			294 1	prepubertal kids, that, in fact, even though people were
	2	thinking they were increasing the dosing, I am not sure how
	3	much of that was really controlled by concentration and
	4	whether, in fact, many of these kids were chewing up drugs
	5	at heroic rates.  I mean look at theophylline, when you
	6	carry kids at 40 mg/kg/day prepubertally, and they drop to
	7	12 postpubertally.
	8		I don't know how many of those studies really were
	9	concentration-controlled studies.  Obviously, you are going
10	to have to titrate individual kids, and from my
11	understanding of depression or schizophrenia or anything

12	else, it really is a titration and an empirical process.
13		But I am concerned that in some percentage of the
14	trials that have been done, in fact, the kids really didn't
15	have exposure despite increasing dosing.
16		DR. CHESNEY:  Dr. Geller.
17		DR. GELLER:  That is a really important point

18	because the kinetics of kids, Dr. Vitiello did this first
19	for lithium, is that they clear it more rapidly, however,

20	just because of that, all of the studies that I know of have
21	been concentration controlled, and usually what we headed
22	for were higher concentrations in kids.
23		In my nortriptyline study of prepubertal
24	depression, we were about a third higher than similar

25	studies in adults based on what they would tolerate by

			295 1	looking first at pharmacokinetic data.  In our lithium study
	2	of prepubertal, we set our mark at 1.2, thinking that maybe
	3	if we did that, we could get response, but really as
	4	unbelievable as it is, although all these drugs do so really
	5	well in adults, it is very, vary hard to find an effect in
	6	kids when you are doing controlled studies.
	7		That really has remained more than the safety
	8	issue and more than concentration issues.  The problem has
	9	been finding things that give the kind of response we see
10	when we are looking at an adult population.
11		DR. SPIELBERG:  That is not surprising on a
12	pharmacodynamic basis either from anesthetics and all the
13	other literature in compounds that CNS in kids.
14		Were you at dose-limiting concentrations?  In
15	other words, if you go up to 1.3-fold what your mean
16	concentration was in the adults, were you seeing things that
17	were sufficiently distressing that you felt that that is as
18	high as you could go?
19		DR. GELLER:  With the tricyclic antidepressants,
20	there were EKG issues, which was a cut-off, right.  With
21	lithium in prepubertal children, you start getting cognitive
22	deficits, so that you have things that limit it aside from
23	the concentration.
24		DR. WARD:  Are the measurement tools effective for
25	children, the ones that you would apply?  In other words, do

			296 1	you think there were changes, but you couldn't detect it
	2	with the measurement tools you were using?
	3		DR. GELLER:  This is really also another extremely
	4	excellent question.  I honestly don't think that has been
	5	the issue.  As Mark and Ben and Dr. Malone were saying,
	6	there has been a lot of effort put into developing
	7	instruments, and I don't think the issue has been that they
	8	are less developed than those in adults.
	9		Of course, the age span, we don't have any
10	biology.  That is probably much more the issue than can we
11	interview well enough.
12		DR. RIDDLE:  Just a comment on the
13	pharmacokinetics and the dosing.  I can't comment on the

14	field's past sins or whatever, but in terms of looking
15	ahead, again, this preschool study, the design is to

16	increase the dosing gradually and to have enough time to be
17	able to get up to what we think are quite high doses or to
18	stop if we have to before that, to be sure that we have
19	given each youngster optimal dosing, and then we are going
20	to be getting plasma levels.
21		We are not going to do individual PK curves, but
22	we are going to get steady-state levels to look at that as
23	part of the study.
24		DR. CHESNEY:  Just refocusing on the first
25	question, Dr. Laughren in his handout has three disorders

				297 1	that you are considering requiring studies:  schizophrenia,
	2	panic disorder, and conduct disorder.
	3		I wonder if anybody in the room or any of our
	4	experts feel that that is something they should definitely
	5	look at or keep that under consideration?  Yes.
	6		DR. MALONE:  One of the things I did want to say

	7	about the age group, I will say this and then I will go to
	8	the point of schizophrenia.  The main concern is long-term
	9	safety, and I think that many of the studies that we get
10	done, say, by industry don't really address that issue, so
11	for that reason partly I wouldn't really be for making the

12	studies be required in younger age groups, because we won't
13	find out the key thing anyway, the long-term safety.
14		DR. LAUGHREN:  But, of course, even if you look at
15	kids, you know, 6 and older, or even if you limit it to
16	adolescents, I mean you still have the same long-term safety
17	questions that are very, very difficult to get at.  I mean
18	i's true of all drugs, it's true of adults, too.  You worry
19	more about kids because they have a longer life ahead of
20	them.
21		DR. MALONE:  And their brain is probably
22	undergoing more development at a younger age, so they might
23	be more at risk for the longer term issues.
24		DR. LAUGHREN:  Right.
25		DR. MALONE:  Although the brain is developing for

			298 1	perhaps a fairly long period of time, perhaps in
	2	adolescence.
	3		I could talk a little bit about the schizophrenia
	4	issue.  If you are talking about preschoolers, you know, age
	5	4 and under, schizophrenia is actually extremely rare.  In
	6	fact, the studies that went to look at the difference
	7	between autism and schizophrenia looked at age of onset, and
	8	these studies were done in the seventies by Lauder in
	9	England, and if you looked at the age of onset and used an
10	age of 5, if you develop symptoms before age 5, you have
11	autism, otherwise, you are more likely to have
12	schizophrenia.
13		DR. RIDDLE:  A comment about these three disorders
14	also.  I think each of them is important and each has its

15	own problems.  The anxiety studies that have been done to
16	date have not included panic disorder.  We know that panic
17	disorder occurs in adolescents.  It is extremely rare in
18	prepubertal kids.
19		I think studies in adolescents of panic disorder
20	are called for.  I don't think I would ask a company to do
21	anything in the prepubertal kids.
22		Conduct disorder, you know, everyone knows is a
23	very thorny issue, is it really a disorder, are we getting

24	into behavioral control, is it really a list of kind of bad
25	acts, if you will, and yet, there is a fair amount of pilot

			299 1	small and controlled data suggesting that some of the
	2	psychiatric medications we use are actually quite helpful to
	3	youngsters with conduct disorder.
	4		I think that we have to pay some attention to
	5	that, and it is a big problem.
	6		You look like you are ready to respond.
	7		DR. LAUGHREN:  Well, I agree, I mean I think we

	8	could probably spend an entire day or more talking about
	9	conduct disorder because I share your concerns about the
10	diagnostic criteria for that disorder.  It is a list of
11	mostly aggressive behaviors.
12		That was, in part, why I brought up the possible
13	alternative route of looking directly at aggression rather

14	than calling it something, you know, giving it another name
15	that is not as nice as aggression, but that is really what
16	is being treated.
17		DR. RIDDLE:  My guess is that the experts in the
18	field would say as long as there will be studies, go either
19	way you want, just go, I think, because I think one could
20	make an argument either way.
21		DR. CHESNEY:  Is that the answer to No. 3 then,
22	just go?  They are asking there should we treat nonspecific
23	symptoms or are nonspecific symptoms acceptable targets for
24	drug development.

25		DR. MALONE:  We study aggressive conduct disorder. 

			300 1	That is the main thing that I do right now is treatment

	2	studies for aggressive conduct disorder.  Aggression is
	3	really a tricky thing.  I think it would be hard to just
	4	study aggression alone because aggression is different in
	5	different diagnostic categories.

	6		For instance, in children, I think aggression that
	7	occurs in conduct disorder and ADH would be different than,
	8	say, aggression that occurs in autism.  I think there are
	9	very many issues about aggression that at this point in time
10	at least, you still might want to restrict it to a few
11	disorders.
12		For instance, in the adult studies, I think when
13	they study, for instance, anger outbursts or aggression,

14	they generally restricted it to personality disorders, and
15	they would really rule out the presence of affecting
16	disorder and psychosis and other disorders.
17		So, I think even though aggression does across
18	many diagnoses, it probably is treated differently in the
19	different diagnoses also.  So, at this point in time, I

20	think if you are studying aggression, you might really want
21	to restrict it to a few disorders.
22		There is even the disorder, I think we had
23	discussed this before, some impulse control disorder, in DSM
24	that you could use partly, although I think it has problems
25	also because I think you are required to have normal

			301 1	behavior in between, and many of the aggressive individuals
	2	have other associated symptoms that go along with conduct
	3	disorder or ADH, in children at least.
	4		DR. RIDDLE:  In addition to aggression, I guess
	5	the other symptom that I think is fairly common and
	6	disabling, and is currently treated with major medicines, is
	7	"psychosis" or psychotic symptoms.
	8		We know that schizophrenia is quite rare, and so
	9	if you have a new neuroleptic that has an indication for
10	schizophrenia in adults, and then you want to go down in
11	age, it is very hard to get much of a population, and even
12	if you do, it doesn't generalize to many kids since
13	schizophrenia in the younger population is fairly rare.
14		But psychotic symptoms in the prepubertal kids are
15	I think fairly common and are treated with neuroleptics, and
16	again with very little data.  So, I would, particularly in
17	the prepubertal kids, think about psychotic symptoms. 
18	Adolescent schizophrenia is okay, yes.
19		DR. LAUGHREN:  So, you think it would be
20	reasonable again in terms of invoking the Pediatric Rule, it
21	would be reasonable to require companies to look at
22	adolescent schizophrenia, that would not be an unreasonable
23	thing--
24		DR. RIDDLE:  Yes, I agree, I think that that is

25	not unreasonable, but I worry also about the prescribing of

			302 1	neuroleptics in the prepubertal kids with no data, and the
	2	only way we will get it is if you would ask for something,
	3	psychotic symptoms.
	4		DR. LAUGHREN:  But there again, the problem is how
	5	to define that.  For schizophrenia, you have well-defined

	6	diagnostic criteria that you can apply in adolescents.  If
	7	you get below that age and talk about psychosis, what is it
	8	that you are targeting, how do you define it, can you get
	9	agreement on that, all those sorts of things.
10		DR. CHESNEY:  Dr. Geller.
11		DR. GELLER:  I want to address that issue, but

12	also add to what I think we need to ask companies to look
13	at.  When I talk to my colleagues around the country who
14	also specialize in prepubertal bipolarity, the group at
15	Harvard, and my own colleagues at Wash U., almost all the

16	children we see with bipolar are on multiple medicines, and
17	again without any data.
18		I think one of the things that if were possible
19	would be to ask the companies to look at combinations,

20	because we have almost no young bipolar children who get
21	well on a single medication, and that is just widespread
22	experience.
23		I have to temper that with how much of that is

24	because we are doing it on an outpatient basis for kids that
25	we most certainly would have hospitalized five years ago,

			303 1	and does that change what you are giving.  I think that is a
	2	question that has to be thought about.
	3		In terms of the nonspecific diagnoses, I could not
	4	have more respect for Dr. Riddle and my other colleagues who
	5	think we should look at psychosis as an entity by itself or
	6	agitation or aggression as entities by themselves, so I am

	7	in the minority on this.
	8		I think it is the wrong way to go because I think
	9	that it undermines the medical model which we have really
10	fought so hard for in the last three decades in child

11	psychiatry.  Before 1970 or so, it wasn't even common
12	clinically to interview children.  You asked the mom what
13	was wrong with them, and because of that, we didn't know
14	depression existed because nobody was asking the child are

15	you suicidal, and children, unlike adults, don't blurt this
16	out when they walk into the doctor's office, you have to ask
17	them, as I did to a child last week who was a consult.

18		Nobody knew she was suicidal, but when she was
19	asked, the reason she has gone from an A to an F student is
20	she is sitting in school all day thinking it would be nice
21	to be in heaven.  I still get chills.  It's kids I have
22	taken care of for years, and it is still startling to see a
23	prepubertal child who wants to die that much.
24		My concern, if we start looking at broad
25	categories is we are going to go back to that.  The only

			304 1	stethoscope we have as we have been talking about in child
	2	psychiatry and an adult is the interview.
	3		I think we are at a point, certainly for bipolar
	4	and for depression, where we can interview very specifically
	5	and attach the psychosis to those diagnoses, and my concern,
	6	if we don't do that, is we will make a cottage industry out
	7	of studies of kids who have the broader categories, when, in
	8	fact, we have the ability to make better diagnoses and to
	9	begin attaching biology to them.
10		DR. VITIELLO:  I don't know if I can comment?
11		DR. CHESNEY:  Yes, please.
12		DR. VITIELLO:  About the so-called nonspecific, I
13	wonder if, in the same way that we can envision and conduct
14	clinical trials of agitation and aggression in demented
15	patients, in Alzheimer's, in the same way we can conceive
16	clinical trials of an agent in children with mental
17	retardation who are developmentally delayed and have brain
18	damage, and who suffer from severe aggression and agitation.
19		It seems to me that that should be feasible and
20	should be quite helpful.  We have several suggestions that a
21	large part of the use of antipsychotics in young children is
22	for kids who are brain damaged in one way or the other.
23		DR. CHESNEY:  Dr. Gorman.
24		DR. GORMAN:  I would also like to be in the
25	majority position for once this afternoon and support the

			305 1	pursuit of symptomatic therapy.  The treatment for ADD, as

	2	far as I can tell, is not curative, it is palliative.  The
	3	children's disease does not go away.  We just control its
	4	symptoms of hyperactivity/impulsivity, perhaps even
	5	aggression, and allow them to concentrate better.

	6		So, you could argue that Ritalin is perhaps just a
	7	symptom controller of some of these symptoms.  Aggression, I
	8	think is a major morbidity for the parents in children

	9	between the ages of 2 and 5, children who cannot attend
10	preschool because they bite.  Whether they bit because of

11	impulse control or conduct disorder or autism, they all have
12	the same morbidity in terms of their parents being unable to
13	keep them in schools.
14		I think it is a very reasonable approach, and
15	taking away a symptom does not always impair your ability to
16	make a diagnosis.  We try to take away coughs all the time,
17	and yet we can still make the diagnosis of pneumonia very

18	effectively and even asthma.  Often, when we don't control
19	those coughs with our symptomatic treatment, we know there
20	is something more serious going on.
21		DR. CHESNEY:  I think I understood Dr. Malone
22	correctly to say that aggression could come from a variety
23	of different causes, is that correct, from a conduct
24	disorder, from autism, from ADHD?
25		DR. MALONE:  Yes, and I wasn't speaking towards

			306 1	whether we would use aggression as a thing to treat, that
	2	aggression itself is kind of a mixed-up symptom.  If you are
	3	looking at different disorders, there might be a different
	4	drug that you would treat a different disorder with.
	5		DR. CHESNEY:  That was the message I heard, that
	6	if you used the same drug for all aggression, you might miss
	7	out on a better drug for the underlying problem.
	8		Dr. Geller.
	9		DR. GELLER:  I wanted to go back to the examples
10	that Dr. Vitiello gave.  It is true that we treat the
11	aggression in dementia, but we often have a particular
12	diagnosis of dementia in mind.  This is true of the multi-
13	site dementia study that just started.
14		There is careful diagnosis using whatever
15	biological markers are available, and then it is treating a
16	symptom of illness much the way we would if somebody
17	coughed, but had pneumonia.  I think that is different than
18	saying let's just take cough and not do everything we can to
19	be sure that we haven't cultured and so forth to find out
20	what the etiology is.
21		The other distinction I think I want to make is
22	between what we do clinically and what we should be
23	investigating.  Clinically, we all treat what we see,
24	because that's the best we can do in psychiatry, but I think
25	research is obligated to go a step beyond that and see if we

			307 1	can better define the entities that we are addressing the
	2	therapy to.
	3		DR. LAUGHREN:  I guess the question from our
	4	standpoint is what is the best model for going after these
	5	different symptoms or diagnoses, and I think what I am 
	6	hearing from most of you is that although it might be
	7	reasonable to focus on a symptom like aggression, you don't
	8	view it in the same way that you might view a nonspecific

	9	symptom like pain or fever, that you would view it in the
10	context of a particular diagnosis, and not a nonspecific
11	symptom that has the same pathophysiology across diagnostic
12	entities in the same sense that you might think of pain as
13	having the same pathophysiology even though it is arising
14	out of a lot of different diagnostic entities.
15		DR. RIDDLE:  Yes, I think that is correct.  I

16	think we could have our cake and eat it, too, in terms of
17	what we are talking about if one was really interested in
18	targeting aggression.  It could be aggression in kids with
19	conduct disorder, or aggression in kids with a pervasive
20	developmental disorder, or aggression in kids with mental
21	retardation, or other examples.
22		I think one can always have a diagnosis to go

23	along with the aggression, but the target of the drug may be
24	the aggression within the diagnostic category.
25		Barbara, maybe that would satisfy or at least help

			308 1	somewhat you and the medical model, and I think one could
	2	also do that perhaps with psychotic symptoms.  There are
	3	quite a few diagnostic categories within the psychosis realm
	4	in the DSM, schizophrenia, schizophrenia form, psychotic
	5	disorder NOS, et cetera, et cetera.
	6		So, I think that there are ways we could have a
	7	diagnosis and still not narrow the field too much and get at
	8	some of these symptoms.
	9		DR. CHESNEY:  Dr. Nelson.
10		DR. NELSON:  But if you did that, are you thinking
11	of a stratification where you would have to do your power
12	analysis on the aggression, so that you have enough to
13	answer within each strata, the question as to whether you
14	have had an effect on the aggression, or do you want to lump
15	that all together?
16		DR. MALONE:  I would think you would be setting

17	one diagnostic category at a time.  So, for instance, if
18	were studying young mentally retarded children who had

19	severe aggression, and so they couldn't function, couldn't
20	go to preschool, that you would really be looking at that
21	symptom, perhaps other symptoms like hyperactivity, but you

22	would be looking at one symptom and one diagnostic category. 
23	I mean maybe several symptoms, but aggression would be one
24	of the key symptoms.
25		DR. CHESNEY:  Dr. Gorman.

			309 1		DR. GORMAN:  Is it the consensus that aggression--
	2	and I am using that because we are talking about it--is a
	3	final common pathway of a biological cascade, or do you
	4	think aggression is unique is each situation as fever is, it
	5	is a final common pathway for many things?  Is aggression
	6	unique in each disease, or is it the result of the cascade?
	7		DR. MALONE:  I would think it depends on the
	8	disease.  For instance, in mania, some patients get very

	9	aggressive, and if you treat the mania, their aggression
10	goes away, whereas, for instance, in conduct disorder, we
11	are not really treating conduct disorder itself basically
12	when we do our drug studies.  We are treating aggressive

13	behavior in conduct disorder, and we really target just the
14	aggression.
15		So, it really depends on whether the disorder
16	itself is causing the aggression, for instance, in some sort
17	of psychotic disorder, like mania or schizophrenia, some of
18	those patients have ideas or become very impulsive and get
19	aggressive, and if you treat the main disorder, their
20	symptoms go away.
21		Yet, there are other disorders like conduct
22	disorder, it is true that most of the symptoms of conduct
23	disorder are aggression, but when we are treating the
24	aggression, I don't think we are really treating the core
25	disorder, conduct disorder, we are really treating a

			310 1	symptom.  So, I think it really depends on the disorder.
	2		DR. CHESNEY:  Dr. Spielberg.
	3		DR. SPIELBERG:  The discussion sounds strangely
	4	reminiscent of some recent discussions we have had about
	5	cardiomyopathy.  I mean basically, you can get a
	6	cardiomyopathy from thyroid disease, you can get it from
	7	amyloidosis, you can get it from hemosiderosis, or you can
	8	get it from viral infections.
	9		So, if you treat the underlying condition, such as
10	the thyroid disease, the cardiomyopathy goes away.  Then,

11	you are left with a large number of patients whom we still
12	list as idiopathic, where you treat the symptoms of heart

13	failure with ACE inhibitors and beta blockers and diuretics,
14	or whatever else it is.
15		It sounds to me like we are saying with certain
16	very specific conditions where aggression is associated with
17	that disease, if you treat the disease, the aggression will
18	get better.  Manic depressive is a great example because we
19	have very specific therapies for that, at least in adults.
20		But then we are left with a group of kids, you

21	know, I used to follow a large number of kids with inborn
22	errors of metabolism, who were retarded and developed
23	aggression particularly around puberty, and the break point
24	there was pharmacotherapy or institutionalization.  These
25	were truly life-threatening conditions where the aggression

			311 1	regardless of the etiology was the primary driver for what
	2	would happen in that child and family's life.
	3		In those circumstances where we don't understand
	4	etiology, just like we treat the symptoms of cardiac
	5	failure, is there a final commonality there, is there a way
	6	of grouping patients to be able to study that?
	7		DR. MALONE:  That is one of the things in our
	8	studies that we are trying to do, but there is only mainly
	9	lore about that.  For instance, same conduct disorder.  You
10	can think of--well, actually, Dr. Vitiello has written about
11	this--you can think of two major categories of aggression. 
12	One would be more impulsive/explosive aggressive behavior or
13	affectively charged aggression, and the other type would be
14	more planned aggression.  You know, if you watch the
15	Sopranos, you see a lot of planned aggression.
16		The idea would be that you could treat with
17	medication the affectively charged type of aggression, but
18	that if you give somebody who plans on doing things
19	medication, they will still continue to do those things.
20		So, there are some gross subtypings, but they are
21	not really that well worked out, and we don't have extremely
22	good measures for determining whether you are in one

23	category or another.  Actually, in fact, probably many
24	people with conduct disorder have both types.  They plan
25	some things, and some things are spur of the moment.

			312 1		DR. SPIELBERG:  I think what we are really all
	2	struggling over, I think we are all saying the same thing,

	3	we are concerned about these kids, we are concerned about
	4	their families, we are concerned about the societal
	5	consequences.  If you had to pick a serious and life-
	6	threatening illness, this outdoes childhood cancer
	7	considerably in terms of numbers.
	8		The issue, though, is how do we study it.  At the
	9	October meeting, I think we are going to have to come to

10	grips with what kind of study designs are reasonable, what
11	kind of drugs are reasonable, and then get on with the
12	business of trying to study the kids, and actually get some
13	data.
14		DR. MALONE:  Amazingly enough, I think it is quite
15	an understudied area, and I think there are so many things
16	that go into, for instance, having a conduct disordered
17	child be aggressive that it is hard to know all of them, you
18	know, the environment, the family situations, and biology. 
19	So, there are all these things going on at the same time,

20	and, you know, for instance, I think, it is just my
21	impression, you know, we have done inpatient studies where
22	the setting is very controlled, and now we are doing
23	outpatient studies.
24		In our studies, you go through a placebo period,
25	and if you are not showing the aggression during the

			313 1	baseline washout period, you don't get into our study.  I
	2	think that was much easier in the inpatient study where we
	3	would then end up with one certain subtype of patient to
	4	show that a medication will work than it would in an
	5	outpatient setting.
	6		I don't know that medications are the total answer
	7	for aggression.  I think there is a lot of psychosocial and
	8	other work that needs to go on before we can learn how to
	9	treat aggression.
10		DR. CHESNEY:  Dr. Laughren and Dr. Murphy, has
11	this group of people given enough input in terms of the
12	three questions, or are there still issues you would like to
13	have to discuss?
14		DR. LAUGHREN:  Let me take a stab at summarizing
15	what I have heard, and see if there is any consensus on
16	this.
17		Basically, in terms of the three entities that we
18	have targeted under written requests - major depressive
19	disorder, OCD, and GAD, what I am hearing is that the age
20	cut-offs that we have been using are reasonable, that there
21	is no compelling reason to go below age 6-7 in terms of
22	those diagnostic entities.
23		For schizophrenia and for panic disorder, it
24	probably makes sense to look into adolescents, but no below
25	at this point.  Then, my sense is that for almost everything

			314 1	else, it is still perhaps too murky for us to be taking any
	2	definitive actions under either the written requests or the
	3	Pediatric Rule.  In terms of even looking at ADHED under 6,
	4	we might best wait until we see more of the results from the
	5	PATS study before we proceed in that area.
	6		Conduct disorder is an interesting, obviously
	7	important problem, but not so clear that there is any
	8	compelling reason for us under our existing tools to be
	9	forging ahead.
10		There doesn't seem to be a consensus at this point
11	that the nonspecific symptom approach makes a lot of sense
12	at this point at least in terms of again these tools that we
13	have before us.  It doesn't make sense for FDA to be taking
14	the lead in encouraging studies when there is so much I
15	think uncertainty about what is the right way to go.
16		In terms of autism, again, obviously, there is a
17	lot of work that needs to be done.  It is not so clear that
18	it is ready again for FDA to be encouraging drug development
19	with the current drugs that we have.
20		Dr. Vitiello pointed out that there is no clear
21	rationale for going forward with those kinds of programs
22	with the drugs that we have, at least in terms of FDA taking
23	the lead in encouraging that.
24		DR. CHESNEY:  Dr. Kauffman.
25		DR. KAUFFMAN:  I just wanted to ask Dr. Laughren,

			315 1	having said what you just said, and given that you would not
	2	take the lead in a couple of these diagnoses, for example,
	3	autism or conduct disorder, would that have an impact on
	4	what you would necessarily do if a sponsor took the
	5	initiative on one of these indications that at this point in
	6	time we don't feel that the FDA should take an initiative

	7	on?  In other words, if a company came to you with a new
	8	chemical entity that they said we would like to try this in
	9	autism, would you listen to them, or would you say we don't
10	think that is something we really want to focus on right
11	now?
12		DR. LAUGHREN:  I agree, that is an entirely
13	different question.  Of course, we would listen, but we
14	would caution them that it is a new area, and we don't have
15	any precedence, and we would have to rely on the advice of
16	outside experts.  Of course, we would listen and would be
17	interested in what they proposed.

18		DR. MURPHY:  I think the quandary here, as you are
19	well aware, is that is why we bring some of these issues
20	forward for public discussion, is that they may also ask us
21	to issue a written request, so that they may gain the six

22	months of exclusivity, because they think there is a need.
23		DR. KATZ:  We did that with the sleeper, with the
24	insomnia.
25		DR. MURPHY:  Right.  So, that is clearly one of

			316 1	the goals we wanted to hear the discussion, because as Tom

	2	has laid out, this is what we are doing right now, this is
	3	what we have heard from you, that we think we should do in

	4	the meantime while we continue to get inquiries into various
	5	areas of a possible study.
	6		DR. CHESNEY:  Dr. Riddle, the last word.
	7		DR. RIDDLE:  I think your summary was very
	8	accurate.  I think the only additional comment is that it

	9	concerns me with the new neuroleptics that are coming onto
10	the market, and the concern we have about the impact of

11	chronic neuroleptics in kids, that given what you said, I
12	think the only studies that would then be done would be with
13	adolescents with schizophrenia, and yet there is so much
14	prescribing going on for conduct disorder or aggression and
15	other "psychotic" symptoms, that it leaves me wishing that
16	you could push that envelope a bit whether it is conduct

17	disorder or something besides adolescent schizophrenia.
18		DR. LAUGHREN:  I am going to encourage Ben under
19	his authority at the NIMH to promote those kinds of studies
20	to look at safety.
21		DR. VITIELLO:  We will try.
22		DR. MURPHY:  I think that is why we are
23	participating in this research meeting, is that we would

24	hope that we can hear some more discussion about how this
25	field can be moved forward.

			317 1		DR. CHESNEY:  As you all know, Memphis is the

	2	Northwest hub, and Northwest prides itself on an on-time
	3	departure, and as a "Memphian," I note that it is 5:25.

	4		I wanted to thank Dr. Laughren, Dr. Malone, Dr.
	5	Riddle, and Dr. Vitiello very, very much for educating us
	6	all and for responding to the questions on our behalf.
	7		Tomorrow's meeting starts at 8 o'clock.
	8		Thank you.
	9		[Whereupon, at 5:25 p.m., the proceedings were
10	recessed, to resume at 8:00 a.m., Tuesday, September 12,
11	2000.]
12