1
		DEPARTMENT OF HEALTH AND HUMAN SERVICES

		FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH
					THE PEDIATRIC SUBCOMMITTEE

OF THE ANTI-INFECTIVE DRUGS ADVISORY COMMITTEE (AIDAC)
						IN JOINT SESSION WITH
			THE PREGNANCY LABELING SUBCOMMITTEE

OF THE ADVISORY COMMISSION FOR REPRODUCTIVE HEALTH DRUGS
				Tuesday, September 12, 2000

									1:00 p.m.
Hyatt Regency Bethesda One Metro Center
							Bethesda, Maryland

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

Robert Fink, M.D. Susan Fuchs, M.D. Barbara Geller, M.D. 
Richard Gorman, M.D., FAAP Mark Hudak, M.D.

	Naomi Luban, M.D.
Robert Nelson, M.D., Ph.D. Victor Santana, M.D.
GUESTS AND GUEST SPEAKERS
Ralph Kauffman M.D.
Steven Spielberg, M.D., Ph.D. Robert Ward, M.D., FAAP, FCP

			THE PREGNANCY LABELING SUBCOMMITTEE
MEMBERS
Michael Greene, M.D. (Chair)
	Bonnie Dattel, M.D.
SGE CONSULTANTS
Elizabeth Andrews, Ph.D., MPH Elizabeth Ann Conover, M.S.

	Patrick Wier, Ph.D.
	Katherine L. Wisner, M.D.
GUESTS AND GUEST SPEAKERS
Philip O. Anderson,, Pharm.D., FASHP
	Cheston Berlin, M.D.
	Jan M. Friedman, M.D., Ph.D.
	Gideon Koren, M.D.
	Julia Scott, R.N. (Consumer Representative)
FDA
	Holli Hamilton, M.D., MPH

Dianne Kennedy, R.Ph., MPH Sandra L. Kweder, M.D. Dianne Murphy, M.D.

					3
C O N T E N T S
Call to Order/Introductions, P. Joan Chesney, M.D.		4
			Michael Greene, M.D.
Conflict of Interest Statement,
	Jayne Peterson, R.Ph., J.D.		7
Background Information and Overview,
	Sandra Kweder, M.D.			9
American Academy of Pediatrics Perspective
	on Breastfeeding, Cheston Berlin, MD	14
Counseling Nursing Mothers,
	Philip O. Anderson, Pharm.D., FASHP, FCSHP	19
Drug Therapy during Lactation: A Maternal and
	Pediatric Issue Requiring Research,
	Robert M. Ward, M.D., FAAP, FCP	31
Subcommittee Questions for Speakers	41
Current Requirements for Providing Information
	in a Product's Labeling on Drug Use during
	Lactation,
	Holli Hamilton, M.D., MPH		58
Open Public Hearing:
	Dr. Sumner Yafee			81
Subcommittee Discussion of Questions	88

				4 1		         P R O C E E D I N G S
	2			Call to Order
	3		DR. CHESNEY:  I just wanted to tell you that in

	4	the "Science" section of The New York Times this morning
	5	there was a full-page article about these meetings and the
	6	pediatric initiative at the FDA, including a picture of Dr.
	7	Murphy.  So, if you haven't bought your New York Times yet,
	8	you might want to get a copy of that.

	9		DR. MURPHY:  Joan, somebody pointed out to me that
10	they promoted me in this article.  So, I wish to deny the
11	promotion -- it is not true.
12		DR. CHESNEY:  I think we are ready for this
13	afternoon's sessions on infants as the recipient of drugs by
14	way of breast milk, another route of delivery, and we will
15	start by having introductions, and I think we will start on
16	the left hand side with Dr. Murphy.
17		For those of you who haven't been here the last
18	day and a half, the green button on the microphone is what
19	turns it on and off, and please be sure to give your name if
20	you are making a comment or asking a question.  So, we will
21	start with the identification first.
22		DR. MURPHY:  I am Dianne Murphy.  I am an
23	Associate Director for Pediatric at CDER.
24		DR. HAMILTON:  Holli Hamilton, Pregnancy Labeling
25	Team.

					5 1		MS. KENNEDY:  Dianne Kennedy, Pregnancy Labeling
	2	Team.
	3		DR. ANDERSON:  Phil Anderson, University of
	4	California, San Diego, Drug Information Service.
	5		DR. BERLIN:  Cheston Berlin, Pennsylvania State
	6	University College of Medicine, at the Hershey Medical
	7	Center.
	8		DR. ANDREWS:  Elizabeth Andrews, Director of
	9	Epidemiology at Glaxo Wellcome.
10		DR. WIER:  I am Patrick Wier.  I am a preclinical
11	scientist with SmithKline Beecham Pharmaceuticals.
12		DR. GREENE:  I am Mike Greene.  I am the Director
13	of Maternal/Fetal Medicine, Massachusetts General Hospital,
14	Harvard Medical School.
15		DR. CHESNEY:  Joan Chesney, Infectious Diseases at
16	the University of Tennessee Memphis, and also in academic
17	programs at St. Jude.
18		DR. PETERSON:  I am Jayne Peterson.  I am the
19	Executive Secretary of both the Pregnancy Labeling
20	Subcommittee and the Pediatric Subcommittee, with FDA.

21		DR. NELSON:  Skip Nelson.  I am a pediatric
22	critical care physician at the Children's Hospital of
23	Philadelphia.

24		DR. GORMAN:  Richard Gorman, general pediatrician
25	in private practice in suburban Maryland.

				6 1		DR. O'FALLON:  Judith O'Fallon, Biostatistics,
	2	Mayo Clinic.
	3		DR. RODVOLD:  Keith Rodvold, Professor of Pharmacy
	4	Practice, Colleges of Pharmacy and Medicine, University of
	5	Illinois at Chicago.
	6		DR. GELLER:  Barbara Geller, Professor of
	7	Psychiatry, Washington University in St. Louis.
	8		DR. DANFORD:  I am Dave Danford, I am a pediatric
	9	cardiologist at the University of Nebraska Medical Center
10	and Creighton University Omaha.
11		DR. FUCHS:  Susan Fuchs, pediatric emergency
12	medicine physician, Children's Memorial Hospital, Chicago,
13	Illinois.
14		DR. HUDAK:  Mark Hudak, Neonatology, University of
15	Florida, Jacksonville.
16		DR. FINK:  Bob Fink, pediatric pulmonologist at
17	Children's Hospital, Washington, DC.
18		DR. LUBAN:  Naomi Luban, pediatric hematologist-
19	oncologist, Children's Hospital, Washington, DC.
20		DR. SPIELBERG:  Steven Spielberg, head of
21	pediatric drug development at Johnson & Johnson,
22	representing PhARMA.
23		DR. KAUFFMAN:  Ralph Kauffman, Pediatrics and

24	Pharmacology, University of Missouri, Kansas City and
25	Children's Mercy Hospital.

			7 1		DR. WARD:  Bob Ward, neonatologist, University of
	2	Utah and chair of the Academy of Pediatrics committee on
	3	drugs.
	4		DR. CHESNEY:  Jayne Peterson, the executive
	5	secretary, will now read the conflict of interest statement.
	6		     Conflict of Interest Statement
	7		DR. PETERSON:  The following announcement
	8	addresses the issue of conflict of interest with regard to

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

20	statement may be obtained by submitting a written request to
21	the agency's Freedom of Information Office, Room 12A-30 of
22	the Parklawn Building.
23		With respect to FDA's invited guests and guest
24	speakers, Dr. Philip Anderson, Dr. Cheston Berlin, Dr. Ralph
25	Kauffman, Dr. Gideon Koren, Dr. Steven Spielberg and Dr.

			8 1	Robert Ward have reported interests which we believe should
	2	be made public to allow the participants to objectively
	3	evaluate their comments.
	4		Dr. Anderson would like to disclose that he owns
	5	stock in Amgen, Ivax, Cell Genesys and Medimmune; and
	6	receives consulting fees from TAP Pharmaceuticals and Astra.
	7		Dr. Berlin would like to disclose that he is a
	8	researcher through a contract with Medeva; receives
	9	consulting fees from Medeva, Pfizer, Merck and Ascent; and
10	receives speaker fees from 3M.
11		Dr. Kauffman would like to disclose that he has

12	grants with Bristol-Myers Squibb, is involved in research
13	for Bristol-Myers Squibb, Astra, Zeneca, Janssen, Merck,
14	R.W. Johnson and Adventis, and is a scientific adviser for
15	Bristol-Myers Squibb, Johnson & Johnson and Purdue Pharma.
16		Dr. Koren would like to disclose that he is a

17	researcher for Duchemay Ltd, and receives consulting fees
18	and speaker fees for Duchemay Ltd.
19		Dr. Spielberg would like to disclose that he is an
20	employee of Johnson & Johnson.
21		Dr. Ward would like to disclose that he owns stock
22	in Ascent Pediatrics and Viropharma; has grants with Wyeth-
23	Ayerst, Novardis, Ascent Pediatrics, Adventis Pharmaceutical
24	and Sepracor.  He receives consulting fees from Janssen

25	Pharmaceutical and is a scientific adviser for McNeil

			9 1	Consumer Products.
	2		In the event that the discussions involve any
	3	other products or firms that are already on the agenda for
	4	which an FDA participant has a financial interest, the
	5	participants are aware of the need to exclude themselves
	6	from such involvement and their exclusion will be noted for
	7	the record.
	8		With respect to all other participants, we ask in
	9	the interest of fairness that they address any current or

10	previous financial involvement with any firm whose product
11	they may wish to comment upon.
12		DR. CHESNEY:  Thank you.  Does anyone have
13	anything else to declare?
14		[No response]
15		We will move on to our first speaker, Dr. Sandra
16	Kweder, who is the Acting Director of the Office of Drug
17	Evaluation IV, FDA, and is going to provide us with some
18	background information and an overview.
19		  Background Information and Overview
20		DR. KWEDER:  Good afternoon to you all.  I don't
21	have any slides.  I am just going to try and put a little

22	bit of a framework of why we are here today, and then let us
23	move on to some of the speakers.
24		Let me start with telling you a little bit, for

25	those of you who don't know, about how we actually came to

			10 1	organizing this meeting.  We have two initiatives at FDA
	2	that converge at this issue.  One is our pediatrics
	3	initiative, which those of you on this side of the room are
	4	very familiar with.  The purpose of that initiative is to
	5	change the way we do business and try to facilitate and
	6	encourage the study of safety and efficacy of drugs in
	7	children.
	8		We have another initiative, our pregnancy labeling
	9	initiative, that the people on this side of the table are
10	familiar with.  Through that initiative we have been
11	dedicated to improving the information available in product
12	labels on appropriate use of drugs in pregnancy.
13		Interestingly, for those of you who don't know
14	that, these two initiatives that have their own independent
15	staffing both happen to be housed in the Office of Drug

16	Evaluation IV, of which Dr. Murphy is the Office Director
17	and I am the Deputy Director.  So, it has been very
18	convenient.
19		But, historically, lactation has always been an
20	issue at the FDA that has run sort of pari passu or in
21	keeping with the pregnancy section of labels.  If you pick
22	up a package insert for any given product, the lactation

23	section follows the pregnancy use section.  That makes some
24	sense.  You know, the focus on the pregnant woman and her
25	use of a particular medicine and its effect on her

			11 1	developing fetus could change at any moment to a lactating

	2	woman taking the same medicine and possible risk to her now
	3	newborn.
	4		Well, as we have gotten involved in trying to
	5	frame what the pregnancy section of labeling ought to look
	6	like, we have rolled up our sleeves and tried to develop a
	7	new framework for that.  Holli Hamilton will give you a
	8	little later, for those of you who aren't familiar with it,
	9	an overview of what we are thinking in that area.  So, I
10	won't dwell on it.

11		But, we held a meeting with the Pregnancy Labeling
12	Advisory Committee on this framework about a year ago to
13	just get some general concepts on the table.  Following that 
14	meeting, we had a very thoughtful letter sent to us by Dr.

15	Phil Anderson, who is here today, that said, "wait a minute,
16	folks.  You know, you're talking about revising this section
17	of the label, well, this section of the label has always

18	included lactation and things are pretty much in a woeful
19	state and you're going to have to confront this.  How can I
20	help?"  So, that is why we are here today, to try to get
21	your help on this.
22		Before we can address what lactation sections of
23	product labels should look like, we need to examine what

24	exists now a little bit.  We won't dwell on that, although
25	Holli is going to provide you with some examples that will

			12 1	probably be familiar to most of you.  More importantly, we
	2	need a sense from you, as clinicians out there seeing
	3	patients and teaching, what is important in this section of
	4	the label; what is the science that is important; and, what
	5	clinically is important.  So, we are seeking your guidance
	6	on the needs of practicing clinicians and, most importantly
	7	for now, what are the scientific issues underlying that that
	8	we need to begin to address.
	9		I would like to emphasize one point.  The purpose
10	of this meeting today is not to ask you whether FDA should
11	require studies of drugs in lactation under the Pediatric
12	Rule or as part of a requirement for marketing exclusivity. 
13	That is a question that people have asked me and I just want
14	to put it right on the table -- that is not what we are here
15	to talk about today.
16		Those of you around the table are mostly
17	clinicians and scientists of other types.  This is only the
18	beginning.  Ultimately, we are going to need to hear from
19	other groups, particularly patient groups or women who often
20	feel very much alone in making decisions about medicines and
21	breastfeeding.  So, as we move forward in thinking about
22	what that section of the label will look like, we are going
23	to have to seek input from those groups as well,
24	particularly in the areas of language.
25		So, unless there are any questions, I am going to

				13 1	thank you again for being here.  I really look forward to
	2	your discussion.  I know it is a big group which tends to
	3	make things a little difficult but we have two very capable
	4	chairs.  I think we should be covered.
	5		DR. CHESNEY:  Thank you, Dr. Kweder.  I wonder if
	6	we could ask everybody on this side of the table that wasn't
	7	here before to introduce themselves, and I think Dr. Berlin
	8	was the last person to introduce himself and Dr. Andrews
	9	started it up again.  So, if everybody else, in order, could
10	tell us who you are and where you are from?
11		MS. SCOTT:  Julia Scott, president of National
12	Black Women's Health Project, and I am the consumer
13	representative guest.
14		DR. FRIEDMAN:  I am January Friedman.  I am
15	Professor of Medical Genetics at the University of British
16	Columbia, currently on sabbatical at CDC.
17		DR. KOREN:  I am Gideon Koren.  I am Professor of
18	Pediatrics Pharmacology and Medicine at the University of

19	Toronto.
20		DR. DATTEL:  Bonnie Dattel, Professor of
21	Obstetrics and Gynecology, Maternal-Fetal Medicine, Eastern
22	Virginia Medical School.
23		DR. WISNER:  Kathy Wisner, from Cleveland.  I am
24	Professor of Psychiatry and Reproductive Biology at Case

25	Western Reserve.

			14 1		DR. CHESNEY:  Thank you very much.  Our second
	2	speaker is Dr. Cheston Berlin, who is at the Hershey Medical
	3	Center, the Penn State University College of Medicine, and
	4	he is going to provide us with a perspective on
	5	breastfeeding from the American Academy of Pediatrics.
	6	American Academy of Pediatrics Perspective on Breastfeeding
	7		DR. BERLIN:  The interest of the American Academy
	8	of Pediatrics in this whole topic arose in the early '80s,
	9	and culminated in the preparation of the initial statement
10	in 1983 of the transfer of drugs and chemicals in human
11	milk.  This statement was revised in 1989 and in 1994.  The
12	current revision was submitted to the Committee on Drugs in
13	May of 1999, and Dr. Robert Ward, who is here, is currently
14	shepherding that through the rather increasingly complicated
15	processes of the Academy.  These statements require a lot of
16	review effort by different organizations within the Academy,
17	and we are hopeful that this will see the light of day soon.
18		The reason for the statement encompassed two
19	issues and I want to be sure that I mention these both to
20	you.  One is to inform the clinician of the possible risk to
21	the nursing infant but of equal importance, I think, is to
22	permit the necessary treatment of maternal illness without
23	necessarily the interruption of breastfeeding.
24		The initial statements and revisions, particularly
25	the revisions, were intended to be as comprehensive as

			15 1	possible and to rely on published primary data.  The first
	2	statement, in 1983, if reviewed, will show a substantial

	3	number of references to two things, one, the Physician's
	4	Desk Reference and, secondly, "personal communication." 

	5	These references have been omitted in subsequent statements
	6	because it was not felt by the committee that this
	7	represents a primary data source.
	8		We continue to recognize that most current reports
	9	of the excretion of drugs in human milk rely exclusively on
10	either single case reports or an N of a very small number. 
11	In addition, some of these reports lack drug measurement in
12	body fluids in either the infant of the mother and rely on
13	anecdotal evidence of clinical effect.
14		The statements in labeling are not helpful.  Just
15	to give you an example, "the clinical should exercise
16	caution."  I don't know what that means.  The other one that
17	I see a lot is that "this drug should not be given to
18	nursing mothers, or mothers who take this drug should not

19	nurse."  The alternative which we like to push is that this
20	drug is, we think, safe for nursing mothers and both
21	maternal therapy and nursing can continue together.
22		Some recommendations for acquiring data for more
23	precise labeling of drug therapy would include the
24	following, and this is not intended to be an inclusive list
25	but just some of the ideas that we have discussed in the

			16 1	Committee on Drugs of the American Academy of Pediatrics:
	2		The measurement of drug disposition in the mother
	3	and, when possible, in the infant in both acute and chronic
	4	therapy -- I want to emphasize the importance of chronic
	5	therapy.  It is one thing to be concerned about the transfer
	6	of drugs for the treatment of a headache or an acute attack
	7	or asthma as opposed to a mother who may be taking a drug

	8	for months and, indeed, for years for a hormonal condition
	9	or increasingly for a psychiatric indication.
10		It should be assumed that any drug that can be
11	used in women can and may be taken during lactation and

12	should have necessary labeling.
13		Consider all routes of administration, including
14	dermal, respiratory routes and transmucosal.  Some of these
15	so-called non-traditional routes are becoming very popular
16	routes for drug administration, and we have yet to learn

17	completely whether or not these routes may transmit into
18	excretion into milk.
19		Consider the possible effects of excipients, that
20	is, the non-active drug ingredients in any formulation,
21	whether it be solid or liquid.
22		Single-study subjects should be avoided.  A series
23	which would provide statistical significance with
24	longitudinal studies involving the same mother should be
25	used to acquire data of the possible changes in drug

			17 1	excretion over the entire period of lactation.
	2		Issues of the mode of collection are also
	3	important.  Do you take individual samples?  Do you have to
	4	pump an entire nursing supply, so to speak?  Emptying the
	5	breast with a mechanical device is extremely artificial, and
	6	possibly the best physiological way to study particularly

	7	quantitative aspects of drug administration is to use what
	8	is called test weighings, that is, weigh the infant before

	9	and after nursing and then take a sample of milk at multiple
10	times during the nursing period.
11		It is very possible that maternal drug metabolism
12	may change during the lactation period.  We have very little
13	data on this -- whether or not a mother who nurses for 6

14	months or 12 months may have different aspects than the
15	mother who nurses just a short period of time.  With the
16	recent emphasis of the American Academy of Pediatrics for
17	human milk being the sole milk for the first 12 months of

18	life, this is an increasingly important piece of information
19	to get.
20		Infant sampling should be very strongly considered
21	in the evaluation of any labeling issue.  Very minimal
22	amount of blood is now necessary for multiple analyses.  The
23	collection of urine does give some data concerning drug
24	exposure but may not provide pharmacodynamic data.
25		Special consideration needs to be given to the

			18 1	issue of psychotropic drugs.  These drugs characteristically
	2	have a very long half-life and their metabolites may have an
	3	even longer half-life.  It may be necessary to observe
	4	infants for a prolonged period of time, perhaps years, to
	5	determine whether or not there has been any neurodevelopment
	6	that will have an effect on the infant by the transfer of
	7	psychotropic drugs during lactation and, indeed, also during
	8	pregnancy.
	9		Many drugs taken by the nursing mother are over-
10	the-counter drugs and/of off-patent drugs.  A consideration
11	should be given to labeling this group of drugs, as well as
12	drugs under patent and currently being developed.
13		A special comment about environmental compounds,
14	these are frequently very lipophilic, with very small or
15	undetectable plasma concentrations in the mother.  Pregnancy
16	and lactation may be the only two ways that these drugs are
17	mobilized from lipid tissue.  This may not be a frequent

18	concern in drug labeling, but there are potentially some
19	compounds which could be transferred in minute quantities
20	and stored for a prolonged period of time in the infant's
21	lipid tissues.  Some of these compounds have been studied
22	using pooled samples of maternal milk, and this should be
23	avoided.  It is also important to recognize that these

24	environmental compounds may have regional differences in
25	distribution within the United States.

			19 1		I think with the emphasis on the collection of
	2	data on drug concentration in both mother and child,
	3	observation of possible clinical effect, prolonged follow
	4	up, it is possible to improve under current labeling status
	5	of drugs during lactation.  It is important to protect the

	6	infant from the untoward effects of maternal ingestion of
	7	drugs, but it also is important not to deprive lactating
	8	mothers of necessary drug treatments.
	9		Thank you for this opportunity to make this
10	presentation.

11		DR. CHESNEY:  Thank you, Dr. Berlin.  I think we
12	are going to have time for questions after we hear from the
13	next two speakers.  Dr. Philip Anderson is speaking next. 
14	He is Director of the Drug Information Service for the UCSD
15	Medical Center, and he is going to speak to us about
16	counseling nursing mothers.
17		       Counseling Nursing Mothers
18		DR. ANDERSON:  Well, part of my role as Director
19	of the Drug Information Service -- having been identified as
20	somewhat of an expert in this area, I get a lot of calls on
21	drugs and breastfeeding, about a thousand a year and 20

22	percent of those are from health professionals, about 80
23	percent are from nursing mothers.
24		[Slide]
25		After having done this for 20-plus years, I would

			20 1	have to say that I would agree with Dr. Scialli that the

	2	label at this point is one of the biggest impediments to
	3	giving good information, and causing the most confusion
	4	among both prescribers and nursing mothers.  So, I would
	5	like to talk a little bit about the impact of this poor
	6	quality of information.
	7		[Slide]
	8		With the Health People Initiative, as probably

	9	most of you know, sponsored by a number of federal agencies
10	and non-governmental organizations, the goals for
11	breastfeeding were first put forth in 1990, and you can see
12	that by 1998 we still haven't reached the 1990 goals, and
13	the 2010 goals are, you know, beyond this.
14		[Slide]
15		The use of drugs during lactation I think is one
16	of the reasons why we are not meeting these goals.  It is
17	certainly not the only one, and maybe not the largest one
18	but it does have an impact.  You can see that several
19	studies that have been done -- none in the United States so
20	far but in many other countries, almost every mother gets a
21	medication during the first month.  In Norway, it was found
22	that at 4 months postpartum 17 percent of mothers had taken
23	a drug in the last 2 weeks, and in 2 very different

24	countries it was found that 5 percent of nursing mothers are
25	taking medications chronically.

			21 1		[Slide]
	2		I didn't know Dr. Koren would be here but I have a
	3	number of slides from his group.  They looked at two groups
	4	of mothers.  One group essentially was taking medications
	5	and one group was not.  They were nursing mothers.  And, you
	6	can see that by one year there was a tremendously different
	7	rate of dropout from nursing among the mothers who were
	8	taking medication and those who were not.  The main reason

	9	that was stated by the mothers was the lack of reassurance
10	by prescribers of this being a safe practice.
11		[Slide]
12		Dr. Ruth Lawrence has done a review of 60 anti-
13	hypertensive drugs, looking at various sources -- the

14	American Academy of Pediatrics lists, Briggs' textbook,
15	Hale's textbook, a local database at Rochester, and the
16	Physician's Desk Reference.
17		You can see that most of the specialty sources
18	recommend that many of these are okay to use during

19	breastfeeding, and the PDR is overwhelmingly to stop nursing
20	and the other ones are this vague cautious warning, which

21	almost leaves the impression that it is really not a safe
22	thing to do but if you want to do it, go ahead anyway.  So,
23	there is really a big disconnect between the labeling
24	currently and more expert opinion.
25		[Slide]

			22 1		I thought one way to kind of get a handle on this
	2	is to look at all of the published literature on adverse
	3	reactions during breastfeeding.  We looked at published
	4	studies, and this part is not quite done yet so there may be
	5	a few more here, but there are only 14 controlled studies
	6	that we could find.
	7		Six of them were on oral contraceptives, and the
	8	primary finding there was that estrogen-containing
	9	contraceptives tend to suppress lactation and cause a
10	dropout rate from nursing.
11		Three are on narcotics, mostly comparing two
12	different narcotics, showing that malperidine is a problem.
13		There are three on povidone iodine, as well as a
14	number of case reports showing that it can cause thyroid

15	suppression; one on fluoxetine that we did at UCSD, showing
16	that the infants of mothers who are nursing, while taking
17	fluoxetine, didn't gain weight at the same rate during the
18	first six months as a control group; and one on mesalamine
19	which found no difference between placebo in terms of side

20	effects.  There were also three observational studies, and I
21	will talk about one of those in a moment.
22		[Slide]
23		The case reports were probably the most
24	interesting part of this.  We only found 79 publications
25	worldwide in all languages.  Most were published since 1950. 

			23 1	These 79 studies reported 88 infants, and there were only 2
	2	very questionable deaths, a methadone which was a postmortem
	3	analysis that found methadone in the serum but there was

	4	really no cause and effect relationship reported, and an
	5	overlying death, the mother was taking phenytoin and
	6	phenobarbital and it was thought that perhaps the baby was
	7	sedated enough that it didn't struggle when the parent
	8	rolled over on it.

	9		[Slide]
10		The most striking finding was the age of the
11	infants reported.  You can see that the vast majority of
12	babies were under 2 months of age that had side effects

13	reported.  In fact, after 6 months, it is very unlikely that
14	a baby will have a side effect from a drug and
15	breastfeeding.
16		[Slide]
17		Now, the classes of drugs that were most commonly
18	reported are here, and you can see that half of the drugs

19	are drugs that cause central nervous system depression.  Of
20	course, this is primarily in the first month.  So, that

21	seems to be a high risk time that needs to be looked at
22	closely.
23		The next 25 percent were drugs that primarily
24	caused gastrointestinal upset, nothing really very serious,
25	and then the rest were just one or two case reports here and

			24 1	there.
	2		[Slide]
	3		This is fairly consistent with what was found by

	4	Motherisk.  In a telephone follow-up of 838 infants, they
	5	found no major adverse reactions, defined as having to seek
	6	medical advice.  There were minor reactions in 11 percent,
	7	but this probably represents some over-reporting because
	8	they basically took what the mother said.  If they reported
	9	that there was diarrhea, they took it as such and as being
10	drug related.  So, there was no control group.  So, this is
11	probably higher than really happens.
12		With antimicrobials there were side effects in 19
13	percent of the infants, with diarrhea being the most
14	prominent, but it is about 12 percent.  Similarly, down the

15	list, analgesics and narcotics, about 11 percent of the time
16	there were side effects reported; antihistamines, 9 percent;
17	and CNS depressants cause drowsiness.
18		[Slide]
19		One thing that people have been trying to do is
20	come up with some standard scheme for assessing the exposure
21	of the infant, looking at the pharmacologic side effects,
22	and there are two or three systems that have been reported. 
23	The most commonly used one is the weight-adjusted percentage
24	of the maternal dosage.  It is fairly simple, the dose of

25	the infant would get during 24 hours of breastfeeding on a

			25 1	milligram per kilogram basis, divided by the mother's daily
	2	dosage times 100.
	3		This was prominently brought forth by the World

	4	Health Organization group that was put together to come up
	5	with a treatise on this topic.  They felt that drugs that
	6	are less than 10 percent of the maternal dosage that the

	7	infant would get are acceptable, with a caution range of 10-
	8	25 percent of the maternal dosage, and it was unacceptable
	9	drug if it was 25 percent of the maternal dosage or greater;
10	if there was some inherent toxicity such as a cancer
11	chemotherapy agent, or that there were credible reports of
12	toxicity in nursing infants.
13		Well, Dr. Bennett went through this book after it
14	had been published, in the second edition, and looked at 205
15	drugs in this book and found that 87 percent of the drugs
16	were below 10 percent.  Another 10 percent were in the
17	cautious range of 10-25 percent, and only 3 percent were
18	greater than 25 percent.  Now, it is interesting that in the
19	book the reported side effects increased as the percentage
20	increased so that in this 3 percent of drugs, each of them
21	had at least one reported side effect.  It doesn't mean that
22	every time you give it there is a side effect, but there was
23	a reported side effect.  So, there seems to be a correlation
24	there.
25		[Slide]

			26 1		Taking this one step further, people have tried to
	2	make a correlation between infant plasma levels and maternal
	3	plasma levels.  That is a little bit more direct, and maybe
	4	one step close to what you would like to know.  Essentially,
	5	the definition is weight-adjusted for percentage of maternal
	6	dose divided by some measure of the clearance.
	7		[Slide]
	8		Begg et al., from Australia, have put together a

	9	classification system that is quite similar.  If it is less
10	than 10 percent of the maternal plasma level it is probably
11	considered safe.  The risk here is a wider range, 10-50

12	percent, and it is not advisable if it is greater than 50
13	percent, and it is contraindicated if there is a potential
14	toxicity and, again, cancer chemotherapy is the best
15	example, on in G-6-PD-deficient infants for those drugs that
16	cause hemolysis.
17		[Slide]
18		Although I like this system for two reasons,
19	because it is a little bit more pharmacokinetically
20	appealing and it also breaks groups down by infant age, the
21	problem is that clearances haven't been measured on most
22	drugs for all these different age groups.  So, they somewhat
23	arbitrarily just divided the adult clearance by a factor to
24	come up with the estimated infant clearance.  So, it kind of
25	throws another variable into the whole thing.  It kind of

			27 1	adds pluses and minuses to the system.
	2		[Slide]
	3		Again, the Motherisk people have come up with a
	4	system called the exposure index, and actually it is based
	5	not on measurements of infants but just on the physical
	6	chemical properties of the drug.  That is one way to measure
	7	the dose, and then just use the adult clearance.  If you
	8	look at their paper for 86 drugs, they again found, somewhat
	9	coincidentally, 87 percent of drugs were less than 10 
10	percent for the exposure index.  It also provides basis for
11	a nice screening method because they found that no drug that
12	had a clearance faster than 5 ml/minute/kg ever fell in the
13	greater than 10 percent range -- so, high clearance; low
14	exposure for the infant.
15		[Slide]
16		This is the graph that shows how the 5 and the 10
17	clearance came out there.
18		[Slide]
19		Another feature that is rarely discussed is drugs
20	that actually interfere with lactation, and that is an

21	important part of the label that needs to be included.
22		[Slide]
23		Of course, all dopaminergic agents, such as
24	bromocriptine can inhibit prolactin release and have an
25	impact on lactation that is negative.

			28 1		Estrogens and antigens used to be used in
	2	combination for mothers who didn't want to breastfeeding. 

	3	That was injected immediately postpartum to dry up the milk
	4	supply.
	5		A group of drugs that is not well appreciated by
	6	most people is the sympathomimetic vasoconstrictors, and

	7	there is essentially no human data that has studied this,
	8	but we see it clinically all the time.  Mothers who are
	9	taking Sudafed or other cold products really have a drop-off
10	in their breast milk in a short period of time.  It is not
11	entirely clear whether this is due to decreased blood flow
12	to the breast from the vasoconstriction or CNS effects that
13	can inhibit prolactin and oxytocin secretion.  Nevertheless,
14	it does have that effect.
15		Diuretics in high doses have been used in some
16	studies to suppress lactation.  Narcotics have been shown in
17	animal studies to inhibit oxytocin release but it is not
18	clear what the human impact of that is.  It may not be
19	great.
20		Again, central anticholinergics appear to decrease
21	prolactin secretion, and the problem there is that older

22	antihistamines and combination cold products are fairly
23	anticholinergic and when combined with the vasoconstrictors
24	the two really have quite an impact.
25		[Slide]

			29 1		So, my idea of what we need for labeling follows: 
	2	First, I think we have to not discourage breastfeeding
	3	unnecessarily.  All too often, the statements in the package
	4	insert, if they don't come right out and say not to
	5	breastfeed, they are quite fear-inducing statements, kind of
	6	vague statements that indicate that perhaps this is really
	7	not a good thing but go ahead and do it if you think you
	8	ought to.
	9		I think, number one, we have to have the age of
10	the infant considered.  As all of you know as pediatric
11	practitioners, a one-month old is not the same as a one-year
12	old, and I get calls from mothers who are nursing one time a
13	day with three-year olds who are just deadly afraid of
14	taking a medication because of what they read in the package
15	insert.  Even the difference between a one-month old and a
16	six-month old is fairly evident.
17		I think there should be some element or some way
18	of expressing the infant exposure, and it should be based on
19	human data, perhaps even in vitro data with some of the
20	newer techniques that we have, but animal data are useless. 
21	In fact, they are misleading because the differences in the
22	amount of protein and the amount of fat in milk varies
23	considerably from species to species and really skews the

24	amount of drug that will pass into breast milk.  So, it
25	could be either the percentage of maternal dosage or some

			30 1	dosage divided by clearance factor of some kind.  There is a
	2	recent paper that came out, but I don't have a slide of it,
	3	that looked at a neural network and 26 different chemical
	4	factors that could be placed into the network, and there was
	5	a 0.96 r-square value compared to clinical study data.  So,
	6	there are some very good computer models now that can
	7	predict this quite well.
	8		We should mention, of course, if there are any
	9	inherent and reported toxicities to the drugs, certainly any
10	pharmacologic concerns, and then any allergic or
11	idiosyncratic reactions, but these shouldn't be used as a
12	way to discourage breastfeeding.  It should be pointed out
13	that these are quite rare and the pharmacologic, of course,
14	should be taken in context of the age of the infant.  Then,
15	we should also report the effect on lactation.
16		[Slide]
17		So, in conclusion, at the current state I think
18	you could almost say that it would be better to have nothing
19	than to have what we have now because it causes so much
20	confusion and so much misinformation, but I am not
21	inherently a nihilist so I think I could also say that there
22	currently exists a sound scientific basis for providing
23	meaningful information in a structured way.
24		DR. CHESNEY:  Thank you very much, Dr. Anderson. 
25	Our third speaker, and last before we can ask questions, is

			31 1	Dr. Robert Ward, who is a Professor of Pediatrics and

	2	Director of the Pediatric Pharmacology Program at the
	3	University of Utah, and he is going to be speaking about
	4	drug therapy during lactation and maternal and pediatric
	5	issue requiring research.
	6	       Drug Therapy During Lactation: A Maternal and
	7		   Pediatric Issue Requiring Research
	8		DR. WARD:  Good afternoon.
	9		[Slide]
10		Some of what I am going to say has already been

11	covered but we will go over some of it.  The obvious first
12	place to start is that there are two participant during

13	lactation, both the mother and the child.  What I have
14	diagramed here is what I refer to as the therapeutic process
15	from drug ingestion, or intravenous or intramuscular
16	administration through absorption, distribution, metabolism
17	and elimination until it reaches the site of action.  These
18	processes will occur in both the mother and in the child,
19	and will certainly influence how much drug reaches the
20	child.
21		[Slide]
22		Dramatic changes happen during the time of
23	lactation.  As a neonatologist, I am very familiar with 23-
24	week gestation preemies and realize that those mothers often
25	donate their milk, and that child is radically different

			32 1	from the older child, and nursing may occur through several
	2	years of age.  During this interval, organ maturation has a
	3	tremendous influence on how we are going to evaluate the
	4	effects of drug upon the child.  Changes in brain, liver and
	5	kidney will influence both the pharmacodynamic and
	6	pharmacokinetic aspects of the drug.  Maternal physiology
	7	also changes dramatically after parturition.
	8		[Slide]
	9		Some of the changes in the mother during pregnancy
10	are pretty ama zing and happen quite early, and they will
11	then reverse after delivery.  During pregnancy, plasma
12	volume can expand 50 percent so that for polar drugs that

13	are contained largely in the circulation the concentrations
14	circulating in the maternal blood stream will decrease

15	during pregnancy.  Fat stores will increase.  So, the
16	distribution of drug during pregnancy will change, and
17	protein concentrations will decrease overall.
18		In addition, elimination increases fairly

19	dramatically for drugs eliminated particularly through renal
20	excretion.  Both cardiac output and renal plasma flow
21	increase, leading to a 50 percent increase in glomerular
22	filtration rate.

23		[Slide]
24		So, these changes in maternal physiology during
25	pregnancy then will reverse after delivery.  There are very

			33 1	few studies that have looked at the time course, however, of
	2	those reversals.  Let me mention one study from Mark Rogers. 
	3	This is a very long time ago.
	4		[Slide]
	5		He followed 7 women treated with digoxin in doses

	6	of 0.25 mg/day orally throughout pregnancy.  These women had
	7	normal renal function.  Their dosages were not adjusted
	8	during pregnancy for concentrations.  He measured the
	9	digoxin concentration at term delivery and one month
10	postpartum.
11		[Slide]
12		What he found was that the concentrations at term
13	delivery were really sub-therapeutic, at 0.6 ng/ml, but one
14	month postpartum the concentrations had almost doubled for
15	the group, indicating that digoxin clearance from the end of
16	pregnancy to one month postpartum had decreased almost 50
17	percent.
18		[Slide]
19		There are a variety of processes by which drugs
20	enter milk -- simple diffusion, carrier-mediated diffusion,
21	active transport, pinocytosis, and reverse pinocytosis, that
22	may allow protein-bound drug to cross into milk.  But, for
23	most drugs, they enter milk by diffusion.
24		[Slide]
25		A number of factors influence how much drug will

			34 1	pass into milk.  The lipid solubility, degree of ionization,
	2	whether they are protein bound and what the concentration is
	3	in the maternal circulation are particularly important
	4	determinants.  Molecular weight will influence, and then the
	5	pKa of the drug.  Strong organic bases, if they are passing
	6	solely by diffusion, will have a higher concentration in
	7	milk.
	8		[Slide]
	9		The diffusion is controlled by the Henderson-
10	Hasselbach equation, as shown here.
11		[Slide]
12		I have translated it here into this equation that
13	shows that for erythromycin base, a relatively strong
14	organic base with a pKa of around 8, the difference in pH

15	between the maternal circulation and milk -- and, here I
16	have used a relatively high pH for milk of 7.2, leads to 60
17	percent higher concentration in milk than in the maternal
18	circulation.
19		[Slide]
20		Milk, itself, is a unique and vary variable
21	nutrient.  Some of these changes I have mentioned here --
22	colostrum varies dramatically from that of mature milk. 

23	During a single breastfeeding the concentration and the
24	composition of milk will change with respect to its fat
25	content and protein content.

			35 1		As Dr. Berlin indicated, manually expressed milk

	2	and pumped milk have different compositions as well, which
	3	changes our analysis and study strategy for drug excretion
	4	into breast milk.
	5		The breast milk of moms who deliver prematurely
	6	differs from that of moms who deliver at term.  The milk
	7	from moms who deliver prematurely will have higher protein
	8	nitrogen contents, lower lactose, higher caloric density,
	9	and slightly higher concentrations of calcium, phosphorus
10	and magnesium.
11		[Slide]
12		Milk concentrations of fat, nitrogen and lactose

13	will vary within a 24-hour period.  So, again, this is going
14	to influence the distribution of fat soluble drugs and polar
15	drugs during the day.  These concentrations vary during the
16	months of lactation, as Dr. Berlin alluded to, so that
17	looking at one point during pregnancy may not give us an
18	accurate picture of what the situation is later in
19	pregnancy.
20		They can also vary by maternal diet.  Dr. Lawrence
21	reported data from 3-hour nursing periods during the day,
22	and the milk volume for that 3-hour period varied as much as
23	2-fold during the day.  If the maternal concentration of

24	drug is perfectly constant, the amount of drug distributed
25	into milk may vary dramatically as well.  These variations

			36 1	in composition and volume can then influence the conclusions
	2	that we are going to draw from various studies about breast
	3	milk drug excretion.
	4		[Slide]
	5		Are animal models applicable to humans?  Fat and
	6	lactose concentrations vary widely.  There are unique
	7	proteins in human milk that differ from human serum
	8	proteins, much less differing also from animal proteins. 
	9	Protein concentrations in milk vary widely.  Some rabbits
10	have as much as 20 percent of their milk as protein, versus
11	0.9 percent in humans.  Immunoglobulins in milk differ from
12	those in human serum as well.
13		[Slide]
14		This shows a series of animals looking at the fat
15	percent on the Y axis versus lactose percent on the X axis,
16	and you can see this enormous variations in fat percentages
17	and lactose percentages in various animals.
18		[Slide]
19		So, I would conclude that animal data, just as Dr.
20	Anderson said, is minimally helpful to us.
21		[Slide]
22		So, what are our research needs?  What I have

23	tried to depict for you are some of the wide variations
24	physiologically in both the composition of milk and in

25	mother and infant during the nursing period.  So, we need to

			37 1	fit these variations into our studies.  We need to look at
	2	global effects on neonates and infants of the drugs
	3	administered via milk, and do systematic prolonged
	4	observations, not single kinetic curves after a single dose.
	5		[Slide]
	6		The changes in milk during lactation have been
	7	documented extensively in many sources, but the factors that
	8	control those changes are not as clear, nor have I found a
	9	good elucidation of those.  We also don't know the
10	interaction of the particular maternal disorders for which
11	that mother is taking the particular drug, and the effect of
12	that upon milk composition and volume.  Those need study as
13	well.
14		[Slide]
15		What I would propose are, first, surveys.  We
16	actually need to look at the longitudinal milk excretion of
17	drugs during lactation from colostrum through weaning.  This
18	is what is reality and this is what the child may be exposed
19	to.  I think the important place is to look in the neonate
20	and the infant for drug concentrations associated with
21	maternal drug therapy.
22		We need to pay attention to unusual occurrences. 
23	These are what constitute a large bulk of the literature,

24	anecdotal case reports of a particular clinical disorder --
25	hyperactivity, somnolence, diarrhea, irritability that has

			38 1	now been attributed to the drug.  Those then warrant testing
	2	in a controlled fashion.  They should help guide us toward

	3	the controlled studies that can better inform us about the
	4	effects of drug intake during lactation.
	5		We need to know more about the epidemiology of

	6	drug use in the United States by region, by sociological
	7	features.  I have listed some here -- race, occupation,

	8	education, age and diet.  Those sociological features may
	9	also influence how much drug is taken and what "food
10	supplements" are taken as well which may be excreted into
11	breast milk.
12		[Slide]
13		We need controlled, blinded comparisons of
14	infants.  For the amounts of drug intake during pregnancy
15	and the number of infants being breastfed, the paucity of
16	literature is really almost inexcusable.
17		We need a comparison of infants exposed to drugs
18	that are age matched in moms taking the medication compared
19	to infants of mothers not taking the medication.  The

20	appropriate control group is, I think, interesting.  We need
21	to consider whether we should be looking at infants of
22	mothers with the same disorder for which the medication is
23	being administered, or whether we should look at infants of
24	mothers who are not affected with the same disorder and
25	obviously are not taking the medication.

			39 1		And, as indicated earlier, we clearly need long-

	2	term medical and developmental follow-up.  We really don't
	3	understand the potential consequences of intake of these

	4	medications via breast milk upon the infant when they are
	5	older.
	6		[Slide]
	7		We need to then study factors that will alter
	8	breast milk drug excretion.  Maternal kinetics,
	9	pharmacogenetics, certainly influence this as well; maternal
10	diet; milk composition.  We need to validate the appropriate
11	models for analyzing this.  John Wilson, who I thought might
12	be here today, has proposed a three-compartment model for
13	this.
14		We should also evaluate the use of saliva samples,
15	a non-invasive means of monitoring.  Certainly, it has been
16	validated for some drugs.  We should do it much more
17	extensively to know whether this is an opportunity that we
18	are missing for non-invasive sampling of both mother and
19	infant.
20		Then, we need to look at the developmental changes
21	in pharmacokinetics.  During this interval of breastfeeding
22	from 23 weeks to a child of one year of age, there are
23	tremendous changes in pharmacokinetics.
24		[Slide]
25		I have listed some of these here.  We need to look

			40 1	at the critical ages when clearance pathways mature, when
	2	renal function and hepatic enzymes mature compared to the
	3	clearance pathways for the specific drug, to guide our
	4	studies.  This is glomerular filtration, generally viewed as
	5	mature by five months.  Depending on how you measure renal
	6	tubular secretion, some estimate it is mature at 30 weeks,
	7	others at a year.  Cytochrome P450 3A4 metabolize more drugs
	8	than any other drugs in the liver.  These generally reach
	9	adult levels by 12 months or so after birth.
10		[Slide]
11		I have shown some of this transition here.  This
12	looks at the cytochrome P450 3A system, and 3A7 is the

13	predominant fetal form, and you can see that in pre-term
14	gestation that is the predominant form of 3A compared to
15	3A4, which is the form that starts to mature shortly after
16	birth and reaches significant levels by 1-3 months after
17	birth, and then by a year of age is mature, and there is
18	this transition between they two.  They do not metabolize
19	all the same drugs equally, but we have to deal with these
20	change in drug metabolism and how we assess the effects on
21	the newborn as well.
22		[Slide]

23		The scope of studies -- I would propose that every
24	effective drug therapy that may be used to treat women in
25	childbearing age which, unfortunately, starts as early 13 or

			41 1	12 years of age and lasts until maybe 45, will be
	2	administered to them, and some will be breastfeeding
	3	infants.  The data regarding human breast milk excretion
	4	should be part of drug development and labeling.  And, I
	5	would propose, as others have -- we did this independently,
	6	by the way, that we should avoid the rating systems for risk
	7	such as the current pregnancy risk system, and maybe just
	8	cite the data so that the clinician can decide.  Thank you.
	9		  Subcommittee Questions for Speakers
10		DR. CHESNEY:  Thank you, Dr. Ward.  We now have
11	allotted a minimum of 15 minutes for questions or comments
12	for the speakers, for Dr. Berlin, Dr. Anderson or Dr. Ward,
13	and I am sure Dr. Kweder will be willing to answer questions
14	also.  Yes?
15		DR. FRIEDMAN:  I guess this is a question for Dr.
16	Berlin and also for Dr. Kweder.  Dr. Ward has pointed out

17	the breathtaking lack of data in this area, and despite Dr.
18	Kweder's admonition that we weren't talking about gathering
19	data, I don't think it is possible to write a very useful
20	label in the absence of data.  Currently, many of these

21	labels are written in the absence of data in a very
22	precautionary way.  Some people have argued that we should
23	make them less precautionary, but we still don't have data
24	and we still don't really know what is safe and what is not.
25		I was struck in Dr. Berlin's presentation about

			42 1	how similar his recommendations regarding gathering data
	2	were to the 1987 statement by the American Academy of
	3	Pediatrics, which was made in response to an apparently
	4	stillborn effort by the FDA to encourage the development of
	5	some of this information.  I was also struck, in reviewing
	6	the American Academy of Pediatrics recommendations, the 1994
	7	ones which all of us use, as to how little information they
	8	are actually based on.  They are based on occasional case
	9	reports, and very small series, and pharmacokinetics in some
10	cases.
11		This is a very serious issue, and it seems to me
12	that the FDA system, which is designed to look for adverse
13	reports after a drug is released on the basis of preclinical
14	studies which, we have heard, are of very little or no value
15	in this context -- we are not really looking for adverse
16	effects here.  What we want is some reassurance that a
17	natural process is, in fact, safe.  So, we have to have, as
18	part of the label-making, it seems to me, some way to gather
19	information on this normal process of breastfeeding. 
20	Perhaps Dr. Kweder can comment on that.
21		DR. KWEDER:  I am not sure I am qualified to
22	comment on that.  I actually have a question for Dr. Ward in
23	that regard.  Why do you think it is that there isn't more
24	research in this area?
25		DR. WARD:  Where is Dr. Yafee?  I think that there

			43 1	is actually little funding for research in this area at this
	2	point.  This is pretty basic, almost mundane kind of
	3	research, in a sense, looking at the extent of breast milk
	4	drug excretion.  It is not very spectacular.  Okay?  Is this
	5	an area of priority for NICHD for funding?  It is really
	6	not.  And, I think that is the predominant cause and, in
	7	some respects, I think it relates to some of the discussions
	8	this morning about the limited number of people interested
	9	in clinical pharmacology and going into clinical
10	pharmacology at this point as well.
11		DR. CHESNEY:  Dr. Koren?
12		DR. KOREN:  I should say that in Toronto we are
13	now collecting -- we have about 30-40 counselings of women a
14	day about drugs in breastfeeding and we do a lot of these
15	mundane follow-ups.  They are not difficult to do.  Many
16	drugs are measurable.  I must say, most industrial partners,
17	even if they don't have an active program on Prozac or

18	anything, they are very happy to measure it for you,
19	actually at no cost even, because they have a laboratory
20	doing it.  So, I don't think there is a good excuse not to
21	do the research, and it is not very expensive research to
22	do.
23		I do want to add one or two points which are

24	important.  Yes, there is a lot we do not know, but there is
25	some generalization about exposure limits and how much

			44 1	really gets to the infant that we do know.  But we do know

	2	the risk of not breastfeeding.  The risks of not allowing a
	3	child to breastfeed are very well known and are measured in
	4	both developing and developed countries.  So, if the label
	5	is supposed to give a risk-benefit ratio, this is known.

	6		As some of the speakers alluded to, I am much more
	7	concerned about the number of women who stop breastfeeding
	8	because of misconceptions of risk.  The real risks of drugs
	9	in breastfeeding is not the chemical risk; it is the risk of
10	women not breastfeeding.  Dr. Anderson showed one of our
11	studies.  We now have studies on five or six different drugs
12	used by many women who just either do not initiate
13	breastfeeding or stop breastfeeding earlier.  For me, this
14	is by many-fold higher than the risk of a potential adverse
15	event that may happen.
16		So, this is kind of the context and somehow the
17	labeling must address this.  We know what the risk is of not
18	breastfeeding.
19		DR. CHESNEY:  Dr. Wisner?
20		DR. WISNER:  I wanted to address the issue about
21	the lack of information and what that may be due to.  I have
22	done a series of papers on mother/infant serum levels for
23	drugs used in psychiatry since 1985, and some of the
24	impediments are that back then we didn't have very sensitive
25	assays for psychiatric drugs.  So, Jim Perel developed much

			45 1	more sensitive assays and, in addition, he had to develop
	2	assays that could be done on small quantities of serum
	3	because the IRBs were very picky about how much blood you
	4	were drawing from an infant to get the serum level.
	5		The other is ethical issues in that I think I have
	6	the only study that is funded by NIMH in which breastfeeding
	7	women are randomized to an antidepressant versus placebo,
	8	and I could spend about half an hour telling you about the
	9	various IRB and ethical objects to that study, the hoops I
10	had to jump through before I could actually get approval.
11		So, there are a number of systems issues that over
12	the last decade, I think, have really inhibited the
13	acquisition of this type of data.
14		DR. BERLIN:  I want to respond to Dr. Friedman's
15	comments, if I could.  I didn't mention the 1987 paper that
16	we wrote on guidelines, but the similarity between that and
17	some suggestions I made are not coincidental because both
18	Dr. Kauffman, who is here for the Academy, and myself were
19	authors of that particular publication, and we have
20	continued to discuss some of these difficulties through the
21	years.  I had the pleasure to see, and I have the permission
22	of Dr. Koren to mention that his colleague, Dr. Ito, in
23	Toronto, has developed what possibly is a very exciting in
24	vitro system for studying the measurement of drugs in
25	mammalian mammary cells which may give us a lot of

			46 1	information so that we may not need to worry about some of
	2	these IRB studies that Dr Wisner mentioned.
	3		DR. CHESNEY:  Yes, Dr. Gorman?
	4		DR. GORMAN:  I would like Dr. Anderson or Dr.
	5	Koren to elaborate a little bit on the statement that
	6	information they received from healthcare providers was a
	7	major discouraging factor for women to breastfeed.  Was this
	8	just a repetition of what was in the PDR, or was it
	9	independent of that that these individuals were discouraged
10	-- the graph that you showed of the falloff of the mothers
11	taking medications in terms of breastfeeding?
12		DR. ANDERSON:  I can let Dr. Koren speak for his
13	own study, but in my experience mothers get very
14	discouraging information from physicians, not especially

15	pediatricians, they are probably more up to date than most
16	people but if they go to their internist or their family
17	practitioner or, God forbid, they ask a pharmacist or an
18	emergency room physician, they are going to tell them to

19	stop right away and it is very often based on what is in the
20	PDR.
21		DR. KOREN:  In July we published a paper in
22	Pediatrics showing that about half of endocrinologists, in
23	that particular example, that treat women with
24	hyperthyroidism told them not to breastfeed.  All the
25	evidence-based knowledge does not suggest that PTU is an

			47 1	issue.  So, clearly, this is a group of highly specialized
	2	people that know the literature; it is not just any
	3	physician in any part of this continent.  So, clearly they
	4	had a major impact on these women to stop it earlier or not
	5	to initiate.
	6		But in another set of studies we looked at the
	7	overall advice that women receive from their mother-in-law,
	8	from the physician, and we marked it as positive or negative
	9	without giving more judgment to this or that.  Again,
10	physicians actually, when they told a woman not to
11	breastfeed or that there is no data, women tended not to
12	breastfeed, as you may imagine, because they were afraid or
13	they stopped the drug they need.
14		Just to show an example, this was very well done
15	by Dr. Anderson about the risk of women not treating
16	themselves.  A month ago, a patient in Toronto, suffering

17	postpartum psychosis committed suicide by jumping into the
18	subway with her child.  She was treated.  She was on an
19	antidepressant but she didn't take it because she was told
20	it would poison the baby.  This particular antidepressant
21	doesn't do anything in terms of adverse events.  So, I just
22	want to throw into the equation the risk of misinformation
23	here.

24		So, it is not just that we need more information. 
25	People don't utilize the information existing, and they try

			48 1	to believe that the baby should not see any molecule of a
	2	particular drug forgetting the risk, of course, of not
	3	because or the risk of a mom not taking a drug and
	4	psychiatry, of course, is a big area although it is not
	5	exclusive for psychiatry.
	6		DR. GORMAN:  In the absence of the sort of
	7	scientific data that we would like to have, would it be your
	8	opinion that changing the labeling and the PDR would be of
	9	benefit to breastfeeding mothers so that it doesn't follow a
10	risk scale?
11		DR. KOREN:  Again, there is huge discrepancy
12	between the PDR, the label and the evidence-based knowledge
13	today.  They lag many years.  I don't want to go into it but
14	the pharmaceutical industry has a very different paradigm to
15	control the business that is medical-legal, and I am not
16	criticizing it; I understand where it is coming from.  But,
17	I guess what I am saying -- Dr. Anderson said it too -- the
18	Academy is doing a terrific job in bringing the information
19	that exists, but it doesn't find its way to the PDR and,

20	even when it does, physicians still tend to be much more
21	conservative in how they use it, and the child and the
22	mother suffer and that is something that we have to take
23	into account very strongly.
24		DR. WIER:  I just wanted to make a comment

25	regarding the utility of animal models.  Both speakers

		49 1	mentioned this in the context of animal models for
	2	lactational transfer of drugs.  Certainly, some
	3	generalizations are made about diverse species such as
	4	rodents and rabbits and now markedly they differ from human,
	5	but I do think it is important to remember that for certain
	6	biopharmaceutical agents those studies have been done in
	7	non- human primates and those may be more applicable animal
	8	models.
	9	          Much more importantly though, the use of animals
10	to predict lactational transfer of drugs is probably the
11	least important use in this context.  The first speaker
12	mentioned that the concerns primarily are going to be infant
13	exposure, but also the potential pharmacologics and
14	toxicological effects in the infant, and also the potential
15	for drugs to impair lactation.  So, I would like to mention
16	that the applicability of animal models in those other
17	instances can be much higher than was suggested today.  The
18	use of animal models then is to help predict those hazards
19	so that one can design safer and more ethical clinical
20	trials, as well as to assist in the design of those clinical
21	trials.  So, I don't think we should overbear on the
22	differences in lactational transfer because that is not the
23	primary purpose of those models.  It is really to look for
24	the value in the animal models for the prediction of

25	impairment of lactation or prediction of potential

			50 1	pharmacologic or toxicologic effects in infants.
	2		DR. CHESNEY:  Dr. Wisner?
	3		DR. WISNER:  I think one of the major issues that
	4	I struggle with that was also raised by the speakers is how
	5	do you assess effects on the infant so that if you give a
	6	mom a medication, what we do, we kind of have her take a
	7	baseline of the infant's behavior.  But invariably questions
	8	like, do you expect the same side effect profile in an
	9	infant that you might expect in a mom may or may not be true
10	depending on the drug.  I mean, in psychiatry we can see

11	agitation in infants where we might see sedation in moms,
12	and now much sedation is really abnormal in infants always
13	comes up in terms of how do you monitor the infant?  Even
14	with long-term development, although we would all like to
15	see studies like that, they are going to involve large

16	numbers of infants because the further you get away from the
17	exposure, the more variables impact on development, the more
18	difficult it will be to assign any adverse outcome to the
19	breastfeeding itself.
20		So, I think there are a number of important
21	methodological issues that we need to clarify before we can
22	advance this issue of behavioral monitoring and development
23	along.  Our own kind of interim solution has been to use the
24	Actograph which downloads a week of activity and sleep-wake
25	data on the baby.  We apply it to the infant's ankle.  But,

			51 1	again, that is just one measure of infant behavior and there
	2	are all kinds of other physiologic measures that we think
	3	should be measuring but we are not entirely sure.  So,
	4	again, the methodological advances I think are going to be
	5	important.
	6		DR. CHESNEY:  I know we have all thought at some
	7	point in time that one reason there hasn't been more done in
	8	this area is that we have gotten away with it; that there
	9	haven't been any severe, immediately obvious adverse
10	effects, but it does make one wonder if in the long-run
11	there on growth and development and maturation that Dr. Ward
12	mentioned.
13		I think in terms of the labeling, that is
14	something that is very much in mothers' minds.  Even if you
15	didn't put anything in the label, I wonder if, given no
16	information, they wouldn't decide on their own not to take
17	it because we don't know about long-term consequences.  That
18	is just my comment.  Dr. Anderson?
19		DR. ANDERSON:  Yes, I think that if we are going
20	to do a lot of this research that is called for we need to
21	focus on areas like the psychotherapeutics where there could
22	be some subtle developmental problems but, you know, we have
23	mothers who are afraid to take amoxicillin at this point,

24	things that are just given to babies all the time and we
25	know exactly how they respond to them.  So, I think that is

			52 1	an issue.
	2		Then, to kind of reemphasize what Dr. Koren said,
	3	there was an interesting study looking at, I believe, Lapps,
	4	people in the North, who ate a lot of whale blubber, and
	5	they took mothers who ate lots of it and they had humongous
	6	amounts of mercury in their breast milk, and they had a
	7	control group with mothers with more normal mercury levels. 
	8	They looked at the breastfed infants with the high mercury

	9	levels and the other babies with normal mercury levels or
10	who were not breastfed, and the breastfed babies
11	outperformed the other babies all the time.  I mean, it
12	wasn't even close.  So, even a known neurotoxin can be

13	overwhelmed by the beneficial effects of breastfeeding.  So,
14	I think we have to keep everything in perspective before we
15	study things to death.
16		DR. CHESNEY:  Are you recommending mercury for
17	infant formulas?
18		[Laughter]
19		DR. HUDAK:  Well, I think as a neonatologist, this
20	issue comes up all the time, and for mothers who deliver
21	babies who are born prematurely two things are true.  One is
22	that those mothers often are on a panoply of medications

23	that is more abnormal or more concentrated who delivered
24	normally at term.  But, the second thing is that I think in
25	terms of a lot of the issues of breastfeeding, certainly

		53 1	doing everything you can to have a mother who delivers
	2	prematurely succeed in her effects to express milk and get

	3	on a good, long-lasting breastfeeding program is critical.
	4	          I can't remember the last time that I counseled a
	5	mother not to pump, not to use the milk and breastfeed.  I
	6	guess I am struck by the data today, especially Dr.

	7	Anderson's review of the literature.  I didn't see one thing
	8	in there that was a serious adverse event.  I mean, this
	9	strikes me as complete much ado about nothing, and I think
10	one has to remember that most of these medications are
11	things which have a very short course.
12	          It is inconceivable to me that this is going to
13	have a tremendous impact on babies, even if you were able to
14	study it and I don't think you would be -- you can find out
15	information about serum concentrations and so forth, but in
16	terms of long-term effect on babies, I think that is
17	unknowable except in maybe some of the long-term
18	psycholeptic medications.  But I really think that, from a
19	practitioner's standpoint, it is critical to do whatever we
20	can, through revision of the labeling or whatever, to really
21	make note of the fact of what we do know, and that is that
22	breastfeeding is an important advantage to babies.  In some
23	studies there is up to a 10-point IQ differential between

24	breastfed and formula fed babies.  There are tremendous
25	other aspects of health that are impacted.  There is a

			54 1	tremendous amount of mother-baby bonding and interaction
	2	that goes on that is not easy to quantify and I think those
	3	are real things, as opposed to these very, very potential
	4	sort of diarrhea and a little sedation and so forth of some
	5	of these medications and very few really significant
	6	theoretical side effects.
	7		I think whatever the FDA can do to maybe write
	8	guidelines to revise some of the lactation labeling, and get
	9	out general education through the Academy to pediatricians
10	and family practitioners about this, and obstetricians too,
11	it would be very valuable.
12		DR. CHESNEY:  Dr. Kauffman?
13		DR. KAUFFMAN:  I agree completely with the
14	statements just made, but one of the things I wanted to
15	address is that I think one of the pitfalls that we
16	frequently fall into in thinking through this whole thing,
17	and this has been true for at least the past 20 years that I
18	have been involved in this, is that we don't think
19	quantitatively about the exposure.  If you just think about
20	it, the drugs are typically taken by the mother in milligram
21	doses.  The concentrations in the breast milk of most of

22	these, particularly the psychoactive drugs which have very
23	large volumes of distribution -- that is why they have a
24	large clearance, because their volume of distribution is
25	very large -- the concentrations in breast milk are in

		55 1	nanograms or picograms, orders of magnitude lower than are
	2	taken for clinical exposure.  So, the exposures in virtually
	3	all of these instances is orders of magnitude lower than
	4	what one would expect for any pharmacologic effect.  So, if
	5	you simply think through it, I agree with you, it is a lot

	6	of ado about nothing in most cases, with rare exceptions.
	7	          DR. FINK:  I am troubled by this.  Although, I
	8	must say, I favor breastfeeding I think you have to be

	9	careful in interpreting those studies as to how much is due
10	to breastfeeding and how much is due to child rearing
11	differences.  We have many mothers who go back to work when
12	the baby is as young as six weeks old, and are in a social
13	environment where maintenance of breastfeeding is nearly
14	impossible in terms of job demands.  And, until the studies
15	are tightly controlled to look at the child rearing
16	differences versus those just attributable to breast milk I
17	think they have to be interpreted with a bit of caution.
18	          And, I am a little concerned about this idea that
19	maybe a little bit isn't harmful.  The allergy side of me

20	says, wait a minute, nobody has brought out on the table how
21	much does early exposure of infants to different antigens in
22	the drugs that they are exposed to predispose them to
23	development of asthma, to allergic disease, and how many of
24	us would feel comfortable if we said we are going to feed
25	children milk that is labeled, "may contain small amounts of

				56 1	psychoactive substances?"  We wouldn't find it acceptable. 
	2	So, I think we really have to look at this and be a little

	3	conservative -- not to discourage breastfeeding but to
	4	really demand that there be some good research on it, not
	5	just whitewash it and say we are going to forget about the
	6	issue of drugs in breast milk.
	7		DR. CHESNEY:  Dr. Wisner?
	8		DR. WISNER:  I have a very strong bias towards

	9	breastfeeding as well.  I think it has to be evidence based,
10	and the issue that concerns me is that, at least for
11	psychiatry, all of the mother-baby serum levels that have

12	been published on antidepressants have been for full-term,
13	healthy infants in which the mother was taking no other

14	drugs, with the exception of one case where one of our
15	babies was a 35-week preemie baby.  So, for premature

16	infants whose mothers take other drugs that could interfere
17	with metabolism, increased serum levels for the prematures
18	that are ill, taking other medications, I am very reluctant
19	to generalize the findings from full-terms to premature and
20	sick infants because I think it is very likely that the
21	levels may be much higher in those infants and that they may
22	exceed some of the guidelines that we have talked about this
23	morning.  So, I see that as more of an issue of being

24	careful about how we generalize the data that we have.
25		DR. CHESNEY:  Yes, Dr. Koren?

		57 1	          DR. KOREN:  Just to add to what Ralph Kauffman

	2	said, the nice thing is that, indeed, for most drugs the
	3	exposure index is very low.  It is less than one percent or
	4	so.  But even more important, based on physicochemical
	5	properties of the drug, there is a good Australian way to
	6	predict drugs that will have milk to plasma ratio above

	7	that, and that is probably the short list that should be
	8	studied more carefully.  They showed very good predictive
	9	value of those drugs that come in the case reports, and I
10	think Dr. Anderson showed it -- phenobarb and so on.  We
11	know these drugs, and when they come new on the market the
12	physicochemical characteristics are measure in the
13	laboratory.  You don't even need tissue culture in humans
14	and not even necessarily animals.  So, I agree that that
15	should probably be a subgroup that should be studied.
16	          I do also agree that the studies about higher IQ
17	in breastfed infants have been very severely criticized. 
18	They were never randomized trials.  Even the mothers who
19	choose to pump milk to give to babies are different in

20	motivation from mothers who don't decide that, and we all
21	know that many of the manufacturers of the formulas now are
22	chasing this missing thing in the formula to find what will
23	improve IQ.  I personally am critically looking at this data
24	because we have to answer about ten such questions every day
25	over the phone, and I do not think there is evidence-based

			58 1	knowledge that breast milk improves IQ, and I think that is
	2	very important not to include in any labeling --
	3		[Laughter]
	4		DR. CHESNEY:  Well, I don't wee any other hands
	5	up.  So, I think maybe we should take a break for 15 minutes
	6	and reconvene at 2:45, if that timing is all right for Dr.
	7	Hamilton.  Please return back at 2:45.  Thank you.
	8		[Brief recess]
	9		DR. CHESNEY:  Our next speaker is Dr. Holli
10	Hamilton, who is with the Pregnancy Labeling Initiative at
11	the FDA, and she is going to speak to us about current

12	requirements for providing information in a product's
13	labeling on drug use during lactation.
14	       Current Requirements for Providing Information
15	    in a Product's Labeling on Drug Use During Lactation
16		DR. HAMILTON:  I am here to explain why we are
17	where we are.
18		[Slide]
19		Three paragraphs control labeling, and we passed

20	out copies.  It is really only one side of a page.  I think
21	this will explain, although may not exonerate us --
22		[Laughter]
23		It was implemented with the pregnancy labeling

24	rule in 1979, and it was part of that rule.  As I said, it
25	is only one page.

			59 1		[Slide]
	2		The first paragraph is a general requirement, and
	3	all that says is that, if known, you are to describe the
	4	excretion of the drug in human milk; the effects on the
	5	nursing infant, and I think it might say serious effects but
	6	that will follow through the next paragraphs; and pertinent
	7	adverse effects in animal or offspring.
	8		[Slide]
	9		The second and third paragraphs are the more

10	specific requirements.  The first part breaks into two
11	areas.  A systemically absorbed drug is expressed in human
12	milk.  Systemically absorbed drug unknown whether it is

13	expressed in human milk.  So, paragraph two is the first
14	bullet; paragraph three is the next bullet.
15		[Slide]
16		With respect to two and three and clarification,
17	the concern was serious adverse event in infants or known
18	tumorigenic potential.  That would be the first cut.  That
19	would be risk.  No serious adverse event in infant and no
20	known tumorigenic potential.
21		[Slide]
22		Then what we did was to tie this to standardized
23	language, and this is the standardized language and this is

24	why so many of the statements when you create charts of what
25	appears in the label appears in the label.  Drug is in human

			60 1	milk and it has a risk for serious adverse event in infant
	2	or tumorigenic potential, and this is the standardized
	3	language.  Because of the serious adverse reactions in
	4	nursing infants -- or potential, actually; it is not known. 
	5	As we have seen, there are not too many known -- a decision
	6	should be made whether to discontinue nursing or to
	7	discontinue taking the drug -- so, don't drink and drive --
	8	taking into account the importance of the drug in the milk. 
	9	So, that is the mandatory statement that must follow.
10		[Slide]
11		If the drug is in the milk but there is no serious
12	adverse event or tumorigenic potential, it says "caution
13	should be exercised when the drug is administered to a
14	nursing woman."  So, that is the caution statement and that
15	is why it is broken up into that.
16		[Slide]
17		Now, paragraph three, with respect to whether it
18	is unknown that it is expressed, says it is not known
19	whether this drug is excreted in human milk because many
20	drugs are excreted in human milk, and then similar language
21	will follow.  That is how this is worked out and why you see
22	the labels reading the way they do.
23		[Slide]
24		The overview of this is basically if it is
25	unknown, you add unknown.  And if it is SAE or tumorigenic,

			61 1	don't breastfeed and take medicine.  And, this is all you

	2	can say.  No SAE or known tumorigenicity, breastfeed with
	3	caution.  And, that is how it breaks down.
	4		[Slide]
	5		The results of this are that we have labels with
	6	no relevant information.  As you have noticed, there is no
	7	safe situation.  I mean, we don't balance benefit and risk,
	8	I don't think, well.  It recommends a risk/benefit decision
	9	without providing information on risk or benefit, which I
10	think is very hard.  There is no requirement for specific

11	information, i.e., stuff you might know that might be useful
12	-- how long after taking the drug is it excreted in breast
13	milk?  I mean, is it rapidly eliminated?  Things like that.
14		[Slide]
15		Current labels, type of information -- we have to
16	thank Terri Toigo and Kelly Clancy who did the onerous job
17	of reviewing the PDR for us.  They went online.  They did
18	not look at biologics or OTC, but they did look at
19	approximately 800 other labels and cut and pasted the
20	nursing language for us and from this I have extracted: 
21	General statements rule of approximately 800 labels, 353 are
22	that general statement only, without any specific
23	information, and then general statement applied to the drug
24	class appears in 52 of them.  Commonly, these were estrogens
25	and thiazides.  That constitutes more than half of the	800.

			62 1		[Slide]
	2		To give you an idea of what standardized labels
	3	without a lot of information can run into, here the
	4	information for patients says -- and this is from a real
	5	label, an actual label and there is more than one that looks
	6	like this -- patients should be advised to notify their
	7	physicians if they are breastfeeding an infant.  Then, under
	8	advice to physicians who are taking care of nursing mothers,
	9	it is not real helpful.  It says, it is not known whether X
10	is excreted in human milk.  Because many products are
11	excreted in human milk caution should be exercised when X is
12	administered to nursing mothers.  So, it becomes circular
13	and it is not real helpful.
14		[Slide]
15		Another label that appears, and it is very common
16	-- it is not known whether this drug is excreted in human
17	milk.  As a general rule, nursing should not be undertaken
18	while the patient is on a drug since many drugs are excreted
19	in human milk.
20		[Slide]
21		It seems to me that this is the only statement you
22	can provide within this arena, right here, that provides a
23	margin of safety, and this does appear occasionally:  X is
24	not excreted in human milk.
25		[Slide]

			63 1		With respect to other labels, and we looked at
	2	these 800 labels, some of them are what I call animal
	3	labels.  They would be great if you were counseling nursing
	4	rats, I suppose --
	5		[Laughter]
	6		The drug is found in rat milk.  There were 84. 
	7	Drug present in other animal milk, and there were 8 of those
	8	roughly -- mice, cow, and there was one or two that said
	9	present in animal milk without giving species.  Level of
10	drug found in rat milk, approximately 46.  It doesn't give
11	you a lot on how this was determined, you know, was it peak,
12	was it trough, was it steady state?  I don't know, but it
13	says level of drug in rat milk is X.
14		Then, adverse events in rat pups, and we found
15	nine labels like that, and that is the information that
16	appears there.  Where human information appeared alongside
17	animal information, I put it into the human category.  Then,
18	there were some hybrid labels that have a bit of both.  I
19	tried to use both.  This is not all comprehensive but it
20	gives you a flavor of it.
21		[Slide]
22		This is an example of an animal label and this is
23	probably information that was submitted, and I am sure it is
24	clinically relevant.  So, bear in mind that things like this
25	can happen with available data of this sort.  You can see

			64 1	this is from a real label:  Drug X appears in breast milk
	2	and the AE was transient growth depression in rat pups.  The
	3	mothers were treated with 600 times the usual human dose. 
	4	Then they say X is detectable in human milk.  But I don't
	5	think there is any way to make a risk/benefit out of this so
	6	I don't think this is terribly useful.
	7		[Slide]
	8		Then, there are human labels, and of those 800
	9	about 126 say it is found in human milk but 89 give you the
10	level of the drug. But, again, steady state, peak -- you
11	know, I don't know how they measured that.  Then, 31 give
12	you adverse events in nursing babies and these are generally
13	drug class, not product specific, and you will see many of
14	them are older and it sounds like the label has just been

15	passed from product to product in expanding the class.
16		[Slide]
17		I tried to pull out some human labels that I
18	thought were somewhat useful.  This is a real drug and this
19	is the label, and the N is as bad as it gets; it is an N of
20	1 but the information conveyed is somewhat helpful.  It

21	gives you the amount of drug the patient received, her
22	levels, the infant levels, and then it said no trace of drug
23	could be detected in infant serum.  As I said, the N is very
24	bad but I think that it could be somewhat helpful and it
25	would be nice if it were better.

			65 1		[Slide]
	2		This is another label that is, again, human
	3	information that I don't think is bad.  I think it has some
	4	balance to it.  X is excreted in breast milk and may cause

	5	irritability or other signs of mild toxicity in nursing
	6	infants.  The concentration of X in breast milk is about

	7	equivalent to the maternal serum concentration, and it gives
	8	you the levels and what the infant would be exposed to over
	9	the course of a day.  Serious effects in the infants would
10	be unlikely unless the mother has toxic serum
11	concentrations.  Now, I think if you were a nursing woman
12	and this were a drug that your physician thought you should
13	take, that would be very helpful information.
14		[Slide]
15		This is something else that could be useful for a
16	drug that you only have to take once, anesthetic drugs for a
17	procedure, something like that.  Concentrations of X in milk
18	are probably of no clinical importance 24 hours after
19	anesthesia.  Because of rapid washout, X concentrations in
20	milk are predicted to be those found with other volatile
21	anesthetics.  If you elected not to breastfeed for 24 hours,
22	you could pump and then resume breastfeeding thereafter, or
23	something like that.
24		[Slide]
25		Future directions -- now, this is where we have

			66 1	been, what we have got, and this is where we are hoping to

	2	go.  The proposed lactation labeling rule will follow the
	3	pregnancy labeling rule in terms of its structure.  There
	4	will be clinical considerations, a summary risk assessment
	5	and a data section.
	6		[Slide]
	7		With the clinical considerations, the goal would
	8	be to provide specific and clinically relevant advice.  I

	9	mean, it is easy to talk about these things but when you are
10	actually trying to write information down and get relevant,
11	useful information inside a couple of sentences because, you
12	have to realize, this isn't going to be four pages, it can
13	be tough because there are going to be few easy cases that
14	never use versus never worry.  I think in some instances

15	there is going to be uncertainty.  I think we need more
16	information and better science and methodology.  I am not
17	convinced that all the issues related to determining the
18	infant exposure have been worked out.
19		Challenges include tackling therapeutic
20	alternatives.  How that is done in a label, that is not

21	something we have traditionally done but good, better, best. 
22	Then providing risk/benefit for mother and infant.  As you
23	can see, we make a risk/benefit statement but we don't
24	provide a risk or a benefit for the mother and the infant

25	and now suddenly we have four issues we have to address.

			67 1		[Slide]
	2		In terms of the summary risk assessment, I think
	3	this is really one of the tough pieces.  It is providing a
	4	concise overview of risk information that bridges discussion
	5	of data and clinical considerations.  Difficulties are, of
	6	course, quantifying risk and extent and applicability of

	7	animal data.  If that is all you have, that seems to be
	8	reasonable.  Reliable human data may be lacking in some
	9	circumstances.
10		[Slide]
11		In terms of the data section, we would like a
12	comprehensive presentation of animal data.  We would
13	certainly like a comprehensive presentation of reliable

14	human data; relationship of animal exposure to actual human
15	dose as it appeared; description of data sources and
16	conditions under which hazard occurred.  Is it single dose,
17	multi-dose?  Was it a toxic dose to the mother?  I mean, we
18	have to know more, I think, sometimes than just providing a
19	summary event.
20		[Slide]
21		I am referring back to this, and this is basically
22	the heading of drugs.  Again, I don't have a lot of
23	information on this but drug use among lactating women
24	probably resembles, in many ways, drug use among women aged
25	15-44.  This is from the National Disease and Therapeutic

			68 1	Index, and we have extracted by drug class.  Antinfectives
	2	lead the list.  Analgesics are second.  Psychotherapeutics
	3	are third, and so on.
	4		[Slide]
	5		That leads us to where we want to bring y.  I
	6	think we can conclude by saying that we think labels need
	7	more useful information.  They should be addressed, we hope,
	8	with science, a good basis for providing the information in
	9	the labels.  We would like to provide accurate and balanced
10	information on the risks and benefit of taking the drug and
11	nursing.  And, all labels must present information that is
12	balanced and scientifically based, I mean, i.e., the
13	risk/benefit issue.
14		[Slide]
15		We are throwing the questions to you in summary
16	now and you will discuss them in a minute:  Is maternal drug
17	therapy during lactation an important health issue for
18	infants?  If so, how should fundamental data be derived to
19	determine if a drug is expressed in breast milk; whether a
20	drug found in breast milk is available to the nursing
21	infant; when drug is available, risk, or lack of risk, to
22	the nursing infant?

23		[Slide]
24		What products or types of therapies are most
25	important to study?

			69 1		[Slide]
	2		Finally, what kinds of information about such
	3	products are needed for inclusion in labels to allow
	4	informed decisions as to the safety of breastfeeding when
	5	taking a medication?  That is all.
	6		  Subcommittee Discussion of Questions
	7		DR. CHESNEY:  Thank you, Dr. Hamilton.  Are there
	8	any questions for this presentation?  Dr. Nelson?
	9		DR. NELSON:  In making labeling changes or adding
10	things to labeling, can you use data from any source,
11	assuming it is quality data, or does it have to come only
12	through certain avenues, such as industry avenues?
13		DR. HAMILTON:  Usually information is submitted by
14	the sponsor.  There certainly have been instances where we
15	have presented information and moved into the label.  Now,
16	in terms of third parties presenting information, I don't

17	know and I am going to defer to someone else.
18		DR. KWEDER:  The labels actually are legal
19	documents that really do belong to the pharmaceutical

20	sponsors.  So, for us to just take something and put it in
21	the label isn't really typically something that would be
22	done but there certainly have been cases, as Dr. Hamilton
23	mentioned, of us becoming aware of some data and then

24	working with the sponsor to say, you know, we think this is
25	important and it needs to be in the label.  Usually, by

		70 1	taking that approach and having a cooperative discussion,
	2	that is the way progress is made.
	3	          DR. MURPHY:  Before you go on, I wanted to say a
	4	little bit more in that area because in the whole are of
	5	pediatric drug development that has been one of the big
	6	issues.  Why can't FDA just take information and put it in
	7	the label?  And, as Dr. Kweder has clearly outlined here, we
	8	have to work with the sponsor in developing the information
	9	that goes into the label unless it is clearly a safety issue
10	-- particularly then, we work with the sponsor in trying to
11	create the message that we think it is appropriate.  So,
12	have there been instances where the agency has gone out and
13	gathered information, published the process in the Federal
14	Register?  Yes.  Rare.  It has been done but it is a very
15	unusual approach and must rise to the level really of a
16	safety issue for us to be able to do that.
17	          DR. NELSON:  Just as a follow-up though, if one of
18	the desires that I heard earlier is just to get information
19	into the labeling, given the difficulty in gathering
20	information even if it is positive information that reflects
21	the safety of a particular drug, not the lack of safety, and
22	if NICHD or other people are sponsoring the research, I
23	guess the question is, is there any way to get that research
24	information into the label so people have access to that
25	information independent of whether it is a safety issue for

			71 1	the drug.  It might be an improvement in safety information
	2	that would lead people to feel that it is safe to use.
	3		DR. MURPHY:  Again, we would encourage them to
	4	work with the sponsor.  I know there are times when this is
	5	additional effort for the sponsor, to do this, and there
	6	have been some situations where a sponsor has preferred not
	7	to do this.  In that situation, as I said, to be able to get
	8	the information in the label we need to have the data; we
	9	need to have the evidence-based information; and then we
10	have to have some public submission that this is a concern
11	or an effort, and then we would address it.  Would we then
12	potentially go to the sponsor and ask them?  That is another
13	possible route but it would, you know, need to come to our
14	attention and that it is a concern that we think needs to be
15	put in the label and then we could approach the sponsor. 
16	So, that is another alternative route.
17		DR. CHESNEY:  Dr. Koren?
18		DR. KOREN:  Thanks.  I think one has to separate
19	two things.  I am sure all sponsors will want to know
20	information which was published and to include it.  But I

21	think the same way the agency expects standards from other
22	parts of pharmaceutical research, for example, if someone
23	claimed bioavailability you have very strict guidelines for
24	what you want to see, and if the sponsor would come without
25	it you probably will send them home to come back with it. 

			72 1	So, I think the issue here is the expectations that the
	2	agency developed towards this field and not so much if
	3	Koren, Atkinson or someone else did the research.
	4		There are several things in the science of this
	5	field that you have to recognize.  First of all, many of the
	6	statements that Holli showed us are not up to date, namely,
	7	there is information out there that no one bothered to put
	8	into the label.  So, I don't know that this should be the
	9	expectation.
10		But, more importantly, the science has moved too. 
11	In Australia, Beggs and Atkinson, about 15 years ago, came
12	out with a formula which predicts very well maternal plasma
13	and milk ratios based on lipophilicity, pKa and protein
14	binding.  This can be calculated for every drug because
15	these three parameters are known.  So, I don't see a reason
16	why they should not be in the label.  They are available for
17	every drug.  So, it can end up based on Atkinson, and so on,
18	not more than one percent of maternal dose can be expected
19	to be consumed by an infant.  That is very useful for the

20	health professional and it exists.  But at the present time
21	there is no such expectation.  So, I would want to see the
22	agency developing new expectations.
23		Last but not least, thousands of American women
24	take medications while breastfeeding every year or every

25	day.  Why won't we expect the manufacturers to conduct these

			73 1	studies the same way you ask for other things?  These women,
	2	unlike pregnancy itself, these women are within the labeled
	3	indication.  Women, when they are breastfeeding, are allowed
	4	to take these drugs by the label but they are exposing
	5	another human being.  So why not have a set of expectations
	6	similar to many other things you do in the industry?
	7		So, my hope, and I am sure it is the hope of many
	8	clinicians in this field, is that the FDA -- as the FDA was
	9	the leading force in FDAMA and many other things -- will set
10	up a new set of expectations from the industry.
11		DR. CHESNEY:  Dr. Fink, I think you were next.
12		DR. FINK:  I think that this is an area that
13	becomes very complex because if I were an industry sponsor
14	of one of these medications I would do everything possible
15	to avoid any labeling of my drug as safe for breastfeeding
16	without tort reform.  We locally have a firm called Ashcroft
17	and Gerel who has been widely advertising on the radio a
18	registry of infants who were exposed to cisapride, where
19	there is medically known toxicity and yet they are already
20	publicizing a class action suit for infants exposed to
21	cisapride.  I think this is one area where there really may
22	be, at least by sponsors, a real perceived liability and
23	without some tort reform you would be somewhat crazy to want
24	to label your drug as safe for use during breastfeeding

25	because some lawyer group or some plaintiff's lawyer will

				74 1	find some way to implicate it in whatever happens to a
	2	child.  I think this is one area where tort reform might
	3	really be important.
	4		DR. GORMAN:  Does the FDA have some ability to
	5	decide where information on the label gets repeated?  Under
	6	the lactation use, could you put that it is approved for
	7	pediatric use, and then put the conditions in there?  The
	8	reason being that if mothers know that if pediatricians give
	9	it to their children therapeutically, they may feel more
10	comfortable taking it themselves.  So, if there is pediatric
11	labeling, could it be then included?
12		DR. KWEDER:  That is certainly something we could
13	explore, how does the pediatric experience translate to this
14	use, for example, where you would have information on
15	neonatal use, at least to understand the safety profile, for
16	example.
17		DR. GORMAN:  What I am saying is if you take a
18	drug like amoxicillin, you say amoxicillin is has a
19	pediatric indication.  Maybe it is not labeled for it at the
20	moment, but if it is labeled that could then be included in
21	the lactation section and the mother would then feel more

22	comfortable if their doctor gave it to their baby.
23		DR. MURPHY:  Actually, I think that is a very
24	interesting suggestion because we do that throughout the

25	label, we cross-reference from warnings to clinical studies

			75 1	and if there is information that might be something that we
	2	could do.
	3		DR. CHESNEY:  I have a question for Dr. Hamilton
	4	which is not originally my question, but is there any reason
	5	you can't put in the label that breastfeeding is well-known
	6	to be an extremely positive experience, or an extremely
	7	positive thing for the infant?  I am not phrasing that very
	8	well but are you precluded from putting that in?
	9		DR. HAMILTON:  I showed you the existing
10	regulations.  I mean, I don't think we are precluded from
11	putting that in but, as I said, we are hoping to move

12	forward with the new regulation and that is why we are
13	soliciting your input.
14		DR. MURPHY:  I think that is a very important
15	point.  We have been working on this in the area of
16	antibiotics for a long time about antibiotic resistance. 
17	For us to have a standardized statement in the label, we

18	have to have, you know, a rule-making process.  So, that is
19	one of the reasons you are here today.
20		DR. KWEDER:  But there are examples where we have
21	done things like that before.  Sometimes with a rule-making
22	process, you know, all labels will now say X, You or Z, but
23	there have been examples -- the one that comes to my mind is
24	with drugs to treat with HIV.  In the lactation section we
25	include a statement about the CDC recommendations against

			76 1	breastfeeding because of the possibility of transmission. 
	2	That only applies to a very narrow range of products.
	3		But I guess I would put the question back to the
	4	committee, and one of the things we are dealing with here,
	5	as I think Holli described nicely, where there is an absence
	6	of information historically we have taken a very cautious or
	7	conservative and almost restrictive posture, not being very
	8	permissive about concomitant breastfeeding and use of a drug
	9	for the mother.  Do you think that some statement that tries
10	to characterize, in the absence of information, what the
11	benefits of breastfeeding are would be an appropriate thing
12	to include in a label?
13		DR. CHESNEY:  Well, back to our questions to be
14	specifically addressed, Dr. Friedman?
15		DR. FRIEDMAN:  I wonder if you could tell us a
16	little bit about what FDA does in an attempt to keep this
17	portion of the label up to date, and what you foresee in the
18	future, as the labels are changed, in terms of keeping it up
19	to date because as we are successful in encouraging people
20	to do more research in this area that will become an
21	increasingly important issue.
22		I also wonder if you can comment on the
23	possibility, although the FDA doesn't pick and choose drugs
24	in a particular class, is there any way you could let

25	physicians know that within a particular class of drugs

				77 1	these ones have information on breastfeeding and lactation
	2	effects and these ones just don't have information?  Because
	3	a physician might prefer to choose a drug from a group that
	4	has information and that would encourage the drug companies
	5	to gather that information.
	6		DR. HAMILTON:  With respect to updating this part
	7	of the label, there are no requirements that I can find. 
	8	With the pregnancy piece, we are looking forward to ICHE2C
	9	which requires periodic updating of pregnancy experience but
10	I don't think that applies to lactation.
11		DR. FRIEDMAN:  And it couldn't be applied to
12	lactation?
13		DR. HAMILTON:  Well, I don't believe that
14	currently it does.
15		DR. KWEDER:  It could be.
16		DR. MURPHY:  We do have a requirement for annual
17	submission of information.  That is not a labeling
18	supplement.  I know we are getting into details you probably
19	don't care about, but we have annual reports in which they
20	are required to update some of the information that is
21	available.  Certainly, if there is relevant information in
22	that annual report which we think would be important to get
23	into the label, we would go back to the sponsor and ask for
24	a labeling supplement update.
25		I think this is an area that the FDA was looking

			78 1	at very hard.  Actually, we have had a number of discussions
	2	that we are embarrassed by some of our labels, particularly
	3	recently somebody was showing me some of the antibiotic
	4	labels.  They are in need of updating, and this is a huge

	5	task and Dr. Woodcock has made it a priority along with a
	6	number of other priorities that we have, for us to try to
	7	begin to look at updating many of our labels which are in
	8	need of such.
	9		DR. FRIEDMAN:  What about the possibility of

10	letting people know which drugs in a class have adequate
11	information on breastfeeding?
12		DR. KWEDER:  I think there are ways to do that
13	creatively that wouldn't even necessarily have to be
14	anything that the FDA did.  I mean, the FDA could collect
15	that data and other groups could certainly collect that data
16	and publish it as they see fit.
17		DR. WARD:  But, Sandy, it would be such an
18	advantage if that were in the back of the PDR as a list by
19	generic drug name, rather than by the trade name even, since
20	there might be multiple manufacturers of a given generic.
21		DR. KWEDER:  Just to make sure that is clear, the
22	PDR is not owned by the FDA.  That is a private enterprise. 
23	But, you know, something on the FDA web page, for example,
24	if there were a component under pediatrics or drugs for
25	special populations.

			79 1		DR. MURPHY:  You know, I think I will take that as
	2	a request that Sandy's group should write a paper on this
	3	area and submit it --

	4		[Laughter]
	5		-- secondly, as Sandy said, one of the things we
	6	have done in pediatrics is to have a web site.  Again, we
	7	can only tell you what is public information.  That is all
	8	you really want to know.  We can work on that.  Right,
	9	Sandy?
10		DR. CHESNEY:  Dr. Koren?

11		DR. KOREN:  I want to go back to the advantages of
12	breastfeeding.  Without being a motherhood statement, I
13	think there must be a way to include it in the risk/benefit
14	assessment, something to the effect that one has to bear in
15	mind that stopping breastfeeding may have its own risk
16	because clinicians don't always think about it, and it is
17	not just happening to poor Americans or Canadians; even with
18	the well to-do people there are very well confirmed
19	advantages of breastfeeding.  So, I think we should be using
20	it as a motherhood statement that needs special ruling but,
21	rather, as you do in any other things.  I think it was Sandy
22	who said that with HIV drugs you have to mention that these
23	also transmit the virus.  Indeed, in North America we tell
24	women not to breastfeed but in Africa the WHO tells them to
25	continue because the risk of not breastfeeding in Africa is

			80 1	a risk of mortality.  So, here is an example of why this
	2	must be there.  The advantages of breastfeeding must be put
	3	in the statements because that is something that we have
	4	relative risks on, on many morbidities, whereas we don't
	5	have it on breastfeeding.  So, I cannot see how a new system
	6	of labeling breastfeeding without talking about the risk of
	7	not breastfeeding makes any scientific sense.
	8		DR. CHESNEY:  Yes?
	9		MS. CONOVER:  One of the interesting things is in
10	the vacuum of lactation information.  I run a Teratogen
11	Information Service, and we get people that use our favorite
12	FDA pregnancy codes to make recommendations about lactation
13	really much more frequently than you might guess.  So, they
14	will call up and say, well, it is a category B and I would
15	like to use it in a breastfeeding woman -- sort of this
16	assumption that the risks are the same and, of course, they
17	aren't.
18		So, you know, very clearly we need to, first of

19	all, I mean it seriously, separate the pregnancy issue from
20	the lactation pretty clearly even just in the labeling
21	because I find it so frequently -- and it sounds humorous
22	but it is really a misconception.
23		The second thing is not only is the impact

24	different on the baby but you really have different
25	strategies you can use in a breastfeeding woman and, for us,

		81 1	when we answer questions on this it isn't an all or nothing. 
	2	There are a few medications you would never use and some
	3	that you don't worry about at all.  But, for us, most of it

	4	comes in between so you start dealing with issues like drugs
	5	with a short half-life.  We suggest that they nurse before
	6	they take the medication.  Or, for example, with certain
	7	agents you can defer nursing for 24 hours.  We have lots of
	8	strategies that we don't have the option of using in
	9	pregnancy women but we do in breastfeeding and we use them
10	all the time for things like dental surgery -- I mean, lots
11	of things.  We used to have people tell people they just had
12	to stop breastfeeding forever.  Now what we do is, you know
13	use a topical instead of an oral; as I say, defer for a
14	certain period of time.  It allows us to give women a lot of
15	peace of mind while they continue nursing.
16	          What that kind of brings me back to is the place
17	in the label when we start discussing clinical
18	considerations of half-life -- that it is not just what is
19	excreted in the breast milk at that minute in time but what
20	might be other strategies that you could use to enhance the
21	safety of the situation.
22	                    Open Public Hearing
23	          DR. CHESNEY:  Good suggestion.  I think we
24	probably need to move ahead to the open public hearing.  I
25	know one person did have something to add and I don't know

			82 1	if there is anybody else who wanted to make comments.  Dr.
	2	Yafee?
	3		DR. YAFEE:  Thank you very much.  Sumner Yafee,
	4	from National Institute of Child Health and Human
	5	Development.  I want to respond to some of the comments
	6	made, particularly those of Dr. Ward, about research
	7	funding.  First of all, I must say, I support the need for

	8	more research regarding the excretion of drugs into breast
	9	milk and, secondly, I certainly support breastfeeding as the
10	best way to go for the health of the newborn infant and
11	mother.
12		From a perspective of research funding, I thought
13	of a number of sources of funds.  Let me start with the NIH. 
14	First of all, anyone in the room can apply for a research

15	grant.  There is no prohibition even for Canadians getting
16	to apply for a research grant.  The chances of success --

17	you know, all research grants at NIH are hypothesis driven. 
18	So, you have to have a hypothesis.
19		Secondly, about 90 percent of the grants at NIH

20	are awarded to Ph.D.'s.  I have nothing against Ph.D.'s but
21	they are not interested in clinical research; they are

22	interested in molecular biology, using the techniques
23	available to ascertain processes of development or of

24	disease mechanisms -- molecular biology, molecular genetics.
25	So, of the 30,000 grants that are submitted a year, if you

			83 1	submit one on lactation and you have a hypothesis and you

	2	are looking at a mechanism, it will probably be assigned,
	3	undoubtedly, to NICHD, National Institute of Child Health
	4	and Human Development.  It will be reviewed by a study

	5	section that may or may not have the same feelings that the
	6	group has expressed today, but they will be looking at the
	7	science.
	8		Now, from the perspective of NICHD, we have
	9	certain priority initiatives that are developed within the
10	source of funding that we have and it is a small amount of

11	money that we get every year from the Congress.  I hope this
12	year we get one billion dollars.  We are approaching that. 
13	We don't have an appropriation yet from Congress, but it
14	looks like we will get a 15 percent increase maybe.
15		Now, there is one study in which lactation could
16	be -- gathering the data that you are talking about, that is
17	on the drawing board.  It depends a lot on politics, and
18	that is a recapitulation of the pregnancy study that was
19	done in the '60s, 50,000 mothers and babies.  The plan is to
20	perhaps expand that to 100,000 provided we can find the 500-
21	plus million dollars that are required to do the study.
22		That would be a natural study in which drugs and
23	lactation effect on the infant, concentration -- everything
24	that we heard today from a variety of speakers could be
25	plugged in because it is going to study the natural,

			84 1	longitudinal history of mothers during pregnancy.  It has
	2	been endorsed by the Secretary of Health and Human Services,
	3	but her tenure is up for grabs because she is appointed by
	4	the President and I can't tell you how that position is up
	5	for grabs too, although according to the polls this morning,
	6	Al Gore was leading by 42 percent, or something.
	7		Anyway, getting back to the seriousness of
	8	funding, within NICHD, which is the natural institute to
	9	fund the study of drugs in breast milk, we have a number of
10	priorities that we have developed in pediatric pharmacology
11	which are already on the drawing boards.  We are interested
12	in mechanisms of developmental pharmacology, basic
13	mechanisms.  That is already out there in applications.

14		We are interested in working with the National
15	Institute of General Medical Sciences on pharmacogenetic
16	bases of drug action and pharmacogenomics, and that is
17	already on the drawing board.
18		So, these take precedence.  Finally, within or

19	priority area at the Institute level, because we have a wide
20	variety of areas to cover and lactation is only one of many,
21	we do have, together with our sister agency, the FDA, a plan
22	to look at drugs and pregnancy, and we have separated drugs
23	and pregnancy from drugs and lactation, as one of the
24	speakers suggested that this be done.
25		This initiative, looking at drugs given to

		85 1	pregnant women for therapeutic purposes will be taking
	2	place.  One conference is later on this month and another
	3	one is in December, and we hope to develop sufficient
	4	interest on the part of policy makers to alert them to the
	5	problem -- I can count on one hand or certainly on two, the
	6	drugs that have been studied in progress women, and there is
	7	an absolute necessity to gather more information so that one
	8	can prescribe drugs -- obstetricians and general
	9	practitioners -- for diseases that occur in pregnancy women,
10	and developing rational therapy for these diseases, which
11	means more research.  The same is true, obviously, for
12	lactation.  We need the information which everyone has
13	suggested that we obtain and Dr. Hamilton suggested that the
14	label change requires that information.
15	          And, where are we going to get it?  I can tell you
16	from my personal perspective, the pharmaceutical industry --
17	and Dr. Spielberg can contradict this -- is not interested,
18	just as they are not interested in studying drugs in
19	progress women.  They have a fear which is justifiable of
20	medical-legal liability, and this will occur particularly in
21	the psychotropic area where drugs' long-term effects are
22	unknown.
23	          So, I would discount the pharmaceutical industry. 
24	I would also discount that the FDA would have funds to put
25	into this area.  But there are a number of places, including

			86 1	NIH and NICHD, that would be interested in receiving
	2	applications.  Again, they have to be hypothesis driven and
	3	fundamental, basic in terms of mechanisms that might be at
	4	work.  But the review of Maternal-Child Health which is part
	5	of Health Services Administration, would be very interested
	6	in receiving grant requests, and anyone in the room can chat
	7	with them but this might be part of the public record.
	8		Also, AHRQ, Agency for Healthcare Research and
	9	Quality, would be very interested.  They are interested in
10	effectiveness of services delivered, and they will be having
11	a meeting on Monday and Tuesday on improving the outcome of
12	pregnancy and I certainly will bring lactation to them. 

13	Just as we have separated, maybe they will incorporate it
14	into their initiatives.  They do have a significant amount
15	of money that will be appropriated to them over their
16	current budget.
17		Then, there is the March of Dimes.  They are

18	interested in pregnancy outcome, obviously, not just
19	restricted to birth defects but they might be interested in
20	funding studies concerned with drugs and lactation.
21		Then, I have singled out ORWH, Office of Research
22	of Women's Health which is at NIH, and you might want to

23	contact them.  Pregnancy is an important part of their
24	mission.
25		Finally, the Environmental Protection Agency is

			87 1	interested in drugs and chemicals in the environment.  Drug
	2	exposure of infants -- breast milk is one method of
	3	exposure.
	4		I might mention that we, as an Institute, have a
	5	global effort to look at developing countries.  We have a
	6	bequest from the Gates Foundation which enables us to
	7	support studies of cooperation between researchers in this
	8	country and in developing countries, improving pregnancy
	9	outcome.  Part of this would involve lactation, and
10	lactation in HIV-positive women where we know that perhaps
11	60 percent of their infants will develop HIV, and these
12	women will be receiving drugs not only for HIV but for other
13	concomitant infections which are common in this disease.  It
14	is possible to gather some information about drugs excreted
15	in breast milk.  Even though I know the CDC has put out an
16	announcement against breastfeeding in HIV, that only
17	pertains to this country.  There is no question that in
18	developing countries breastfeeding is the only method of
19	survival of infants.
20		Finally, since Bob Ward posed the question, I
21	wanted to mention the American Academy of Pediatrics.  The
22	Academy has a PROS network, Pediatric Research in an Office
23	Setting, in which there is now a new center for child health
24	research.  This involves the 55,000 members of the Academy
25	of whom a significant number have agreed to do research with

			88 1	little remuneration.  Now, this is an area where a lot of
	2	research could be done regarding concentrations of drugs in
	3	breast milk.  There is a small amount of money available
	4	within the Academy to do this study.
	5		The last suggestion about funding is just go to

	6	Congress -- not the government people but go to Congress;
	7	tell them what a problem you have about drugs and breast

	8	milk and get congressmen or congresswomen interested in the
	9	problem and then money will flow.  Just as FDAMA originated
10	basically from the Elizabeth Glazer Foundation, having to do
11	with HIV and the basic concept of FDAMA and the pediatric

12	section of 111 came from people on the Hill that were paid
13	for by the Elizabeth Glazer -- not congressmen, but other
14	people.
15		Thank you very much.  If there are any questions
16	about any of this, I would be pleased to answer them.
17		  Subcommittee Discussion of Questions
18		DR. CHESNEY:  Thank you very much for your

19	comments.  I think the PROS network is an excellent
20	suggestion.
21		We have three questions that the FDA has asked us
22	to address.  The first one, is maternal drug therapy during
23	lactation an important health issue for infants?  Is there
24	anybody who would disagree with that statement?  Is there
25	anybody that would say, no, it is not an important health

			89 1	issue for infants?
	2		[No response]
	3		Maybe we can then go on to the specifics.  Moving
	4	on to the bullets of that question, how should fundamental
	5	data be derived to determine if a drug is expressed in
	6	breast milk; whether a drug found in breast milk is
	7	available to the infant; and, when it is available, what is
	8	the risk or lack of it to the nursing infant?
	9		Comments for question one?  Dr. Nelson?
10		DR.  NELSON:  I have been wearing my IRB hat here
11	for a little while, trying to think about how a design might
12	look to me if I received a protocol, and it strikes me from
13	Dr. Koren's remarks that the first question can be
14	calculated from known data.  So, the real issue is not so
15	much whether it is or is not expressed, although perhaps you
16	might want to confirm that, but what its bioavailability is,
17	with breast milk being considered a formulation, and then
18	what is the impact on the infant.
19		So, I was thinking to myself, well, how could that
20	be studied.  I mean, you recruit women who become pregnant
21	on a protocol -- the usual approach is to exclude that
22	individual and I can't imagine a pharmaceutical company that
23	is dealing with an unapproved agent, where there is an
24	approved agent on the market for the same indication, would
25	feel comfortable keeping that woman on the protocol just for

		90 1	the sake of finding out what would happen when she decides
	2	to start breastfeeding after birth.  So, you are looking at,
	3	if there is no approved agent dealing with that as a

	4	naturalistic experiment, or you are directly going to
	5	recruit women who are breastfeeding into your particular
	6	trial.
	7	          So, then the question comes down to what

	8	circumstances would you think that a woman who is
	9	breastfeeding would imagine remaining on a drug, and that is
10	going to be no different than the kind of clinical
11	circumstances you get in the office, meaning where a woman
12	believes that the importance of that medication to her own
13	health outweighs the risk that might be presented to the

14	infant, putting aside the question whether the data that
15	they receive when they make that decision is accurate. 
16	Let's assume it is accurate data.  So, they make that

17	judgment.
18	          Thinking of it from a research perspective, I
19	mean, if you believe that that medication is essential or

20	important to the health of the woman you would consider the
21	incidental risk to the infant as a justified risk.  Then the
22	research question would be on the effect on the infant and
23	measuring drug levels in the infant, which could be seen as
24	minimal risk research, giving a blood test and doing
25	whatever psychological or outcome studies, regardless of how

			91 1	hard that would be to do but doing some kind of study.
	2		But it would be clear to me that this would have
	3	to be a naturalistic -- I mean, the key assumption is that
	4	the medication is essential to the health of the woman.  So,
	5	I think the focus ought to be on those kind of medications,
	6	the medications where a woman would independently make a
	7	decision to remain on that medication, understanding that
	8	there is the potential for risk, with the potential for risk
	9	being the unknown question.
10		Once you answer that for a particular drug class
11	the problem is going to be in the informed consent process. 
12	We already have the information about this drug and you are
13	on this one.  Do you stay on this one we don't know about so
14	you can enter into this incidental study to look at the
15	effect on nursing, or do you switch to this one where the
16	information is known?  I suspect most women would probably
17	switch to the one where the information is known.
18		So, just from a practical matter, those are some
19	of the things I was trying to think through as I was sort of
20	designing a study that could answer that question.
21		DR. CHESNEY:  Dr. Spielberg?
22		DR. SPIELBERG:  Those are some of the same musings
23	I have had.  Looking at the question, I think there really
24	are two levels and one I think can already be addressed by
25	data that Dr. Koren has already developed.

			92 1		From all of our experience cumulatively, we know a
	2	small number of drugs which do carry high risk which have
	3	been established as causing risk, and a lot of compounds for
	4	which we have no information but for which we don't even
	5	have anecdotal reports of risk.
	6		Just as Dr. Koren did a bunch of years ago, I put
	7	together a list of ten compounds where a single dose or a
	8	single pill can cause toxicity and bringing the child to the
	9	poison center.  Okay?  That is terribly important
10	information because it eliminates an enormous portion of the
11	pharmacopeia for which a single pill basically is not a
12	cause for bringing a child into the poison center but if you
13	are on that list, you know immediately that is there.
14		That can't be put into something like the PDR
15	because that is not an appropriate place but, on the other
16	hand, the information on distribution, likely
17	concentrations, the kinds of things that you can calculate,
18	those compounds with known risk can be very well put
19	together in places like the USP and other sources where you
20	have a single source which is authoritatively reviewed, and
21	peer-reviewed internally by committees, etc., etc., with
22	knowledge in the area.  With that key information, those few
23	compounds that really are contraindicated are there and can
24	be added to as new compounds come by.
25		The second issue is what would we design in terms

			93 1	of a prospective study?  And, I think Skip got it exactly
	2	right, you are not going to design a double-blind, placebo-
	3	controlled trial where you are going to put people on drug
	4	and see what happens.  By definition, this is serendipitous
	5	exposure.
	6		Then, what kinds of systems work for ascertaining
	7	serendipitous exposures?  We have heard a couple of ideas
	8	around the table.  We have heard about registries and things
	9	like Motherisk and other places where people come in who

10	are, indeed, breastfeeding where at least the opportunity
11	might exist in the context of obtaining some information on
12	serum concentrations.  But even more than serum
13	concentrations it is really outcomes that we are really

14	concerned about.  Long-term outcomes I think, indeed, are
15	not going to be ascertainable.  I mean, no matter how much
16	we would like to know, if you are exposed to a
17	benzodiazepine when you are three months of age, what are
18	you going to be like at twenty?  I don't know, and there are
19	too many intervening variables anyway.  So, I think we
20	should at least just erase that from issues.  We just can't
21	do that.  But we certainly can look at the short-term
22	outcomes.
23		The PROS network is an interesting kind of an
24	approach.  I am looking basically for large, simple designs
25	where you can have a group of physicians who see

		94 1	sufficiently large numbers of children whose moms are going
	2	to be periodically exposed to drug, and a protocol where
	3	that serendipitous exposure occurs in the context of
	4	appropriate therapy for the mother because the mom needs the
	5	drug, be it short term or long term, the people involve don
	6	the pediatrics side will be monitoring those kids. 
	7	Sometimes it will involve a serum concentration.  More often
	8	it will be looking at outcomes and seeing if anything,
	9	indeed, happens to the baby, and accumulate that information
10	in the form of registries in a prospective way.  I think the
11	perinatal study was really a retrospective look.  I think we
12	can, in fact, do this prospectively through a PROS network
13	type mechanism if you have enough pediatricians involved

14	around the country or, for that matter, in Canada as well,
15	and use whatever serendipitous information comes in and in
16	an iterative way, over time, accumulate information.
17	          My guess is that other than the compounds that
18	really on basis of theory would accumulate in high
19	concentrations or would be likely to cause toxicity, or
20	those compounds which we already know cause toxicity --  my
21	guess is we probably will have relatively few problems.
22	          The other thing that I think we really should do
23	because we are studying so many drugs now in children, is
24	get that information in there because if we know in

25	therapeutic use what the side effect profile looks like, and

			95 1	if we know in ten-fold compared to what the breastfeeding
	2	exposure would be, that will be fine.  Having said that, the
	3	number of compounds that will be studied in the perinatal
	4	period is going to be relatively limited compared to the
	5	pharmacopeia that moms might be exposed to, and the types of
	6	drugs, other than the antibiotics and such, are likely to be
	7	different.  We are not likely to use lots of psychotropics
	8	and such in one-month olds.
	9		But, again, those are just some thoughts about how
10	to try to ascertain things, and it might well be worthwhile
11	discussing in the AAP context how to do some of these PROS
12	studies, and in the USP context how to pull together in a

13	systematic single source what we do know, and iteratively
14	update that.
15		DR. CHESNEY:  Thank you.  Dr. Friedman?
16		DR. FRIEDMAN:  I think we also need to give some
17	emphasis to the large number of drugs for which there is no
18	information even on pharmacokinetics.  One can do the
19	calculations but this is a 1986 recommendation that came

20	from the FDA, or a guideline that came from the FDA about
21	how to get information on how much drug is actually in the
22	milk, and in most cases it is going to be an extremely small
23	amount, much less than we worry about for pharmacologic
24	effect.  Knowing that, having that information in the drug
25	labeling would be very valuable.

			96 1		I would think that 14 years is probably enough

	2	comment period for this, and I wonder if maybe we can get
	3	these guidelines out and get information at least on the

	4	pharmacokinetics and what is available with respect to the
	5	amount of drug that the baby might ingest on every drug that
	6	has been approved.
	7		DR. CHESNEY:  Dr. Wisner?
	8		DR. WISNER:  I actually have a double-blind,
	9	placebo-controlled study which is being done in postpartum
10	women, and am beginning to appreciate that that is unusual.
11	The hypothesis, though, is rather different than what we are
12	considering here.  My hypothesis is that because postpartum
13	depression can be predicted to some extent -- women who have
14	had previous episodes are at high risk, all this study seeks
15	to do is show whether starting an antidepressant immediately
16	post birth is more effective in preventing recurrences in

17	this high risk sample compared to placebo.  The original
18	study was nortriptyline versus placebo.  The babies have
19	serum levels done at week three, and we had to build in a
20	set of toxicity monitoring.  So we have a pediatrician who
21	looks at the levels at that point and breaks the blind if
22	they are above a certain amount, and they are tracked for
23	the kinds of global pediatric type symptoms that one would

24	typically monitor in a study like this.  This is a study in
25	which we are doing the Actograph data because we felt it was

			97 1	very important to be able to look at that activity level
	2	information in an antidepressant-exposed group compared to a
	3	placebo-exposed group.
	4		Now, the sad news is that, in fact, we built in a
	5	planned interim analysis which showed that, in fact,
	6	nortriptyline was absolutely no better than placebo, and we
	7	pulled the trial because the justification for exposing the
	8	babies, that is, prevention of depression, didn't occur.  We
	9	are now repeating the trial with cetraline.  So, we will
10	have that same kind of data about cetraline.
11		I guess my point is that even though you are
12	saying this kind of data has to be collected
13	naturalistically, there are certain kinds of hypotheses in
14	other fields, like mine, where there is a chance to collect
15	data with a placebo control that can be justified.
16		DR. CHESNEY:  Excellent.  Dr. Nelson?
17		DR. NELSON:  Just to clarify as I was thinking
18	about it, I think it would be more accurate to say that
19	whether or not a placebo group is justified is based on the
20	hypothesis driven towards the women and not towards the
21	babies.  There are circumstances, and it sounds like that is
22	one of them, where a placebo group is appropriate for the

23	women's health and question, and then you collect the data
24	in terms of the impact on the infants, which is a more
25	accurate way in terms of what I was saying.  So.

		98 1	          DR. CHESNEY:  Yes?
	2	          DR. DATTEL:  I am a little troubled by the thought
	3	that we will be able to label products as completely safe
	4	for breastfeeding, with the exception of a handful of
	5	things.  I think despite no matter what elegant studies one
	6	designs, the variables are so overwhelming in terms of
	7	environmental exposures, individual exposures to different
	8	things based on their habits, vagaries of metabolism and
	9	methodologies of individuals in terms of how they breastfeed
10	that we will never be able to completely say that.  And, I
11	think that labels probably shouldn't say that unless there
12	is absolutely, basically 100 percent certainty that we
13	could.  Rather, it might be better to provide information

14	that we do have and that is available in terms of allowing
15	people to make a relative risk/benefit decision for
16	themselves because we are not going to be able to say for
17	100 percent of all babies ampicillin is safe.  You know,
18	that may not be the case for 100 percent; it might be for

19	99.9.  But we can say it is used in children.  These are the
20	pharmacokinetics of it, and it is expected that very little
21	is transmitted in breast milk -- whatever information
22	actually is tangible.  And, I think the studies are great

23	and I think they should be done but I am not sure that in
24	terms of labeling that is going to give the information we
25	need right now.

			99 1		DR. CHESNEY:  Thank you.  Dr. Koren?
	2		DR. KOREN:  I agree with Dr. Spielberg.  I think

	3	that we now have prospectively looked at thousands of women
	4	on medications and the babies, for the most part, didn't
	5	have any complaints that even led to going to a physician,
	6	let alone going to a hospital -- it is naturalistic but it
	7	has a lot of information in it.
	8		How safe is safe is always an issue, and it has

	9	its own merits and we talk in terms of powers and everything
10	else we know, but do remember that many of these women go on
11	misinformation and some of the way the labeling goes now is
12	clearly scary -- stop breastfeeding or stop medications, and
13	by itself each one has a much higher risk than that little
14	something we haven't found yet.
15		So, if the name of the game is to balance risk
16	with benefit, the risk of the label now is much larger than
17	the risk of the exposure.  And, I don't think our job is to
18	create risk by our labeling.  I hope I don't sound too
19	cynical, but we also do studies on how women perceive the
20	risks when they read these labels and, I can tell you, these
21	are very, very scary labels.
22		For example, as Holli showed, you should be
23	careful because many drugs go into breast milk.  Actually,
24	almost all drugs go if you have the right machine to measure
25	it but it is meaningless -- garlic too.

				100 1		[Laughter]
	2		It is true.  It is a small xenobiotic and unless
	3	something is large enough or polar enough, it will go.  So,
	4	this is an example where a wrong concept is introduced -- if
	5	something exists, it is dangerous.  It ignores totally the
	6	dose-response curve.  And, I agree that some allergic
	7	reactions and other idiosyncratic reactions don't need many
	8	molecules but, still, show me one child that had anaphylaxis
	9	from oral penicillin even when they are treated.  I don't
10	think you will find it.  So, I think the science of
11	pharmacology, as it is being practiced in 2000, has to find
12	a way into the label.  It is now not there.  First year

13	pharmacology students would not approve these labels.
14		DR. CHESNEY:  Thank you, Dr. Koren.  I think
15	probably we would all agree that this is a strong

16	recommendation we would like to make, which is that we don't
17	want to create more risk by discontinuing breastfeeding, as
18	you so aptly described in the young woman in Toronto who did
19	not choose to take the drug that might have saved her life
20	because she wanted to continue breastfeeding.
21		Dr. Kweder, have we answered question number one
22	to your satisfaction?  Can we move on to number two?
23		DR. KWEDER:  Yes.
24		DR. CHESNEY:  Thank you.  What products or types
25	of therapies are most important to study, those for

		101 1	conditions common in young women:  Those for chronic
	2	conditions?  Or, those for life-threatening conditions?  Why
	3	did we prioritize, if we prioritize, and are there
	4	characteristics that are common across products or groups

	5	that make them a high priority?  Who would like to start
	6	with that?  Dr. Nelson?
	7	          DR. NELSON:  Thinking about just the feasibility
	8	of study design, if you are sitting down to talk with a
	9	woman who is nursing about the relative risk and benefit of
10	being in the study, the drug involved would have to be
11	important enough to her health for her to consider taking
12	it, or to continue taking it with the question of risk to
13	the infant.  Whether that is common condition, chronic

14	condition -- I mean, clearly, life-threatening would fit
15	that but it would be more towards something where a woman
16	would make a reasonable choice to continue, otherwise we

17	would end up with everybody deciding to go out of the study
18	or not remaining on it for that purpose.  So, that would be
19	my guess.
20	          MS. CONOVER:  I mean, I think those are really
21	important in terms of the questions that we answer, I would
22	remind you there is suboptimal length of continuing
23	breastfeeding that really is based on how many barriers we
24	place to women in terms of that, and that means that if you
25	have really bad hay fever and you want to do something about

		102 1	your allergies, and you can't breathe at night and your kid
	2	doesn't sleep very well anyway, and we suggest that, you
	3	know, it is hard to make a decision about antihistamines and
	4	breast milk -- those may not be critical to her health but

	5	they are involved in her comfort and if we say month, after
	6	month, after month, after month -- you know, if we don't
	7	know very much about antihistamines and breast milk; they
	8	weren't in the group we chose to study because they aren't
	9	crucial to your health -- I mean, we can always use that as
10	an argument and you will find that women will discontinue
11	breastfeeding earlier.  So, there are a lot of these things
12	that are not absolutely critical to health but they do
13	involve comfort.  I don't mean that women take that lightly

14	because they care deeply about their babies, but if you just
15	keep making things uncomfortable in that sense -- so, it is
16	not like an antihypertensive; it is not like an
17	anticonvulsant, but it makes a difference in her life, even
18	things like NSAIDs or things like that which she might take
19	for a headache -- it makes a difference in whether someone
20	breastfeeds for six months or a year.
21	          DR. CHESNEY:  I think that is a very important
22	point.  Dr. Spielberg?
23	          DR. SPIELBERG:  I think one interesting aspect of
24	this that is very different from pregnancy is that an awful
25	lot of pregnancy exposures occur before anyone knows they

			103 1	are pregnancy.  Here you do, indeed, have choice of types of
	2	medication because you know you have a baby and you know
	3	that you want to breastfeed.
	4		There are old statements about therapeutic

	5	nihilism and don't adopt new drugs that are less well
	6	studied in favor of drugs that you know well and have been
	7	well studied.  For many of the classes of things like
	8	medications for headache or antihistamines and such, in
	9	fact, data for just a few compounds would be tremendously
10	useful, just knowing that those few compounds are, indeed,
11	safe and have no problems have developed because there are
12	always going to be choices of drugs available out there. 

13	So, for those kinds of things and for OTC products and such, 
14	I think it would be worthwhile having some basic information
15	but we already do have an awful lot of information on a lot
16	of these products because these tend to be rather widely

17	used.  Having that information systematically available to
18	moms and to physicians is obviously of real benefit.
19		For the other kinds of things, again, one is going
20	to make a choice.  For symptomatic things you are going to
21	make a choice of whether I would rather have a slight
22	headache or whether I would rather take a pill, and if you
23	are going to take a pill, have advice on which one of those
24	to take.
25		For more serious illnesses, indeed, there are

			104 1	going to be situations where, indeed, maternal health is
	2	really an issue.  I think of those compounds which, in

	3	general, tend to be more, if you will, potent directed
	4	towards specific receptors, really looking for significant
	5	therapeutic effects, it is those groups of drugs where moms
	6	really are going to be taking them either acutely for a
	7	life-threatening infection, a life-threatening what-have-
	8	you, versus those compounds which are going to be used

	9	chronically for serious illnesses where, indeed, there isn't
10	going to be a choice of whether to be on a drug.  You have
11	to be on a drug and, therefore, those drugs need to be
12	studied.
13		DR. CHESNEY:  Dr. O'Fallon?
14		DR. O'FALLON:  I have been very troubled by this
15	implicit attitude or information concept here that because
16	lots of women have been treated with these things and no
17	particular problems have been reported, therefore, therapy
18	are probably okay.  This comes out of my 25 years in
19	clinical trials.  I have seen loads -- I mean, just name it,
20	if you don't look, you don't find.  And, stuff is constantly
21	under-reported because there weren't absolute rules in place
22	or procedures in place to make the observations.  So, sort
23	of waiting for people to tell you about it I think is going
24	to lead to an under-reporting of the problems.
25		I wasn't real happy with the answer to that first

			105 1	question because I don't think we have a very good idea
	2	about what the risks really are and I think that they have
	3	to be studied.  Now, it is such an overwhelming problem with
	4	all of the stuff out there that it would have to be done
	5	very, very carefully, and I think the idea of a data bank,
	6	with well-defined rules for observation, might very well
	7	work if you picked certain types of medications.  That sort
	8	of thing could be done, but I don't think the fact that we

	9	haven't heard anything bad about it really tells us
10	anything.
11		DR. CHESNEY:  Dr. Koren?
12		DR. KOREN:  I agree with this comment.  We do
13	everything prospectively and we have a protocol that is
14	followed very accurately.  The question whether diarrhea

15	reported by a mother is diarrhea that the pediatrician would
16	agree with, but then you have controls.
17		But I would say there are three groups I would

18	recommend to study.  One is drugs that have theoretical
19	basis to assume that the exposure is high, based on known
20	methods to calculate it.  And, it can be a drug that just
21	entered the market yesterday.  We know the pKa; we know the
22	protein binding; and we know the lipophilicity.  These are
23	measured by relatively simple physical ways.  So, this is
24	one group that must be.
25		The second are common drugs for reasons that were

			106 1	mentioned, and I don't think we should underplay the
	2	importance of women treating their pains because women tend
	3	to orphan themselves and to be martyrs, and lose their teeth
	4	because of many reasons.
	5		The third group are drugs for chronic illnesses
	6	because the three studies we completed clearly show that
	7	women exposed to 5-aminosalicylic acid, antileptics and PTU
	8	-- these are three things we followed, stopped
	9	breastfeeding.  They stopped breastfeeding although these
10	drugs are safe based on evidence collected by different
11	people.  So, I would be concerned about that too.
12		Now, this sounds like a large group of women and
13	compounds but, to reiterate what Steve Spielberg said, out
14	of all analgesics if one can come up with ones that look to
15	be at lower level in breast milk, this is very important
16	information for the physician to make a decision as to what
17	to give.  Clearly, the high exposure ones should be higher.
18		Last but not least, there are drugs that you don't
19	want a baby to be exposed to such as anti-cancer drugs and
20	radionuclides, which almost goes without saying, and there
21	may be new, very potent molecules that just
22	pharmacologically don't make sense to expose a suckling bay
23	to at all.
24		DR. CHESNEY:  Dr. Anderson?
25		DR. ANDERSON:  Yes, I would like to just emphasize

		107 1	a little bit opioid products, narcotics.  I think that is
	2	one instance where we see sometimes a little bit cavalier
	3	prescribing and we do see babies getting very sleepy, to the
	4	point where they are not nursing enough to gain weight
	5	adequately.  You know, it is dose related, but it is an area
	6	that I think sort of goes the other way from everything se
	7	have talked about today, and that might be something to put
	8	some effort into.
	9	          DR. GORMAN:  I am putting on my IRB hat, like Dr.
10	Nelson, now.  The naturalistic studies where women choose to
11	continue to take medicines while they are breastfeeding seem
12	to me to have very few problems going through an IRB.  The
13	woman has already made the decision for her risk/benefit. 
14	But if you wanted to do a control group, getting back to "if
15	you don't look for it you don't find it" or are they really
16	different from other babies, what control group would you
17	suggest?
18	          DR. KOREN:  I can just tell you what we do.  If we
19	have 30 calls a day, most of them with no problem, we follow
20	up that group too.  So it is an observation that is
21	naturalistic, but if the drug in question is an opioid, say,
22	codeine or anyone you choose, you choose a group exposed to
23	a drug, say acetaminophen.  You have control on the
24	reporting bias.  They are using the same.  And, still you
25	measure many characteristics of the two groups to be able to

			108 1	covary on them, say, women who use narcotics are very
	2	different from other women.
	3		Observational studies, as we said this morning,
	4	just recently compared to RCTs in several New England papers
	5	back to back, we did the same in pregnancy now on anti-

	6	hypertensives.  There is a lot of value in well-designed
	7	observational studies.  Yes, if we could do RCTs, but I
	8	totally agree with you that ethically, except for a

	9	situation like described by Katherine, and then actually she
10	proved with a placebo trial that the tricyclics did not work
11	-- so, very rarely will you have that paradigm.  Mostly, I
12	don't think an IRB in North America or anywhere would

13	approve an RTC, but that does not mean that you cannot
14	control.  I mean, there are many observational ways to

15	control and we do it all the time.  It is not ideal because
16	you may not know what you didn't control for.  That is
17	always a problem, but if you have a good hypothesis and good
18	thinking, and you have a good collection of data, you can

19	address most of these things, including socioeconomic and
20	including the IQ of the parents.  We do those too.
21		DR. CHESNEY:  Thank you.  I would like to make a
22	comment.  I would like to add psychoactive or psychotropic
23	drugs to be sure they are included under chronic illnesses
24	because I think many of these drugs we haven't had around
25	for very long.  So, although we may have gotten away with

			109 1	other drugs, we may not get away with these, and I have
	2	significant concern both for the health of the mother if she
	3	discontinues those, as we have already had the example, and
	4	concerns about the effect on the immature or developing
	5	brain.  So, I would just like to be sure that they are
	6	included in the chronic illness category.  Yes?
	7		DR. DATTEL:  In thinking about what types of
	8	therapies or drugs are most important to study, a little bit
	9	different than the discussion on pregnancy where you can
10	group women of reproductive age, you actually do have data
11	sources to tell you -- and they are going to be different --
12	one of the most common drugs, during labor and delivery and
13	the immediate newborn period are exposed to, and I would
14	make sure that I included those, and that takes into account
15	a lot of opioids.  Most people have some type of analgesic. 
16	They may have long-standing epidurals, they get a 30 percent
17	C-section rate and antibiotics of all sorts.  So, you are
18	going to have a list of things that are going to be
19	concentrated in breast milk for the first couple of days. 
20	So, if you are going to prioritize, rather than do a whole
21	global thing of the most commonly used, I would look at
22	labor, delivery and postpartum as well as chronic illness.
23		DR. CHESNEY:  Yes, Dr. Luban?
24		DR. LUBAN:  I think we also have to remember that
25	many postpartum women take naturopathic medications, and

				110 1	those may do something to alter the transmission of the
	2	drugs in breast milk.  So, they should not be forgotten.  As
	3	a pediatric hematologist, I am diagnosing more and more
	4	infants with easy bruisability because the mothers are
	5	taking echinacea and they are breastfeeding.
	6		DR. CHESNEY:  Is that a thrombocytopenia?
	7		DR. LUBAN:  No, it probably is an inhibition of
	8	thrombin.
	9		DR. CHESNEY:  Do we have to add alternative
10	medicine as a priority?
11		DR. LUBAN:  Not necessarily as a priority because,
12	obviously, the FDA does not license those but clearly it
13	should be added into a variable in the studies.

14		DR. CHESNEY:  Important point.  Yes?
15		DR. BERLIN:  I would like to mention one group of
16	women to answer Dr. Gorman's question about IRB concern. 
17	That is, women who have decided to terminate breastfeeding
18	but are still lactating.  This is how we were able to get
19	data concerning INH, hydrocortisone and Azulfidine because
20	the mother had decided that she would no longer nurse and
21	wanted to resume taking these medications, and we took
22	advantage of that rather natural situation by collecting
23	samples of saliva, milk and serum and being able to
24	demonstrate passage of the drug or lack thereof.  So, there
25	was no infant put at risk.  And, one of the many wonderful

				111 1	characteristics of lactating women is that they are usually
	2	pretty enthusiastic about participating in these kind of
	3	experiments if you can assure them that the baby will not be
	4	harmed, and since they are no longer breastfeeding the baby
	5	has no exposure.
	6		DR. GORMAN:  Could I just ask one follow-up
	7	question?  Did you get IRB approval for the very special
	8	Hershey-sponsored study?
	9		DR. BERLIN:  Yes, as a matter of fact, I did. 

10	This was the administration of chocolate to nursing mothers. 
11	I did get IRB approval.  That was approval for the
12	administration of one Hershey bar to a nursing mother.
13		DR. NELSON:  What type of toxicity monitoring did
14	you have --
15		[Laughter]
16		DR. BERLIN:  Well, that particular compound has no
17	toxicity but there can be significant withdrawal features.

18		[Laughter]
19		DR. NELSON:  No dose response.
20		DR. BERLIN:  For those of you who may not know,
21	the herbal content of chocolate, we were interested in
22	theobromine which is a relative of caffeine.  So, we did get
23	IRB approval for that.  It was an industry-sponsored study. 
24	Chocolate, by the way, is quite safe for breastfeeding and
25	may actually be one of the required food groups for

					112 1	successful lactation.

	2		[Laughter]
	3		DR. CHESNEY:  I have had a recurring fantasy
	4	throughout this discussion about a whole bank of lactating
	5	women who are wet mothers or whatever they were called --

	6	wet nurses, who are available for all of these studies.  It
	7	is like the volunteers who volunteer to let medical students
	8	examine them.
	9		Dr. Kweder, have we given you enough information
10	for question two?
11		DR. KWEDER:  Yes, you have.  Thank you.

12		DR. CHESNEY:  Number three, what kinds of
13	information about such products are needed for inclusion in
14	labels to allow informed decisions, by someone, as to the
15	safety of breastfeeding while taking a medication?
16		DR. KWEDER:  I would say informed decisions among
17	clinicians.
18		DR. CHESNEY:  Among clinicians, not mothers.

19		DR. KWEDER:  Well, patients and doctors who may be
20	making these decisions together.
21		DR. CHESNEY:  Informed decisions by patients and
22	physicians.  Yes?
23		MS. CONOVER:  Let's see, I know the things I find
24	the most important when I am trying to counsel somebody, so
25	I would sort of like to see those show up.  They have all

		113 1	been mentioned so far but the age of the infant, or if the

	2	infant is medically fragile really makes a huge difference
	3	in terms of whether agents are acceptable, for lots of
	4	reasons -- you know, the permeability of the gut, or how
	5	much milk makes up their diet, or how much of an effect it
	6	will actually have on an older infant versus, say, a one-
	7	week old.  Similarly, preemies are medically fragile and

	8	really almost fall into their own category as well.  So, we
	9	really handle newborns differently.
10	          Then, I would just remind you that although I am
11	always kind of interested in how much is in the milk, what I
12	really care about is the impact on the infant.  So, I pay a
13	lot more attention to studies that actually look -- and that
14	doesn't involve drawing blood on the infant really or
15	anything else, just things where you actually see jaundice
16	or sedation.  It is not that I don't care but it actually
17	tells me that the infant got absorbed and had an adverse
18	effect.  So, I am always really interested in those.
19	          We use a rule of thumb, which has been mentioned
20	before, which is if you can prescribe it to a newborn or a
21	two- or three-month old you don't worry as much about it in
22	the breast milk.  Although, again, we are not cavalier about
23	that, we don't want an exposure that you don't have to have
24	but it still gives me more of a sense of peace of mind and,
25	similarly, I think to patients.  So, that information is

				114 1	always very helpful, and side effects that you might see in
	2	infants, things that you might observe, are interesting to
	3	me as well.
	4		Then, just to remind you again, I really like the
	5	information on half-life, peak levels, things like that and,
	6	you know, you can find those and you can't rely on them
	7	completely but they do give you, again, some sense -- and
	8	you might even put in suggestions -- I mean, there are
	9	strategies and Dr. Anderson has a very elegant, you know,
10	ladder of ways you might make a decision about whether you
11	would use an agent, and ways to make the use of it safer. 
12	So, I always find those things extremely helpful.  Again, it
13	is never a black or white decision, and so to help people
14	with that I think those things come in handy.
15		DR. CHESNEY:  Thank you.
16		DR. WARD:  Can I ask for a clarification about the
17	preemie being medically fragile?  We give them a multitude
18	of drugs.  They are extremely tolerant of that.  Could you
19	amplify on how you counsel with respect to that?
20		MS. CONOVER:  not to pick on your children, of
21	course, but we do, in fact, consider them differently than
22	we would a 12-month old.
23		DR. WARD:  In which ways?  Seriously?
24		MS. CONOVER:  Well, of course, for one thing, they
25	are newborns --

				115 1		DR. WARD:  Yes.
	2		MS. CONOVER:  So, they fit into that category, and
	3	they may respond differently to an exposure.  In fact, we
	4	have had some situations where the infant was getting
	5	something through breast milk and ended up with a sepsis
	6	workup because it was kind of floppy and lethargic.  It was
	7	also actually a pregnancy exposure as well.  So, it was a

	8	combination of things present at delivery and the breast
	9	milk, and maybe would have gotten a workup anyway but, in
10	fact, it turned out to be a psychotropic medication.

11		DR. CHESNEY:  It is the kind of information though
12	that I think would be helpful to have in some of these
13	labels.
14		DR. WARD:  Right, and we are giving them opioids;
15	we are giving them antibiotics; and we are giving them

16	benzodiazepines, etc.  But it would be helpful for us to
17	know the degree of passage of those into the breast milk,
18	and to know that the mother was taking that medication. 

19	That would be very helpful.  But we do administer an awfully
20	large number of almost every therapeutic class, except
21	probably intentionally giving them the anti-tumor drugs.
22		DR. FINK:  As these studies are done, I think one
23	thing that needs to be looked at prospectively and make sure
24	it is recorded is whether the mother is a smoker or not,
25	because that is going to affect both her liver metabolism of

			116 1	the drug, possibly the infant's clearance of the drug, as
	2	well as a lot of confounding factors that are going to show
	3	up in breast milk from the cigarettes themselves.
	4		DR. CHESNEY:  Good point.  Dr. Koren?
	5		DR. KOREN:  Just to give you my wish list of what
	6	I hope to see in a new label, the first are two generic
	7	statements that I believe have to be everywhere.  One is the
	8	one I made about the risk of discontinuing breastfeeding. 

	9	It should be done in the context of that particular drug.
10		The second is a statement that will reverse the
11	many years of statements here that says that most drugs can
12	be measurable in breast milk.  Because many physicians say,
13	"oh, God, they measured it in milk; we have to stop it." 
14	But when I give a lecture to medical students, when they
15	hear that most things are measurable -- the same with the
16	fetus -- it changes the whole gestalt.  So, it is not a yes
17	or no anymore; it is a dose response.  So, if the labeling
18	is supposed to educate, that is something that should be
19	there.
20		Then, of course, I think, as my colleague said,
21	you want to give as much information about the kinetics --
22	how much is there?  What does it mean per dose for a baby? 
23	And, last but not least, if we have data on levels in
24	babies, such as Katherine does in some studies, and follow-
25	ups, short or long, should be there.  So, that is the best

			117 1	label that should be there.
	2		Animal studies I probably wouldn't even put in,
	3	unless there is a reason which I can't think of now.  It is
	4	very confusing.  It is a little bit like teratology, telling
	5	physicians that the tail is shorter in rats and they call us
	6	to ask what it means for a baby.  So, I don't know that an
	7	animal study, unless it has a very important mechanistic
	8	reason, should be there.
	9		DR. CHESNEY:  Dr. Wisner?
10		DR. WISNER:  I think the other piece of
11	information I would put in is whether the drug has active
12	metabolites and what the half-lives of the metabolites are. 
13	So, for example, for a premature ill baby, a mom who might
14	be breastfeeding there would be less theoretical risk if the
15	mom took a drug, say, like certraline which has a metabolite
16	that has a relatively short half-life than, say, the
17	metabolite of fluoxetine, and there would be less potential,
18	particularly in a compromised infant, for accumulation.  So,
19	I think those kinds of pieces of information would help in
20	the selection of drugs in situations where we don't have a
21	lot of data to inform the decision-making process.
22		DR. WARD:  The other thing we really need is the
23	issue of displacement of bilirubin from protein binding, and
24	it is done for most drug classes but we need whether that
25	concentration can produce significant displacement.

				118 1		DR. CHESNEY:  Good point.  Dr. Anderson?
	2		DR. ANDERSON:  I would also add for those groups

	3	of drugs that do affect lactation, that information should
	4	be in there also.
	5		DR. CHESNEY:  Excellent.  Dr. Danford?
	6		DR. DANFORD:  I see a potential problem with the
	7	issue of inclusion or non-inclusion of long-term outcome
	8	data because I think I agree with Dr. Spielberg's comments
	9	earlier that the long-term outcomes, particularly
10	neurodevelopmental issues, are probably not going to be
11	available to us.  Either acknowledging that or not
12	addressing it in the label would seem to be a difficult

13	choice to make because if we acknowledge that lack of
14	information we may be half way back to the uncomfortable
15	situation that we are in now of making a statement that
16	bothers people a lot that may not be as important as it
17	sounds.  If we don't include that information, or don't

18	acknowledge that we don't have it, then are we withholding
19	something that the public and the prescribing physicians
20	ought to know we don't know?
21		DR. KOREN:  Except for several situations, say
22	antileptics for example, children receiving antileptics --
23	phenytoin is an example -- may affect their IQ and some

24	other cognitive, versus some of the others which do not. 
25	So, if mom is on phenytoin, this may be irrelevant

			119 1	information even to speculate what that level of exposure
	2	would do.  But to repeat, I mean, we have the data on
	3	febrile seizures and the reversal of IQ after it was
	4	stopped.  Not many women are now breastfeeding on
	5	barbiturates as they used to, but I agree with you, in most
	6	cases we won't have that information but I can see instances
	7	when it may be important.  I can see a woman saying, you
	8	know, I'm on phenytoin.  What will happen to my baby's IQ?" 
	9	And, we ask these questions, so if you can make a statement
10	based on what is available -- for example, if the level of
11	exposure is one-tenth of what children are receiving in
12	epileptic therapy you may make some inference, but I agree
13	with you that we should be careful not to cause more damage
14	than anything else in these statements.
15		DR. GORMAN:  I would like to reiterate my previous
16	suggestion, realizing the difference between the non-
17	therapeutic use of drugs and breast milk and the therapeutic
18	use that we prescribe them for, that reference from the

19	pregnancy label to the pediatric label be put in there so
20	that parents will have that information of what the

21	experience is in the pediatric population when given
22	therapeutically.
23		DR. CHESNEY:  I think there are probably an awful
24	lot of drugs that we don't know what the long-term effects
25	are.  Dr. Spielberg?

		120 1	          DR. SPIELBERG:  The other quandary that we will
	2	always face is what was alluded to before, which is how safe
	3	is it.  For the vast majority of drugs my guess is, even if
	4	we had in place a good surveillance system and good
	5	ascertainment either through an Academy network or other
	6	ways, and even if we have relatively well-defined protocols
	7	for looking at outcomes, and I think that obviously is key;
	8	it is not just saying there is nothing there because, you

	9	know, no one complained about it -- even assuming we did
10	that, for the vast majority of drugs we are going to get
11	relatively small numbers, and when we think about what we

12	are talking about an NDA for a new drug and, you know, 3000
13	human exposures, 5000 human exposures with postmarketing
14	commitments so that we are collecting data on relatively
15	large numbers and using either the rule of 3 or the rule of
16	5 in terms of what numbers that will rule out for a 1/100

17	event, a 1/10 event, a 1/10,000 event.  I think we are never
18	going to be able to eliminate 1/10,000 events.  We will
19	probably never be able to eliminate, for many drugs, 1/100
20	events.  But, what we are going to be able to do is provide
21	information on the outcomes of the babes and, in thinking
22	about how to write those labels we are going to have to be
23	very careful about how we write those outcomes.  It probably
24	is going to be something like in X numbers of infants,
25	examined for such-and-such, no adverse effects were noted. 

		121 1	We are not going to get to the standards of "safe and
	2	effective."  Effective is not an issue for the babe, but
	3	certainly even from the point of view of safety, I think it
	4	is probably going to be a relatively descriptive label but

	5	that is helpful information.
	6	          The hard part with labels right now, frankly,
	7	particularly in this area is that physicians might be able
	8	to read them pretty well.  The trouble is everybody reads
	9	them now.  You can pick up the PDR in any store; you can

10	pick it up online.  Looking at all of our labels, you know,
11	as a lay person looking at a label of almost anything -- and
12	I could write a label for water that would scare you from
13	drinking ever again.  You know, large quantities of this
14	stuff can cause hyponatremia, death -- pretty rough stuff. 
15	So, we really want to write very honest labels based on what
16	the data really show us, and not make generalized statements
17	about safety or what-have-you.  I think really provision of
18	data is going to be our best way to go, recognizing, and we
19	are going to have to be honest with ourselves, that for
20	many, many drugs the database is going to be very, very
21	small.
22	          DR. CHESNEY:  This issue of the long-term
23	outcomes, what I meant to say was I don't even know that we
24	know what the long-term outcome for children taking dilantin
25	for years is because we have never done a prospective,

			122 1	controlled study for most of the drugs that we give to
	2	children so that we can say after 30 years your IQ is the

	3	same as it would have been, or something like that.  So,
	4	that is a tough one for me.
	5		But, I think if we should maybe always emphasize
	6	the risk/benefit ratio, taking in the many considerations

	7	that Dr. Koren and others have mentioned.  Other comments? 
	8	Dr. Wisner?
	9		DR. WISNER:  The other thing that I think we need
10	to be clear about is the quality of the data in the sense
11	that for some drugs the data is going to be for exposures
12	both during pregnancy and for breastfeeding, and the class
13	of agents that I come across most in that line is for

14	anticonvulsants where I will look for information just about
15	their use during breastfeeding, say, for a bipolar patient,
16	but the only information I can find is data through
17	pregnancy and breastfeeding so it is hard to know how to use
18	that for my particular patient.  And, just making the point
19	clear that the exposure during breastfeeding is very

20	different than during pregnancy and breastfeeding, and
21	wanting to make sure that those lines are separate in our
22	recommendations.
23		DR. CHESNEY:  Dr. Kauffman?
24		DR. KAUFFMAN:  I wanted to step back to some

25	comments earlier this afternoon, and that has to do with

		123 1	this is all very important and this information is very

	2	important, and we have talked a lot about how to get the
	3	information but that is somewhat moot if we don't have a

	4	regulatory mechanism to get that information into the label. 
	5	There are some 400 primary references in the AAP guidelines
	6	since 1986 or 1987, and it keeps expanding.  Very little of
	7	that information is in the current labeling for those drugs. 
	8	The USP monographs have this information in virtually every
	9	monograph if it is available anywhere.  And, I would like

10	to, I guess, ask Dr. Kweder or Dr. Murphy, do you have some
11	idea of what the regulatory mechanism can be as you rewrite
12	these regulations to get this information into the label
13	because right now, I gathered from what you said that there
14	really wasn't a systematic, proactive way to get this
15	information into the label reliably.
16	          DR. KWEDER:  Yes, I can answer that question.  We
17	are in the positive of revising the regulatory framework for
18	the pregnancy section of the label that includes the
19	lactation section.  So, when a new regulation is developed
20	to cover that section, lactation will be part of that.
21	          DR. KAUFFMAN:  Can you be proactive then?  Let's
22	say Merck does not particularly have any incentive to put
23	that information in their drug that is 15 years old and
24	doesn't have it but the information is available, can you be
25	proactive to get that information into their label then?

					124 1		DR. KWEDER:  Yes, yes.
	2		DR. KAUFFMAN:  Minus a safety issue?
	3		DR. KWEDER:  For the most part, products will be
	4	required to comply with this.
	5		DR. KAUFFMAN:  Okay.  That is very reassuring.
	6		DR. KWEDER:  Like most labeling changes, it will

	7	probably be phased in over time but ultimately, hopefully,
	8	we will get there.
	9		DR. KAUFFMAN:  That would be a major step forward. 
10	Excellent!
11		DR. ANDREWS:  I would like to make a comment about
12	that.  Similar to a discussion that we had in the morning

13	session, that is, in all likelihood the label will never
14	have all of the information that is publicly available in
15	the published literature because it is not only the sponsor
16	recommending certain articles and scientific evidence to be
17	included in the label, but it is also a process of

18	negotiating with the FDA what type of evidence is allowable. 
19	Current standards for clinical type data usually revert to

20	the randomized clinical trials.  It is very difficult to get
21	epidemiologic data included in the labels today, and I think
22	that is changing and I think that is very good.  But we
23	might want to also think about referring the reader to other
24	sources of information that are available and compendia of
25	information that can be more comprehensive and that are

			125 1	updated more frequently than the labels are.
	2		DR. CHESNEY:  Thank you.  Dr. Kweder?
	3		DR. KWEDER:  I just wanted to clarify.  I think
	4	the people on this side of the table are probably more
	5	familiar with the pregnancy labeling initiative than the
	6	pediatric group.  We are in the process of trying to develop
	7	a proposed rule on pregnancy labeling.  We don't have
	8	anything published in The Federal Register.  We have met
	9	with our committee a few times to go over some general
10	concepts related to that.  It is extremely difficult and we
11	are just beginning to tackle the lactation subset of that,
12	which is what brings us to this meeting, but you didn't miss
13	anything.  There is nothing out there in The Federal
14	Register of published at this point in time.  And, some of
15	the issues that Elizabeth raised are issues that we have to
16	grapple with in any section of the label.  This will be a

17	very complicated process because we are not talking about,
18	for the most part, labeling that rests on randomized,
19	controlled trials, which is the gold standard of what has
20	the agency has always been the most comfortable with.  We
21	are talking about how to bring other kinds of data to the
22	label so that it will provide useful information for people
23	who are making decisions about drugs in their own life
24	circumstances.

25		DR. CHESNEY:  This situation reminds me of what we

		126 1	went through when we discovered -- what was the mercury
	2	compound as a preservative in vaccines? -- thimerosal, when
	3	spent hours and hours and hours adding up the concentrations
	4	of mercury that we were giving to premature infants and
	5	older children, and many, many experts on many, many
	6	conference calls, and really we knew absolutely nothing

	7	about what we were doing, except that it seemed like an
	8	excessive amount of mercury.  But George Petaire, who has
	9	been the editor of The Red Book for many, many years said,

10	very wisely, lack of information has never prevented us from
11	making definitive decisions.  We need a lot more
12	information.
13	          There were some questions over here.  Yes?

14	          MS. SCOTT:  I have been listening to all the
15	discussion, both this morning and this afternoon, and I
16	think we have progressed but I am still feeling for women

17	the issues of safety -- somehow I am not comforted by much
18	of what has been talked about today, and I think women, with
19	access to information -- it is so confusing.  While I can
20	appreciate, you know, burdens that have been mentioned
21	several times on FDA and industry for making these changes,
22	I kind of see myself probably in that role twenty years from
23	now dealing with some of these same issues because I don't
24	think we are quite ready to bite the bullet and insist that
25	there be a new standard for the regulation of drugs that

			127 1	really looks at this whole issue of pregnant women and
	2	lactating women.
	3		I know we are trying to make incremental changes
	4	here but I really get a sense that we are going to be moving
	5	much too slowly to be helpful to women for the safety of

	6	their own health and for their children.  So, I think in
	7	order to have options and choices, and to be able to weigh
	8	risk and benefit, not only on life-threatening situations
	9	but the quality of life that has been brought up several
10	times.  You know, women also have to be concerned about

11	their quality of life in taking these drugs, and I don't
12	think most women would be satisfied to hear or be convinced
13	that a medication is safe because it has been given to a
14	premature infant.  I mean, it hopefully was given for some
15	indication and we are really talking about how these drugs
16	are going to act on healthy children and what those
17	ramifications are.
18		So, I would like to urge the FDA, by whatever
19	means necessary, that you be stronger in requiring the data
20	gathering both in the application for a drug and
21	postmarketing or registries, whatever; that you really take
22	a strong stand in getting this information because women

23	need it because they need medication and for the safety of
24	their children.
25		DR. CHESNEY:  Thank you.  Yes?

			128 1		DR. KOREN:  Just to reiterate what Julia said, it
	2	is not the information, the scientific information, but how
	3	women perceive risk and what they do about it.  Very few

	4	groups deal with this.  So, it will be very effective to
	5	bring the knowledge base here.  Then, how to write it will
	6	take a different science.  We are doing it now in Toronto,

	7	and we have big surprises of what you show to women and what
	8	they understand even if you are sure that it is safe.  So, I
	9	am just throwing it in; it is not to do with the questions
10	we were asked but more for the FDA.  We will have to ensure
11	that what we write women will understand even if it is
12	written for physicians.  We also have interesting results on
13	how physicians perceive risk.  In other terms, what we write
14	is not what people understand and that has to be
15	acknowledged and included in this very valuable process,
16	otherwise it will be another thing on the shelf that doesn't
17	really go to public health effect.
18		DR. CHESNEY:  Communication is everything.  Dr.
19	Wisner?
20		DR. WISNER:  Very much along the same lines as

21	what Dr. Koren was saying, for the American Psychiatric
22	Association, we had a work group and what we decided to do
23	was develop actually a process model that really defines

24	what the practitioner says to a woman, what kinds of things
25	should you include if you are talking to her about

		129 1	treatments during pregnancy?  So, there are all the
	2	available treatments and the pluses and minuses, and then
	3	what is the natural history of the disorder, and then a
	4	whole section on medical-legal aspects because what we felt
	5	was this same gap, that the information may be there -- and
	6	then there are all the different aspects of how women
	7	understand the information, but there is also this idea
	8	about how do you structure the information in a way so that
	9	it really becomes one that respects her values and her
10	making the choice but delivering a complete set of
11	information as well?  So, there is another element to all
12	this.

13	          DR. KWEDER:  I would just like to respond to that. 
14	We have recognized from the very beginning that this is

15	going to be one of the toughest rows to hoe for this.  We
16	are well aware of the fact that when people read current
17	labels what might make perfect sense to a scientist comes
18	across very differently to someone who is a lay person

19	reading it or a clinician in an office who is worried about
20	her own medical-legal risk.  We are trying to tend to that
21	and we will be bringing in to help us some experts in risk
22	communication.  We think that this is something that we have
23	not done very well, and I want to acknowledge, Dr. Koren, we
24	are very appreciative of some of the research that the
25	Motherisk group has done in this area, where they have done

			130 1	specific studies where they have attempted to be reassuring
	2	in how they characterized risk, and found out that what was
	3	reassuring to a clinician was not at all reassuring to a
	4	patient.  So, that has been very helpful.
	5		DR. MURPHY:  Let me start with the bad news,
	6	again, the Food, Drug and Cosmetic Act is for us to look at
	7	products that are proven to be safe and effective and our
	8	professional labeling is the way that we are supposed to
	9	spell it out in the patient insert.
10		As anybody who has listened to us for the last
11	year and a half knows, it has taken us two decades of
12	pleading with people to look at products in children, and
13	you have heard these numbers numerous times and they haven't
14	been studied.  You are right, it is an arduous process.  It
15	has to be based on a very carefully thought out -- and this
16	group is trying to do that and seeking external advice on

17	how we do it.
18		The good news is that just a decade ago we didn't
19	even have any gender differences.  I mean, we all know men
20	and women are different but for some reason that was never
21	something we were going to look at until recently.  So, we
22	are making progress in being able to look at the areas that
23	we think are important and where we might find differences
24	or areas that are not being addressed at this time.
25		I think one of the really exciting things is the

			131 1	one that Dr. Kweder just brought up, and again I mention Dr.
	2	Woodcock because I think this has been an initiative of
	3	hers, and that is the whole concept of risk management and

	4	how the agency communicates the information that we have. 
	5	Right now, we are not the research arm of NIH; we are not
	6	the health professional societies.  We seek input from all

	7	of those so we can provide the best information, but we look
	8	to all of these entities to participate with us in moving
	9	the field, be it risk communication for women, for children,
10	for antibiotic resistance, whatever it is, all of that we
11	need to leverage each other in our collective knowledge in
12	moving this field forward.
13		So, I guess what I am saying to you is we will
14	keep working on this.  You need to go back and talk to your
15	individual organizations and also work on this.  So, thank
16	you.
17		DR. CHESNEY:  Dr. Kweder, do you or Dr. Murphy
18	want to do summary comments or do you need more information?
19		DR. KWEDER:  I think you have done a great job of
20	outlining for us a lot of the concerns that you have, both
21	in the area of the science and also some of the really
22	practical considerations about how we might do this better. 
23	I really just want to thank you all for taking the time to
24	really think about these issues.  We truly appreciate it. 
25	It is really refreshing.

					132 1		DR. CHESNEY:  Let me once again thank Dr. Murphy
2	and all of the people who have worked with her to make the
3	last two days so informative and so well organized, and four
4	totally different topics that we have all enjoyed
5	participating in.  Thank you all.
6		[Whereupon, at 4:51 p.m., the proceedings were
7	adjourned]