FOOD AND DRUG ADMINISTRATION

	CENTER FOR DRUG EVALUATION AND RESEARCH

	PREGNANCY LABELING SUBCOMMITTEE

	OF THE

	ADVISORY COMMITTEE FOR REPRODUCTIVE HEALTH DRUGS

	9:15 a.m.

	Tuesday, March 28, 2000

	Crystals Ballroom
	Hilton Hotel
	620 Perry Parkway
	Gaithersburg, Maryland

	ATTENDEES

SUBCOMMITTEE MEMBERS:

MICHAEL F. GREENE, M.D., Chairman
Associate Professor of Obstetrics,
  Gynecology and Reproductive Biology
Department of Obstetrics and Gynecology 
Massachusetts General Hospital
Boston, Massachusetts  02114

SANDRA TITUS, PH.D., Acting Executive Secretary
Advisors and Consultants Staff, HFD-21
Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane
Rockville, Maryland  20857

ELIZABETH ANDREWS, PH.D., M.P.H.
Director
Worldwide Epidemiology
Glaxo Wellcome
5 Moore Drive, Box 13398
Research Triangle Park, North Carolina  27709-2298

ELIZABETH ANN CONOVER, M.S.
Coordinator
Nebraska Teratogen Information Service
Munroe Meyer Institute for Genetics
  and Rehabilitation
University of Nebraska Medical Center
985440 Nebraska Medical Center, Room 2074
Omaha, Nebraska  68198-5440

CHRISTINA CHAMBERS, M.P.H.
Epidemiologist
California Teratogen Information Services
UCSD Medical Center
Department of Pediatrics
200 West Arbor Drive
San Diego, California  92103-8446

JANET DARDEN CRAGAN, M.D.
Division of Birth Defects and Genetics
Centers for Disease Control and Prevention
MS F45, 4770 Buford Highway, N.E.
Atlanta, Georgia  30341-3724

	ATTENDEES  (Continued)

SUBCOMMITTEE MEMBERS:  (Continued)

MARY G. HAMMOND, M.D.
Reproductive Endocrinologist
Reproductive Consultants, PA
1053 Fearrington Post
Pittsboro, North Carolina  27312

JAMES A. LEMONS, M.D.
Professor of Pediatrics
Indiana University of Medicine
699 West Drive, Building RR208
Indianapolis, Indiana  46202

ALLEN MITCHELL, M.D.
Director
Slone Epidemiology Unit
Professor of Epidemiology and Pediatrics
Boston School of Public Health and Medicine
1371 Beacon Street
Brookline, Massachusetts  02446

KAREN ROSENE MONTELLA, M.D.
Department of Medicine
Women & Infants Hospital
101 Dudley Street
Providence, Rhode Island  02905

JULIA SCOTT, R.N., Consumer Representative
President
National Black Women's Health Project
600 Pennsylvania Avenue, S.E., Suite 310
Washington, D.C.  20003

SHEILA WEISS, PH.D.
Assistant Professor
University of Maryland
100 North Greene Street, 6th Floor
Baltimore, Maryland  21201

PATRICK WIER, M.D.
Group Director
Reproductive Toxicology
SmithKline Beecham Pharmaceuticals
709 Swedeland Road, Mc#UE0465
King of Prussia, Pennsylvania  19406

	ATTENDEES  (Continued)

SUBCOMMITTEE MEMBERS:  (Continued)

KATHERINE L. WISNER, M.D.
Professor of Psychiatry and
  Reproductive Biology
Director, Women's Mental Health Care Program
Case Western Reserve University
11400 Euclid Avenue
Triangle Building, Suite 280
Cleveland, Ohio  44106

NON-VOTING SUBCOMMITTEE CONSULTANTS:

JAN M. FRIEDMAN, M.D., PH.D.
Birth Defects and Genetic Diseases Branch
Centers for Disease Control
4770 Buford Highway, N.E.
Mail Stop F-45
Atlanta, Georgia  30341-3724

KEN LYONS JONES, M.D.
Professor of Pediatrics
Department of Pediatrics
Division of Dysmorphology and Teratology
University of California, San Diego
200 West Arbor Drive, #8446
San Diego, California  92103

SUSAN KING, M.D.
Division of Infectious Disease
The Hospital for Sick Children
555 University Avenue
Toronto, ON M5B 1X8 Canada

DONALD MATTISON, M.D.
Medical Director
Birth Defects Foundation
1275 Mamaroneck Avenue
White Plains, New York  10605

	ATTENDEES  (Continued)

NON-VOTING SUBCOMMITTEE CONSULTANTS:

JAMES MILLS, PH.D.
Senior Investigator
National Institute of Child Health
  and Development
National Institutes of Health
6100 Executive Boulevard, Room 7B-03
Bethesda, Maryland  20892

NANCY WADE, M.D., M.P.H.
Council of State and Territorial Epidemiologists
NYS Department of Health Aids Institute
Corning Tower, Empire State Plaza, Room 412
Albany, New York  12237

GUEST SPEAKERS:

LEWIS HOLMES, M.D.
Professor of Pediatrics
Massachusetts General Hospital
Genetics and Teratology Unit
Waren 801
32 Fruit Street
Boston, Massachusetts  02114-2696

AUDREY ROGERS, PH.D.
Adolescent Medicine
HIV/AIDS Research Network
National Institute of Child Health
  and Human Development
6100 Executive Boulevard
Bethesda, Maryland  20892

ROBERT SHARRAR, M.D.
Merck and Company, Inc.
Sentry Parkway West
P.O. Box 4, BLB-30
Building West, Mail Stop BLB-30
Blue Bell, Pennsylvania  19422

CATHY SPONG, M.D.
National Institutes of Health
Pregnancy Branch
6100 Executive Boulevard
Bethesda, Maryland  20892

	ATTENDEES  (Continued)

FOOD AND DRUG ADMINISTRATION STAFF:

JOSEPH DeGEORGE, PH.D.
HOLLI HAMILTON, M.D., M.P.H.
FLORENCE HOUN, M.D.
DIANNE KENNEDY, R.PH.
SANDRA KWEDER, M.D.
EVELYN RODRIGUEZ, M.D., M.P.H.

ALSO PRESENT:

MARY TETER, D.O.
Pharmaceutical Research and Manufacturers Association

	C O N T E N T S

AGENDA ITEM	PAGE

CONFLICT OF INTEREST STATEMENT
  by Dr. Sandra Titus	8

BACKGROUND INFORMATION, UPDATE ON THE PREGNANCY
LABELING PROPOSAL AND OVERVIEW
  by Dr. Sandra Kweder	12

PRECLINICAL GUIDANCE DOCUMENT - STATUS REPORT
  by Dr. Joseph DeGeorge	30

NICHD PERSPECTIVE ON NEEDS FOR THE STUDY OF
THERAPEUTIC DRUG USE IN PREGNANCY
  by Dr. Cathy Spong	41

OPEN PUBLIC HEARING PRESENTATION
  by Dr. Mary Teter	53

METHODOLOGICAL AND OPERATIONAL CHALLENGES IN
RUNNING/DEVELOPING A PREGNANCY REGISTRY
  by Dr. Elizabeth Andrews	60

ESTABLISHING PREGNANCY REGISTRIES - 
GUIDANCE FOR INDUSTRY
  by Dr. Evelyn Rodriguez	82

QUESTIONS FOR THE COMMITTEE AND DISCUSSION	100

CHARGE TO SUBCOMMITTEE MEMBERS
  by Dr. Sandra Kweder	173

OVERVIEW:  CURRENT STATE OF THE ART
  by Dr. Allen Mitchell	175

INFORMED CONSENT - by Dr. Audrey Rogers	202

	P R O C E E D I N G S
	(9:15 a.m.)
		DR. GREENE:  Good morning.  I'd like to thank everyone for coming and call the meeting to order.  My name is Mike Greene and I'll be the chair for your meeting.
		I think the first order of business is -- is Jane going to do the conflict of interest statement, or are you going to do that?  Okay, fine.
		DR. TITUS:  I'm Sandy Titus and I'm with the Advisory Committee staff. 
		Regarding this meeting, the following announcement addresses the issue of conflict of interest with regard to this meeting and is made a part of the record to preclude even the appearance of such at this meeting.
		Since the subcommittee's discussion will not have a unique impact on any particular firm or product, but rather may have widespread implications with respect to all pharmaceutical firms and their products, in accordance with 18 U.S.C. section 208, general matters waivers have been granted to all special government employees participating in the meeting.  The general matters waivers permit them to participate fully in today's discussions.
		A copy of these waiver statements may be obtained by submitting a written request to the agency's Freedom of Information Office, which is located in 12A-30 of the Parklawn Building. 
		In the event that the discussions involve any products or firms not already on the agenda for which an FDA participant has a financial interest, the participants are aware of the need to exclude themselves from such involvement and their exclusion will be noted for the record.
		DR. GREENE:  Thank you.
		The first speaker this morning will be -- fine.  Before we get started then -- I was not sure whether you wanted everybody to introduce themselves.  Why don't we do that then?  Why don't we start all the way at that corner, please.
		DR. HOUN:  Florence Houn, Director, Office of Drug Evaluation III.
		DR. KWEDER:  Sandra Kweder, Deputy Director, Office of Drug Evaluation IV.
		DR. KENNEDY:  Dee Kennedy.  I'm with the Pregnancy Labeling Team.
		DR. HAMILTON:  Holli Hamilton, Pregnancy Labeling Team.
		DR. DeGEORGE:  Joseph DeGeorge, Associate Director for Pharmacology and Toxicology in the Office of Review Management.
		DR. RODRIGUEZ:  Evelyn Rodriguez, Director of the Division of Drug Risk Evaluation II in OPDRA, Office of Post-marketing Drug Risk Assessment, at CDER.
		MS. CHAMBERS:  Christina Chambers representing the Organization of Teratology Information Services.
		DR. LEMONS:  Jim Lemons.  I'm a neonatologist and Director of Newborn Intensive Care Programs in Indiana University and chair the Committee on Fetus and Newborn for the American Academy.
		DR. ANDREWS:  Elizabeth Andrews, Director of Epidemiology at Glaxo Wellcome, also the President of the International Society for Pharmacoepidemiology.
		DR. WEISS:  Sheila Weiss.  I'm an assistant professor and epidemiologist at the University of Maryland.
		DR. SPONG:  Cathy Spong.  I'm a perinatologist, as well as a program director for the Maternal Fetal Medicine Unit Network at the National Institute of Child Health and Human Development, National Institutes of Health.
		DR. FRIEDMAN:  Jan Friedman.  I'm Professor of Medical Genetics at the University of British Columbia and Director of the TERIS project.
		DR. TITUS:  I'm Sandy Titus.  I'm with the FDA, the Advisors and Consultants Staff. 
		DR. GREENE:  And I'm Mike Greene.  I'm a maternal fetal medicine subspecialist at Massachusetts General Hospital in Boston.
		DR. MILLS:  I'm Jim Mills.  I'm an epidemiologist at the National Institute of Child Health and Human Development.
		MS. CONOVER:  Beth Conover.  I'm a genetic counselor and I run the Nebraska Teratogen Information Service.
		DR. MATTISON:  Don Mattison.  I'm the Medical Director of the March of Dimes.
		DR. MONTELLA:  Karen Rosene Montella.  I'm the Chief of Medicine at Women & Infants Hospital at the Brown University Hospital, and we teach medicine residents to take care of sick pregnant women and run a fellowship.
		DR. MITCHELL:  Allen Mitchell, Director of the Slone Epidemiology Unit at Boston University.
		DR. WIER:  I'm Patrick Wier.  I'm a reproductive toxicologist for SmithKline Beecham Pharmaceuticals.
		DR. WISNER:  I'm Kathy Wisner.  I'm Professor of Psychiatry and Reproductive Biology at Case Western Reserve University.
		MS. SCOTT:  I'm Julia Scott, President of the National Black Women's Health Project, and a consumer representative on this committee.
		DR. ROGERS:  I'm Audrey Rogers.  I'm an epidemiologist at the National Institute of Child Health and Human Development, and I was a government representative to the Antiretrovirals in Pregnancy Registry.
		DR. CRAGAN:  I'm Jan Cragan.  I'm a medical officer in the Division of Birth Defects, Child Development, Disability, and Health at CDC.
		DR. HAMMOND:  I'm Mary Hammond.  I'm a reproductive endocrinologist in Raleigh, North Carolina.
		DR. JONES:  I'm Ken Jones.  I'm in the Department of Pediatrics at the University of California, San Diego.
		DR. SHARRAR:  I'm Bob Sharrar.  I'm Senior Director of Worldwide Products Safety and Epidemiology for Merck & Company, Incorporated.
		DR. WADE:  I'm Nancy Wade.  I'm a pediatrician in the AIDS Institute, New York State Department of Health.
		DR. KING:  I'm Susan King.  I'm a pediatrician at the Hospital for Sick Children in Toronto, Canada.
		DR. GREENE:  Thank you.
		Now I'll introduce the first speaker of the morning who is Dr. Sandra Kweder from the FDA.
		DR. KWEDER:  Good morning, everyone.  I'm Sandy Kweder.  As I mentioned before, I'm the Deputy Director of the Office of Drug Evaluation IV, which I know means nothing to any of you.  We oversee the regulation of all products to treat infections in three divisions. 
		But the other job that I have is I'm the Director of the Pregnancy Labeling Team, which is a crosscutting group within our organization that is charged with dealing with matters related to collection of data and labeling drugs for use in pregnancy.
		This morning I want to begin by introducing what our goals are for this meeting.  First, we're going to spend a little bit of time giving you a general update on FDA activities related to pregnancy labeling, but the labeling itself won't be the major focus of the meeting.
		The more important subject over the next few days is collection of data to address safety of products in pregnant women.  In particular, we'll focus a lot of the discussion on pregnancy registries.  We're using as a springboard for that discussion a draft guidance document that many of you have already seen and some of you who are on the Reproductive Products Advisory Committee have already had an opportunity to comment on, at least briefly.  We've structured some of the questions for you to help get your feedback on the document as we move towards finalizing it.
		Then beyond that, we think that this is an appropriate forum to engage you in a discussion that's much broader about strategies for collecting data related to safety of products in pregnancy, thinking about how we can work with those running studies or thinking about studies to get the most out of each effort, and thinking beyond some of the current models that most of us think of when we think about registries or surveillance.
		The goals for my talk are really within that first goal of the meeting, in the way of updates.  I'm going to give you a flavor of our progress on a new model for labeling, and I'll also then move on to discuss some of our ongoing activities related to data that would feed into those models, some about registries, but beyond that.
		Now first, though, I want to point out that there are a few people at the table who weren't at the table when this committee last met, and those are Holli Hamilton and Dianne, or Dee, Kennedy.  We have so much activity going on at the agency related to this general topic of pregnancy and drugs in pregnancy that we've been able to secure two full-time staff to work on this with me.  This is only a piece of my job, but Holli and Dee are pretty much full-time committed to this.  They both started in October of last year. 
		Holli comes to us from our Division of Anti-infective Products.  She's an infectious disease physician and an epidemiologist who is well versed in a lot of the methodology and clinical issues surrounding use of products in pregnancy.
		And Dee Kennedy is a pharmacist who many of you may have encountered at FDA before.  She spent many years in our Post-marketing Division.  When you think Dee Kennedy, I think MedWatch.  For those of you who know what MedWatch is, Dee invented MedWatch.  She invented it and then she directed our MedWatch program for a number of years, and I feel that we are really lucky.  I about turned cartwheels in the office when she said that she had come to work for us.  So, that's some good news that I have.
		Now, to get to the proposed label concept that many of you had an opportunity to comment on last June, the next few slides are just reminders of what that was.  Our goal in moving away from a model that uses letter categories to describe risks or appropriate use of products in pregnancy is to develop a format that has structure and organization that we can adapt to widely varying bodies of data that might be available for a product and for products that cross vastly different disease states.  
		Specifically, our goals are, in the labeling, to distinguish clinical considerations from risk information, attempt to provide different levels of information for different needs that users may have, and finally to use narrative text to describe and provide information as opposed to simplified letter categories that we don't think facilitates sound risk management.
		The model that we showed you has three basic components that would be incorporated into each label.  One, it would be clinical considerations, a brief section that would link risk assessments to practical application that might be useful for a prescribing or advising clinician.  A summary risk assessment that would incorporate both human and animal data into the risk assessment and clearly state what the relevant factors were in arriving at that assessment.  And then the third section would be a brief summary or discussion of data to convey the underlying data that went into the risk assessment.
		I have a few bullets here that I think summarize most of the discussion that this committee had about that label format and content.  In general, I think there was agreement that we were off to a good start.  You advised us to give clinical directives and advice sparingly.  As we've tried to move along, I will tell you I'm the hand-waver.  Remember what they said.  We have to give this advice sparingly.  My colleagues are sick of me.  But I think that was one of the major messages we took from that meeting last year.
		I think that through much of the discussion, you recognized the importance and challenge of us developing an approach that would lead to consistency across labels, and toward that end, there might be a role for some sort of standardized terminology, perhaps in the risk assessment statements, but that we would need to do some more work on that.
		Since June, we have been working on this extensively.  I will tell you this is extremely difficult. We have a group of about eight people that meets every other week to hash through different iterations of models and where are we going, how do we get there.  But what I have on this slide is what I think have been the key decision points that we've had to confront as we've tried to move from a concept paper to what I would call a truly robust model that would be applicable.
		First we had to make a distinction between what elements would actually require a regulation because this all does require that we develop a new regulation.  That isn't easy.  And we want to be careful that we don't box ourselves in to a point where we have to do that again in a couple of years.  So, we need to tease out what are the components of this that actually require a regulation, and what are those that are more appropriate for what we call a guidance document, something that's more flexible, the "shoulds" not the "musts," the things where we need to be able to have some give and take.  
		We need to sort out, as we move forward, how would we exactly implement this.  It would be an impossible task to say that starting tomorrow, all labels need to have this new format.  Companies couldn't handle it.  We couldn't handle it.  We couldn't review them all and do the project justice.  So, figuring out how to do that is a challenge. 
		In all of this, we need to figure out, as we think about what needs to be in that label, how to make room for human data and experience because most labels don't contain human data and experience.  The human data and experience that usually clinicians are interested in or that is available to address considerations in pregnancy is not the same kind of data that you see in the rest of product labels.  They aren't controlled clinical trials and that makes a lot of people uncomfortable.  People like certainty.
		Then, of course, how specific to be in clinical considerations remains something that we grapple with every time we meet. 
		Now, I know that all sounds really pointy-headed and bureaucratic, and you guys are probably thinking, yes, but come on, let's just get on with it.  So, why is this so hard?  Just make a decision.  But I think that there are some reasons why this is so difficult.
		One is the complexity of the science and the context of use of this information really mandates that we be very clear as we give guidance to companies and to our colleagues internally about how to write a label for use in pregnancy.  
		Yet, uncertainty predominates in the data that are likely to be available.  Animal data, for the most part, continue to be and will continue to be the basis for most risk assessments, and the human data we have available are not common and they are scattered all over the place in the literature in a variable quality.  Even when there are both animal data and human data, I think it's fair to say that experts often disagree on their interpretation which adds to the complexity of this. 
		Yet, we recognize that the breadth of user needs out there for people who are prescribing or considering taking medicines is great and that we need in the process to leave room for their clinical judgment about what is best for patients.
		So, why does it take so long?  Well, I've told you it's complex.  For God's sake, it has been almost a year.
		I think one of the things in this complexity that we are coming to terms with, particularly as we begin to think about making room for human data, is some of this really involves a paradigm shift in our thinking.  Really when you think about the topics that we're addressing today in the context of labeling, we are moving our labeling from and our data collection efforts from a search or a hunt for the smallest and largest detectable toxicity to coming at this from a different view.  How can we get our arms around what the margins of safety are?  And I think that's a very different way of looking at this, and that's one of the reasons this is so difficult.  We're approaching this differently.
		Also, regulations.  I will tell you, as someone who has been around the FDA for a while, regulations are never easy to write.  They take a long time.  Even once we make decisions ourselves, you wouldn't believe how many other people who know nothing about the subject will have to look at this and comment on it, things like financial impact.  There's a person who spends all their time thinking about what is the financial impact to many parties of any regulation we write.  So, that sort of thing has to happen.
		This is also one of several very large labeling initiatives that we have going on at FDA, and we need to make sure that they dovetail and don't contradict each other. 
		Increasingly, as we move forward, we are recognizing that it is not enough just to change a regulation that says what should be in a label.  Efforts to enhance data collection and facilitate submission of that data to the FDA absolutely must be part of this effort.  Just saying here's the way it ought to look on a piece of paper is not enough.  The goal is to have more information.
		So, toward that end, I've talked about our label model development and where we are going with that.  I want to give you a flavor of what some of the activities are that we're engaged in to improve data and to expand thinking in this area internally and externally about what are some other aspects of risk management that are appropriate for pregnant women.
		In the area of improving data, I think that historically and currently the main focus does remain on fetal and infant outcomes following exposure in pregnancy.  Registries are one of the principal tools available as methods of surveillance to collect this type of data, but they do remain rare.  We have historically and continue to rely on product sponsors to conduct those surveillance efforts.  Where there are other types of data in the literature or where others have conducted similar studies, currently there is no specific regulation or incentive for companies to come to us with those data and ask us to include those in labeling, and that's a problem that we're beginning to try to address.
		As we begin to do that, we recognize that, in addition to this paradigm shift, we have to confront and engage in discussion with folks like yourselves about what we see as somewhat a controversial area of the value of normal outcomes when the numbers of exposures are small.
		Now, in the area of improving registry data, we have a draft guidance document that you have in your packet and you'll have an opportunity to address later this morning.  Dr. Rodriguez will walk you through it.  That is one tool that we have toward enhancing data.
		FDA also has a new regulation that's actually circling through the agency -- it hasn't been published yet, but we've already promised that we will publish it -- that will require sponsors to address all data relevant to safety of products for special populations.  And pregnant women is listed as one of those special populations.  That regulation will be critical to getting data into labels.  It is essential. 
		Right now what we get is oftentimes -- companies are required to send us annual reports on their products, safety reports.  All companies don't do this, but it's not unusual for someone at a company to do a literature search on a product and maybe buried in a stack of reprints like this that comes in among four or six volumes toward an annual report, there will be a couple of articles about a drug in pregnancy or something about it.  But there's nothing that says that companies must take that data and specifically make an evaluation of it and propose labeling changes on the basis of that data for use in pregnancy.  And so most don't.
		We also feel that we need to expand our discussion of registries.  This meeting is one way to do that.  We are also engaged in discussions with groups outside of the FDA like the CDC and the March of Dimes to begin to think about other models for registries and how we can collect data.  We also are beginning to work with the International Society of Pharmacoepidemiology to get some other expert opinion, particularly in the areas of methodology and how to do this well.
		What about thinking more broadly?  Well, I've said that registries remain our principal tool and a major focus, and they are very important and can be helpful for collecting certain types of data such as general pregnancy outcomes or fetal outcomes and providing us with some general margins of safety that are rather broad brush.
		But there are other elements of safety and rational prescribing that need to be considered, and two of them I have listed on this slide.  One is pharmacokinetics and pharmacodynamics of drugs in pregnancy, and the other is what about lactation.  We're just beginning to engage in discussions and try to figure out how we can help enhance data in these areas.  
		But I think most of you who have taken care of pregnant women or been pregnant yourself know that once the patient and clinician cross a threshold and make a decision that a pharmacologic intervention is necessary, then the question becomes what dose.  If you go through the literature and textbooks that talk about prescribing in pregnancy, most of them say prescribe the lowest effective dose.  Well, the lowest effective dose in the general population of non-pregnant people may not be the best dose for the pregnant woman.  Particularly for products that have a narrow therapeutic margin but perhaps there is therapeutic monitoring by drug levels is impossible, there is a risk for certain types of products that a woman may be taking a drug and receiving no benefit, exposing her baby to an effect unknown for very little benefit.  We think that that's not the way people ought to be prescribing.  We think that there ought to be better information out there for people who need to prescribe particularly for drugs that are used often or where therapeutic margins are narrow.
		The medical literature in this area on dosing in pregnancy, pharmacokinetics, pharmacodynamics, is quite limited, but where it exists, for the most part, it does not appear in product labels.  My favorite example of that is amoxicillin.  There is plenty of PK information out there about amoxicillin.  Therapeutic levels in antibiotics are pretty well characterized and described, and yet most clinicians don't know that there's information out there about the pharmacokinetics of amoxicillin.
		Entering into data collection and research in this area are, of course, the physiologic effects of pregnancy and how those may make a difference in what happens in the pregnant woman when she takes a medicine.  I often think of this as, the pregnant state is like this little window of -- like the most female state and the most intense hormonal effects on metabolism of the drugs are likely to be seen in pregnancy.  There is at least one study that shows that one of the isoenzymes, the P450, is changed when women are pregnant, and that may be important for some medications.
		So, what is FDA doing in this area?  Well, the new safety regulation will help us in this area.  It will encourage companies to bring those sorts of data that are out there in the literature to our attention and begin to evaluate them.
		We are also collaborating with the NICHD to try and facilitate more research in this area.  Dr. Cathy Spong later this morning will be telling you about some of their activities, including a workshop that they're going to be sponsoring this fall to try and bring together experts in obstetrics, other fields, and clinical pharmacology to try and develop a research agenda in this area.
		Later in the fall, FDA, NICHD, and probably several other groups are going to sponsor a larger workshop to try and generate broader interest and sort of assess the state of the art in this area.  
		We are already planning a workshop or symposium at the annual meeting of the American Society of Clinical Pharmacology and Therapeutics for spring 2001.
		Then on to lactation.  I think it's fair to say, and I think this is a nice way of saying, that product labels are rarely informative in this area.  I've had people say to me, well, you know, it may as well not even be in there.  And you know what?  For the most part, it's true.  Those product labels say very little that's helpful about this.
		Yet, increasingly the health benefits of breast feeding are recognized.  Healthy people 2010, the American Academy of Pediatrics, and on and on and on increasingly encourage women to breast feed longer rather than shift to formula after the first few weeks of life.  It's safe to say that many women need prescription medicines while they're breast feeding and we know very little about how much of any given drug gets into breast milk and how the developing infant metabolizes those products once they're there, once they're ingested.  Those effects may be very different in the neonate and the 6-month-old.
		The way I think of this from where I sit is lactation is sort of the next frontier for us.  The FDA has a large initiative ongoing in pediatrics.  Fortunately for us, the pediatrics initiative is housed in the same part of the organization that we are, which makes things very convenient.  We think that thinking about the safe use of products from a public health standpoint, there is a natural link from pregnancy to nursing mother to baby.  So, we need to think about the science and the safety of these products as a continuum.
		This is an area that we feel is really uncharted territory for us.  We are beginning to work with the pediatrics team to work on this collaboratively internally and try to integrate our concerns, first, by assessing the state of the art in science in this area.  We know that there's a lot out there but it doesn't come to our attention in any organized way.  We will likely, as part of our efforts to begin to explore this, bring together members of this committee with our Pediatrics Advisory Committee hopefully in the fall of this year to begin to explore where we need to go with lactation.
		Then I don't think I would be complete without just making reference to dietary supplements.  Many of you are aware that there is a public hearing on Thursday of this week that is to take testimony on a new proposed regulation by our Center for Food Safety and Nutritional Products related to structure-function claims for dietary supplements and how those are distinct from disease or treatment claims, which would make something a drug, but specifically the issue at hand for Thursday is how do we deal with pregnancy in the context of structure-function claims and yet still ensure that these products are used safely.  That is not a topic for the meeting over the next two days.  There is a very formal, organized public hearing with the Center Directors from Foods and Drugs who will take public testimony on that on Thursday.
		So, in summary, I think we are making steady progress as we move toward developing a labeling model for pregnancy.  We recognize and are trying to attend to an increasing emphasis on addressing data needs, specifically what we consider the broader area of risk management of drugs in pregnancy.  Elements that we are involved with toward doing that are trying to find ways to encourage the development of sound registries, but also think outside of usual models for data collection on fetal outcomes. 
		We also think it's important to find ways to increase pharmacokinetic, pharmacodynamic, and dosing data in pregnancy and begin to develop scientifically a regulatory framework for dealing with lactation.
		One of the things that's increasingly apparent to us is that we can't do this alone.  We really need to work with people like yourselves and collaborate with other groups who share similar interests to make progress in these areas.
		So, again, just to introduce the rest of the meeting in the way of other updates that will be on the agenda this morning, Joseph DeGeorge will give you an update on some activities related to work in the preclinical area, reproductive toxicology, that will feed directly into our labeling attempts.  Cathy Spong from the NICHD will speak about PK/PD and their efforts in that area.  Dr. Evelyn Rodriguez will walk you through the guidance document on pregnancy registries to help launch the discussion of that topic.  And then later in the meeting, we have a number of speakers lined up to help stimulate your thinking about a broader discussion of strategies for data collection, how to get the most out of each effort, and thinking beyond the current models for registries, particularly that we know of, sort of -- you know, always a pharmaceutical company, one drug, one company.
		So, thank you very much.
		(Applause.)
		DR. GREENE:  Thank you.
		Are there any questions for Dr. Kweder?
		(No response.)
		DR. GREENE:  Thank you.
		We move on now to Dr. DeGeorge please.
		DR. DeGEORGE:  Good morning.  
		My task today is to actually give you an update on what our nonclinical efforts are in evaluating reproductive risk, and I'm not going to go through as much detail as was presented, I think, in October -- maybe it was our June meeting -- where you actually got a preview of our concept and how we were thinking about evaluating reproductive risk.  But instead, I'll focus on telling you what we have done since that time in our various efforts.
		As I think it's clear to everyone in this room, at the time that products are approved, we have very little information from humans on reproductive risks.  In writing labels for products into the foreseeable future, we're still going to have to rely on nonclinical information in drafting that label.  The focus of this meeting, of course, is mainly clinical information and its sources, but this is an attempt to begin to reconsider our evaluation process for reproductive risk using animal information.
		Our effort begins with the defining of the issue about generally we're not going to have human information.  Yet, we're going to have to make some estimate of human risk.  We recognize the fact, however, that not all animal risks or all animal findings represent a true human risk for reproductive toxicity, just as not all negative findings in animal studies indicate no risk for humans in the same area.  And there are plenty pharmaceutical examples which demonstrate those principles.
		What we also recognize, though, as a regulatory agency is we really have to have a standardized approach for evaluating risk that we can then use to communicate the relevancy of findings to humans, and that this needs to be science based within our current context of reproductive evaluation.
		Now, this is just a view of the landscape of the various activities that are going on within the center.  The Pregnancy Labeling Task Force, which is chaired by Sandy Kweder and Bern Schwetz, is really something that is actually organized out of the Commissioner's Office, and it has representation from all of the centers, not just the Center for Drugs, not just the Center for Biologic Products, but from CFSAN and the Commissioner's Office, and many other people contribute to this effort.
		There are a number of working groups that are tasked under this overriding committee to, in fact, generate the various documents that you have heard about in the past and will hear about today as well.  I'm going to talk about the documents that are in the lighter green color, and that is the preclinical guide for reproductive study evaluation and the integrative analysis for reproductive risks.  These are actually coordinated through CDER's Pharmacology and Toxicology Coordinating Committee.  One is a product of our Reproductive Toxicology Committee, whereas the other is a product of an integrated group of reproductive toxicologists and generalists in toxicology information assessment.  
		And there are the other task forces, that which is drafting the proposed rule and guidance for labeling, the various task forces that are working on establishing registries, which you'll focus on today, and also a guidance which I think you've seen already in a draft form on how to evaluate reproductive risks from human data.
		I'm going to begin with the integration working group because this document is actually fairly advanced and we plan to have our last meeting of our drafting committee this week.  Then we will begin the laborious process of clearing FDA to be publicly available for draft and comment.
		The people on this committee have meet I think, since about two and a half years now, every other week for three hours late in the afternoon to try to reach a consensus on what is a reasonable approach.  We've been modifying this document over and over as we get more information about new approaches and new things we need to consider.
		The task for the group was really to develop something for reviewers within primarily the Center for Drugs and the Center for Biologic Products, which is where we do product labeling in terms of reproductive risks primarily, to use to interpret findings from reproductive toxicology studies in light of other kinds of information, and to be sure that in applying such an assistance or a reference document, that they would come to reasonably consistent conclusions based on an identical data set.  However, I need to point out that this document, that we will hope to make available this summer, is not a guide on how to evaluate reproductive toxicology findings.  That's the other document I'll talk about later on.
		So, the objectives of this working group were to standardize a method for judging and evaluating the relevancy of nonclinical findings for human reproductive risk, to try to characterize those findings in the context of the total data set that we have, whatever human information we do have, such as drug metabolism, exposure, how that relates to the animal studies and how they were conducted, and then to organize these findings in a consistent manner so that we could effectively communicate and discuss our conclusions with others, with the rest of our stakeholders.
		The approach is, in fact, to enumerate and to codify thought processes which people who have seen the draft concept paper say are not that much different than what they have thought about generally in the past, but it's not been organized.  We tried to group information that address similar questions.  Such as, exposure information can come from kinetics.  It can come from comparative biomarkers.  It can come from a variety of sources.  We try to group that information that addresses a particular kind of question together and separate that, in essence, from were there findings in a particular toxicology study.
		It then tries to assign weights to these various groups -- and I'll go through the categories in a moment -- and then come to some consistent evaluation about what those developmental risks are for each endpoint that is normally evaluated in reproductive toxicology.
		The document actually describes the overall process.  There are three flow charts that have been generated out of this document.  One is are there sufficient information to even make an evaluation of reproductive risk.  Not every study provides sufficient information to do that.  To try to determine, where we have complete studies and there are, in fact, no findings, whether or not those studies are adequate also to say there is no apparent risk to humans.  Then finally, when we have positive findings in either reproductive toxicology studies or general toxicology studies that address reproductive risk, trying to make a decision as to whether those findings do, in fact, generate some concern or risk for the effect.
		Now, I'm just going to talk about the context of the proposal that is going out on the integration.  This has been shared as a concept paper, and it really divides information into six groupings.  We have something called signal strength 1 and signal strength 2, and that is to make sure that we give adequate weight to reproductive findings in and of themselves.  
		In the signal strength 1, we're looking at issues of concordance of findings across species, the multiplicity of those findings within a species, and the time dependency.  Do you only have to treat once to get the effect?  Or does it take multiple treatments to get the effect?  Or can the effect occur with single treatments across multiple time intervals?  All those are important considerations in evaluating the risk.
		We have signal strength 2.  Are the findings independent of something like maternal toxicity or are they caused by it or so closely associated with it?
		The pharmacodynamics of the product itself.  How relevant is that to the finding?  Is it an expected finding of the intended pharmacologic activity or not?
		The concordance of the animal model with humans.  Are they making very different metabolic profiles than the human would use with this, and can the finding be related to those differences or not?
		And then finally, exposure comparisons, and of course, class alerts.  Is this something that's in a class of compounds where we know there is human risk?
		Now, we've presented this concept paper at a number of different forums.  We first presented it in 1998 in a very general format to see whether we had thought about the right issues.  We then had a presentation last June at this advisory committee.  We followed that up with  a presentation that was a whole day industry public meeting with FDA where we presented the approach, the details of that approach, went through case studies, and got feedback on the concept.  We've since also presented that later on that month at the Drug Information Association, and then we've had a recent presentation where more data was brought forward by industry representatives.  Dr. Wier on this committee presented some of their experience with using this approach and what their issues were.  And we've also made presentations to a number of scientific societies.  So, we've gotten lots of feedback already on this early concept.
		I would have to say that some of the feedback we received officially has been very encouraging.  A number of pharmaceutical representatives have indicated that they find it useful in organizing and evaluating data.  The European regulatory community has also commented on the concept paper.  Individual regulators in Europe have as well.  They've been fairly favorable.  Of course, everyone has comments and recommendations for change.  It's not unexpected. 
		The two major kinds of comments that we've had, though, really focus on something that was not in the concept paper and that is the use of biomarkers as exposure indicators, and we are considering that, and also views on how the factors, those six factors, are weighted, whether our approach of weighting, which counts each of those factors equivalently, is adequate or not.  We'll have to address that and we are trying to address that in our current drafts.  We'll make that available when the document is available soon.
		We expect, as I said, to finalize the draft within this week, at least by our group, then try to get it cleared, and hopefully have it available by July.  That is probably a little bit wishful thinking, but we'll do what we can to get it out because we know it is important to have comment on it. 
		Once we make this draft document available, we intend to have a workshop on it to describe its application.  It's a very densely written guidance, a guidance to reviewers.  It needs a lot of discussion.  Once we have that discussion of how it may be used, hopefully we'll get feedback that will be based on what at least our intended approach of its use is so that can advise our revisions before we go to a final document. 
		The other group I mentioned is our Reproductive Toxicology Committee, which is made up entirely of people who have expertise in reproductive toxicology, not generalists included such as myself.  This group is working on a document as to how to advise reviewers to evaluate those studies which are reasonably done usually conducted in pharmaceuticals to specifically evaluate reproductive effects, what we used to call segments 1, 2, and 3, and now call under our International Conference on Harmonization sections A through, I think, it's F in terms of segments, studies.
		This committee serves as a resource to reviewers when they have findings.  Are they relevant or not?  And it is also generating the guidance so that people who are more generalists can evaluate reproductive toxicology studies hopefully by having some sort of reference material.  So, the objective of this committee is to provide some reference for the average reviewer within FDA who reviews toxicology findings to have a baseline to make sure they've addressed all the important elements in evaluating those reproductive toxicology studies.  The approach taken is really a systems approach for reproductive toxicity.
		The various chapters are in their final stages of preparation of the first phase of preparation.  They have not been seen by anyone outside that committee except as a text editor.  What we still need to do is get internal review, and then we intend to seek peer review in the scientific community on this document because clearly this is a document where we need some expertise that goes beyond the agency.  I would say we have a target for the first quarter of '01 to actually get some available as a general comment.
		So, in summary, we have two projects ongoing.  One is integration, which is the one which will feed most directly into the efforts of this committee and the Labeling Task Force, and the other effort is our document to help reviewers understand and make sure they address all the important points in evaluating reproductive toxicology studies.
		Thank you.
		DR. GREENE:  Thank you.
		Any questions for Dr. DeGeorge?  Yes, Don.
		DR. MATTISON:  Your slide bullet about biomarkers talked about biomarkers as integrative approaches.  But as you spoke about it, you talked about the use of biomarkers for dose characterization.  Those are a little bit different, and I wonder if you could maybe comment a little bit more about that.
		DR. DeGEORGE:  Well, I don't know that I'm free to comment to any great detail about specifically how we are incorporating biomarkers, but we think biomarkers as a general concept can be used both as evidence of exposure and relative exposure, but also as evidence of where are you on a dose-response curve in relation to an individual effect.  So, biomarkers are considered within our approach in multiple elements I think is the best I can say.  Does that answer your question?
		DR. MATTISON:  Does that also include mechanism?
		DR. DeGEORGE:  No.  Mechanism is a separate issue within the pharmacodynamics.  The mechanism of the finding is considered one of those separate elements.  It may contribute to that mechanism.  Evaluation as a -- if you saw the effect which was presumably the effect related to the reproductive toxicity and you can measure some -- let's say, cholinesterase inhibition somehow is related to your effect and you could measure that inhibition, you would know where you were exactly on that dose-response curve in humans.
		DR. GREENE:  Other questions for Dr. DeGeorge?
		(No response.)
		DR. GREENE:  Thank you.
		We'll move on to Dr. Cathy Spong, please.
		DR. SPONG:  Good morning.  I'd like to thank you for inviting me to give the NICHD perspective on the needs for the study of therapeutic drug use in pregnancy.
		As Sandy Kweder so elegantly pointed out this morning, there are many issues surrounding the use of drugs in pregnancy.  First and foremost, the use of therapeutic drugs in pregnancy is not only common, it's also necessary.  As a maternal-fetal medicine specialist, I take care of patients who have high risk medical conditions, and it's very, very common to give these patients medications.  Sometimes we give these medications to treat the mom, sometimes we give them to treat the fetus.  It's an area that we don't have a lot of guidance on.
		Other issues include that during pregnancy there are many physiologic changes that affect drug levels.  In addition, the fact that when you give a drug to a mother, there is a transfer to the fetus, and the difficulty of actually assessing that and the fetal drug levels that subsequently occur.
		Finally, the issue of ethical considerations and study designs which are inherently difficult in the model of pregnancy.  These are the issues that I'd like to touch upon this morning and then go into a little bit about the workshop that we plan in collaboration with the FDA.
		Again, therapeutic drug use is very, very common in pregnancy and it's required for both maternal conditions, pregnancy related conditions, and fetal conditions.  Maternal conditions that require therapy during pregnancy are many and varied, but these are probably the more common.  Conditions such as asthma and hypertension, psychiatric disorders, and diabetes can occur before pregnancy and we're just continuing medications that patients were on prior.  However, not only do you need to give the same medication, perhaps you need to change it because the medication that they were on is not considered to be safe or efficacious.  In addition, the dosage required may change as the pregnancy progresses.
		In pregnancy in addition, there are other conditions that occur just because the woman is pregnant such as gestational diabetes or gestational hypertension.  These can be longstanding conditions where the pregnant woman is going to be needed to be treated for a long time during pregnancy.
		Alternatively, there other conditions that can be very acute requiring medications for a couple of days or a couple of weeks, not the entire time of pregnancy.  Those include preterm labor and preeclampsia where the treatment is typically later in gestation, in the third trimester after the fetus is predominantly formed, or very early on such as in the condition of hyperemesis and morning sickness.
		Finally, there are fetal conditions that commonly require drug therapy.  These again are in two varieties:  cardiac conditions where we actually treat the mom in order to get to the fetus, such as supraventricular tachycardia and complete heart block.  Sometimes these fetuses need to be treated in utero and one method of treatment is actually giving the mom the medication and allowing it to be transferred to the fetus.
		Also, we will give mother medication such as impending preterm delivery where we'll give mom steroids in order to attempt to prevent respiratory distress syndrome in the fetus.  This is a more acute condition where you'd give the dose once or twice as opposed to a cardiac condition where you may be giving this to the mom for the fetus for a prolonged period of time.
		So, drug therapy in pregnancy is a balancing act where we're giving maternal treatment and we're weighing that upon the fetal effects.  It's often better to go ahead and treat the mom if it's a maternal condition because if the mother is untreated, it may have significant impact on the pregnancy.  However, the treatment that we're using -- there is little scientific for us to base it on.
		I'd like to touch a little bit on the maternal physiologic changes that affect therapeutic drug administration.  These include the cardiovascular system, the GI system, renal effects, as well as effects on enzymes, as Sandy pointed out this morning.
		Cardiovascular changes are gestational age dependent.  You get a plasma volume expansion and with that you get a subsequent decrease in serum albumin concentrations which may significantly affect certain drugs that are administered.  In addition, you get an increase in cardiac output, as well as alterations in the regional blood flow.  All of these have significant effects on the pharmacokinetics of drugs.
		Cardiovascular effects include plasma volume expansion.  This occurs very early on, just around 6 to 8 weeks of pregnancy, and it peaks around 32 weeks of pregnancy.  Again, a longstanding effect that we often wouldn't consider as occurring in the first trimester, but in fact it does.  By the end time point, the increase in plasma volume is about 1 and a half liters.
		In addition, cardiac output increases by 30 to 50 percent.  Initially this is due to an increase in stroke volume and later on felt to be more due to an increase in maternal heart rate.
		Alterations in regional blood flow include an increased in-flow to the uterus, to the kidneys, to the skin, and to the mammary glands, and a decrease in blood flow to the skeletal muscles.
		Finally, looking at other systems, they include gastrointestinal changes where there is a delay in gastric emptying and an increase in transit time.  So, drugs that are administered orally to patients have significant changes in how they are metabolized and how they get through the GI system.
		Renal changes include an increase in the glomerular filtration rate which has a significant impact on drugs that are metabolized through the kidney.
		Finally, there are enzyme activity changes that are felt to be related to pregnancy hormonal changes. 
		So, the consequence of all of these physiologic changes are the following.  With the volume expansion, we will often get an increase in the free fraction of drug that we administer to patients.  This is due to a decrease in the overall serum albumin levels.
		In addition, there are clearance changes both due to the effects on the kidneys as well as enzymatic changes. 
		Finally, the changes in the GI system result in problems for administration of oral drugs. 
		The result of all of this is that often dosages need to be changed during pregnancy and throughout pregnancy.
		In addition, as Sandy pointed out this morning, this doesn't stop once pregnancy ends.  Postpartum you get a significant diuresis of the plasma volume that the patient had been accumulating, and there are significant impacts when patients continue to breast feed that drugs that you administer to them will also cross over to the fetus. 
		Finally, there's a significant variability between individuals that cannot totally be accounted for.
		Next, taking the shift of administering drugs, we need to remember the effects of gestational age.  Very early on, the embryo is not totally formed.  The embryo is undergoing embryogenesis and organogenesis, and toxicities are very different than when drugs are administered later, although the fetus does continue to develop both in the second and third trimester as well as a neonate.
		The maternal-fetal transfer of drugs is well known.  There's placental transfer as well as once it gets into the amniotic sac, transfer across mucosal membranes, such as the GI tract, and early on in pregnancy, before 25 weeks, there's actually transfer across the fetal skin.  Finally, after pregnancy is over, there is transfer via breast milk when lactation is occurring.
		Monitoring fetal drug levels obviously is very difficult since the pregnancy is self-contained.  We often rely on the clinical exam and on the response, just evaluating and monitoring the fetus externally using sonography.  Again, we aim for the lowest effective dose because our feeling is that giving less is better, but this may not be the case if it's not being effectively treated.
		We can evaluate the fetus using ultrasound.  We can also do cordocentesis where you're sampling the blood of the fetus, but this has risks whenever you're doing anything invasive.
		Ethical considerations and study design are very important when you're looking in pregnancy.  Again, drug labeling is inadequate for our guidance in pregnancy, and the research that's available on the drugs in pregnancy is sparse.  Pharmacokinetic studies in pregnancy, as we've mentioned many times this morning, are inadequate, and this is in part due to incredible difficulties getting IRB approval for these studies.
		Finally, pharmaceutical companies are not particularly interested in doing these studies, as it's much easier to say just don't use these drugs during pregnancy rather than taking on the liabilities of giving a statement as to whether or not these drugs are safe in pregnancy.
		From all of this, the FDA and NICHD have found that research on pharmacokinetics and pharmacodynamics of therapeutic drugs is very important.  We focused on the second and the third trimesters of pregnancy because inherently looking at the first trimester of pregnancy when organogenesis is ongoing brings problems in and of itself.  So, initially we'd like to focus just on the second and the third trimester. 
		Again, we are focusing on a workshop to be held in the fall of this year where we'd like to discuss ideas and generate research interest and activities looking at drug use in pregnancy.  Ultimately, we'd like to generate certain mechanisms for the study of pharmacokinetics of drugs in pregnancy.  This will be followed up by an FDA meeting hopefully in November. 
		So, the bottom line is that therapeutic drugs are common and required in pregnancy.  Research is needed to evaluate the efficacy, the safety, and the required alterations in dosage, timing during pregnancy.  These are issues that pharmaceutical companies will never provide.
		Thank you.
		(Applause.)
		DR. GREENE:  Any questions for Dr. Spong, please?  Yes, Don?
		DR. MATTISON:  You began by laying out maternal pregnancy related and fetal conditions for therapy, but then ended by talking about the fact that the workshop and the initiative between the NICHD and FDA focuses on the second and third trimesters.  Yet, maternal conditions, fetal conditions, and pregnancy related conditions can be expressed in the first trimester.  I guess it would seem to me that one of the complications of understanding how to improve treatment would have to focus on where the systems were changing the most rapidly in terms of their impact on both kinetics and dynamics.  Comments on that?
		DR. SPONG:  I certainly agree that research in the first trimester is equally as important as in the second and third.  My two comments are, one, the most pregnancy related changes occur in the second trimester -- that is, on the mother, on the cardiovascular system, the GI system, the hormonal changes.  They're mainly more in the second and third trimester.  
		In addition, to get research done in the first trimester, to get studies done is going to be incredibly difficult for IRBs to approve these studies, and we agree that that needs to be done.  But we've got to start somewhere, and let's start somewhere that's not as touchy.  So, we're going to focus on the second and third trimester.  We'll go back to the first trimester, but the second and third trimester is equally as deserving of study and less difficult for the IRBs.
		DR. MATTISON:  And then just a definitional question.  One of the slides that has the check mark and says, "result:  dosing changes," do you mean both frequency and amount?
		DR. SPONG:  Yes.
		DR. MONTELLA:  I actually would like to comment further on the point about the first trimester because I do think it's a really valid point.  You are changing certainly metabolism of drugs and volume is on its way up.  So, you really are changing during that time.  It's also the time at which people are inadvertently exposed to drugs most frequently.  It's also the time during which there's a lot of bias against use of needed drugs in terms of trying to lessen exposure, and it's a time when you may be specifically underdosing people or withholding drugs.  So, I think it's a really critical period for us to look at.
		DR. SPONG:  We certainly agree.  We absolutely agree.  Our reason for choosing the second and third trimester is just to start the interest.  If you cannot get anything going, you're never going to get to the first trimester.  We realized that no matter what -- this has been a very neglected topic for a long period of time.  If we can at least get something going where it's not so difficult in the second and third, the first will follow.  We absolutely agree.
		DR. MONTELLA:  I certainly applaud that effort.
		DR. SPONG:  We absolutely agree.
		DR. FRIEDMAN:  Just to follow up along the same line, I'm not sure I understand the statement that you made several times about the difficulties with IRBs.  It seems to me that if you have a group of women that are being treated because they need to treated or they have already been treated anyway, gathering information on drug metabolism, on elimination, and so forth from the mother shouldn't present tremendous ethical problems.
		DR. SPONG:  Gathering information on currently treated drugs is probably not going to be difficult, especially noninvasively.  But when you start to talk about labeling drugs, talk about trying different drugs, yes, there is going to be -- obstetricians typically use things that work.  And we've just used the same drugs typically for a long period of time because they've worked.  The exposure of a woman to a drug because you wanted to test that drug is somewhat difficult.
		DR. FRIEDMAN:  Well, even the things that work don't always work.
		DR. SPONG:  That's true.
		DR. FRIEDMAN:  And the things that work we don't often have a lot of information on.  It just hasn't been collected even though the drugs have been used for a long time.
		DR. SPONG:  This is very true.
		DR. FRIEDMAN:  And it seems to me that there aren't tremendous IRB restrictions for gathering that information.  That ought to be an area of intensive research.
		DR. SPONG:  I agree.  Gathering information, as you describe, would not be difficult for an IRB and certainly should go forward.
		DR. GREENE:  Other questions for Dr. Spong?
		(No response.)
		DR. GREENE:  Thank you.
		We now have some time for open public hearing comments.  We've been notified of one person who would like to speak, Dr. Mary Teter.  At this time I'd like to give her an opportunity to speak, and also to ask if there is anyone else who would like to speak, to please let us know at the front desk.  
		I think many of you will have copies of her handouts in your packages.  I think there was a shortage.  I'm not sure everybody has them, but I think most people do.
		DR. TETER:  We do have a few extra copies if you need them.
		Thank you very much for allowing us to speak today.  My name is Mary Teter.  I'm a physician and a Director of Drug Safety and Pharmacovigilance with Bristol-Myers Squibb Pharmaceutical Company in Princeton, New Jersey.  By medical training I'm a pediatrician, but I'm here today to present comments from PhRMA, the Pharmaceutical Research and Manufacturers of America, and we would like to comment on the FDA draft guidance for industry on establishing pregnancy registries.
		A little bit of background about PhRMA.  PhRMA represents the country's leading research-based pharmaceutical and biotechnology companies.  Members invest over $26 billion annually in the discovery and development of new medicines.  Because of our commitment to patient safety with the products we develop and market, we are interested in the use of pregnancy registries as a research methodology in specific circumstances.
		First, a few general comments on pregnancy registries.  PhRMA supports FDA efforts to provide consistent guidance to industry regarding pregnancy registries.  We recognize the potential of a guidance document to enhance the validity and utility of data obtained through registries, and we hope that a revised guidance document will minimize confusion about the regulatory status of adverse events reports received through pregnancy data collection.
		We would like to touch on a few points, the first of which is the definition of a pregnancy registry.  A clear and concise standard definition of a pregnancy registry should be developed with an explanation of how a registry differs from standard clinical trials and other epidemiologic methods, such as cohort studies.  Key features of a pregnancy registry as outlined in the guidance indicate that it must be prospective in nature and include active collection of data.  However, pregnancy registries are alternatively described in the guidance as:  A, a system to collect information on specific drug/biologic exposures; and B, cohort studies of women exposed to a particular drug compared with a nonexposed cohort.
		Similarly, the difference in design between an active surveillance program for signal detection and hypothesis generation and study for hypothesis testing is blurred in the guidance document.
		A pregnancy registry should be an efficient means to assess, with sufficient statistical sensitivity and specificity, the relationship between exposure and pregnancy.  
		It should be made clear that registries do not have to have concurrent internal comparison groups.  That comparison can be made using external rates.  And noncomparative registries can be used for hypothesis testing.
		Comparative cohort study design may be more appropriate when there is sufficient suspicion of a signal that requires confirmation.
		The second point that we would like to address is the objectives of pregnancy registries.  A statement of the scientific and regulatory objectives of pregnancy registries, including clear guidance on when a pregnancy registry is needed and the information to be generated, should be presented in the guidance.  The limitations of a pregnancy registry should be clearly described.
		The public health need for a specific registry or study should be defined by the likelihood of drug use during pregnancy and the potential risk to the mother or fetus.  Potential risk should be based on a drug's chemical structure or principal metabolites, pharmacologic class or similarity of its mechanism of action to other drugs in a chemical class, animal toxicity findings, or human case reports of abnormal outcomes.
		Registries should be established for new products when there is a signal detected or suspected.  Registries should not be required for all products.  In general, we see no need to implement registries for well-established marketed products where no risk has been identified. 
		The specific goal of a registry will drive design, data collection methods, and the enrolled population.  All registries need not be alike and there should not be one standard design.  However, clear endpoints for study conclusion must be established prior to registry initiation.
		A registry guidance should also describe how information on normal pregnancy outcomes will be disseminated to medical providers or used to support product-specific labeling.
		Recognizing the limited experience with pregnancy registries to date PhRMA urges FDA to assess, in conjunction with industry, the value and experiences gained with pregnancy registries using specific metrics.
		Finally, we'd like to address an area that's very important to us and that is adverse event reporting.  It's very important for FDA to provide a clear discussion of the regulatory requirements for adverse event reports arising from pregnancy registries and the rationale for these requirements.
		FDA has not addressed by regulation the reporting of adverse events from pregnancy registries, and FDA's guidance to various sponsors may not have always been consistent in the past.
		The guidance document does not clarify whether pregnancy registries should be considered post-marketing studies or part of an active surveillance program.
		We do have recommendations.  PhRMA strongly recommends that FDA consider reports from pregnancy registries to be solicited reports as outlined in FDA's Guidance for Industry, Postmarketing Adverse Experience Reporting for Human Drugs and Licensed Biological Products:  Clarification of What to Report, which was issued in August 1997.
		Under this guidance, solicited reports are to be handled in the same way as reports from clinical studies and only submitted to FDA on an expedited basis, that is, within 15 days of learning of the event, if they involve serious, unexpected events for which the sponsor or the investigator concludes that there is a reasonable possibility that the drug caused the event.  However, all adverse event data should be filed as part of a complete summary of the registry experience, at the conclusion of that registry.
		In summary, we ask FDA to consider and review our comments on the guidance document, with particular attention to three areas:  one, the definition of pregnancy registries; two, the objectives of a pregnancy registry; and three, how to handle adverse event reports arising from pregnancy registries.
		Additional commentary has been submitted by PhRMA to FDA in a letter to the docket which was dated August 31, 1999, but we certainly appreciate the chance to participate in this meeting and to present our comments directly to the committee.  Thank you.
		(Applause.)
		DR. GREENE:  Thank you.
		Any questions for Dr. Teter, please?  Jan?
		DR. FRIEDMAN:  I have concern about your recommendation or your statement that there's no need to implement registries for well-established marketed products where no risk has been identified.  How do you decide if no risk has been identified for most products when there haven't been any studies?
		DR. TETER:  Well, I think obviously that's an area that's open for discussion.  But certainly we would be driven by or think or approach the need for a pregnancy registry where there is some suspicion that there may be a risk.  Many products have been marketed for many years and have been used in pregnant women, and there are not reports of adverse effects reported.  So, I don't think that that would be a place to start with a pregnancy registry.  We would feel that the place that that should be directed would be where there is a suspicion of a risk either based on animal data or previous human exposures.
		DR. WIER:  I just follow up on Jan's comment, and that is, historically I think we're hard-pressed to find many examples, perhaps aside from isotretinoin, where risk was expected, anticipated, identified in advance.  Virtually all known human teratogens were not expected to be that.  And I would just urge that caution and thinking.
		DR. GREENE:  Other questions or comments?
		(No response.)
		DR. GREENE:  Thank you very much.
		DR. TETER:  Thank you.
		DR. GREENE:  We are right on time, quite remarkably.  I want to thank all of the morning speakers for remaining right on time. 
		We have a minute or two if there is any other further public comment, and then we'll take our break as scheduled on our agenda.  If there's no other public comment, thank you.  We stand adjourned for 15 minutes.
		(Recess.)
		DR. GREENE:  Could we reconvene, please?  Let's get started please with the second half of the morning.
		The next speaker will be Dr. Elizabeth Andrews.  Dr. Andrews, please.
		DR. ANDREWS:  Thank you.  One thing I'm going to do is point out that there are a couple of themes that came up in the earlier session that you'll see as common threads in this talk, and one is Dr. Kweder's comment about understanding the general margins of safety.  The other was from Dr. Spong, you've got to start somewhere.  What I'd like to do is talk about our experiences with our registries.
		My first lesson I think is that had we thought about the implications of the use of the term "registry" when we created our first registry, we probably would have called it a follow-up study rather than a registry because registry, as a term, leads to a lot of confusion.
		What I'd like to do is to illustrate one approach to pregnancy follow-up studies using the examples from our own experience, and then I'd like to describe a few of the practical lessons that we've learned from hands-on experience over the years.  Then I'd like to spend a couple of minutes talking about future possibilities on the horizon, and then to identify three key issues that I think simply must be addressed if we are to move ahead in the direction that the FDA, the CDC, the pharmaceutical companies, and providers and women would like us to move in, and that is, providing much more information that's available in decision making as regarding medicines in pregnancy.
		First, let me mention that pharmaceutical companies monitor the safety of all of their products through their surveillance programs in which they collect, analyze, and report to the FDA spontaneously reported adverse experiences, and increasingly, because of international harmonization, we also undertake periodic reviews of all the safety data for better understanding of the safety profile of each drug. 
		In addition to what we do for every drug, there are occasionally areas of study that require more rigorous and systematic study.  One of those areas obviously is safety of drugs in pregnancy.  This slide presents some of the points that we use within Glaxo Wellcome to help us, as we think about each new product as it approaches the marketplace, in determining when we should actually conduct a pregnancy follow-up study. 
		What will be the likelihood of first trimester exposure?  
		Will there be a potentially large exposed population of sexually active women of reproductive age?
		Are there suggestions of hazards from animal data that we think translate into adverse effects on the human fetus? 
		Is the underlying medical condition itself a risk factor for adverse effects in the offspring?  
		Does the medication's mechanism of action give us some reason to expect an increased risk with this drug? 
		And again, the pregnancy category rating.  We would be more inclined to pursue additional data for drugs that have an existing category C rather than a B labeling.
		The example that I'll use is our completed study of acyclovir.  I have to apologize for increasing the thickness of your binder in providing this extensive final report which tells you more than you ever wanted to know about acyclovir in pregnancy.
		Acyclovir is a drug used to treat herpes simplex virus infections, and we established a registry, or follow-up study, in 1984 because of the potential for wide scale exposure to a population of sexually active women of reproductive age and because of the background history of antivirals to that time which were less specific in their action and more toxic.
		When the study was established, it was part of a broad epidemiology program that was looking at the general safety of acyclovir, so we were conducting a number of other studies using databases from health maintenance organizations and other approaches.  This was also a joint effort with the Centers for Disease Control who had similar questions and were contemplating a similar kind of study.
		Our objective was to monitor for risks of birth defects following antenatal exposure.  And we naively thought in those days that we could use a hands-on intensive registry approach until we were able to conduct the same kind of study in an existing database, such as the HMO databases, and that never happened.
		As we considered possible study design, we faced a number of different decisions.  What were the exposures of interest?  There were three formulations of the drug.  We were mainly interested in oral acyclovir because that was the formulation used to treat genital herpes, but we didn't want to miss information about IV exposure which produces a much higher level of drug.  But we felt it was inappropriate to include topical acyclovir which is poorly absorbed systemically.  
		We made a conscious decision to look only at maternal exposures, not that paternal exposures were less relevant but were more difficult to study.
		Our primary focus was on exposures during the first trimester of pregnancy despite the fact that the obstetrics and infectious disease community were primarily interested in us using these methods to look at the safety and efficacy of acyclovir when used in late pregnancy to prevent neonatal herpes.
		As our outcomes, we were looking at the overall risk of major birth defects and we also intended to look at specific birth defects for any evidence of a pattern or cluster that might suggest that we could follow that up using a case-control study for more definitive study.
		We recognize that many other outcomes could be interesting but were beyond the scope of our methods, and in fact we had the scientific rationale to pursue them at that point.
		As we considered our objectives, we explored a number of different study designs.  It was clear the cohort study was not ethical and a study using only a few sites to enroll patients prospectively would unlikely be successful because of the relatively rare outcome of birth defects, especially specific birth defects. 
		A case-control study wasn't feasible at this point because the exposures in the population were too rare, and also we had no a priori hypothesis of the specific defect that might be associated with this exposure.
		And we looked for existing data resources, and there were none available that could answer this question.
		We therefore, determined to conduct an exposure registration and follow-up study in which exposures would be reported and included in our analysis only if they were reported prospectively before the outcome of pregnancy was known.  
		We needed some type of birth defect comparison group, and in this particular case, we chose the population rate because we felt that the primary exposed group was women with genital herpes who had no other a priori risks for delivering a baby with major birth defects over other populations. 
		And we chose the definitions used by the CDC and the Metropolitan Atlanta Birth Defects Program.
		We also determined that other outcomes were beyond the scope of this approach.
		The next slide attempts to depict how we determined which cases reported to the program would be considered retrospective versus prospective.  Any exposure that was reported after the outcome was known was considered to be retrospective, and that includes births -- and we received a lot of those -- as well as cases in which a prenatal diagnosis had confirmed the presence of a birth defect.  So, we only enrolled throughout pregnancy those reports that were made to us before we knew the outcome of pregnancy.
		At our initial data collection, we did a lot of learning in this process.  We started out with a very ambitious approach, an 8- to 10-page data form that asked for every conceivable information on occupation, environmental exposure, all the drugs that were suspected to have some relationship to birth defects, and other potential confounders.  And we quickly realized that if we were to obtain any useful data, we had to structure our data collection strategy in a very minimalist approach.  So, we restricted our data form, as you can see in the binder, to a very limited set of information basically asking for exposure, timing, estimated date of delivery, prenatal testing, and depending on the registry, potential confounders specific to the individual drug or condition.
		We also chose to collect basic information from a single reporter.  We had many, many discussions with our advisory committee about how we might conduct long-term follow-up through pediatricians, and we decided that our best approach, the most successful approach to maximize data collection would be to stick with the general reporter who called in the exposure, which was typically an obstetrician who was contacting the company through our drug information hotline for information about the drug in pregnancy.  We felt that with using those reporters, they were more likely to be motivated, they were likely to have the relevant exposure and key outcome information which was major birth defects identified at birth, and that collecting information from them would not require additional steps such as gaining consent and contacting other providers.
		In follow-up, we sent a form to the health professional at the estimated date of delivery, monthly reminders for 3 months after that if we didn't obtain information, and then used a last-ditch phone call or data form to try to minimize lost to follow-up.  
		The patient identifiers that we used to enable the reporting physician to identify the patient again at delivery -- not names, but it could have been a chart number, date of birth or initials -- were deleted at the completion of data collection.
		We sent each of the reporters a thank you letter long after delivery with the encouragement to report to us other exposures and also as an attempt to solicit other outcome information they may have become aware of for the infant involved in the exposure.
		Targeted follow-up was conducted by the registry staff relating to specific birth defect cases, and that was based on a teratology review conducted at CDC, as well as questions from our own surveillance physicians.
		In the analysis, we separate prospective from retrospective reports, estimate a birth defect risk, a proportion, from the prospective reports.  And I'll show you an example in a minute.  And we compared that risk against the expected risk, which varies depending on the study that we're talking about.  We also evaluated all of the specific birth defects reported either through the prospective reporting or retrospective, and we analyzed those for patterns or uniqueness that might suggest a common etiology.  And all of the data were reviewed by a multi-disciplinary advisory committee before releasing interim reports.
		One of the challenges in trying to recruit exposures is getting the right message out.  We really struggled with this in the early days of the acyclovir program.  In trying to get the word out about the fact that we were conducting registry, we needed to avoid implying that we felt the drug should be used in pregnancy or that we were suggesting that we think there's an increased risk when, in fact, neither was true.  
		We looked at a number of options for obtaining information, including referrals from different groups, scientific meetings, and I have to say that one of the most successful things we did was to include information in the package insert.  
		Sources of calls and referrals come from a variety of sources.  The key point I wanted to make here was that our registries have tended to be international.  So, we've made use of the local operating companies in different countries and wide use of our intranet to make available information about our programs to try to educate people in our local operating companies to increase awareness in reporting of these exposures.
		Each of our programs has an advisory committee that helps in the review of data and also is another way of trying to disseminate information and encourage reporting in the sectors that they are a part of.
		This next slide shows the data from the acyclovir registry.  What I'd like to show is that of those reported cases over 14-plus years, we had a total of 1,246 pregnancies with outcomes known.  Of those, 756 involved first trimester exposure to oral or IV acyclovir.  When we calculate the risk of birth defects among first trimester exposures, we look at the number 19, which is the outcomes of birth defects.  That includes live births with birth defects, as well as prenatally diagnosed birth defects that may have not advanced to delivery.  So, our nominator is 19 birth defects over a denominator of 19 plus the live births without birth defects, the 577, excluding the spontaneous and induced abortions.
		So, we calculated a proportion of birth defects of 3.2 percent with a fairly tight confidence interval and compared that with a proportion from all exposures across all trimesters and concluded that when we compared this with the general population rate of about 3 percent, that our experience does not differ from the general population.
		In addition, when we looked at our overall sample size, we concluded that regarding individual birth defects, that we had 80 percent power to detect a 7-fold increase in the risk of a birth defect that occurs in the general population with a rate of 1 per 1,000.
		Our conclusion from study was that there were also no patterns among the birth defects to provide a signal of potential common etiology.  We certainly need to recognize the potential limitations, which include under-reporting of exposures, under-reporting of birth defects, the inability to identify all birth defects within the first year of life, potential differential reporting, and losses to follow-up.  
		But despite these limitations, we felt that the information was useful in the course of counseling women following inadvertent exposure.  And in terms of the value of this study, the greatest benefit clearly was that more information is available for patients and their providers. 
		It was clearly useful to our company in our evaluation of safety of this medicine.  It taught us a lot about how to do these studies.  We were able to include this general information in our product label, changed the labeling category from a C to a B.  
		And the information was also useful as the CDC developed their sexually transmitted disease treatment guidelines relating to genital herpes.
		We participate in a number of pregnancy follow-up studies looking at a variety of medications, and let me just highlight that we're involved in two studies, the antiretroviral registry and the North American Antiepileptic Drug Registry, that are multi-company collaborative projects.  The AED pregnancy registry enrolls women themselves, rather than enrolling through physicians, and the antiretroviral registry, which is managed by PharmaResearch is a registry looking at 14 different products of 8 companies.
		Let me turn to some of the lessons that we've learned from just practical experience over the years in trying to conduct and improve these kinds of studies.  I'll take these five points in order, but first of all, let me mention that these are all very labor intensive studies that require numerous attempts to contact patients or physicians for very limited amounts of information.
		So, as we decide how to study any hypothesis relating to drug safety, we clearly must balance the ideal study design against the probability that we'll actually obtain useful data.  If we build a perfect study, will the study population rise up to enroll, provide years of intensive follow-up information?  Probably not if we're talking about a hands-on study. 
		We must also tailor the design of our study to the specific question at hand and not ask one design to answer all possible questions of potential interest.  For many drugs, the first level question is, is this drug associated with an increase in major birth defects?  If that's the question, then some variation of a basic approach makes sense.
		However, if the question is what's the likelihood that this drug causes a specific defect -- and we've had examples.  One example was a drug that's widely used, and there was a signal of a possible relationship with a very rare abdominal wall birth defect that occurs in about 1 in 10,000 pregnancies.  Clearly we would not set up a prospective study to evaluate that.  We'd conduct a case-control study, which is underway I think.
		If we were looking for subtle defects or delayed effects way beyond birth, we'd certainly not select this basic design for a registry.  But if we're looking for the general margins of safety, some variation of a basic approach might, indeed, be tailored to meet the needs of a particular medication.  So, it's critically important to select the right method for the outcomes of interest. 
		I'd like to make another point, which is that some outcomes like spontaneous abortion and maternal outcomes may occur more commonly than overall, certainly, specific birth defects and require a different type of study design, different amount of data, different types of data, and would be very difficult to squish that into the context of one of these studies looking at birth defects.
		So, the optimal method really needs to consider two dimensions that often work at cross purposes in a hands-on prospective study and those are sample size and study complexity.
		A large sample size may be obtained best by using a very simple approach and that may be appropriate for these studies of major birth defects.
		Studies requiring more complexity or a multi-step design will have extreme difficulties in attaining a large sample size and will require enormous resources and may, even with enormous resources, not be able to achieve its objectives.  Those would include studies of delayed effects.
		Success of recruitment in the follow-up is also dependent on study simplicity.  There are providers and patients who elect to contact a registry and provide information.  The patients and physicians who do come forward are still only a small sample of the exposed populations, but I take as my 100 percent starting point the people we do find out about.
		Retention is a major concern.  Among the total population, we can look at the effects of different levels of complexity and study design.  If patient consent is required in order to obtain additional data from the patient or to be able to go to a number of different providers for different kinds of information, the participation rate will be significantly lower, and anecdotal evidence suggests that it might be 50 percent.
		Other exposures are lost when referrals are required.  For example, if a physician must ask a patient to contact a registry, the patients who are intimidated by the health care system may not actually be referred.
		As duration of follow-up is extended, then the likelihood of obtaining complete information is further diminished. 
		The potential for lost information, selective information, must be considered, and this is not a trivial issue as we are talking about very labor intensive data collection.  At best we'll still find ourselves with many cases that are basically irrelevant to the study question because the exposure occurred in an irrelevant trimester or the exposure was reported retrospectively.  I can't emphasize enough the importance of trying to recruit exposures very, very early in pregnancy.
		So, such a labor intensive method and imperfect method is fine because it still provides us with substantially more information than we would have otherwise.  But it's fine as long as there are no better and more efficient alternatives.  And I do think that it's within our 10-year horizon to realize the prospect of large linked databases to help in making this data collection strategy much more efficient and less dependent on active hands-on follow-up.  The advantage of using an existing database is that all exposures can be identified.  It's not dependent on voluntary reporting.  Follow-up information is already collected.  It's much easier to get back to the individual patient information should it not be in an automated database.
		While these databases currently are not sufficient, because they don't have enough detailed information and they're too small, I think the movement is for automated medical records databases to be much more comprehensive including kinds of information that we'd really like to see like LMP dates, that we might be able to see over the next 5 to 10 years that consolidation across multiple databases might be able to be a helpful addition and keep us from having to reinvent these kinds of hands-on studies again and again.  But, of course, those will still probably not take the place of case-control studies which remain a mainstay in being able to test hypotheses that arise.
		Let me highlight three issues that I think must be addressed if we're to move forward in the kinds of registries that we're talking about today.  One is the issue of consent and IRBs.  Those of you who know me know this is a pet issue for me.  I'm very concerned that the evolving legislation, HHS regulations, and practice guidance that's being developed in many sectors is moving in a direction that may, in fact, stifle our ability to conduct this kind of research by requiring informed consent and perhaps putting some constraints on our ability to do this research which, in effect, may help us to conspire against collecting this kind of information.  So, I think it's very important that we stay tuned to the evolving policy development and have our voices known so that we don't find ourselves unable to study these issues.
		You've already heard the comment about adverse event reporting, and clearly we need some clear guidance with the FDA about how to report events that emerge from these kinds of studies.  Our preference is to use study guidelines rather than the spontaneous event guidelines.  This lack of clarity creates a significant barrier when multiple companies are collaborating on a single study.
		And there needs to be greater understanding of how information coming from these kinds of studies can be used and how they should be interpreted.  The public and providers are a bit in the dark.  We need ways to disseminate this information in ways that are helpful to providers and women who are pregnant or considering pregnancy in the face of enormous pressures that suggest that any exposure to any medication will be hazardous.
		So, let me stop there and see if there are any other questions.  I could probably go on and on, but I'll stop there.
		DR. GREENE:  Thank you.
		Questions for Dr. Andrews, please.  Jim.
		DR. LEMONS:  That was very interesting data.  I had a couple of questions related to the acyclovir study to see if there were any other conclusions you could draw.  One is, do you have any estimate of what percent the prospectively followed cohort represented of all pregnant women that might have been exposed?
		Secondly, do you have any data from that study or other studies that would reflect upon the quality of evidence that might be collected from a retrospective sampling?  That is, do you know, in fact, that the retrospective sampling, looking at least major birth defects, would have been inaccurate or misleading?
		DR. ANDREWS:  Good questions.  The first question.  We tried many times to estimate the total exposed population, which requires understanding the use of the drug and making some estimation of fertility in women with genital herpes, and we had very wild estimates.  I think our bottom line is that we know that we only captured a fraction of the exposed population, and how big a fraction I really don't know.
		Your question about retrospective reporting.  It's very clear that when people have identified an outcome and want to tell us about it, there's a reason.  So, there are a number of providers who are very interested in using acyclovir to prevent neonatal herpes.  So, they pick up the phone and call us routinely to tell us how safe the drug was, and we have no idea how representative that experience was.  It's clearly not.
		DR. GREENE:  Ken?
		DR. JONES:  Elizabeth, I'd like to make a comment and also ask you a question.  It relates to one of your slides here on design considerations.  First of all, you say that cohort studies are not feasible because outcomes are too rare, and I agree with you on that if what your outcome is is single major malformations, which you clearly make as your outcome.  
		However, I think as many of us believe -- clearly not all of us because I know Allen Mitchell is down there.
		(Laughter.)
		DR. JONES:  But I think as many of us believe, human teratogens are primarily associated with a pattern of minor malformations as opposed to a single major malformation.  So, I would take exception to the issue that outcomes are too rare because I think when one is looking at minor malformations and patterns of minor malformations, you can do this with much smaller numbers.  And that's the first point that I'd like to make. 
		Now I'd like to ask you a question, and that relates to your comment that cohort studies are not ethical.  Could you explain to me what you mean by that?
		DR. ANDREWS:  Simply that we felt at the time that acyclovir was being introduced in the mid-1980s, that trying to enroll women prospectively, we would not be enrolling them in a clinical trial to expose them intentionally to acyclovir, and it would be very difficult to, through a set number of centers, identify those with inadvertent exposures.
		DR. JONES:  Okay, well, that may be true with acyclovir, but I think that there are many drugs that are being marketed that women are taking today that inadvertent exposures are relatively frequent, and if we are looking for outcomes again other than major malformations, in particular, if we are looking for outcomes in terms of neurobehavioral development, which I think is a critical issue as far as this is concerned, which has to be determined at 4 to 7 years of age, we have to be enlisting mothers as opposed to obstetricians in terms of the individual that we're talking to.  Therefore, we have to be going to IRBs and we have to be getting consents of mothers to allow us to evaluate their pregnancies, their newborn baby, and then follow their baby up through 7 years of age.  I don't think this is unethical.  I think this is very ethical.
		DR. ANDREWS:  And I would completely agree with you.  I would say on my little diagram with study sample size and complexity, that is over there on the high end of complexity and, fortunately, requires a smaller sample size because that would be extremely difficult to do for hundreds or thousands of exposures.  Absolutely agree.
		DR. WISNER:  My question is about exposures.  As a clinician, as I listened to the information, I'm wondering how generalizable it is to the patients that I see in my office.  So, for example, for this study for acyclovir, would exposure mean that patients who were included who perhaps had a dose or two, found out they were pregnant, and discontinued, as well as patients who perhaps used the maximum dose for an extended period of time?  So, my question is whether you could comment on your experience with creating operational definitions of exposure and how you could present that kind of information to clinicians who have to use the data?
		DR. ANDREWS:  We struggled with that, and we used a variety of approaches.  The most complicated approach was to actually pictorially describe every single case with a graph of every week during pregnancy, and we've actually put the exposure time, as best we could infer from the reports, and dose and indication.  That for hundreds of patients became incredibly too detailed.  We felt that clinicians would like to be able to refer to something like that, and in fact, I think it turned out not to be that useful.  
		We used a variety of other ways of looking at dose, indication, duration of therapy, and that's going to be a different issue for every particular drug. 
		So, I guess one answer to that is when people called for information, we could actually refer to specific information in the cases. 
		DR. GREENE:  Are there any other questions for Dr. Andrews?
		DR. ANDREWS:  Let me just add another comment.  Most of the questions that come in to these hotlines aren't that specific.
		DR. GREENE:  Thank you.
		The last scheduled speaker for the morning is Dr. Evelyn Rodriguez.  Please.
		DR. RODRIGUEZ:  Good morning.  I want to open up by saying that this guidance was really drafted by a large group of dedicated individuals, part of the Pregnancy Registry Working Group.  Carolyn McCloskey, an epidemiologist on my staff, worked on this document, along with Sheila Weiss, who is on the committee today, Jean Manson and others who are too many to list this morning.
		The guidance was drafted by this committee and then published in the Federal Register in June of 1999.  You have a copy of the draft and the comments that we received regarding the draft in your background package.  What I'd like to do now is to bring you up to date on the agency's current thoughts in preparation to seek your advice on how we proceed toward finalization of this document.  I think PhRMA and others who have submitted comments will recognize that we've incorporated many of the concerns into our current thoughts.
		This is the outline of what I'll be covering today.  I'm going to be discussing the agency's reason for drafting a guidance document to industry, describing what a pregnancy registry is.  Every registry needs a protocol, so I'll be talking about the purpose of establishing a protocol, and a little bit about the registry study design, touching upon recruitment, considerations in reporting source, issues regarding follow-up, comparison groups that can be used, issues in data analysis, and finally reporting results.
		Why a pregnancy guidance document?  Well, the agency felt it was important to provide useful data to health care providers in caring for their patients.  Clinicians really have a dearth of data to refer to regarding issues arising in the use of drugs or medical products during pregnancy, and because those data are lacking, we felt it was important to address it in a guidance document.
		Well, what is a pregnancy registry?  I'm going to use the S word.  A pregnancy registry is a study and it could have many, many designs.  There's not a cookbook approach that one can use to design a pregnancy registry.  Often it's hypothesis generating if the risk is unknown.  It could be hypothesis testing if, for example, animal studies point to a particular possible adverse outcome of concern.  The design would depend upon the hypothesis and outcomes of concern, and ideally prospective enrollment of subjects would be actively pursued.  It also would outline how information will be collected in a proactive manner for providing the scientifically based outcome data that's needed.
		What is the purpose of a pregnancy registry?  Well, we need to determine the risks associated with drug use during pregnancy, and we need to provide a measure of this risk and, whenever possible, to determine the risk factors associated with the adverse outcomes.  Very importantly, as Sandy had described earlier this morning, we need to put our arms around the margins of safety regarding either risk or lack of risk.
		We have limitations of current data resources.  We have population-based surveillance systems, and what I'm referring to is Medicaid, automated databases, HMO-based automated databases.  But presently there's no easy linkage of maternal exposures that we can connect to fetal outcome.
		Spontaneous reports, just by virtue of what they are, are biased in the kinds of reports that are received and no incidence rate is available.
		There is a lack of meaningful data available in clinical trials because all of us know that women are specifically excluded from these trials and that once women become pregnant in these trials, they're frequently terminated or excluded from this trial.
		What is the purpose of a pregnancy registry protocol?  Well, the protocol should assure the quality and the validity of data elements that are going to be collected and should assure the documentation and consistency of the research methods.
		Registries are observational, nonexperimental studies that actively enroll subjects.  The registration is ideally prospective as early as possible in pregnancy, especially if the outcomes of concern are impacted upon early in pregnancy, recognizing, of course, that drug exposure can be anytime prior to pregnancy or during gestation.
		One should determine rates of outcome among mothers exposed to the drugs and one should consider the use of comparison groups.  The easiest is to use known background population rates, but one can also consider concurrently enrolling unexposed mothers with or without the underlying disease of interest.
		Baseline information should be carefully collected at enrollment that can be risk factors for the outcome of interest, and the focus should be on the enrollment of prospective subjects who are enrolled during pregnancy when there is an unknown fetal outcome in order to provide the unbiased type of risk estimate.
		Retrospective subjects, although not part of the prospective analysis, can be collected to develop a case series and a description of these cases reported to the registry.  These, of course, would be subjects who are enrolled or information obtained after the outcome of pregnancy is already known.
		Another consideration in design of a pregnancy registry is the consideration of the feasibility of successfully completing the study.  One should anticipate the patterns of drug use or product use relative to fetal development, and one should specifically have case definitions in mind and have a method for the identification of those adverse outcomes specifically delineated in the protocol.
		What products are good candidates?  Products, if they're used frequently where inadvertent exposures are apt to occur, should be considered, and products initiated or continued during pregnancy as therapy.
		Also, when available information suggests a need, such as a concern about a pharmacologic class, concerns that arise because of animal reproductive data, any chemical structure/activity relationships that one is concerned about, or when isolated human case reports lead to a concern.
		When in a medical product's lifetime should a registry be established?  It should be established when the need is perceived, either at the time of approval, which we hope would be most likely in the future, or possibly with a new indication for a specific medical product, and when a post-marketing signal is observed.
		What are the elements to consider in the pregnancy registry design?  Well, the protocol should assure consistency in data collection and analysis, and we would encourage industry companies to consult FDA in the design.
		The background section in the protocol should outline the animal reproductive toxicity studies and any concerns that have arisen because of those studies.  They should cite relevant pharmacologic and toxicologic studies and any human experience from spontaneous reports or earlier human studies and should also provide an estimate of risk in human pregnancy in order to guide the sample size and power issues.
		The research methods should carefully outline patient recruitment which hopefully would consist of very proactive enrollment strategies and clearly outlined follow-up plans.  Any drafts of registry announcements should be included as well, such as informational pieces containing contact telephone numbers and website addresses, and the product label should contain the contact information as well.
		Announcements may appear in professional journals, women's magazines, professional and maternal/infant advocacy group newsletters, Internet sites, mailings to specialists, lectures, and informational booths at professional meetings. 
		However, unless specifically approved for use during pregnancy, any recruitment effort should not promote the use of the product during pregnancy.
		All product-specific promotional materials must be submitted to FDA at the time of first use, and review prior to use is not necessary unless the product was approved under expedited approval regulations.
		The protocol should also include scripts that will be used in response to registry announcements and in order to recruit and enroll subjects.  To increase awareness, sponsors are encouraged to work with FDA, CDC, the Organization of Teratogen Information Services, the March of Dimes, and others who have interest in this area.
		The FDA plans to develop a website page that will list known pregnancy registries as well.
		With regard to research design and reporting source, there are several sources of information that one may use.  One may use subjects in obtaining baseline and follow-up information or health care providers, or both.  Each has its advantages and disadvantages.
		The use of subjects may minimize loss to follow-up and may facilitate multiple follow-up during pregnancy and also enhance the number of contacts and enhance the quality of infant data.  It also would facilitate informed consent in the event that a medical record would need to be pulled in order to validate specific infant outcomes.  But it may be more expensive because there would be more frequent and extensive follow-up.  However, that would need to be balanced with the loss of follow-up that can be expected in a registry study.
		Health care providers are a convenient and good source of medical data.  It's a very economical way of collecting data and may require fewer contacts.  However, data collection on maternal and infant events may be incomplete, especially if these are obtained mostly from obstetricians or family practitioners who may not follow the infant and may lose track of the infant after the child is born.  And loss of follow-up may be substantial because, frankly, busy clinicians are busy and this is not going to be on the top of their priority list.  So, they may not be as motivated as perhaps individual subjects.
		Patient follow-up.  Of course, these plans would need to be guided by the outcomes of interest, and the challenge, as Elizabeth noted earlier, is to balance the quantity of the data along with the quality of the data.  Follow-up plans should outline and describe the follow-up procedures in the protocol.  
		It should update drug exposure and risk factor information and obtain results of any diagnostic tests when these are available.  
		It should plan on collecting information if these are available, on spontaneous abortions, elective terminations, and the medical reasons for these events if these impact on the outcomes of concern of the study.
		There should be consistent, standardized, similar follow-up for all women in order to avoid bias.
		And criteria should be prespecified to define subjects that are pending versus those who are lost to follow-up.
		Considerations for prespecified, standardized case definitions for all outcomes should be made, and these can include, depending upon the outcomes of interest again, on maternal, labor, and delivery events, major categories of anomalies, developmental effects, and so forth.  One should try to confirm as many of these outcomes as possible, perhaps by accessing autopsy and pathology results, birth and death infant records, expert evaluations of the infant, and perhaps long-term follow-up depending upon the focus of the study.  Again, the feasibility of obtaining all of these outcome data needs to be considered.
		One should define the outcomes of concern and hypothesis and define the characteristics of the exposed population that one is expected to enroll.  One should have some information and define the biological impact of the treated underlying medical conditions upon the adverse event being ascertained and describe what is known about drug exposure during pregnancy.  One should be able to anticipate the likelihood of discontinuing the treatment upon the diagnosis of a pregnancy which would, of course, impact on enrollment and follow-up considerations.
		In the selection of comparison groups, one can try to enroll women who have the underlying medical condition or women who are exposed to a similar product for the same indication or perhaps use multiple comparison groups.  But we recognize that the easiest comparison group to use is known background rates that are already published and available.
		Statistical considerations include having an adequate sample size to address the hypothesis of concern if a hypothesis is postulated, to estimate the risks of suspected outcomes of scientific interest, and of course, estimate the power to exclude certain levels of risk.
		In the data analysis, as Elizabeth pointed out earlier, prospective and retrospective cases should be separated.  Pregnancy outcomes and fetal abnormalities should be described and looked at very carefully.  The subjects lost to follow-up should be compared to the subjects who continue to be enrolled in the study to see if there are any issues with possible bias.
		In a cohort design, one should calculate a point estimate and 95 percent confidence intervals which would help us our arms around levels of risk, and one should compare these levels then to population background rates. 
		Well, registry reports, I'd like to address, are considered information derived during active solicitation of information from patients.  So, I think PhRMA and the companies are relieved that FDA is now a little bit clearer about what the reporting requirements are.  We took that comment very much to heart and wanted to provide clarity to encourage registries to be developed.
		So, as such, they should be handled as safety information obtained from a study as the 1997 guidance which PhRMA had referred to earlier.  I do want to highlight the fact that FDA post-marketing safety reporting regulations are in the process of being updated, and so considerations of registries and reporting requirements will be considered and part of those safety regulations.
		Additional information in the registry guidance includes references that were used in developing the guidance.  We also developed a long laundry list of elements for possible consideration in pregnancy registries knowing full well that this is just a laundry list from which companies and persons involved in a research design can select from depending upon what the outcomes of interest are.  Also sample size determinations by specific adverse pregnancy outcomes are also included in the document.
		Thanks a lot.  I think I'm humbled by the previous speakers before me and would like to now entertain any questions regarding the guidance document.
		DR. GREENE:  Questions for Dr. Rodriguez, please?  Jan?
		DR. FRIEDMAN:  I'd like to make a comment and ask you a question.
		First, the comment returns to one that both Allen and I made before.  I don't really understand why the default position would be that there should not be a registry for a drug unless there's some reason to think that there's concern because I don't think we know when there's reason to be concerned.  It seems to me a more reasonable position would be the default position should be there should be a registry unless there's clear indication there's no need for one, for example, the drug isn't absorbed, a topical that's not absorbed.  That's the comment.
		The question is it seems to me that part of the reason that both you and Dr. Andrews see the difficulty of collecting these data, the detailed data, has to do with where you're sitting.  If you're actually taking care of patients, most of these data are available.  Babies are examined.  There are sort of routine developmental evaluations, maybe not detailed, but there is information that's available.
		When information is gathered on animal studies, there's some cost in obtaining the data from the animals, and it seems to me if you weren't just depending on voluntary compliance, asking, begging people to provide information, it might be easier to get it if you were to develop a system where someone like Ken Jones was encouraged to actually look at some of these babies and gather the data that you need and provide them to you in a reasonable fashion.  You might find that the quality of the data and the detail of the data and the ability to get these syndromes and some of the things that we want to look for would be a lot easier.
		Would you like to comment on that?
		DR. RODRIGUEZ:  I think your point is well taken.  As I had mentioned, the design of a registry would really be predetermined by the outcomes of interest.  So, it would be very important, though, to be very careful in the data collection that one performs to do it in a very standardized manner.  So, one may not be able to cast a wide net and try to solicit information from every possible source.  Perhaps some targeted study is needed depending upon the outcome of interest.  For example, if it's a developmental delay question or a behavioral question, that may be handled in a more focused study as you just described.
		Does that answer your concern?  Certainly you'll have a chance to discuss this when the committee convenes to talk about the questions that we posed to you.
		DR. GREENE:  Lew?
		DR. HOLMES:  Evelyn, I have one question and one comment.
		The question.  I run the AED pregnancy registry.  It would be very helpful to us if the guidance document said a registry can report adverse outcomes every 6 months just as a matter of fact rather than now where it's up to the individual company and we've been given the option of having the companies apply for permission to do it every 6 months.  But it would be a lot easier if you just made it a priori when you have a registry that meets certain guidelines, this is then automatic.  It would save an enormous amount of personnel time.
		The second point concerns this follow-up question that Jan is speaking to.  We have a hospital-based registry.  We talk to the mother.  We get her consent to request information from the doctors, and what he's talking about is certainly obtainable if you're willing to provide the support for the personnel that walk through that.  It's not the same as having Ken do the exam, but it's a more efficient system when you're covering a large geographic area.
		I'm not convinced any existing database is an adequate control, and what we're going to try to do, if we get enough money, is to start the process of trying to recruit controls which, as you might guess, is not going to be automatic or easy or we know exactly what to do.  Because I really think a registry, where you're asking a woman to make a phone call is different from any database like the CDC database or any other that has a totally different design.  
		So, I'd say, as we talk about pregnancy registries, I don't think you can just accept a priori that you can use historical controls.  I think quite the opposite.  The data is going to be much more believable if you have intrinsic controls.
		DR. RODRIGUEZ:  I'd just like to address one thing you said in your statement regarding expecting women to call up and make reports.  I think it would be much more useful for designers of these registries to actually call up the subjects rather than relying upon the subjects to call in to the registry to make a report.  That would allow for more standardized collection.
		DR. HOLMES:  You don't deal with IRBs.  An IRB would never accept that.
		DR. RODRIGUEZ:  Is that right?
		DR. HOLMES:  Automatically step number one, part of the consent process is she has to pick up the phone.  I can tell you as someone who is convinced I'm a great persuader of a lot of women to call this number, I know they don't.  So, it's one of the rate limiting steps in a pregnancy registry.  She is actively doing it.  Fewer shes do it, but the lost to follow-up rate is less than 5 percent.  So, she's engaged.
		DR. RODRIGUEZ:  Right, understood.  However, once a woman is enrolled in terms of obtaining follow-up information, I think what we're encouraging is that instead of relying for the woman to make a phone call to provide follow-up information, that the study would call the woman in order to obtain the information, as is done with providers, I would imagine.
		DR. HOLMES:  Sure, as long as it's part of the consent process.
		DR. MONTELLA:  You can get consent up front to call patients, though.  You have to get it up front for everybody.  Particularly in pregnancy, everybody registers very early on.  Many people register early on.  Some people don't come at all.  But those that do, you can get consent up front to make a phone call.  It's a very specific consent:  Is it all right to call you?  You can do that.
		DR. GREENE:  Yes, please.
		DR. WEISS:  I'm a little concerned because you were the third speaker this morning that talked about maybe not using concurring controls.  I agree with Dr. Holmes there that if you don't get some sort of comparison group that's enrolled in a similar manner to the women you're enrolling, then you're losing the critical information that you really need to make a risk assessment.  
		I started looking at this in the literature and found that the rates of spontaneous abortions in women who enrolled in these registries is about half the population rates because of the way that they are enrolled and even perhaps because of what their risk might be.  
		Also issues about therapeutic abortions, if the drug causes anomalies and they're discovered early, the people taking the drug might have higher rates of therapeutic abortions.  You won't know that unless you have a comparison group from a similar population and be able to make that comparison.  
		I think the lack of comparison group is one of the reasons that prior data has not made it into the label because you don't have that thing to compare them to to understand what your results really mean.  And I urge you and the committee working on this to really think about this issue before you agree that that's a valid design, not to have a comparison group.
		Thank you.
		DR. GREENE:  Other questions or comments?
		(No response.)
		DR. GREENE:  Well, I think we're right about on time, and I think we will adjourn for one hour for lunch please.
		(Whereupon, at 12:01 p.m., the subcommittee was recessed, to reconvene at 1:00 p.m., this same day.)

	AFTERNOON SESSION
	(1:12 p.m.)
		DR. GREENE:  We'd like to reconvene, please.
		This afternoon our first task is to address some of the questions that the agency is posing to the committee.  Before we address the questions that are formulated for us in our agenda packet, I would like to take a minute or two to ask a few questions of my own.  I will take the prerogative of the chair to do that.
		As I reviewed the responses of various sponsors and industry to the draft guidelines, I thought that there were several themes that came though, and I'd like to address some of these themes first before we get straight to the questions as proposed in our agenda books.
		The first is recognizing the preponderance of academicians around the table and the preference that everyone would have for the perfect study, I would like to ask whether it's necessary really, for the kinds of information that we want to glean from registry data, for the sponsors to enroll contemporary controls.  It seemed that that was a consistent theme in the objections of industry to the draft guidelines, that they thought that was unduly and inappropriately onerous.  And the question is, is that really necessary?  I'd like to open that question for discussion for starters.  Lew? 
		DR. HOLMES:  You know my general attitude of being in favor of it. 
		Let me just give one example.  If you take the common seizure meds like phenytoin, phenobarb, carbamazepine, they're probably a reasonable example of something that a registry would address.  They are associated usually in most studies with roughly a twofold increase in the frequency of major malformations.
		Well, you've heard people already today citing a figure, an historical figure.  Well, the historical figure we have from our work with newborns at Brigham and Women's is that the baseline rate is 2 to 2.5 percent.  Others use a figure if 3, 3.5, 4.  So, just picking that one example, if you're trying to show 4 percent is a high number and you pick a baseline of 3 or 3.5, you'll never show it.  Whereas, if you've generated your controls from a system that would truly show it is 2 percent, then you've got a chance to show a doubling in the usual kind of sample size you need for that.  But you won't know that it's really a low number unless you have concurrent controls to prove it.  
		This 3 percent comes out of the ceiling tiles. There's no study of newborn infants that's going to show it's really 3 percent I don't think.  Maybe there's a reference somebody knows.  I'd love to hear it.
		DR. GREENE:  I'm sorry.  What that 3 percent number is --
		DR. HOLMES:  I don't think, Mike, there's a study of newborn infants that shows a prevalence rate of 3 percent with the kinds of definitions we're using in our registry and I would bet most people use in their registries.  I think the numbers are generally going to be lower than 3 percent.
		DR. GREENE:  Yes, I agree with you.  Certainly the Collaborative Perinatal Project, which was a very large project obviously with a huge number of infants, had a lower number than that.
		DR. MILLS:  That's obviously a very difficult question, and I think there are several areas that need to be considered.  One is, if you select controls, are you really getting a good match?  Are you getting people that do what a control should do in terms of being similar to the cases in -- are they exposed in the ways that you need them to be similar.  You always have to ask yourself in that context are there major biases in the people who agree to participate in these things.  As we've discussed, there are certainly some studies where participation demands a lot of commitment where the only people likely to do it are the people who have their own concerns or their own problems.  So, as a general rule, you may find that the easier it is to be a control, the better chance you have of getting people who actually represent the population you want to represent.
		The second part of that question is, obviously, are there alternatives?  One of the ways that this can be addressed, sometimes more satisfactorily than others, is to look in a birth defects situation at the people that are exposed during organogenesis who therefore are at risk versus the people that you identify who come in exposed after organogenesis.  This has the attraction that you're getting both your populations from the same general source and they're people with the same general thoughts about participating in the studies.  Whereas, in the first group, you know that they have the potential exposure and in the second group you know that they do not, so that they, in effect, do form a control group, so that that in some instances can be a satisfactory response to that problem.
		DR. GREENE:  The question I would further ask then is, is the bar that we want the registries to clear eliminating a twofold increase in all congenital malformations or eliminating a 10-fold increase in a specific malformation like valproic acid neural tube defects?
		DR. MITCHELL:  Well, at the risk of giving away my talk, that's really the issue.  I think the way I like to think about it is -- and to put sort of names to your numbers -- is the first task, which I think everyone would probably agree, to be sure they're not thalidomides and Accutanes.  That has its own set of questions in terms of sample size.  It has its own set of questions in terms of the need for controls.  I think most of us would agree that a sample of 50 exposed moms for thalidomide or Accutane is sufficient to identify the problem and you probably don't need controls other than historical controls because the risks are so high.
		When you get into valproic acid, as Lew points out, there are an awful lot of other issues you need to take into account, and valproic acid is a good example in terms of a high rate for a specific kind of outcome.  
		As you get further out to the right side of the curve that I'll show -- and it's probably analogous to Elizabeth's curve as well -- then the issues of confounding and bias become paramount.  If you're talking about twofold increased risks for rare defects for infrequently used drugs, apart from the issue of whether it's even feasible to try to get that information, then the issues of controls become absolutely critical.  
		I think Jim's suggestion is a very useful one, but it's what we all struggle with.  Thalidomide and Accutane is a no-brainer in terms of the need for controls and the concerns about bias, by and large.  On the other hand, if someone were to come up with an allegation that an anticonvulsant was associated with a doubling in the risk of neural tube defects, we'd be very concerned about what they were using for controls.  So, I don't think there's a single answer.
		DR. WISNER:  I think whenever there is a discussion of controls, the first question I always ask myself is, control for what?  Because, for example, in some studies that I'm doing where we're looking at antidepressants in pregnancy, one control group might be a normal population who's unexposed to just look at malformation risks.  But in fact in a study we're doing, we're comparing the antidepressant treated to depressed non-antidepressant treated patients and a normal control group because for drugs you almost always have an indication.  So, you have the underlying disorder that could be an additional exposure.  So, the question about contemporary controls for me really means what's the question specific to the study and what kind of control best answers the specific question at hand.
		DR. GREENE:  Yes, please.
		DR. ANDREWS:  I'd like to make a couple of comments on controls.  I think one of the key questions to ask is are you comparing data across methods or databases where the ascertainment method has been the same.  That's really the point that Lew was making earlier.
		There was a very useful study that was performed by the CDC that was in the package in which the ascertainment from registries was compared against the Metropolitan Atlanta Birth Defects Program.  They categorized birth defects as external birth defects easily identifiable at birth and internal defects.  And we compared some of the registries that we've participated in against those external defects identified at birth.  There was very good concordance.  The methods were fairly similar, although we certainly have under-ascertainment of those categorized as internal that were less obvious.
		A couple of strategies that we've looked at, in terms of comparison groups using similar methods, is in the antiretroviral registry to compare exposures that were in the first trimester to exposures that began in the second or third trimester.  So, that gets to the point that was raised earlier.  It's not always easy to do because not many drugs are used fairly chronically.
		Another thing that we've begun to do is to look across our different registries, and we've been amazed at how similar our results are across drugs that we've studied using the same method.
		DR. GREENE:  Yes.
		DR. FRIEDMAN:  I like the point that Allen made that it depends on what you're looking for.  It seems to me that there's another group, though, that we haven't talked about.  At one extreme there's the Accutanes and the thalidomides, where if you look at 50 or 100 kids, you're going to see it and you probably don't need controls.  At the other extreme there may be a lithium where you look at 1,000 kids and you still may not see it because the frequency is so rare.  The issue of valproic acid and neural tube defects sort of is in between, and clearly controls are very important there.
		The other place that controls are very important is if you're looking for a syndrome.  Could the acyclovir registry have picked up a fetal alcohol syndrome?  I think not.  And the reason is that you need to have a control for minor anomalies and for subtle patterns of anomalies.  The expectation is probably zero in unexposed that you'll see them, but the identification is subjective and you need a control to deal with the subjective identification not just the frequency of the defect.  The frequency may be high enough so that you wouldn't have any trouble seeing it if you had a sensitive enough assay.
		DR. WEISS:  I think another thing we were talking about left and right truncation earlier, and if the defect is identified during pregnancy and there's a therapeutic abortion, you'll never see it.  And if there's an increase in therapeutic abortions in the group that are exposed, you'll never know that without a comparison group.  That is very specific to populations and areas of the country.  You can't just take a number from the literature.
		The same with other outcomes that we're interested in besides birth defects such as spontaneous fetal loss, which is an important outcome I think we should think about.
		So, I don't see why there would be a question that scientifically or methodologically do you really need a control group to answer the kind of questions that we would like to see answered.  
		I think the big issue is with the method that's been done in the past with the typical surveillance based registry that it may not be doable in an industry setting because of the constraints on them.  I don't know if there's an argument there that it should be done. 
		DR. GREENE:  Other thoughts about this issue.  Please.
		MS. CHAMBERS:  I think it's also important to think about the issue of lost to follow-up.  Whatever the rate of lost to follow-up is, you're interested in how those people might differ from the people who completed follow-up.  And it's important in registries I think, or any other type of prospective study, to have a control group that generates a lost to follow-up as well, and if you use population resources, you don't have that.
		DR. GREENE:  Further discussion of this issue before I move on to my next question?  Yes, please.
		DR. MONTELLA:  I think, as you listen, this is just screaming for collaboration between industry and clinical centers because what's going on is we're trying to figure out a reason why you don't need controls because they're hard to get, and that's not a reason not to use controls.  So, if we establish that the best way to do this scientifically is to have controls, then the real issue at hand is how you can do that and how you can collaborate to do that.  I think what you need is collaboration between industry and clinical centers to do that.
		DR. GREENE:  The next issue that I'd like to raise dovetails with this in a way.  What we've spoken about so far is how big an increase in risk is it reasonable to need to detect.  
		The other question that logically flows is how big an increase in risk of what.  Much of what we've addressed is risk of major malformations which are generally determinable within a short period of birth.  
		The next question, of course, then comes how about other things that are more subtle that don't show up until somewhat later.  Short-term follow-up would be 6 or 7 years when you can do a valid IQ study, but there are other issues, obviously, that don't show up until even later than that.
		One of the great sayings is that the advantage of experience is that it helps you to recognize your mistakes when you make them again.  It may be that we need to acknowledge that there is just no way to detect the next DES, for example, in which case let's just say it up front and acknowledge it and move on.
		So, beyond control groups, the next question is, how long is a reasonable follow-up period and how subtle an abnormality do we want to -- again, where's the bar?
		DR. MITCHELL:  I'm always happy to speak to that.  Again, I would translate your "what's reasonable" to what's feasible.  Again, to give away -- I can just not give the talk.
		(Laughter.)
		DR. MITCHELL:  But we cannot delude ourselves into thinking that we're going to resolve uncertainty in this process.  There will always be uncertainty, and the uncertainty is going to be directly proportional to the statistical power that we have to resolve it.  So, a frequently used drug has public health consequences beyond clinical consequences.  For that, we may very well choose as a society to demand more information of that drug, and we might go to the point of 7-year follow-up and IQ, and in certain circumstances we might even go further.  
		For other drugs that are less commonly used, you can do the math.  There are about 4 million pregnancies a year, and I'm going to do some of that.  And there's a finite resource in terms of exposed pregnancies, which also has public health implications.  If there aren't very many pregnancies, it would seem to be a lesser order of concern than the commonly used drugs.
		So, I think ultimately the task will be to create a hierarchy of priorities, and they may differ for different drugs.  So, a drug that's used by 15 percent of the pregnant population might demand -- FDA and others might demand of it much more information about risk.  We might demand IQ information.  We might demand to know what the risks are of relatively rare malformations.  Whereas, a drug that's used by perhaps a half of 1 percent of the population, we may say, well, let's at least assure ourselves it's not a thalidomide or Accutane.  And if we can do a little better, let's do a little better.  But I can't imagine a situation where we can reasonably have the same demands for all drugs.
		DR. MONTELLA:  I would be really cautious about that in terms of being consistent about those demands, however, because you can influence the outcome of that just by saying a drug we're not using as much we don't need to look at as hard because it's not being used as much. 
		Well, alpha methyl dopa is a perfect example of this.  It's the most frequently used drug for the treatment of hypertension in pregnancy.  It's probably not been used in internal medicine circles for hypertension in 15 years.  Yet, it's the only drug -- and it's quoted over and over again -- for which there's data followed out to 6 or 7 years with no neural developmental delay in the offspring and no IQ lessening in the offspring.  So, that's the reason the drug is used.
		So, if we take that approach, then we're going to study alpha methyl dopa 15 more times for 20 years and we still won't know could we have used a different drug with comparable data.  So, I'm worried about that.  I'm worried about the effect that's going to have on how we look at it and would argue for some consistency there so that we don't end up making bad choices.  
		I personally don't think it's a great drug, in case you didn't notice.
		(Laughter.)
		DR. MITCHELL:  But I need to qualify what I was saying off the cuff.  It's still a clinical question that you're raising, and I think that if there's a clinical basis for concern, then that ramps up the priority.  And that clinical basis may be that we need to consider drug B as an alternative to drug A and therefore it becomes important for us to collect a lot of information on it.  So, I don't mean to suggest that it's only driven by the current clinical use or the projected clinical use.  It may be driven by the projected reasonable clinical use.
		DR. MONTELLA:  And in that same vein, then anytime you choose a category, maybe we need to address that our priority is to choose two or three drugs in a category, as opposed to a single agent for a category.
		DR. WISNER:  I would like to push the point about exposure and the operational definition of exposure a little further here because I think it's related to a technical question.  And that is, right now, when we report outcome information, exposures seem to be linked or seem to be kind of lumped to somebody who took one dose and discontinued it, somebody who perhaps took a moderate dose or the typical dose chronically, or perhaps people that took a high dose.  And all those folks are put together as being exposed to the meds and their outcome is here.  Depending upon how that population is constructed, if there are a lot of one-dose and discontinued patients, we may actually be deflating the risk for reproductive toxic outcomes that we're looking out at here. 
		The technical point is that if we could divide those exposures into strata and then begin to look at them more carefully, we would know, first of all, which populations the reproductive outcome data may be generalizable to. 
		But the other issue is, in terms of thinking about a hierarchy of how we might spend our resources, I would argue that I would like to know, in that population of exposed patients, the outcomes longer term for those patients with high risk exposure than perhaps a lower risk exposure if we're thinking about hierarchies of expenditures.
		DR. GREENE:  Ken, you had your hand up a minute ago.  Did you want to make a comment?
		DR. JONES:  I did but my comment has been taken by others.  I would like to say I agree with Allen Mitchell completely on this issue.
		DR. GREENE:  Jim?
		DR. LEMONS:  This issue of neural developmental outcome and subtle changes I think is really an important one.  My reaction is similar to Jan's; that is, I can't imagine that a registry in any fashion could accurately discern subtle effects on neural development no matter when you test them because of the confounders, the lack of adequate controls.  Most people who have done follow-up studies of newborns I think recognize how incredibly difficult it is and the arguments concerning appropriate controls, whether it's siblings, whether it's maternal IQ, which would have to be included, which varies tremendously in populations around the country, socioeconomic factors, whether they breast fed or didn't breast feed, if you believe those data.
		So, unless I guess the question of subtle outcome can be tied to clear dysmorphism even with fetal alcohol -- I mean, now that fetal alcohol association has been touted to be linked to learning disability and hyperactivity, that's a very dangerous association to draw.  It has a lot of social implications and stigmata attached to it. 
		My sense is that as difficult as that is and looking at a minimalistic database for this and the incredible lost to follow-up issues and control issues, I would be afraid of even going into that arena with a registry.  Plus the bias from an unmasked trial.  We know there's tremendous bias, both in the investigators and if you ask subjects to report.  There are accurate ways to do that, but there is such inherent bias built into a mother responding, for example, to her child's development versus a blinded or masked expert who's assessing.  
		But those are very focused, very expensive studies to do and would have to be designed very, very carefully prospectively I would think.  So, I can't imagine this type of methodology could be applied effectively to address those issues.
		DR. MATTISON:  Some of the comments and the draft document talked about two types of outcomes for registry studies.  One was hypothesis generating and the other was hypothesis testing.  I think thinking about both the need for controls, the characteristics used to define exposure, as well as the kind of risk that the studies would potentially describe are going to be different for those two kinds of approaches.  In a sense, you go into a hypothesis testing study with a much more potentially precise set of guidelines.  But if we're concerned about identifying maybe less structural but more functional endpoints, then we're probably going to find ourselves in the context of hypothesis generating studies.  And the issues of controls are going to be very critical.
		Coming back to the issue of biological markers, are we going to require the actual expression of adverse health consequences in these studies, or can we identify steps in the progression of the endpoints that we're looking at or the disease states, whether they're either functional or structural, and ask if we will allow biomarkers to be surrogates for the actual expression of disease?  And then if we do, how does that change the precision with which these kinds of studies can be conducted?
		I think actually we ought to spend a little bit more time thinking about not actually requiring the development of disease, but some antecedents and the use of those antecedents in potentially enhancing the sensitivity of studies.
		DR. GREENE:  Do some of the epidemiologists want to comment on use of proxies for endpoints?
		DR. MITCHELL:  How can I not take the bait?
		I guess I'd have to ask you, Don, what you're thinking about.  I have enough difficulty identifying endpoints.
		(Laughter.)
		DR. MITCHELL:  And I think that the discussion here reflects the frustration that we all have in being able to quantify, in a reproducible and structured way and systematic way, endpoints.  I mean, good gosh, cleft palate.  That ought to be easy, and yet I'm sure there are clinicians here who would differ in the way they would design a study to do that.  
		So, I guess the question would be, what's the endpoint?  Is it removing us one step further from the outcome of interest?  And while it would be attractive, if it existed, I can't think of any.
		DR. MATTISON:  Yes.  I think you're right in that context because it does require a mechanistic understanding, and the issue of how many of the individual endpoints that we might be interested in looking at can we quantify mechanisms and antecedent steps.  But for some of them we may be able to.  
		Just what I'd like to do is raise the possibility that as we begin to look more in a hypothesis generating mode, we may end up having to look at alterations in gene expression or alterations in levels of protein produced in a particular set of tissues and use that as the surrogate for disease.  But it does require that we have a fairly good understanding of the disease process itself.
		DR. GREENE:  Lew?
		DR. HOLMES:  Just to follow up on the point about how long do you continue the follow-up, if you think of what Don is talking about with the biomarkers, if you think of the question of IQ as an outcome, to me all of these are spinoffs from a registry.  If a woman has enrolled in a registry through an informed consent process and you include in that permission to contact her later and she agrees to that, then if you develop a hypothesis about a biomarker, you could contact folks, and those who said yes could then be enrolled in the study where you would then explore among that subset whatever you wanted to explore.  
		The same would be true for IQ.  If you developed concern that cognitive function was impaired, then folks in some geographic area could contact everybody that enrolled in the registry and ask would you be willing to participate and so forth.  So to do those as spinoffs rather than trying to prolong the follow-up of the registry as a whole because the personnel involved in that would be enormous and I think you'd want to focus.
		DR. GREENE:  Jim?
		DR. LEMONS:  Just a quick question, Lew.  How would you become concerned about the risk of decreased IQ?  Are you thinking that some type of animal data or unusual reporting?  Because that is a very subtle --
		DR. HOLMES:  Let me just use my neighbor here as my example.
		(Laughter.)
		DR. HOLMES:  It's not his IQ that I'm worried about.  
		If Ken did a clinical study in San Diego, of a group of children with a specific exposure and said I don't have a sample size that is big enough to resolve this, but as an experienced clinician, I see cognitive issues, major anomalies, minor anomalies, whatever pattern he saw in a focused, case-driven study that came along after the registry was established, then you could say, okay, we could address this with less bias in a group of folks who enrolled in a registry prospectively in pregnancy.  And Ken would be representing clinicians all over who are going to continue to develop these hypotheses from their own personal experience.  So, it would just be that.
		DR. GREENE:  Jan?
		DR. FRIEDMAN:  It seems to me that the issue of how far you go, whether you go to these spinoffs, whether you look at IQ, for example, or other behavioral or developmental endpoints, is clearly not something that you do for every single drug that's out there.  In the decision of which ones to include, we're sort of suggesting that that group of drugs would generate itself.  
		It seems to me there might be a more useful way of doing it.  If there were sort of two levels of information or two levels not exactly of approval but two levels of drugs with respect to pregnancy -- in other words, if there were a pregnancy formulary where the drugs on that formulary were required to have a higher level of knowledge, those are drugs that you, like the anti-hypertensives, that you might feel comfortable using in pregnancy.  If you know you're going to be using them, if you know you're going to be using them in the third trimester and the second trimester largely, that's the kind of information you'd gather.  And if you concentrate on just a few drugs, you can gather enough information for it to be meaningful.
		In order for there to be that sort of thing, there has to be some sort of a carrot.  There has to be some benefit to gathering those additional kinds of a data and getting into that kind of information.  That carrot could be some sort of legal protection for physicians and companies that have drugs that meet that higher level of standard perhaps.  I don't know.  
		But I think that thinking about having two levels, having a pregnancy formulary where we have some drugs that we are more comfortable prescribing during pregnancy and others that have to meet a minimal standard ‑‑ we can't allow them at all -- is worth doing.
		The other point that I would make about this is these others studies go beyond the registry, so they can't be seen just as part of the registry.  But they still need to have a tie back to the label.  One of the frustrations I have is that there's often lots of information out there about certain drugs and it never seems to see the label.  So, if there are good data, if there are good studies, if there is good information that suggests there's something in humans, it seems to me that should supplant the animal data that is sort of the stuff that we usually see on the label.
		DR. GREENE:  This gets naturally into one of the other questions that I wanted to address and that is among the questions that we've been asked to address by the agency.  So, before we get into the issue of this information feeding back onto the label that Jan has sort of opened up, are there any other comments on the original question that I asked, which is how high and how far do the registries have to go?
		DR. MITCHELL:  I just want to offer sort of a general comment on whether there really is a duality in the registries for both hypothesis generation and testing.  I think without question they serve a very useful purpose in generating hypotheses.  I'm not sure if registries ought to be viewed as the appropriate construct for testing hypotheses for a number of reasons, which we can talk about, but not the least of which is that once a hypothesis is out there, biases become even worse than we had feared in the sort of naive state.  I think there are other approaches, case-control studies and perhaps databases, that may be able to respond to hypotheses that are out there.  
		I think Lew's point is a very valid one, that the existence of a registry can be very helpful in responding to hypotheses that come along the pike.  But to set up a registry specifically with the notion in mind that we're doing it to test this particular hypothesis is probably not the most efficient way to go.
		DR. GREENE:  Let's address then the issue of labeling and information getting back on to labels.  That again was a theme that came through in the industry responses to the draft guidelines.  Specifically with respect to reassuring information, negative data, how should this get back onto the labels, and should it or shouldn't it?  Comments about that.
		Then it was also brought up this morning with respect to the acyclovir registry in that the data did come back and change the label and change the grade according to the classification.  
		Thoughts about that issue.  Jan, it seems to me that your group regularly reviews information to rewrite your database.
		DR. FRIEDMAN:  Well, I think the answer at the first cut is simple.  The labels should reflect all of the information that's out there and not just the animal studies.  Clearly when both animal studies and good human epidemiological data are available, I would leave the animal studies off and put the human epidemiological study on there because it's more relevant to the clinicians.
		DR. GREENE:  Other thoughts.  Yes, Jim.
		DR. MILLS:  This is another question that comes up all the time and you'll be asked, I'm sure, or have been asked by the press or by lawyers, how do you know that this drug doesn't cause birth defects or this birth defect?  Of course, I'm just stating things that we probably all know but need to go on the record, and that is that it's difficult to rule out a drug being a cause of birth defects globally with the sample sizes that we often have available, and it's extremely difficult and often impossible to rule out a specific birth defect, which of course is the real issue in most of these cases.  
		I think that in many instances, in terms of the label being helpful, we have to put down what we do know.  In other words, this has been the subject of a number of studies, the rates in the exposed were in the same general range as we expect to see in the general population. 
		I also think sometimes it can be helpful to note that if a study is large enough, that the spectrum of birth defects that are seen are the garden variety birth defects in the garden variety distribution because sometimes that's also helpful to say that you did not see 7 cases of a particular birth defect, but you saw the heart defect and the neural tube defect and the cleft and all the things that you would expect to see in a general population.
		DR. GREENE:  Yes, please.
		MS. CONOVER:  Just to follow up on what Dr. Mills said, one of the things, sort of the S word, for teratogen information services is that we never use the word "safe."  When I talk to clinicians, that's the very word they want to hear, and they want to know is this agent safe.  Give me a list of safe agents.  So, it's extremely difficult to handle and complicated, but we don't use it.  We use the words "low risk" or something of that sort.
		But I think that one of the sad things in being a teratogen information service is that we don't use the labels and we don't use them because they aren't very helpful for the kinds of questions we're being asked in terms of risk assessment or choice of agents during pregnancy.  So, it is telling you that the information that is out there -- and we certainly have lots of other pieces of information we use in counseling, providers who are prescribing or counseling patients.  The information is there.  It doesn't make it onto the label.  
		So, it's sort of like we have our little secret in the teratogen information services.  You know, we know the secret answer about this information, but it's not being disseminated to the greater group because it doesn't show up on the label.  So, the question is how to mechanize feeding that information back in so that it does show up there. 
		DR. GREENE:  Yes, please.  
		DR. WEISS:  Thanks.  I think one of the problems as kind of a traditionalist here that I have with putting, you know, we saw a 3 or 5 or 6 percent rate of adverse events and that compares with the population, so therefore there's no problem, or 100 people had pregnancies and there were 2 adverse outcomes, I think it leads to a false sense of security and also false sense of knowledge and tells people that we think we know more than we do.  I think it's interpreted wrong.
		I think Dr. Kweder had a good point when she put her arms out and said margins of safety.  I think maybe we need to train clinicians more to look at confidence intervals and maybe think about putting those on the label where we say we can never rule out a risk.  However, given the data, it's no higher than 3 or 4 times, and while we don't want it to be 3 or 4 times and we're pretty sure it isn't that high, that's as good as we can do with the data that we have.  With better and more data, you could continually narrow that window.  I'd like to see us go towards something like that.
		DR. GREENE:  Some years ago, Abby Lipman Hand wrote an editorial in JAMA, the title of which was something like "If Nothing Went Wrong, Is Everything All Right?"  It deals with the issue of how do you deal with a zero numerator.  If you have whatever the number of observations is, but the numerator is zero, how do you convey to people what an estimate of risk that really means?
		I think that one of the senses of the committee that we could certainly convey to Dr. Kweder and her colleagues is that we would like some statement to become routine in labeling as to what does this observation mean in terms of the maximum risk estimate, not simply we saw 3.  But what does that mean in terms of the maximum level of risk given the denominator, given the number of observations made?  Presumably if that became a standard part of the labeling, eventually clinicians would become educated to its usefulness and meaning.
		Other comments?  Allen?
		DR. MITCHELL:  Yes, but that's the easy part.  That's just math.  
		How do you compare the validity of two different studies that may find similar or different things?  While of course the studies we do are perfect, everyone else's are quite poor of course.  It's a real conundrum.  
		I think a reasonable example of that is diazepam in oral clefts.  We've done studies that have shown no meaningful elevation in risk.  Others who have done very nice studies have found perhaps some evidence of concern.  How is that reflected in a quantitative way?  
		What I would argue is that somewhere along the line, the agency, or some group anointed by the agency, needs to be able to make a qualitative as well as a quantitative statement.  It may be something that says, well, for this drug there's conflicting data, but given the level of conflicts, the upper magnitude of risk, if there were a risk, may be this high.  So, it's a modification of what you're proposing but one that somehow takes into account a validity assessment, which is to me the most contentious difficulty because it's very hard to reach agreement even among so-called experts.
		DR. GREENE:  Dr. Kweder.
		DR. KWEDER:  I'd just like to comment that we have taken the approach that Dr. Mitchell just described.  We're simply putting in labels what's out there and acknowledging that the data do conflict in other parts of the labeling, not specifically for pregnancy instances that I can think of, although there may be some, but for other adverse events.  I've seen it recently for several drugs, particularly neuropsychiatric where there are studies that are done, surveillance type studies, that show different findings, and we're not sure what that means and put the information out there and try and characterize where there's controversy as best we can so that at least their prescriber has the information and can made a judgment about how much risk or uncertainty they're willing to accept.
		DR. GREENE:  Jan, you have some experience with an expert panel reviewing data and sort of adjudicating differences of observations.  Do you care to share that with the FDA?
		DR. FRIEDMAN:  Well, I think the bottom line is that there isn't an easy way to do this, but you have to face it.  In other words, you're never going to be able to do it with a computer.  You're not going to be able to do it with a policy that says every case has to be handled like this and these are the rules and this is how it works.  It's going to take some expertise.  It's going to take people who know what they're doing and have experience in the area, and you're going to have to treat these decisions on a case-by-case basis.  
		But you've got to have the information.  You have to take into account all the information that's out there, and someone has to take the responsibility of looking for it and getting it and putting it together and actually reading it and thinking about it and making these decisions.  So, there isn't going to be an easy way or an automatic way to do this.
		DR. GREENE:  Jim.
		DR. MILLS:  I was just thinking about sort of a case example of this, and that is intrasitus cytoplasmic sperm injection where there was a controversy recently about a study in Belgium where they followed a large group of couples undergoing this procedure.  They reported that there was not a significant increase in birth defect rates in the offspring produced by the procedure.  This was published.
		Then a group from western Australia reclassified the birth defects the Belgians had reported, compared the rates to their own registry rates, in western Australia and came to exactly the opposite conclusion, that there was, in fact, an increased risk of birth defects.
		Then the Belgians wrote a response and said, well, if you take out cases such as atrial septal defects that were diagnosed ultrasonographically, basically en passant, and had no clinical importance whatsoever, then you would discover that we were right in the first place and that there wasn't any increase in the birth defects rate.
		I think this is useful for illustrative purposes because, first of all, it shows that just a rate is not terribly useful, even with confidence intervals, that you have to have some idea of what's going in to determining that rate. 
		Secondly, it shows that even if you're going to use controls, that you better have concurrently evaluated controls, evaluated using the same procedures, because had it not been for those ultrasounds -- and I never did figure out why they did the ultrasounds in those particular instances -- they would never have found those atrial septal defects that seemed to have caused a good deal of the confusion in those studies. 
		So, it can be very, very tricky, even if you have a control group and you can calculate a rate, to know what's going on unless you have it very, very clear in your mind what your malformations are and how you're going to look for them and you look for them consistently throughout the entire study population, exposed and controls.
		DR. GREENE:  I suppose the cynic would view that experience and ask if there's anything quite as suspect as the advice of experts.
		(Laughter.)
		DR. GREENE:  Yes, please.
		DR. ANDREWS:  A couple of other comments.  I think this is a very tricky issue and I don't think there's any way of getting around judgment.  There's no cookbook way of presenting the information.
		One of the things that's been the most useful in all of the registries that we've been involved with is pulling together an advisory panel that has helped advise, steer, evaluate the methodology, and more importantly evaluate the data, the specific cases, the bulk of the data, along with everything else we know about the drug in pregnancy, to help come up with what we call our committee consensus of what the data mean.  That has been an enormously helpful process.  
		So, when we did get some information in the acyclovir label, it was couched very carefully, and I think it probably is appropriate to have some description from some basic registries that talks about the scope of the study, the size of the study, and puts the observed rate of birth defects with the confidence interval with a notion of what the baseline comparison rate was in a population with similar monitoring. 
		I think where the tricky issue comes in is trying to present the upper bounds of detectability of specific birth defects.  I mentioned in my talk that with our acyclovir registry, we felt that we had the statistical power to detect a 7-fold increase in the risk of a birth defect that has a 1 in 1,000 baseline risk.  That's a lot of information to convey to clinicians and there are all kinds of permutations of that that aren't covered in that statement.  It's not an assuring statement.  It raises a lot of alarms.  It takes a lot of education for people to understand what that means.  So, I think I would be very cautious about what kind of standard we move toward in trying to put that in a standard way on labels.
		DR. GREENE:  Other comments?
		(No response.)
		DR. GREENE:  I'd like to ask the next question or make a statement maybe, and that is, as an obstetrician I was struck by the desire to circumscribe really these registries to the notion of fetal and neonatal effects.  There was no specific address of potential maternal toxicity.  We know that the maternal liver, and possibly to a lesser extent kidney, is uniquely sensitive to toxins during pregnancy.  We don't know exactly why that is, but we learned that lesson the hard way certainly in the 1960s with high doses of tetracyclines when they were one of the few acts in town available to treat severe pyelonephritis.
		Without looking specifically for evidence of maternal toxicity, are we going to not notice the next pregnancy troglitazone, if you will?  I worry about maternal toxicity, and that wasn't really addressed in any of the registry information.  Thoughts about that.  There aren't any other obstetricians here.
		DR. MONTELLA:  I'm not claiming that I'm an obstetrician, but I'll claim that I'm a clinician.
		I completely agree with you, that we really have to look at maternal toxicity as well.  It's very, very important.  When you see it most importantly is when the mother is used as a vehicle for treatment of a fetal arrhythmia, for example, and what level of toxicity are you going to tolerate in a mother to use her as a vehicle in that way.  And yet, you have to treat those arrhythmias in fetuses.  So, there's a whole host of that.  
		I think it comes up most with us with probably INH and liver toxicity, if I had to pick the time it came up the most.  But it's there and we do need to address it, and it would be a pity to gather all that data and not find out outcomes in mothers.
		DR. GREENE:  One of the jobs this afternoon or the opportunities this afternoon is to include a public discussion.  In raising the next couple of questions, I would like to invite members of industry to participate in the discussion.  Specifically what I'd like to do next is to really address the gauntlet, if you will, that was thrown down earlier today about which drugs need registries.  Is it only drugs where there's a suggestion in animal data that there could be a potential problem for humans?  Or, as was pointed out, most human teratogens that have been recognized have been recognized without a priori thoughts that they would be teratogenic in humans.  
		So, I'd like to invite industry in particular to respond to that issue.  What are the criteria for suggesting or requiring that a registry be established for a new drug or of an old drug, for that matter?  Please.
		DR. ANDREWS:  Well, my slide number 3 was points to consider that we find particularly useful because it addresses the issue of is there some background reason because of the class of drugs, the underlying disease, the animal studies, but also the intended population and the extent of the exposure that have to be considered in terms of understanding the possible public health risk as well as understanding feasibility of addressing the question.
		DR. GREENE:  Well, certainly target population and numbers of individuals that might be expected to take the drug is one set of criteria.  That's very different.  That's fairly straightforward.  It would be, for example, probably not very useful to establish a registry for a new drug that was to be used to treat Alzheimer's disease.  But that's fairly straightforward.  
		That still doesn't get to the central question which is if it is a drug that is to be used in young people, particularly women in their childbearing years in relatively significant numbers, whatever the drug is, should that be the only criterion or ought there be other criteria to set up a registry?  Dr. Teter, would you care to comment?
		DR. TETER:  I think Dr. Sharrar had his hand up.
		DR. GREENE:  Oh, okay.  Please.
		DR. SHARRAR:  I'm Bob Sharrar from Merck & Company.
		I can tell you the registries that we've established at Merck and why we've established them.
		The first registry that we established a number of years ago was for our new Varivax or our varicella vaccine.  It is a live attenuated viral vaccine.  
		We know that natural chickenpox infection that occurs during pregnancy can lead to a syndrome called congenital varicella syndrome.  So, the question we asked ourselves is can our vaccine do likewise.  Clearly anything that can lead to an infection in the newborn isn't one that we should do.
		The other ones that we've established registries so far would be Singulair, Vioxx, Maxalt, and Crixivan.  Singulair, Maxalt, and Vioxx are new chemical entities.  Consequently, we have a lot to learn about what impact they have.  This isn't just on the newborn.  This is also on the mother during pregnancy.  So, we do collect information on the mother as well.  The Crixivan registry we do in conjunction with the PharmaResearch thing done with Elizabeth Andrews and that group.  So, these are new entities.
		We have not established any registries for drugs that have been on the market for a long time, and I'm not sure if we ever are going to do that either, to be honest with you.  They're difficult to establish and I guess we still have to give more thought to it.  But clearly drugs that can affect the newborn, new chemical entities, these are the ones we're interested in evaluating.
		DR. GREENE:  But at least in the case of Vioxx, it's related closely enough to other medications which are known to be associated with adverse effects if used during pregnancy, it's a small leap. 
		Other comments.
		MS. CONOVER:  I can tell you again in the teratogen information service we see really remarkable exposures.  I think I'd be more interested in hearing someone from industry describe which ones that are medications that are going on the market now that you would choose not to study really again with the exception of things that might be topical where you wouldn't get any fetal exposure.  For me, the medications are a question mark until shown otherwise, and it is remarkable how women in childbearing age get exposures to agents you wouldn't automatically think would be first-line drugs for them.  
		So, I guess I'm kind of interested.  Have there been new agents that you've chosen not to set up a registry for and why?
		DR. SHARRAR:  There hasn't been a new drug that we've put on the market at Merck that we have not developed a registry for in the last four or five years.  But I'm not saying that that's going to go on forever, but that's currently what we've done. 
		We have had some ophthalmic products that have come on that we haven't done birth registries for, but I'm not aware of any new product that we really haven't set up a registry for.
		DR. GREENE:  Other comments.  Please.
		DR. TETER:  I would just mention two small points.  One is that we still have in place spontaneous reporting, which means that physicians can call the pharmaceutical companies to report any cases of what they think is an adverse outcome related to pregnancy.  That may in some cases be the kind of initial signal that is being detected that would indicate, whether it's to industry, to sponsors themselves, or also to the FDA who are eventually getting these reports as part of the normal reporting process, that there is a risk and that a particular agent should be looked at.  
		But we still also feel that our animal data has been done and studies have been done for many years, and they're done to look at that very possibility of could this drug cause a risk in humans.  It may not.  It may strictly be an animal effect.  But that might be the drugs that you would start with and that you would want potentially to set up a registry for, either initial signal in humans when the drug is first marketed or because of the animal findings.
		DR. GREENE:  I think my colleagues at the table would say we're not worried about the drugs that cause a problem in animals that then are okay in people.  What we're worried about is the studies in animals that are negative and yet turn out to be a problem in people.
		DR. TETER:  Were you thinking of any specific drugs besides thalidomide?
		(Laughter.)
		DR. GREENE:  Well, that's a good start.
		DR. TETER:  I guess we were testing and maybe Patrick might want to comment on that because we only tested in one species in those days years ago.  So, it wasn't picked up.
		DR. GREENE:  Yes, but in fairness, even after it was tested in multiple species, humans turned out to be uniquely sensitive.
		DR. TETER:  No, not really.
		DR. WIER:  I don't think really you brought this up to debate the merits of the preclinical testing, so let's just put that aside. 
		But one comment I did want to make is that the chairman brought this up as if the question would be answered in absolute terms, and there's really no need to approach the question in that fashion.  It's not a matter of absolutely we would not do a registry on a given compound.  Unfortunately, it's always a matter of practicality in terms of resource availability.  
		Where I think we could probably have more fruitful discussion is in terms of what are the characteristics of a compound that would suggest it to have a high priority for a registry and that that's where the resources should be applied, rather than to pretend that other than drugs that are absolutely not absorbed or that would only be used in an age population or the third one I can think of is some questions about ethics of doing a registry in my mind, especially a registry defined to be proactive and prospective if the drug is outright contraindicated in pregnancy because ostensibly some exposures would be identified at a time when the exposure could potentially continue if you did not contraindicate, which is sort of the antithesis of the purpose of the registry in a way.  
		So, I think there are those three sort of exclusionary causes that we could probably all agree to.  I think beyond that it's a matter of priority setting, and there are so many factors that go into that it's difficult to codify them, but I think the group could begin to prepare a list of the considerations that make them particularly suitable to a registry approach.
		DR. ANDREWS:  Just another couple of comments to that.  I'd echo the comment about feasibility.  I think that clearly it would be desirable to know this kind of information for every single medicine that's taken by pregnant women.  I think we would all agree we would really love to have that information.  
		If we're talking about very labor intensive physician or patient intensive follow-up studies, then what's the feasibility of actually doing that kind of study for every single product?  So, I think we have to be very selective.
		While it's perhaps hard to come up with a list of those drugs you wouldn't study, because we do want the information, I think case examples are instructive.  Just looking through our experiences, the antiretroviral registry was clearly important because we knew that there was a real possibility that retrovir and perhaps other antivirals would be taken and recommended in pregnancy to reduce maternal-fetal transmission. 
		The antiepileptic drugs -- obviously, we really need to understand the risks of these drugs because some are known to be associated with an increased risk, as is epilepsy.  Women have to keep taking medicines for control of their disease, and we really need comparative information.  So, it needs a different kind of study and a more carefully designed comparative study.
		We're also looking at bupropion which is used for treatment of depression and smoking cessation.  I'd have to say we've had not very good success in recruiting exposures when it's given for depression.  Smoking cessation I think is a very big issue because it's suggested that women stop smoking when they intend to become pregnant.  So, we thought that the likelihood of exposure to this drug in pregnancy would be higher.
		With our migraine products, we've had good success with one of the registries and very poor enrollment in another, but these products are vasoactive.  We tried to study sumatriptan using a prospective follow-up study enrolling patients through physicians, using consent in a typical clinical program.  That wasn't successful.  A registry has proven to be much more successful.
		DR. MATTISON:  I think the focus on practicality is important, and from that perspective simply exposure to a large number of reproductive age women needs I think some refinement.  For example, what are the structural domains that are present in the drug and what do we know about those structural domains?  If they do represent classes, for example, of structures that we have no information on in terms of development, then I think it's critical.  But if the domains are all those for which we have good experience from other drugs, and more than just class, but I think a real critical structural analysis, it's probably less important.
		I think the highest priority ought to be given to those drugs with large exposures which represent new chemical domains for which we can't draw any inference at all.
		DR. MONTELLA:  One of the more clinically useful ways to look at it may just be categories of use.  The AED registry is a good example of that.  Because what a clinician or a patient wants to know isn't is this new drug that's put out by Glaxo going to be okay in my patients.  What they want to know is if I have a patient who has asthma or a seizure disorder or hypertension, what's going to be the drug that has the most data on it, what is going to be the drug that feels the safest to me and my patient.  So, maybe looking at things in categories of drugs.  
		Again, that makes us have to cross the board.  We have to have collaboration between industry and the rest of us.  We have to have collaboration inter-industry in order to accomplish that.  But that kind of registry by category seems more clinically useful to me.
		DR. FRIEDMAN:  Just to follow up on that point, an issue that I know we're going to talk about tomorrow is having a central registry that might collect data on all or a large group of drugs.
		I think from a practical point of view, new agents are easier to start with than all agents.  
		But the issue of choosing ones that are or are not used, if you had a central agency where all were in and somehow had the cost reflect how many cases were actually ascertained of each type, it might be that drugs that turn out not to be used wouldn't cost that much to gather some information on, whereas the ones that turn out to be used, whether you're anticipating it or not, might be a little more expensive to investigate. 
		There are two other advantages of a central registry.  One is that you can compare drugs within a class or within an indication group sort of side by side, and the other is you can use one as a control of sorts for the others and you deal with this issue of controls.
		DR. GREENE:  Yes, please.
		DR. WEISS:  I think this question is really unfair.  I'd like to answer the question when should we do a study, when should we gather information, as opposed to when should we do a registry.  I think it's very difficult to answer this question.  If you're saying this type of study design is one question, if you're saying where do we want information, it's another.
		I'd like to go back to what Franz Rosa had said to WHO on where we should collect data on pregnancy exposure, and he said all the things that have been coming up:  when there's a condition that's either chronic so that there will be a chance of exposure during pregnancy or if a lot of women are going to be exposed.  I think we all agree that we want comparative data, that we want to know which antihypertensive, which AE, antiepileptic drug, which antidepressant is the best.  That's a different question.  If we have a drug that is a new molecular entity and we don't know anything, we want to do maybe a registry study and follow that specific drug.  If it's a drug where there's a suspected risk in animals, there's maybe a different design.  If it's a drug that we have some signals in humans, we might want something more intense than a registry design.  I think we have to look at not just the registry but all types of data collection and studies, including even clinical trials, depending on what the question is, what's feasible to do, and the fit between the question and the design.
		DR. GREENE:  One other question that came up in the responses to the draft guideline was the understanding, it seemed, that it would not be necessary to have any sort of a registry for a known teratogen.  I guess the question that I would ask is, is that true and necessary?
		Obviously, on the one hand, you don't want to have a registry implying that people ought to continue taking a known teratogen.  On the other hand, if there is some method in place for disseminating information about this drug that it shouldn't be taken in pregnancy, should there not be some way of knowing for sure that people aren't taking it during pregnancy? 
		Allen, you have some experience with that.
		DR. MITCHELL:  Yes.  It's an interesting question because I think I could imagine a situation where a drug is a known teratogen and a clinician and female patient may choose that drug as the best treatment for their condition.  Multiple myeloma is certainly one for thalidomide these days, but I could imagine others. 
		I think Pat raised a provocative question which is if the contraindication is somehow absolute -- and I suppose someone could always come up with something that isn't -- then there's an inherent ethical problem.  Again, I think it's a no-brainer.  I don't think society could justify that. 
		It would in my mind come down to an individual judgment.  Is it useful to collect more information on the frequency and distribution of birth defects associated with thalidomide or Accutane?  I don't think so.  I would rather put our resources into things we know.  Whether those drugs have a 60 percent penetrance or 30 percent penetrance isn't really going to change the clinical judgment, isn't going to change the public health equation very much.
		DR. GREENE:  I'm sorry.  I didn't mean do we really need to define whether there's a 30 percent or a 50 percent incidence of malformations, but rather how effective a job are we doing in avoiding those exposures.
		DR. MITCHELL:  Oh, yes, I wouldn't think that normal registries would be able to do that.  That I think is a specialized activity. 
		Frankly, I think from a public acceptance standpoint, to mix known teratogens with the registries that are trying to eliminate ignorance may have a deleterious effect on the perception of the public of what registries are all about.  So, I'd just raise that as a concern.
		DR. GREENE:  Lew?
		DR. HOLMES:  If we go back to the anticonvulsant model, if you look at monotherapy and do your power calculations to identify a twofold increase for phenytoin, phenobarb, carbamazepine, and you take a sample of 300, 350 infants, so you could say, well, all of those are on my list of teratogens, and yet none has been studied in sample sizes that big.  So, you could say, well, yes, they're drugs we're concerned about but they haven't been studied well enough.
		Then the other point that you made earlier was most people think in terms of all malformations and of course most teratogens don't produce an increase in all malformations.  So, even if you had drawn a circle around a drug and said, well, I'm worried about that, the registry could not only establish it with greater statistical certainty, but begin to address the important issue of the increased frequency of specific disorders, which takes a lot longer time.
		DR. JONES:  Furthermore, to go back to the Accutane issue, as far as this is concerned, a registry permits you or at least ascertaining patients prospectively permits you to delineate the total spectrum of abnormalities, be they functional or structural, that are associated with prenatal exposure.  Accutane is a perfect example of that where data is coming out now indicating that even children who lacked the structural abnormalities associated with prenatal exposure to that drug do, in fact, have problems with neurobehavioral development.  So, I think I would say that despite the fact that we know of drugs that are known human teratogens, we should be subjecting them at least to follow-up and through some kind of a registry methodology.
		DR. MONTELLA:  I think the purposes are just different.  If you have a known teratogen, what we really want to know is really what Dr. Greene is saying.  What we really want to know is are people still using it anyhow, and if they are, who is, where are they, how can we disseminate that information differently.  I think that's a different question.
		But there's plenty of models for having very good information available and having it not disseminated properly or used properly.  Glucose is a good example of a teratogen that we've known about for a long time, and yet many, many patients and physicians don't do pre-pregnancy counseling or pre-conception control of their diabetics.  So, there's something about the way we disseminate that information that's at issue there, and I think that may be a separate issue than registries of drugs we don't have information about.
		DR. GREENE:  One question that Jan raised a few minutes ago and I'd like to pursue for just a minute is the idea that there may be some advantage to having more detailed knowledge of safety to some medications and that, if you will, a carrot might be a pregnancy formulary, if you will, that drugs for which there was extensive experience and demonstrated safety could be listed as such.
		The question that came to my mind, as I listened to that, was given the current realities of finances, of how many dollars worth of drugs you could expect to sell to pregnant ladies, the magnitude of the potential liabilities involved if there were a problem later on down the road, could that ever possibly really be an attractive idea to a manufacturer?
		DR. FRIEDMAN:  I'd just mention there are other possible carrots that might have to do with prolonged patent protection, for example, across the spectrum of the whole drug if it was known it was safe.  At least the idea ought to be explored that we would like to have drugs that we have more confidence about the safety.  You'd never have complete safety, but about which you have more information so that we're not shooting in the dark so often.
		DR. GREENE:  Other thoughts.
		(No response.)
		DR. GREENE:  Well, I'd like to then proceed to address the questions that we haven't already addressed in our discussion so far this afternoon.  I think that question number 1, specifically, under what circumstances are registries most useful, I think we've discussed that reasonably thoroughly.  Sandra, you are okay with that.
		We haven't really addressed number 2, the most important data elements that should be routinely collected in a registry.  Thoughts about that?
		DR. ANDREWS:  The epidemiologist's answer:  it depends.
		DR. GREENE:  Lew?
		DR. HOLMES:  I think the good quality information on the phenotype of the infant alleged to have a birth defect.
		DR. GREENE:  Other comments?
		One of the issues again that was raised in some of the responses from the industry to the draft guidelines was the whole notion of trying to accumulate lots of other data about potential confounders, including illicit drug exposure, smoking, lifestyle and behavioral issues, that while they might be desirable to have in terms of eliminating confounders and dealing with confounders, they might have a negative on your ability to garner the core information that you're really interested in gathering.
		How much potential confounding information is necessary to collect in a registry?
		DR. MATTISON:  I'd actually like to go back to the previous question, but maybe comment on this a little bit.
		The issue of data elements.  I think as much as we need to characterize the outcome of the pregnancy, we need to characterize the exposure.  I think simply looking at frequency and amount of dosing is probably inadequate for a good characterization of exposure.  That's why I think it was important that in some of the earlier presentations the discussion of the use of biological markers as providing a better characterization of exposure will be important.
		With respect to the confounders, again in the context that they can potentially modify other kinetics or dynamics probably should be given consideration in terms of how that data needs to be collected with respect to exposure.  And similarly, with respect to outcome, what is the likelihood that these exposures may also be produce or be associated with these types of pregnancy outcomes.
				DR. MITCHELL:  Again, I think it's, you know, "you pays your money and you takes your chance."  It seems very clear and almost intuitive that the less information you collect per patient the more patients you'll collect.  At the same time, the less information you collect per patient, the more likely the result is to be confounded in ways that you can't handle, you can't understand.  That would be quite an unfortunate circumstance.
		So, I think again it has to do with the nature of risk that the registry is being designed to identify.  My own view is that we should go for the big ticket items.  Let's get the first circle of certainty.  Let's get the Accutanes and thalidomides, and if we're lucky, the valproates.  But even a valproate is subject to much confounding.  
		In the example that Elizabeth cited about a medication that might be used for sinus conditions and found to be associated with an abdominal wall defect, one really has to know about the indication and what other drugs might be taken for that indication before one blithely indicts the drug. 
		So, it's not an easy question to answer, and I think that there needs to be a sense of priority.  Again, I'll come back to, yes, we all want everything, but I think we really need to be sure we're not letting a major teratogen loose upon the land, and then I think the second tier, if you will, needs to be explored in conjunction with other approaches, whether they're computerized databases or case-control surveillance or case-control studies.  I just don't think one size fits all.  It's a theme that I'm echoing from others.
		DR. GREENE:  Yes, please.
		DR. SHARRAR:  If you're looking at post-marketing surveillance data, you have to realize the limitations of the data from which you're working.  We try to restrict our questions to demographic data and to pregnancy history and to actual drugs they've taken.  So, we think we get a better response rate that way. 
		I think really what we're trying to do is to generate a signal here, and if in fact we identify a signal, then we have to design a more formal epidemiologic study to evaluate that.  Then at that time you might want to ask those additional questions.
		Furthermore, I don't think it's possible to get accurate information about drug abuse, alcohol abuse, or tobacco use because people really don't want to admit all the different things that they do.  So, we keep our questionnaire focused on those things we're concerned about.
		DR. JONES:  Yes, but you're not talking to the mother, are you?  You're talking to the obstetrician.
		DR. SHARRAR:  Yes, we're talking to the obstetrician.  That's true.
		DR. JONES:  Right.  And so, you're not going to be able to get that information in that way.  And if you're talking to the mother in a situation like this, there's much greater likelihood of being able to get all that information.
		I would really just like to echo again the need to be very individual, as far as these particular issues and the way you want to design these studies.  We're doing a study right now on this new drug for rheumatoid arthritis, Arava, or leflunamide.  One clearly needs to know information about the severity of the rheumatoid arthritis and a variety of other issues related to that in terms of being able to evaluate whether the drug or the disease or whatever is leading to the outcome.  So, one really has to design one's study based upon the drug that one is studying.
		DR. GREENE:  Jim?
		DR. LEMONS:  I know this is obvious, but in discussing these kinds of data, usually the fewer data that are collected, the clearer the definitions can be made, but it's important to have very consistent, clear definitions, depending on whom you're asking the questions of.  
		Secondly, some control over the quality of the individual submitting that data which may or may not be the obstetrician or the nurse or whatever.  I know with the vital statistics form evaluation, that has been a major concern as to who's really entering the data and from what source.
		DR. MILLS:  It's been said already several times that it depends on what you're going after, but I think in the case of looking at developmental outcomes, it's particularly difficult.  For example, at a minimum you'd want to be thinking about education of both parents, family income, what the native language of the parents is, what the IQ particularly of the mother is, who the primary caretaker is, what the family constellation is in the home, and the last items, of course, over time since you're going to have to wait 4 years, 5 years, 7 years to get the data.  I think it illustrates it's extremely difficult sometimes to get even the minimum amount of information you need for these things.
		DR. GREENE:  Thank you.
		DR. MITCHELL:  I hope that most people would agree that no data are better than poor data.  I don't know that that's universally held, but I think that when it comes to some of these issues about confounding variables, one of the points that Jim made, that rather than say, well, we can't be assured that the confounders or potential biases that you're collecting are going to be collected rigorously, but we'd still like you to collect them.  I think we know up front that's a recipe for disaster and ought to be avoided.  Even though it's a tough decision, I would hope the committee would feel comfortable with that. 
		DR. GREENE:  Let's move on to the group of bulleted items here under number 3, several aspects with respect to really sort of concrete details of recommendations in terms of follow-up here.  In general, what is the minimum length of follow-up required to assess pregnancy outcome?  
		That's obviously going to depend on what outcomes you want to look at.  Again, I'm not sure that a one-size-fits-all response is ever going to make it here.  Dr. Kweder, you're not looking for a one-size-fits-all I trust.
		DR. KWEDER:  No.
		DR. GREENE:  Okay.
		Under what circumstances is it most helpful or appropriate to end data collection and follow-up?  Yes, Sandra.
		DR. KWEDER:  Let me just add to that.  Let's just take the big picture scenario.  If what you're looking for is what would generally be considered major congenital malformations, is it enough to end follow-up at delivery?  Because that's an issue we frequently confront.
		DR. GREENE:  Does anyone care to respond?  Lew?
		DR. HOLMES:  Sandy, I would argue that budgets are always limited and you'll do a lot better enrolling a lot more people in stopping at birth than you would spending an enormous amount of time to follow them in that period after birth, which is a very labor intensive process.  I'm not sure you will get as much for the personnel time as you would enrolling more people.
		DR. WIER:  Mike, I want to make a general comment about both these questions that deal with registry design.  I think it's worth reminding ourselves of the obvious, and that is not only is not one-size-fits-all, it's not the only time we may go to buy a suit, if you will. 
		That is to say, we have to remind ourselves that research is largely an iterative process and this includes both the preclinical studies as well as the clinical studies.  It's possible that the first registry generates some questions that require further preclinical assessment, and that in turn suggests other clinical assessments that should be done.  I think that allows you to take a more sanguine view of the registry.  Maybe the first registry can be designed with more practical considerations in mind, but we have to keep our eyes open to subsequent clinical studies.  They may not all be registries, of course; they could be other types of epidemiology studies.
		Maybe it helps to illustrate this with a specific example.  We can talk about the case of a drug where preclinical studies in mice showed the possibility of a neural tube defect and then suppose the registry is designed looking for this and finds, in fact, there is significantly increased incidence of neural tube defects.  It still could only be in 1 to 2 percent of the exposed pregnancies.  That's a big increase above background, but you're left wondering, well, what is the exact susceptibility determinant here.  And you go back to the preclinical setting where you can ask those types of questions and perhaps identify susceptibility biomarkers now that could be then assessed in a clinical evaluation. 
		I think if we take this view of an iterative process, it also helps to understand how both the preclinical studies and the clinical studies work together, that neither one is ascendant, but their both important and they both work back and forth.
		DR. GREENE:  Other comments on this issue?  Yes, please, Jim.
		DR. MILLS:  Lew gave, I thought, a good practical answer to the question because it's certainly true that by decreasing the time, you can increase the number of people you can see, but I'll give more of a theoretical, scientific answer and that is that if you follow longer you can perhaps double the number of even major malformations you'll be able to diagnose.  And that's a consideration in the sense that you will be finding different types of malformations with a longer follow-up so that if you have a teratogen that causes the type that isn't that obvious at birth -- the classic thing being fetal alcohol syndrome where even very sophisticated observers may not be able to spot it at birth -- you may be able to find things that you would totally miss.
		There is also some payoff in the sense that by being able to find malformations, you would decrease the sample size required in some cases to find an effect.
		DR. HOLMES:  To follow up on that, Mike.  If you think about it though, Jim, the things that are picked up postnatally in that first year or second year, one of the problems will be the chance nature of some of the discoveries.  One of the things that haunts you when you do studies is when you have a group of people who by chance had studies other people didn't have.  That's one of the reasons why I exclude anatomic variance picked up prenatally.  It's worthless in this process because you can't have every fetus have the same exam by the same skilled sonographer and so forth. 
		Likewise if you have children who by chance have an ultrasound of the kidney or by chance have a this or a that, and yes, you get another item in your numerator, I think it's a dangerous addition to your numerator because everyone hasn't had the same evaluation.
		DR. LEMONS:  Plus, I think the fetal alcohol syndrome was pursued because there was the typical clear phenotype in the newborn that was recognized initially and then it was backtracked to look at the longer term and broader -- is that not true, Ken?
		DR. JONES:  No.  To be honest with you, Jim, that's not true.  The initial children that were picked up with a fetal alcohol syndrome were 5 and 6 years of age, and then it was backtracked to the newborn period.
		On the other hand, I'm not sure to follow a child up to 6 months to a year is any better in terms of picking up the fetal alcohol syndrome in the newborn period.  You have to wait till probably 4 years of age to feel very confident about the fetal alcohol syndrome.
		I would, however, take exception to Lew on this issue.  I think that there are a number of things that you're going to miss, central nervous system abnormalities, renal defects that are picked up by virtue of urinary tract infections and the like, not just due to a chance ultrasound, and a variety of other even cardiac defects that you're going to miss in the newborn period if you're not following these kids, I would say, at least to 6 months of age.  So, I would go beyond the newborn period at least to 6 months of age to follow up these kids.
		DR. GREENE:  Other comments on this issue?
		Just let me ask one question of Ken and Lew.  Would you be better off doing a more extensive set of studies on everybody in the immediate newborn period in the first 48 hours of life and study them from guggle to zatch rather than leaving it to chance 6 months later?
		DR. HOLMES:  Are you talking about the registry model?
		DR. GREENE:  Yes.
		DR. HOLMES:  I think in the registry model you're totally dependent on the routine pediatric exam, and for me that's your gold standard you've got to work with.  Given a lot of children are now in the hospital very short periods of time, it's true some things can be missed, but I think that's got to be your gold standard.  It's only when you do these offshoot studies that you're going to be able to do the guggle to zatch exam by someone like Ken.
		DR. JONES:  And I would agree with that.  Furthermore, one would have to do guggle to zatch in your control group, which Lew just pointed out, which I think would be absolutely unmanageable.
		DR. GREENE:  Sandy?
		DR. KWEDER:  I think that Lew has clarified, to some extent, the question that I had for him because I think that, Lew, you're talking about the model of actually using the pediatrician's exam, which is quite different than getting information from the word of the obstetrician.
		DR. HOLMES:  Absolutely.  I think there's a lot of reason to believe that relying on the mother's self-reporting, the obstetrician's best effort versus the pediatrician's exam -- those are your three usual alternatives.  Or I guess the fourth would be reading the medical record.  Clearly the pediatrician's input would be the best.
		DR. KWEDER:  And you would have information by the pediatrician, generally likely to have a little bit more information than the obstetrician whose contact with the infant ends in the delivery room.
		DR. HOLMES:  Right.
		DR. GREENE:  One issue that we really haven't addressed yet, which is the next bullet, is what strategies might registries consider to enhance patient recruitment and retention, as well as facilitate follow-up.  Any thoughts about that?
		DR. MITCHELL:  I would certainly defer to Lew on this.  But it seems to me that one of the major incentives -- this is from our own somewhat different experience -- is that if the physician promotes the activity to the patient, it is an amazingly strong incentive.  So, in much the way that folks at NICHD are working to try to reduce sudden infant death syndrome by getting to the grandmothers, I think that getting to the physician may have much more bang for the buck than any sort of general advertising.  To the extent that community of practitioners can be encouraged to see this as an asset to them in their management of patients rather than a risk or a pain in the rear end, I think it would enhance greatly.  I can't prove that and I'd defer to others.
		DR. GREENE:  How do you do that?
		DR. MITCHELL:  It's not easy.  But I think physicians tend to operate, as most people do, in their own self-interest.  I think the very problem that obstetricians face in not knowing what drugs to use has its roots in the fact that there isn't information.  I think that both using a little bit of guilt-tripping and a little bit of carrot to say that here's an approach that will help you -- and it has to be structured in a way that doesn't suggest that the physician prescriber is going to be nailed by this.  This isn't a way of identifying blame.  It's tricky but I would think that would work well.
		Lew, I would just invite you to comment on it.
		DR. HOLMES:  The model we have, as you know, is the one where the woman herself calls.  We are convinced that that has made a difference in retaining her.  It has not been as easy to get her in because she has to decide to call.  We do a second call at 7 months gestation.  We call her, and we find about 10 percent of the people have changed address and/or phone number.  So, if we wait until the postnatal period, we'd never find them.  Our lost-to-follow-up rate after about 1,700 to 1,800 enrollees is about 2 or 3 percent with a system where she is the person you work through.  So, that's an argument for doing it that way.
		But it may be you could argue if all doctors reported their patients, it would clearly generate a lot more enrollments, but I don't think all doctors would.
		DR. GREENE:  Yes, Dr. Wisner.
		DR. WISNER:  Just thinking about this from a clinical perspective, I have a point similar to yours to make, and that is when you do that risk-benefit decision making with the patient and you look at what are the possibilities in different reproductive toxicity domains, you have this kind of partnership where the patient begins to express what they want or what they value as far as components of that decision making.
		But what always happens is I'm always saying there are certain things that we know with limited amounts of certainty and that there are a lot of unknowns.  I would see joining a registry as kind of making a partnership with a patient that we need more information and this is a way that we can work together to help collect the information, almost like a responsibility to contribute to the information for our daughters.
		The second issue has to do with in all the material I looked at, I didn't see much about engaging the pharmacist.  The reason I thought of that is, although I don't usually have a lot difficulty with pharmacists, I had a recent experience where the pharmacist, in screening my patient for giving her the medication, was distressed that the medication was one that he was uncomfortable with.  So, I thought how could we switch that around.  Well, we certainly could use pharmacists in terms of educating about registry materials.
		DR. MONTELLA:  I think when you're dealing with physician recruitment, you have to make it incredibly easy, and somehow you have to do that.  You have to put a post card attached to the prenatal record.  You have to get to office managers.  You have to do something that makes it very, very easy, and then be very careful to offer to share the information that comes out of it with them, to do a mailing of 6 months' worth of data, 5 years' worth of data.  Whatever comes has to get back there so that it was worth it.
		DR. GREENE:  The next question, the last one under this group of questions, is:  Should an additional mechanism be put in place to recontact subjects after an extended period of time, should the need arise?  If so, considering the practical aspects of conducting registries, under what circumstances should it be done?
		Lew, you said that you recontact your subjects.
		DR. HOLMES:  Our system is three interviews.  So, initially she calls.  The informed consent document is the next step.  Then she has her initial interview.  Then we call her on the 7 month roughly and then call her between 4 and 8 weeks after expected date of delivery.  So, we initiate that.  We do not do a year later or 2 years later.
		DR. GREENE:  Yes, please.
		MS. CHAMBERS:  Through the TIS collaborative studies, we contact the women three times during pregnancy, sometimes twice depending on how late they enroll, and then we contact them either by mail or by phone every 6 months up to 5 or 6 years of age.
		DR. GREENE:  What additional information do you glean from those contacts out to 5 and 6 years of age, and how do you use it?
		MS. CHAMBERS:  The primary purpose of the contacts, after about the first 6 months of age is the one that Lew brings up because otherwise we would have a huge lost-to-follow-up when it came time to offer them neural developmental follow-up.  So, we try to keep in touch with them basically to control for the moving issue.
		But the other issue does come up, the one about getting information on birth defects or developmental problems that wouldn't have been identified or were not identified in the first few weeks after birth.  So, we do collect information on that in the long term, but it's treated differently, obviously, because of the issue that we don't have that length of follow-up on everyone.
		DR. GREENE:  Other comments about this issue, relatively long-term follow-up?
		(No response.)
		DR. GREENE:  The fourth question is the criteria that should be used to determine when a registry should be closed.  You closed a registry on acyclovir.  Would you like to speak to that?
		DR. ANDREWS:  You've got to start somewhere.  When we started that registry, it was our first effort, and we struggled in defining what our overall objectives were.  So, we went back and forth and said, well, we're shooting for a target of 300 first trimester pregnancies followed completely, but we didn't have as clearly defined an endpoint as we would have liked.  
		We found that our need for information changed over time.  So, when we got to the 300 patient mark, we were interested in pursuing over-the-counter status for this medication for the treatment of genital herpes, and we felt that in order to do that, we wanted significantly more information.  So, we kept it open beyond our sort of predetermined target.  But I would say that the optimal thing to do is to establish a target number in the beginning and go for that.
		The other thing that happened along the way is that information about safety was out there.  So, we were receiving fewer calls because so many different organizations were generating and distributing information.  So, we found that enrollment was, in fact, decreasing and we weren't learning that much more by the additional information.  So, at that point we decided to shut it down.
		DR. GREENE:  Dr. Sharrar, I believe Merck has closed the Varivax registry.  Haven't they?
		DR. SHARRAR:  No.  The Varivax registry is still very much in operation.
		DR. GREENE:  Oh, I'm sorry.
		DR. SHARRAR:  It has been in operation about 5 years.  We have about 400 and some people registered in there.  The day may come when we feel that we have a sufficient sample size to close it, but that has not happened yet.
		DR. GREENE:  Do you have a number in mind right now, a notion of when that day will come?  What's your target?  What's your goal?
		DR. SHARRAR:  We'll keep it going until we decide.  It is a collaborative registry with the Centers for Disease Control and we have an advisory board.  I think once we all come to an agreement that we've done it long enough, then we'll stop it.  But we're certainly not at that point yet, and I don't expect to be at that point for a number of years.
		DR. GREENE:  Certainly even the CDC eventually closed the rubella vaccine registry.
		DR. SHARRAR:  Yes.  They closed the rubella registry I think after about 10 years, and I think they had something like 700 reports in there.  So, it will vary.  And we may in fact reach that point.
		But they were also looking for a specific syndrome, the congenital rubella syndrome, and that's very similar to the Varivax registry.  We're looking for a specific defect, which is the congenital varicella syndrome.  So, I think you do reach a point where you could say enough is enough.
		DR. GREENE:  But at least you do have some idea of what the incidence of the congenital varicella syndrome is in people who are exposed at the right time in pregnancy to natural varicella.
		DR. SHARRAR:  There are a lot of advantages to the varicella syndrome, which I'll tell you about tomorrow.
		DR. GREENE:  Okay, great.
		Other comments about this issue of closing down a registry?
		(No response.)
		DR. GREENE:  Then the last question.  I think we talked about this really in terms of labeling.  Dr. Kweder, have we not given you adequate guidance in any particular area?
		DR. KWEDER:  No.  For us, question number 5 really is critical because when we speak with companies about conducting registries, this is understandably one of the issues that's on the table.  What are we going to do with this information?  How will we get information from registries out to clinicians?  Then we get into lots of discussions about because registries don't offer us sometimes the level of certainty we would like, is the information still worth putting in labels.  So, if anyone else has any further comments on that, please feel free to make them. 
		I guess the only other question that I have was one regarding a comment that Elizabeth made earlier in the day and it's something that we struggled with ourselves.  It may be because we're not always all talking about the same thing when we say pregnancy registry.  Maybe "registry" isn't the right term and maybe we ought to discipline ourselves to be calling some of these things something else.  I would love to hear what folks' suggestions might be.
		DR. GREENE:  One of the issues that came out of the June meeting was the fact that labeling drugs the first time around is going to be a herculean task.  The idea of revisiting it at a regular interval is daunting.  Has the agency given any further thought to that issue?  Because that certainly would impact upon this.
		DR. KWEDER:  This will necessarily be revisited with the new regulation that requires safety update reports, where if there are additional data to bring to bear, it will naturally be revisited.
		DR. GREENE:  Jan?
		DR. FRIEDMAN:  With respect to incorporation of pregnancy registry or follow-up study data into the label, I guess I don't fundamentally understand why this is different from a study that happens to be done in Czechoslovakia or a study that's done from the CDC or from an OTIS study.  
		It seems to me that all of these studies have limitations.  All of these studies have certain strengths, and all of them provide a certain quantity of information that has to be evaluated on a case-by-case basis.  I would think that whether or not and to what extent the data gets put into the label has to do with its overall quality and significance in the context of the whole body of data that's out there and that there should be no bias toward or against putting pregnancy registry data in because it happens to be under FDA auspices or is funded by the sponsor or whatever.
		DR. MITCHELL:  I'd absolutely second that.
		DR. GREENE:  Any other comments before we take our break?
		(No response.)
		DR. GREENE:  Okay, then we are adjourned for 15 minutes.  Thank you.
		(Recess.)
		DR. GREENE:  We'd like to reconvene please and see if we can keep the meeting moving roughly on time.  First I'll give Dr. Kweder to make a few remarks.
		DR. KWEDER:  I'll only make a few.  I want to thank you for your discussion.  I think that I speak for all the FDA people who aren't back at the table yet and say that your discussion has been very, very helpful. 
		While the questions that we asked you to discuss are not specifically related to the draft guidance document on registries, your discussion does help us in identifying areas where we need to be more clear in that document, where we need to leave room for flexibility, and how we can develop some of those areas further. 
		My other comments are simply to remind you that at this point we feel that you've addressed most of the questions for the first-day questions 1 through 5 adequately, although I would not be surprised if some of these issues don't come up again further on in the meeting.  You shouldn't feel that you can't go back to those things if you've changed your mind or you have additional things that you want to say about them. 
		As we move into the next section of the meeting, when I gave the introduction this morning, I suggested that one of our goals is to get people to think beyond what they've always thought about as a pregnancy surveillance study or a pregnancy registry, to think creatively about additional ways of collecting data, to think creatively about how FDA and others at this table can build partnerships to facilitate better and more data collection of a type that would be useful to clinicians.  This is not something that we've heard discussed at an advisory committee meeting before.  We've had lots of internal discussions trying to brainstorm about this, but we'd like to hear what some of your thoughts are.  So, that's where we take it from here.
		DR. GREENE:  Without further ado then, I'll introduce Dr. Allen Mitchell, my fellow Bostonian.
		DR. MITCHELL:  Thank you.  I know you're not supposed to begin with an apology, but I apologize for two things.  One is that my voice is terrible, worse than usual, and the second is that many of the points that you've heard have already been made by me, as well as probably others.  But bear with me because now they're in context. 
		I was asked to give a talk called "state of the art" and was given no more direction than that, which could be dangerous.  I'm going to try to give what amounts to a bit of a personal perspective, I hope not one that's completely out in left field, but to try to address some questions that I think are relevant to the considerations of this subcommittee.  What I will do is provide you with a perspective which I would like to argue is complementary to the work that the committee has focused on.
		I guess I ought to start with the first slide.  Really, the issue here is identifying teratogens.  I think for starters, we ought to focus on the critical questions.  From my point of view, the clinician and the patient alike really want two questions answered.  I'm focusing on structural birth defects, but I would like to believe that the same outcomes could be applied with some modification, of course, to other considerations.
		First of all, is this drug another thalidomide or isotretinoin?  It just seems quite obvious that that is the first question that needs to be answered.  But a second and important question are, are there other less frequent teratogenic risks associated with a given drug?  Those are the questions that the clinician and patient need to answer.  But in addition, I think the regulatory agency and the public also need to know what is the teratogenic impact on the public health.  
		While those seemingly may be the same question over again, it's not, and let me just give you two extremes.  These are both hypothetical for the purpose of discussion.
		For carbamazepine, let's assume that .6 percent of women use the drug in pregnancy.  Lew, I took that from yours.  I hope it's close.  That would amount, if you believe that there are 4 million pregnancies a year, plus or minus, to 24,000 exposed pregnancies a year.  Let's assume that there's a 4-fold increase associated with that drug in oral clefts.  Remember, it's 4-fold, not 30-fold, but not 2-fold either.  And the baseline for oral clefts is roughly 1 in 1,000.  Well, if you do the math, the drug would cause an extra 72 cases of oral clefts a year in this country.  Well, it's certainly not trivial. 
		But let's consider another example.  Let's consider ibuprofen and let's assume for the moment that 15 percent of women use the drug in pregnancy, and I would argue that's a conservative estimate.  That would amount to 600,000 exposed women per year.  And now let's assume a 4-fold increase in the risk of something like TE fistula, which has a baseline rate of roughly 2 per 10,000.  If I've done my math right, that drug would then cause 360 cases a year.  We're talking about cause.  So, you have to subtract baseline.  Well, that's roughly 4-fold or more cases attributable to that drug exposure.  Of course, ibuprofen is largely a nonprescription drug. 
		I think the point here is that we need to consider the public health impact as much as we need to consider the clinical and patient side of the equation.
		This is nothing new to anyone here.  The post-marketing approaches for identifying teratogens rely on case reports, experimental studies, which are almost never informative for reasons that have been discussed, and epidemiologic studies which largely fall into the cohort and case-control design.  
		Just to very quickly summarize the kinds of study options that we have available as a cohort study, we can have broad-based studies which might look at a wide range of exposures.  I think the best American example of that is the U.S. Collaborative Perinatal Project that recruited 58,000 women in about seven centers throughout the U.S., followed them through their pregnancies.  They were not selected based on their drug exposures.  These were all comers.
		There are also focused cohort studies which look at specific exposures, and of course, registries, whether they're run by manufacturers or TISs, are clearly in that category.  And computerized databases might also be seen as a focused kind of cohort study.
		Case-control studies, on the other hand, are broad-based as one form, and this would include case-control surveillance, which is what we happen to call our design, risk factor surveillance, which is what CDC happens to call its design.  They're both the same in design where a wide range of defects are investigated.  I gave the two examples, ours which began in the mid-1970s and the CDC's large effort, with which a number of us here are involved, began more recently, in the last 3 years.
		There are also focused case-control studies which examine specific defects rather than a broad range of defects.  The examples are simply too numerous to count.  For those of you with clinical background, that's all I remember.  
		One can spend a lot of time talking about the problems and the strengths of focused case-control studies, but I won't.  What I will do is try to suggest to you that I can play both sides of the street because while we have certainly focused our attention since the mid-1970s on our birth defects study, which has enrolled over 19,000 malformed infants in a number of centers, which is a case-control design, we really did our intellectual teething on the Collaborative Perinatal Project data, which was a rather large cohort, as I've mentioned, and since then, have had about 11 or 12 years' experience with the Accutane survey, which is a form of registry, where we've enrolled a little over 500,000 women, and in more recent years, 1998 and since, have been involved with the thalidomide survey which has enrolled somewhere under 10,000 women.
		That gives you a little bit of sort of my background in terms of how we come to this, but one message that I think I will carry to the grave is that prospective does not necessarily mean it's good and retrospective does not necessarily mean it's bad.  There have been people who have tried to make that argument.  I would argue that there are bad prospective studies and good retrospective studies.  I will also admit that there have been a lot of bad case-control studies which have given this study design a bad name.  But there's nothing inherent in the designs that make one better than another.  They have different strengths and weaknesses.  You'll be surprised to know that I'm going to touch on some of those.
		Well, keep in mind the epidemiologic nitty-gritty.  We need to talk about exposure.  We need to talk about outcome, covariates, bias and confounding, and estimating risk.  I'm only going to touch on some of these. This is a sort of stream of consciousness presentation.  But we have to keep in mind that the approaches we're talking about are by definition epidemiologic studies, and like it or not, you can't escape epidemiologists in this sort of undertaking.
		When we talk about exposures, we're talking about medications on the one hand.  Prescription medications are the focus here, but I want to remind everyone that OTC medications are an important source of both exposure and potential confounding.  The issue of diet supplements I guess has to wait for another day, but maybe not a different place.
		Again, to emphasize the OTC concern, they are the most prevalent medications taken in pregnancy.  Their exposure is independent of a health care provider.  It's direct consumer advertising if there ever was any.  And they are generally perceived to be safe and not just by the public, but I would argue that they're generally perceived to be safe by the physician community.
		So, here's one example, a snapshot in time, if you will, from our own data for LMP years 1992-1993, of the drugs most commonly used in pregnancy based on 686 interviews in Boston and Philadelphia.  We left off the Toronto interviews because Canadians have somewhat distributions.  But you can see that roughly two-thirds of women reported exposure to acetaminophen, 17 percent to ibuprofen in those years, 14 percent to pseudoephedrine.  You can see that there are relatively few prescription products on this list.  The most common exposures are, indeed, nonprescription items.
		But it's not enough to, I think, look simply at a snapshot in time.  It's a dynamic.  This gives an example, first trimester exposure to selected benzodiazepines among, this is now, 15,000-plus women over roughly a 20-year period from our data.  The red line is diazepam and the yellow line is chlordiazepoxide. 
		So, while we and others have had a lot of concern about diazepam, which at one point was used by over 3 percent of pregnant women, at least according to our data, the data in the mid and late 1990s would suggest that this is not a drug of common use, and that has to have an effect on how we conceive -- you'll pardon the term -- of a registry's purpose.
		The other side of the equation, of course, is what about drugs that may be increasing their use over time?  This is a variety of cough, cold, and allergy medications, some of which have been increasing, some of which have been relatively stable, but one that strikes you is pseudoephedrine, which has taken off rather appreciably since it was made over-the-counter and now included in a wide variety of cough/cold medication.  So, if one were asking me what drugs would I be concerned about, that would clearly be a drug of concern where I would say that I have an intellectual affinity for the issue of diazepam, but as a clinical and public health problem, it's taken somewhat of a back seat.
		I don't consider this an absolute statement, but it's something I call the fallacy of class action teratogenesis.  There's a presumption that members of a give class of drugs have the same teratogenic or non-teratogenic activity.  What I would argue the fallacy is is that's not necessarily the case.  
		What is problematic in the area of teratogenesis is we don't know what causes malformations.  We don't know that it's the pharmacologic effect of the drug.  We don't know that it's not some methyl group hanging off the end of one drug compared to another.  Until we know that -- I think the argument could be made even for retinoids -- a drug class doesn't necessarily behave as one.
		The example I'll give is these two chemical entities which are both comprised of a glutarimide ring, and this is the extent of my biochemistry.  I apologize for it.  If one were to go on that basis, one would say, well, maybe we should assume that they have similar teratogenic potential.  In reality, the one on the left is thalidomide and the one on the right is glutethimide, which used to be sold in the 1960s and the 1950s under the brand name of Dordin, a common sleeping pill.  Actually there are data in the Collaborative Perinatal Project which indicate that it isn't a thalidomide.  
		So, I think it's very dangerous to make the assumption that, gee, this drug is safe, therefore we don't have to worry about this, and conversely, this drug is dangerous, therefore we need to worry equally about this.  I'm not suggesting that this being the case, one shouldn't worry about glutethimide, but the opposite is not necessarily the case. 
		So, moving on to outcomes, this has been a theme of this morning and afternoon, and so I won't spend a lot of time on it.  But we have to make judgments about what defects are of interest and importance and recognize that the prevalence of birth defects -- this is from the Collaborative Perinatal Project -- varies considerably depending on whether you're talking about any major defect, which might occur in 3 percent of the population, or any selected, specific defects, which can be as common as 1 percent for inguinal hernia; oral clefts, about 1 in 1,000; and hemimelia, phocomelia, 1 in 10,000.  TE fistula, as I pointed out, was about 1 in 5,000.  So, the specific birth defects are extremely rare events in the normal setting.
		I believe that back when we analyzed the Collaborative Perinatal Project data, we made a fundamental mistake in collapsing categories of outcomes based on cardiovascular defects or urogenital defects.  I think we've learned a lot since then, and I think it would be a mistake -- and the same would be true of oral clefts and other groups of malformations.  So, as we learn more, we raise our level of anxiety about the specificity of teratogens.
		On that theme -- and this is an area where I think Ken Jones and I will agree to disagree, that most drugs that we know cause marker or signal birth defects or a cluster of birth defects.  There certainly may be teratogens that cause syndromes.  I wouldn't challenge that.  But by and large, the teratogens that we know of are associated with a peak increase in one or a few particular defects.  That makes for some difficulties in study design.
		I'm probably the only one here who's using this antique form of audiovisual presentation called the slide projector, but I didn't call them lantern slides.  So, that's probably good.
		(Laughter.)
		DR. MITCHELL:  This is really going back.  This was a chart that we photographed that Dennis Slone, for whom our group is named, presented to Congress in the late 1960s to a congressional subcommittee, trying to educate them about the forms of study design.  What's remarkable is it hasn't changed.  This is here for clarity but also for sentimental reasons, and you'll see two of these slides for cohort and case-control.
		The point is that in a cohort design of 100 pregnant women -- this is not exposed to any drug in particular necessarily, but perhaps in most cases, even when exposed to a drug -- 97 of those women will deliver a normal infant from the perspective of malformations.  From a human reproduction standpoint, that's a good thing that it's no more than 3 percent malformed, but from a study design standpoint, it's a terribly inefficient way to collect information because for every 100 women you follow, there are 3 malformed, more or less, and then you take some controls, but you're still essentially not using 90 percent of the data.
		But there are definite strengths in selected cohorts, and by selected cohorts, I'm referring to registry designs.  First of all, this is where prospective is good.  The registries allow the opportunity to identify exposed pregnancies before the outcome is known, and that in and of itself is a major contribution.  They are also able to assemble a study in a relatively short period of time.
		Here's an example.  This is Ed Lammer's paper in the New England Journal 15 years ago.  Oh, good grief.  It's 15 years.  I'd like you to ignore the spontaneous case reports, those 23.  That's really not the point of the slide.
		The point of the slide is that with a cohort of 36 pregnancies, in the bottom half, there was a cohort of 36 exposed pregnancies identified before the outcome was known, and out of those 36, there were 5 malformed infants.  That in itself was a trigger for concern.  But what really sort of put the icing on the cake -- and I think Jim or someone had mentioned -- was a distribution of malformations.  Now, they had collapsed the spontaneous case reports with the cohorts and there was no way from the paper to separate them, so let's leave them collapsed.  
		If you use the expected rates from the Collaborative Perinatal Project, what they found was that for the marker malformations that we now associate so clearly with isotretinoin, there was a 237 times increase of microtia and anotia over the expected, and for congenital heart disease, it was 3 times; for face and skull defects, and particularly micrognathia, it was 32-fold.  So, a small cohort can really identify very quickly and effectively an Accutane or a thalidomide.
		But not all small cohorts have that same capacity, and this is just one paper focused on calcium channel blockers where the concern going into the study was that animal studies had suggested digital and limb defects.  The cohort included 78 women with first trimester exposure to five different calcium channel blockers.  There were 66 liveborn infants, 2 with major malformations, a 3 percent overall malformation rate.  There was no evidence of risk, and they were able to rule out a 5-fold increase for the overall rate of malformations.  But remember, in this case the concern was limb reduction defects, for which there was simply no power in a cohort of even 78.  And what about other specific defects?   So, there are certainly situations where one is extremely useful and another may not be quite so useful.
		The limitations of cohorts in general terms have the same limitations that any epidemiologic study has.  I'm not picking on them particularly.  Bias and confounding are the major concerns in terms of the cohort designs we're talking about.  We're worried about selection and referral bias, confounding by smoking, health behaviors, and other factors, and as many people have mentioned, what is called confounding by indication.  Is the disease state itself accountable for the increased risk that might be observed in association with the drug exposure and how does one separate that?  One even has to consider the severity of the disease state.  Ken was talking about in the Arava study looking not just at the disease but how severe the disease was, so that it becomes a real issue.
		But the particular concern that I want to focus on today is the specific concern of a cohort study which is statistical power.  Let me just give you a couple examples.
		If we're concerned about specific birth defects -- and I'm trying to make the case that that needs to be an area of concern, for a relative common specific defect, which might be oral cleft or neural tube defect with 1 in 1,000 births baseline, one can identify a risk of, let's say, at least 20-fold in an exposed cohort of 300 with 600 comparison pregnancies, for a total of 900.  I'm not going into the various statistical givens here.  Just accept that they're all the same for all the examples, so that's being held constant.  This is actually really the case for valproic acid, that the estimates, as I can best determine, are in the neighborhood of 25-30-fold risk for neural tube defects, so you need cohorts of even less than 300, and that's indeed what's demonstrated the risk for valproic acid.
		If you want to identify a 5-fold increase in risk for a common, specific birth defect, you need 2,000, 6,000 total.  
		If you want to go down to a 3-fold risk, it's about 5,500 for a total of 16,500.  Those are big numbers.
		You can look in your own references or the references that were attached to the FDA document.  Every sample size table is different, for reasons that I've never understood.  But suffice it to say, they're close enough for government work.
		(Laughter.)
		DR. MITCHELL:  For a rare defect, though, affecting 1 per 10,000 births, everything goes up by 10-fold.  So, now to identify that 20-fold risk, if it's not neural tubes in valproic acid that we're concerned about, but let's say, tracheoesophageal fistula roughly, then we would need 3,000 exposed, and if we have a 2 to 1 comparison group, a total of 9,000 to be followed.  And if you really want to get down to the 3-fold area, we're talking about gigantic numbers to be followed.
		So, my sense is that while cohorts have sufficient power and can have enough rigor to identify the thalidomides, isotretinoins, and even the valproic acids, they don't have the sufficient power and may not have the sufficient rigor to identify lesser but still important teratogen.
		So, where does that leave us?  It leaves us with the other poster that Dennis Slone prepared, which is the case-control design, disparagingly referred to as the retrospective or, even worse, the TROHOC design.  Alvin Feinstein uses that term.  It's "cohort" spelled backwards.
		(Laughter.)
		DR. MITCHELL:  The idea here is that you begin with infants with specific malformations.  So, let's say we're interested in clefts and absent limbs and heart defects and spina bifida.  Then you determine, after you've identified this study group, the maternal exposures.
		That's the typical case-control design, and in fact the typical design is where you have an exposure B -- let's say this is diazepam and an outcome A, or here 2, which might be clefts.  And you examine the prevalence of exposure to diazepam among mothers of cleft infants.  Of course, you need some comparison group.  So, the typical, what might be called the semi-specific case-control study is you identify clefts and then you might look at different kinds of exposures.  While you're at it -- you're obtaining the information -- why not obtain more?
		Well, the novel recognition that Dennis Slone and colleagues, Sid Shapiro from our group, actually made, which seems so obvious in retrospect, was to develop what they called at the time the non-specific case-control study, but it is really case-control surveillance.  You're no longer constrained to look at one malformation only, but rather while you're at it, you identify clefts and limbs and whatever else you want, TE fistula, and then you obtain medication histories broad-based on all three.  That is the nature of case-control surveillance, and it's different from a typical case-control study.  
		This just happens to give the selected defects in our database as of 1998.  It's not even current anymore.  We had over 2,100 cleft lips and palates, 1,600 VSDs, 1,200 spina bifidas, and so on.  Even when you get into extremely rare malformations -- tracheoesophageal fistula, 411; hypoplastic left heart, 241 -- you can develop huge numbers.  The CDC Centers for Excellence anticipates having 12,000 malformed infants in its database over a 5-year period. 
		So, these designs are quite powerful in being able to collect information on specific malformations.  So, the strength of the case-control study is statistical power.
		Let me give you the sort of flip-side example.  Now the power analysis has to flip around.  Now we're looking not at the prevalence of the defect, we're looking at the prevalence drug use in the controls or at baseline.  So, if one wanted satisfy one's self that we need to identify a 20-fold risk for a case -- let's call it cleft palate -- we can do it with 10 case and 20 controls.  If one wants to identify a 3-fold increased risk -- this is a very frequent drug exposure, bear in mind -- you can do it with 125 cases of cleft palate, let's say, and 250 controls.
		Incidentally, these numbers don't take into account what you're using as a control.  That's an issue of validity, not statistics.  But I'm playing the numbers here, so to speak. 
		For a drug used by 1 percent of controls, which is now getting much closer to the anticonvulsant area and some of the other prescription drugs, a 20-fold risk could be identified with as few as 33 cases, but even a 5-fold risk could be identified with 200 cases and 400 controls.  Oh, my gosh.  I'm sorry about the math on the right.  These are the correct numbers.
		Now, there are clearly limitations to case-control surveillance.  First of all, there are constraints on identifying teratogens that increase all defects across the board.  Now, I think that that's a largely theoretical concern.  I think Ken and some others might argue that it's a real concern, but nonetheless, it needs to be on the table that if there are teratogens that systematically increase risks uniformly of all defects, a case-control surveillance is going to miss it.  In addition, teratogens that produce high rates of specific constellations of defects may be missed.  So, the clinician's job security is not compromised by this approach.  The fact of the matter is that it has some limitations that are quite real.
		And case-control surveillance may be relatively slow to complete, and power is by no means absolute.  To give you an example of that, let's look at a drug used by .1 percent of controls, 1 in 1,000 pregnant women.  If one wants to identify a risk of at least 3-fold, you would need 5,500 cleft palates, for example, in order to identify that kind of risk for such an infrequently used drug.  The bottom line is there are some questions that I don't believe -- and I think most of us would agree -- that no study design can answer.
		This is something that I developed in an effort to try to reflect two concepts, and I hope it does.  The first is if we look here at the required sample size, I think it should be pretty clear to people now that if you want to identify a thalidomide or isotretinoin, you don't need very many numbers.  A valproic acid, you need more.  A diazepam, you need more.  A lithium, you need a lot more.  Then you get to the point where the curve just really takes off.  And in fact, those sample size requirements pretty much relate to the kind of design that might be used to deal with them.
		Thalidomide and isotretinoin are the classic small cohort.  Who cares about confounding design?
		Valproic acid is a good example of something that's sort of on the edge of the cohort's capacity and one has some concerns about it, but it can still be identified and was identified within a cohort.  
		Case-control studies are really required for things like diazepam.
		And I deliberately tried to put lithium on the border between case-control and unrealistic because, in fact, lithium is probably a good example of something that is so infrequently used and associated with such a rare malformation that there's really no study design, short of spontaneous reports, case reports, that are likely to make that connection. 
		What I wasn't able to do, or more properly I should say, what our skilled word processor was not able to do, was to color this line in an intensity that reflects the need for information on bias and confounding.  What I wanted to do was start out with this being white and this being pink and this being bright red.  As you move along this line, the concerns about bias and confounding go with the takeoff in the line.  It just makes life more complicated.
		So, coming to a conclusion here, I would like to posit that cohorts provide a very necessary and critical first line of defense in that they are able to identify or rule out teratogens that have unusually high risks.  That's not to say that's their exclusive domain, but I would argue that that is their first and foremost objective and that case-control surveillance provides a second line of defense that allows the identification of teratogens with lesser risks.
		Now, the fact that I did not say rule out teratogens with lesser risks was not a typo.  I think that the cohorts can rule out the isotretinoins and thalidomides, and that when those cohorts are complete, it is fair to say to the world, this drug is not one of them. 
		The case-control surveillance approach can help identify teratogens with lesser risks, can, to use this morning's phrase, help us as a society put our arms around some sense of confidence, but it can't rule them out.
		So, in conclusion, clinical and regulatory questions on teratogenesis I believe can most realistically be answered by taking advantage of the complementary strengths of focused cohort studies and case-control surveillance.
		Thank you.
		(Applause.)
		DR. GREENE:  Yes, we will take a couple of questions, please.
		DR. WISNER:  I was interested in your comment about the class action teratogenesis, that if you can't really make any kind of conclusions based upon chemical structure of a particular agent, that it might have a reproductive outcome effect because a similar agent has, say, a teratogenic effect.  
		My question is about grouped exposures.  What we're seeing now are studies similar to the study you showed with the calcium channel blockers, where we have five different drugs grouped together as an exposure, or for example, the recent study of three serotonergic antidepressants.  They are grouped together as an exposure and then outcomes are looked at down here.
		I wonder if you could comment on the interpretation of these kind of grouped exposure studies and whether you would argue that each agent ought to be studied independently.
		DR. MITCHELL:  Hubris is a real problem in birth defects epidemiology.  It wasn't that long ago that we believed the fetus was impervious to external influences, and then we never could imagine that something like DES could happen, and on and on and on.  So, I think it's very important that we maintain a perspective that isn't absolute. 
		I think that the approach that you've described is not necessarily good or bad.  I think that one is limited in what one can do.  In the calcium channel blockers, I think it's not unreasonable at all to group those exposures according to drug class, if for no other reason, if there is a teratogenic effect, it may operate through the therapeutic action of that class of drugs, and that's very important to know.  
		However, I don't think it's enough, and I think what ought to be done, albeit with small numbers, is to stratify on the specific drugs, recognizing that you're getting into a small number situation and chance is going to play a role here, but to try to see whether there may be, for a given drug, any suggestion of an increased risk, it's dicey because the numbers get vanishingly small, but I think that it's important.  As a concept I think it's important.  If I were king, it's not that I would throw away those data and say, well, because they're grouped, their useless.  They're not at all useless.  They're more than what we had.  It's just how we interpret them and whether we've gone as far as we can go with the data.
		DR. GREENE:  Yes, please.
		DR. MATTISON:  I'd like to take a little bit of issue with your structure activity example --
		DR. MITCHELL:  I figured you would.
		DR. MATTISON:  -- in part because I think visual recognition of structure probably isn't the best way of looking at the potential for developmental toxicity.  I think just the fact that there are structural elements that are similar doesn't really say very much about how we might want to think about structure and its potential for impact.
		DR. MITCHELL:  But, Don, would you not agree that even if we took a much more sophisticated approach, until we know the mechanisms by which drugs cause birth defects, whatever commonality we look for among members of a drug class could be a red herring, and that in fact, we don't know exactly what aspect of the pharmacodynamics or pharmacokinetics, the structure itself are posing the risk for birth defects?
		DR. MATTISON:  I think that's right, and I think basically structure activity right now is in the hypothesis generating mode for the most part.
		DR. MITCHELL:  Which is terrifically valuable.  It's not as though we don't need hypotheses.
		DR. MILLS:  This is just a comment.  I think there's one other group that we need to just keep in the back of our minds in terms of your curve there, and that's even farther over to the left.  I'm thinking in my own experience of three young people who suddenly developed Creutzfeldt-Jakob disease, which is not a disease in young people, and all of them turned out to have received pituitary growth hormone.  Or children who came in to the ophthalmologist's office with cataracts and I think the mothers were smart enough to say, gee, you had rubella during pregnancy too. 
		The reason for mentioning it in this context is just that while you're doing the registry or while you're thinking about doing a registry, sometimes the answer is there even before you start, and the key thing is to be tuned into the very rare outcome in the wrong group or the very rare outcome with the very rare exposure.
		DR. MITCHELL:  I absolutely agree with you.  I think that again if you look at history, the majority of teratogens, the majority of adverse drug effects are identified alert clinicians.  Let's not kid ourselves.  Epidemiology is really not the ultimate first line.  The alert clinician is, whether it's DES or growth hormone issues.  I agree with you.
		DR. SHARRAR:  The two examples that you used, the cohort analysis and the case-control surveillance, require two very different mechanisms for collecting case information.  The cohort study is consistent with the pregnancy registry concept, as we've been discussing it today.  The case-control surveillance is a very different mechanism and is actually I think conducted in an entirely different fashion.
		If you were to go back to the cohort study, could you come up with a number that you would use that once you, say, sampled or collected enough information on a certain number, you feel reasonable that at least we're not dealing with a drug like thalidomide?  Is there some reasonable number that you can come up with that's reasonable to try to collect information on?
		DR. MITCHELL:  I hadn't thought about it.  I would guess under 100.  If we're using the example of thalidomide or Accutane, I think 100 gives us a fairly comfortable cushion.  If I did my math, that would probably identify 10-fold risks for overall malformations quite nicely.  Am I answering your question?
		DR. SHARRAR:  Yes.  I was just trying to get some idea in terms of if we were to, quote, conduct pregnancy registries on a number of different compounds or drugs that are out there, how long do they have to go on and what's a reasonable number of information you collect on people when you feel as if you have gone as far as you can go with that system to try to identify a problem.
		DR. MITCHELL:  The answer to the first question is how long should they go, and I don't mean this facetiously.  A little longer is the answer.  No matter where you are, there's going to be a voice that says let's go a little longer.  So, I think your question cuts to the quick.  You've got to set some criteria.
		I would not suggest folding the tents on a registry at 100, and I hope no one interpreted these comments to suggest that.  
		I can't give an answer.  So much depends on what your priors are, what the hypotheses are, what the outcomes of interest are.  If someone is going into a pregnancy registry concerned about fetal varicella, that's a very specific outcome.  If one is looking to assure the prescribing and public community about a drug's safety, however we want to avoid that word, then it's a very different message and a very different process.  So, I'm being deliberately unresponsive because I don't know the answer.
		DR. GREENE:  But when you say how long you're going to go, you mean long in numbers or long temporally?  Because obviously, that's going to depend upon the frequency of the exposure.
		DR. MITCHELL:  Right.  One of the comments that I was going to make earlier was that in some of these scenarios we're painting ourselves a picture where we'll follow the drug until it's no longer used.  At that point, the information becomes of historical interest but not of clinical interest.  Drugs tend to have life cycles.  Although as Karen points out, you get alpha methyl dopa that may arise from the grave, but by and large, that's what I think has to be put into the equation.  If I were responsible for deciding about a registry where a drug at the outset of the registry was being used by 3 percent of women and now it was being used by virtually none and we're dealing with finite resources, I'd say, well, as a public health and clinical matter, I think we need to shift those resources into an up and coming drug.
		DR. GREENE:  Thank you.
		The final speaker for the afternoon will be Dr. Rogers, who will talk about informed consent, please.
		DR. ROGERS:  Good afternoon.  Is there anyone in the room who doesn't envy me being the last speaker talking about the Code of Federal Regulations?
		(Laughter.)
		DR. ROGERS:  I've entitled this Individual Privacy and the Public Health.  What is the good balance?  I chose this title and posed the question about balance specifically because I think the interaction between individual privacy rights and the public health needs to be carefully evaluated to strike that balance that best serves society while at the same time protecting the interests of the individual.  
		We've viewed the area of drug safety as a surveillance issue in this country as the public expects an alliance among prescribers, sponsors, and government officials to protect them from unsafe pharmaceuticals.  But the definition of research in the Code of Federal Regulations would encompass the activities that are involved in our efforts to identify unsafe drugs, and this pushes the assessment in a totally different direction.
		Today I will review the basis of the code and its provisions and explore the course of the deliberations of the advisory committee to the Antiretrovirals in Pregnancy Registry.
		First of all, though, because HIV is my case study here, I'd like to make a few points about HIV.
		HIV infection in women occurs predominantly in racial and ethnic minority populations who reside in urban areas in the rural south, who are not usually aware of their HIV status, who have many unmet socioeconomic needs, and are cared for in resource-poor, understaffed hospitals or public clinics.  So, to place this discussion in clinical context, I will eventually come to the very specific experiences of having served as government staff to the Antiretrovirals in Pregnancy Registry, or the APR,  from 1993 through 1999.
		Not only are these particular characteristics important, but the other thing that one has to note about this, choosing HIV infection in pregnant women as a case study, is that their pregnancy represents a situation in which the Public Health Service is actively encouraging and promoting drug exposure during pregnancy.  So, the importance of obtaining safety information is really quite important.
		The features of the APR were that it was initiated in 1989 to examine the effects of inadvertent exposure, and while it was originally intended to capture inadvertent exposures, the exposure status became intentional after the results of PACTG 076, which was the successful trial to interrupt perinatal HIV transmission, and finally to the latest PHS guidelines in which pregnant women are to be treated first for their own conditions. 
		It was modeled on the acyclovir registry that Dr. Andrews spoke about this morning.  It was prospective in nature; that is, it collected both numerator and denominator data.  The collection of the denominator data is the key component since it means the data were collected on births to women who had not experienced a reportable adverse drug event.  
		In the registry, the staff interacted only with obstetrician reporters, and this design feature prevented the need or omitted the need for disclosure of identifying information as the child's care moved to the pediatrician.
		No informed consent from women was obtained because there was no need for identifying information, and indeed no IRB review occurred.  This was reviewed frequently by the advisory committee who continued to believe, up until relatively recently, that this was a surveillance activity which was conceived of as an extension of the spontaneous reporting system of the FDA.
		The limitations of the APR.  Interacting only with the obstetrician meant that we only received reports of structural defects that were apparent during the immediate postpartum care of the mother.  It relied on voluntary reporting of very busy and stressed clinicians.  And it could not be promoted by the sponsors, and consequently, very small numbers were enrolled.
		At the same time, we had really compelling needs for data.  The results of PACTG 076 and its implications for care required a balancing of information that clinicians would give to pregnant women when they were counseling them about making the decision to take antiretroviral therapy.  Our recent PHS guidelines for the treatment of pregnant women really encourage, and, in fact, we in the federal government have supported initiatives to promote the implementation of 076.
		There also is the inadequacy of the safety data on fetal exposure to antiretroviral therapy during pregnancy, and we also have had recent scares.  Some information a few years back emerged on very low birth weight infants who had been exposed in utero to antiretrovirals and then the mitochondrial disease that was reported by the French last year.
		So, really where we find ourselves is we're looking at whether we're doing public health surveillance or whether we're doing research.
		The counsel of the APR's advisory committee, prior to 1998 when it really became crystallized to the advisory committee, was that the APR activity constituted surveillance not research, and it was uniformly viewed by the committee that the APR was an extension of the spontaneous reporting system for adverse drug events.  
		The advisory committee strongly discouraged staff from accepting any patient names unless no other way to receive the report was apparent.  This was consistent with sponsor practice around receiving other adverse drug event reports.
		The feedback from clinicians was very important.  Many staff members were interacting with reporting physicians in those understaffed hospital, inner city and rural clinic/hospital structures where the infrastructure was clearly inadequate, and the response back to the committee through staff people was that if there were a requirement for any other additional burden, other than providing the information, the information would not be forthcoming.  They had difficulty in accessing charts.  They had difficulty in making sure that patients were seen in a timely fashion, and they usually were quite understaffed.
		This issue and these deliberations were revisited every time the APR advisory committee met.
		But in the end the assessment came down to what kind of activity was the APR.  In behalf of adverse drug reaction reporting, it did collect ADE data.  It interacted with the clinician/prescriber as the spontaneous reporting system does, and it was fulfilling regulatory requirements in collecting information on adverse drug events. 
		What made it different from regular adverse drug event reporting, however, was that by including a denominator, it collected information on women who did not have adverse drug events but simply had exposure, and it provided regular summary reports to clinicians.
		So, at this time, given that background and that context, of that case study and where we found ourselves, I'd like to now really bore you to death with the Code of Federal Regulations.
		The definition of research.  "Research means a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge.  Activities which meet this definition constitute research for the purposes of this policy, whether or not they are conducted or supported under a program which is considered research for other purposes."  
		This is extraordinarily broad, and this definition must be applied to all federally funded efforts.
		Furthermore, if an institution is receiving federal funds for any research efforts and has a multiple project assurance, these regulations are uniformly applied to all of its research activity.
		I'd like to just tell you what the basis of the code is.  It is linked to the Nuremburg Code and to the Declaration of Helsinki.  Both the Nuremburg Code and the Declaration of Helsinki are alike in their instance that subject autonomy be respected and in their elevation of concern for the rights of the individual above scientific and societal goals.
		Specifically, principle 5 from Helsinki says that every biomedical research project involving human subjects should be preceded by careful assessment of the predictable risks in comparison with foreseeable benefits to the subject or others.  Concern for the interest of the subject must always prevail over the interest of science and society.
		Principle 6 says, the right of the research subject to safeguard his or her integrity must always be respected.  Every precaution should be taken to respect the privacy of the subject and to minimize the impact of the study on the subject's physical and mental integrity and on the personality of the subject.
		What you see is a very strong theme in the declarations that I've just pulled out, the principles I've just pulled out.  That theme is that individual rights prevail over societal goals.
		This is very different from regulations that come out of state law that really address communicable disease surveillance and investigations.  They would emphasize society's benefits over individual rights in order to prevent transmission.  In fact, to some extent in terms of adverse drug event reporting, we have expected that the information from individuals would be gathered to serve broader societal goals.
		In the Code of Federal Regulations, there are categories of research.  One is exempted research.  In exempted research, what we have is, in order to qualify as exempted research, there is only involvement of human subjects in research that involves a collection or study of existing data, documents, records, pathologic specimens, or diagnostic specimens, if these sources are publicly available or if the information is recorded by the investigator in such a manner that subjects cannot be identified directly or through identifiers linked to the subjects.
		This does not happen in any of the registries that we have because there are specific coded subject identifiers that -- with some effort in most situations, but there can be a link back to the subject from which the information is being collected.  So, I don't think that in terms of any of the registry formats that we've discussed this morning and for the APR that it can be considered exempted research.
		Another category of research is expedited research, and this category refers to research activities which involve no more than minimal risk and in which the only involvement of human subjects will be in one or more of the following categories.  There are a number of them, but number 8 is relevant to our discussion.  Number 8 says the study of existing data, documents, records, pathologic specimens, or diagnostic specimens.
		What is very important here is that the term "minimal risk" is suddenly in the mix, and let me tell you what the definition of minimal risk is in the code.  That is those activities which an average person encounters during an average health care visit or in the course of average daily activities of life.  
		It is not a sliding scale so that you can say, oh, these are inner city women with HIV infection who live in communities where there is a great deal of violence and drive-by shootings, and therefore the risk that's allowed for these women is considerably more than the risk allowed for a housewife in Utah.  That's not what minimal risk is.  It is not a sliding scale.  It is the average. 
		So, for it to be expedited research, it does have to meet that bar of minimal risk, and it does have to be preexisting information, information that's collected not specific for the purpose of the study but being evaluated like a secondary analysis.
		Much of the registry activity could be conceived of as expedited research for many of the drugs that we've discussed today.  However, it's very unlikely that any institutional review board would view our APR as expedited research because it's dealing with HIV infection and HIV infection, because of the increased sensitivity around inadvertent disclosure, represents a special case.
		I want to talk about the issue of informed consent and to tell you in the code what items have to be addressed in an informed consent and what items an institutional review board would be looking at in order to make sure that an informed consent is adequate.  
		These are the required elements.  The purposes, the duration, and the procedures of the study have to be disclosed.  Any foreseeable risks or discomforts, reasonably expected benefits to the subject or to others, the disclosure of any alternative procedures that would be available to the subject that he or she could access without being in the study, the confidentiality measures that the investigators have put into place to protect the subjects, compensation, if any, for injury that might occur as being part of the study, contact people for the study in case there are questions or concerns, and the fact that participation is voluntary.
		The IRB may also require some additional elements.  These would be risks to the fetus, circumstances under which participation may be terminated, additional cost to the subject that that subject would incur by participating in the study, the consequences of the decision to withdraw from the study, which should be none, new findings that may emerge from the study would be provided to the subjects, and the approximate number of study subjects.
		Therefore, we're looking at a rather large number of items that are either required or could possibly be added at the discretion of an institutional review board.  The consent process, when it is informed, may be a prolonged process.
		What we have for a registry like the APR -- and other registries may have the same concerns -- is the fact of the feedback we've gotten from the clinicians who are in the inner cities and in the rural clinics that are understaffed, that this additional process, superimposed on the consent that they are required to give by state law for HIV testing and for the regular care, the issues that are involved in the regular care of pregnant women -- superimposed on that and in addition to that, many of the clinicians also do get involved in some of the perinatal transmission trials, that this is such an additional burden, that reporting wouldn't happen.
		In that instance and because of that consideration, one of the things that can be done is a request for a waiver of informed consent.  This is allowed under Code of Federal Regulations, 46.116(d).  These particular requirements have to be met.  The research can be no more than minimal risk, which I defined before.  The waiver will not adversely affect the rights and welfare of subjects.  The research could not be practically carried out without the waiver, and whenever appropriate, the subjects will be provided with additional pertinent information after participation.
		So, given all of this information that I've shared with you, the advisory committee to the APR, seeing that there was a growing focus on institutional review of projects, the fact that this project fell under the Code of Federal Regulations definition of research, and the involvement of federal officials on the advisory committee, the advisory committee in 1998 recommended that the registry protocol be submitted for IRB review.
		We also recommended that all data be collected anonymously and coded, that the reporting forms be revised because of the way that they had collected information, and we recommended that they seek a waiver of informed consent.
		Seeking a waiver of informed consent really depends on the study design, which of course follows the study question.  For the APR, who is simply looking at structural defects with the potential for detection only during the perinatal period, the waiver seems to be an appropriate mechanism.
		Finally, the last slide.  The experience of the APR I wanted to share with you in their efforts to seek this IRB review.  They've approached several major universities, all of whom refused, citing that they had their own institutional overload with their own protocols, and they questioned their authority and their jurisdiction to be doing a review for a registry supported by sponsors.
		Private IRBs -- and there are a few across the country -- required an unreasonable fee to review.
		I had an off-the-record discussion with OPRR about exploring whether the APR could establish an IRB of their own.  What we were trying to see was if OPRR would issue a single project assurance and allow them to establish their own IRB that would review.  OPRR said that because there was no federal funding involved, they really had no jurisdiction to do that, and besides, they were very busy too.
		So, finally, what the APR is doing is the second option up here.  They're collecting that unreasonable fee from all of the cooperating sponsors and moving forward.
		I think in summary I wanted to make five points, and I'll make them quickly.
		Efforts that collect denominator or exposure information essentially move outside the standard and traditional adverse drug event reporting.  I think that's a very clear conclusion to make.
		The second point is that to maintain public trust and confidence, information on women and pregnancy outcomes must be carefully protected.
		The third point is that this protection is best ensured by external and objective review of procedures that are in place.
		The fourth one is using the Code of Federal Regulations and the IRB structure that's in place seems to be the best vehicle for accomplishing the protection.  It is established, accepted, and known.
		And five, requesting the waiver of informed consent is an option.  It is very study-specific and really requires a compelling justification to occur.
		Thank you.
		(Applause.)
		DR. GREENE:  Thank you.
		This presentation is open for discussion or questions, please. 
		I have one question with respect to guaranteeing the confidentiality of data.  It seems as though as time goes on, we realize that less and less is really confidential and really protected.  The specific example I guess that I would cite is one recent experience of Dr. Sharin Gabriel in Minnesota.  She collected data which suggested very strongly that there was not, in fact, a relationship between silicone breast implants and rheumatologic disorders.  In the course of the lawsuit that the plaintiffs brought against the companies, her data which suggested there was no relationship was subpoenaed.  She found herself in a position of either refusing to comply with the subpoena and possibly facing criminal pains or trying to fight the subpoena for which she had no money or agreeing to hand over the data and violating the pledge that she had made of confidentiality to her subjects or abandoning her research and agreeing never to publish the data.  It was a conundrum that she faced and she elected just to agree to never publish the data and to basically bury the results.
		What reassurances are there that should there be determined and clever attorneys, that this data will remain confidential?
		DR. ROGERS:  And you want me to answer that.  They subpoenaed names?
		DR. GREENE:  They subpoenaed her entire database.
		DR. ROGERS:  I think one critical piece there that seems to be missing for me is, did she put specific identifying information in her database or did she keep that separate?  I think IRBs are very careful to have separate records for clinical shadow records, and there should only be a subject IDs in a database.  I think one should be making a distinction in practice and one could make a distinction legally in what one surrenders.
		DR. GREENE:  Well, I think most researchers will tell you that if you're collecting enough demographic information about patients, you only need a half a dozen fields that are sufficiently unique that you can pretty figure out who the individuals are whether they're specifically identified or not.
		DR. ROGERS:  Again, if I were in that position and I were concerned, I would have not only my identifying codes locked over here, but I also would have two subset databases that I could merge on an ID, one with those identifying information -- I mean, there are levels of individual protection I think that one could undertake to prevent one's self from being in that situation. 
		It's wonderful to do that on Monday morning, but I think if we could all learn a lesson from the terribly unfortunate experience that she's had, it would be to put those kinds of layers of personal and subject protections in order to do that, to be able to give that kind of guarantee of confidentiality.
		DR. GREENE:  Allen.
		DR. MITCHELL:  I'm not sure that I agree that the layers -- they offer some protection, but there's no reason the attorneys can't go after every aspect of it.
		I would offer two responses to that situation, Mike.  First of all, I gather she was not part of an institution.  But we've had that situation where we've had data subpoenaed and we fought the subpoena.  I think it's very common for academics to roll over when they receive a subpoena.  Whether she did or not, I would urge people who are confronted with subpoenas not to roll over and to seek institutional support.
		The other is a federal certificate of confidentiality, which seems to me very relevant.  It's something we've gotten in our studies where we have sensitive information.  CDC has done that as well in its study and it provides substantial protection.
		DR. ROGERS:  Well, actually I'd have to correct that.
		DR. MITCHELL:  Am I wrong?
		DR. ROGERS:  We all think it does.  It has never been tested.
		DR. MITCHELL:  I'm sorry.  Yes, I'll qualify that.
		DR. ROGERS:  It makes us sleep easier.
		DR. MITCHELL:  But at least conceptually it offers a layer of protection that would at least make some attorneys think twice about going after the data and does put the federal government on the line.  I think that some courts might view that as a higher authority than simply what we would consider a contract between us and the patient, which we would consider inviolate and a higher authority than any subpoena, but the courts may not agree.
		DR. ROGERS:  Right.  I think too the institution would have to have some relationship with the federal government in order to obtain one for data.
		DR. MITCHELL:  No.
		DR. ROGERS:  Well, in our experience it has been study-specific.
		DR. MITCHELL:  Yes.  Oh, it's study-specific, for sure.  But it only requires a demonstration that there's some sensitivity to these data.
		DR. ROGERS:  And federal funds not involved?
		DR. MITCHELL:  That's correct.  I'd have to look but I think that's correct.  I'm not sure, Audrey.
		DR. ROGERS:  I'm not sure either.  
		DR. GREENE:  Yes.  In this particular case, she was part of an institution.  She went to the institution and they said we don't have the money to fight this.  It could be many hundreds of thousands of dollars and there's no guarantee of success.
		DR. MITCHELL:  That's why they get overhead rates.
		(Laughter.)
		DR. GREENE:  Dr. Kweder, you had a question, comment?
		DR. KWEDER:  Yes.  Audrey has made the comment that when you begin to collect denominator data, you move quickly out of the realm of traditional post-marketing surveillance.  I think we have to think carefully about making that sort of a general statement.  I think in many respects the kinds of registries we're talking about really are hybrids. 
		One reason to think carefully about that is that historically we have considered data that comes to us from standard post-marketing surveillance, protected information, and where courts have sought to seek identifying information about those individual cases, the FDA has been very rigorous in defending and protecting that information so that the courts couldn't take on and use or lawyers couldn't take on and use that information in malpractice cases or in other types of injury cases.
		When MedWatch was developed, one of the things that FDA did to try and encourage more reporting was develop a regulation that specifically extended the same kinds of protections to cases that we received from the industry.  That was a very important step because previously those protections only covered practitioners who reported to the agency directly, but we developed a regulation to extend that.  And it is something that we may need to think about how that applies to registries as well.
		DR. ROGERS:  Yes.  The distinction I was making was not the classic case report.  I think with the Office for Protection from Research Risks moving from the Office of the Director of NIH to Under Secretary level in the Department of Health and Human Services, that the FDA and the CDC, as well as NIH -- all of the activities will be more closely scrutinized.  I think it will serve us all well to understand what their definition of research is.
		DR. ANDREWS:  I'd like to make a comment basically echoing Dr. Kweder's comment that it may not be crystal clear what falls under the definition of research versus surveillance.  One could certainly make a case that certain types of registries more appropriately fall under a definition of broad public health surveillance and a number of organizations, including ISPE and PhRMA have suggested to HHS in response to their regulations on data privacy that these kinds of surveillance programs be considered under the surveillance definition for purposes of being able to collect data without these potential barriers.
		But I think it's an open question and there's really no clear answer.  Part of the reason there's no clear answer is the point that you illustrated well, Audrey, and that is, IRBs have not yet developed a mechanism for evaluating privacy risks uniformly across the country.  
		I think that it would be very useful for additional training to be available to IRBs so that when they're looking at studies where the primary risk to patients is a breach of confidentiality, that the use some standard and consistent measures, which just aren't there now.  Researchers should never be in a position of shopping for the appropriate IRB to review a study.
		DR. ROGERS:  I would strongly encourage the committee, as it deliberates, to consider interacting with an organization called Public Responsibility in Medicine and Research, which is the professional educational organization for IRB members.  We took on an aggressive educational campaign around adolescent participation in research, which if you think you're in trouble, you might try that.  It's worth the investment in trying to educate them through that organization.
		DR. GREENE:  Yes, please.
		DR. SHARRAR:  I'd just like to make one additional comment.  Part of the problem is that when you're dealing with HIV infection, you're dealing with a disease that has all other sorts of confidentiality ramifications.
		DR. ROGERS:  Absolutely.
		DR. SHARRAR:  This is not a normal disease process nor a normal registry.
		DR. ROGERS:  Absolutely.  I'm glad you emphasized that.  I tried to make that point.
		DR. GREENE:  Other questions?  Dr. Kweder?
		DR. KWEDER:  I actually thought that maybe Lew Holmes could comment on his experience using informed consent as part of your study or registry and sort of the pros and cons of that.
		DR. HOLMES:  You mean in terms of the institution's ability to understand what we're doing or the problems with the women themselves?
		DR. KWEDER:  Both.
		DR. HOLMES:  I bring up the institutional issue because I work at a big university hospital.  When we said we were going to set up this pregnancy registry, they were not immediately accepting of why this made any sense as an activity to do at the hospital.  One of the problems is IRBs contain an incredible spectrum of people who do different kinds of work, and I think just by chance, we might have gotten somebody else who had no trouble with it, but IRBs are made up of an interesting spectrum.
		We're at a time when our IRB process -- and I suspect everybody else at universities would echo this -- are very slow and lumbering because of the hot button issues of confidentiality.  If you ever take a blood sample, heaven help you, because the DNA issues slow your process down to a snail's pace.  The fact that your approval for last year ran out six months ago is your problem, not theirs.
		Coming to the women themselves, the IRB has standard paragraphs that they insist are present in consent forms.  When you look at a registry that doesn't have a lot of the components that would require those paragraphs -- like for example, if you're injured in the process of participating in the study, we will pay for your care -- well, that kind of thing makes the form longer, and the longer the form, the more it puts off the woman who is reading it, even though the content might not be worrisome.  So, it has not been an easy step.  
		We have not found very many women actually read the thing and close the door and say, forget it, I'm not going to do this.  But there is a small group, probably less than 1 percent, who when they see the consent form, that's it.  So, it's not a trivial issue.
		I think Don has talked about biomarkers, as should be discussed, because I think this whole work has got to go in the direction of biomarkers.  Clearly, there are going to be DNA-based markers that will pick out the high risk and low risk people.  That's clearly where we're going, but that is the same path that the public is scared about and the IRBs are scared about.  
		So, it's complicated now.  I think it's just going to get more complicated.
		DR. GREENE:  Any other comments?
		(No response.)
		DR. GREENE:  Well, a few announcements before we finish up.
		DR. TITUS:  I just want to address a couple of things.  Tomorrow's meeting starts an hour earlier, so please be here at 8 o'clock.
		Regarding dinner tonight, most of you are going to dinner.  We have a van arranged to take you there.  It can only hold about half of you at one time.  The first van is going to try to leave at 6:30, and the second van will leave 15 minutes later.  But you all can't be in that second van.  So, somebody has to come down and mill around and socialize.  So, I would encourage you all to come down at 6:30.  You're really welcome to dress casually.  There's no reason for you to go dressed up.  You can be normal.  You can dress down. 
		See you tomorrow morning.
		DR. GREENE:  Thank you, everyone.
		(Whereupon, at 4:48 p.m., the subcommittee was recessed, to reconvene at 8:00 a.m., Wednesday, March 29, 2000.)