FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

PEDIATRIC ADVISORY SUBCOMMITTEE

OF THE

ANTI-INFECTIVE DRUGS ADVISORY COMMITTEE

8:15 a.m.

Monday, March 3, 2003

Advisory Committee Conference Room

Food and Drug Administration

5630 Fishers Lane

Rockville, Maryland

ATTENDEES

ANTI-INFECTIVE DRUGS ADVISORY COMMITTEE MEMBERS:

MARY GLODE, M.D.

University of Colorado Health Sciences Center

Children\'s Hospital of Denver

ANTIVIRAL DRUGS ADVISORY COMMITTEE MEMBERS:

JAN ENGLUND, M.D.

Children\'s Hospital and Regional Medical Center

Seattle, Washington

COURTNEY FLETCHER, PHARM.D.

University of Colorado Health Sciences Center

School of Pharmacy

LAUREN WOOD, M.D.

HIV and AIDS Malignancy Branch

National Cancer Institute

CONSULTANTS: (Voting)

ELLEN GOULD CHADWICK, M.D.

Northwestern University

PATRICIA CHESNEY, M.D., Meeting Chair

Professor of Pediatrics

University of Tennessee College of Medicine

DAVID DANFORD, M.D.

Associate Professor of Pediatrics

University of Nebraska Medical Center

ROBERT FINK, M.D.

Chairman, Department of Allergy and Pulmonary Medicine

Children\'s National Medical Center

NORMAN FOST, M.D., M.P.H.

University of Wisconsin Hospital

RICHARD GORMAN, M.D., FAAP

Pediatrician

Pediatric Partners

ATTENDEES (Continued)

CONSULTANTS: (Voting) (Continued)

MARK HUDAK, M.D.

Professor and Chief

Division of Neonatology

University of Florida at Jacksonville

ROBERT NELSON, M.D., PH.D.

Associate Professor of Anesthesia and Pediatrics

Children\'s Hospital of Philadelphia

KEITH RODVOLD, PHARM.D.

Consumer Representative

VICTOR SANTANA, M.D.

Associate Professor

Dependent of Hematology/Oncology

St. Jude\'s Children\'s Research Hospital

JOHN SEVER, M.D.

Children\'s Hospital National Medical Center

GUEST SPEAKERS: (Non-voting)

LYNNE MOFENSON, M.D.

National Institute of Child Health and Human Development

National Institutes of Health

BENJAMIN WILFOND, M.D.

Bioethics Research Section

National Institutes of Health

GUEST INDUSTRY REPRESENTATIVE: (Non-voting)

STEVEN SPIELBERG, M.D.

Johnson & Johnson Pharmaceutical

ATTENDEES (Continued)

FOOD AND DRUG ADMINISTRATION STAFF:

MELISSE BAYLOR, M.D.

JULIE BEITZ, M.D.

MIN CHEN, M.S.

TERRIE CRESCENZI, R.PH.

SOLOMON IYASU, M.D.

LINDA LEWIS, M.D.

DIANNE MURPHY, M.D.

SHIRLEY MURPHY, M.D.

THOMAS PEREZ, R.PH., M.P.H., Executive Secretary

ALSO PRESENT:

JAMES OLESKE, M.D., M.P.H.

C O N T E N T S

ISSUE: ANTIRETROVIRAL DRUG DEVELOPMENT

IN HIV-INFECTED AND HIV-EXPOSED NEONATES

AGENDA ITEM PAGE

CALL TO ORDER AND INTRODUCTIONS

By Dr. Joan Chesney 7

MEETING STATEMENT

By Mr. Thomas Perez 11

OPENING COMMENTS

By Dr. Dianne Murphy 14

STATE OF THE ART: PERINATAL TRANSMISSION

By Dr. Lynne Mofenson 17

ETHICS OF NEONATAL RESEARCH

By Dr. John Sever 42

FDA PERSPECTIVE

By Dr. Linda Lewis 56

OPEN PUBLIC HEARING 90

DISCUSSION OF QUESTIONS 98

C O N T E N T S (Continued)

ISSUE: PEDIATRIC UPDATE

AGENDA ITEM PAGE

OVERVIEW: DIVISION OF PEDIATRIC DRUG DEVELOPMENT,

OFFICE OF PEDIATRIC THERAPEUTICS

By Dr. Dianne Murphy 206

MEDWATCH

By Ms. Min Chen 215

ADVERSE EVENT REPORTING

By Dr. Solomon Iyasu 233

DIVISION OF PEDIATRIC DRUG DEVELOPMENT UPDATE

By Dr. Shirley Murphy 257

NEW EXCLUSIVITY/RULE STATISTICS

By Ms. Terrie Crescenzi 271

P R O C E E D I N G S

(8:15 a.m.)

DR. CHESNEY: Good morning. I think we\'re ready to get started. I wanted
to welcome everybody here this frigid morning.

We\'re gathered today to discuss the issue of the need and importance of
continuing to request pharmacokinetic and safety studies of
antiretroviral drugs in infants under 28 days of age, as I understand
it. If the recommendation is to continue to study these agents, the FDA
has asked us under what conditions they should be studied. That will
take up most of the day, and then we\'ll have two other topics I believe
at the end of the day.

Before we do the introductions, I wanted, for the benefit of the
committee, to try to clarify for you, as I think I have clarified for
myself, all the changes in the office, and Dianne is probably also going
to review that. But I think it bears repeating for all of us. We can\'t
hear it too many times.

But Dianne, as you know, is going to speak next, and she\'s the Director
of the Office of Counter-Terrorism and Pediatric Drug Development within
the Center for Drug Evaluation and Research.

Dr. Shirley Murphy is now the Director of the new Division of Pediatric
Drug Development. Shirley, can you put up your hand? Okay.

Dr. Susan Cummins is the lead medical officer in the Division of
Pediatric Drug Development. Susan?

And Rosemary Addy is the project manager in the new Division of
Pediatric Drug Development. And Rosemary has just stood up.

So Rosemary Roberts, who we\'re all familiar with, is now on temporary
assignment with Dr. Dianne Murphy. And as they joke in the group now,
they\'re looking for Rosemary Murphy. She will have an instant job.

(Laughter.)

DR. CHESNEY: You have to be either a Rosemary or a Murphy to work in the
new Division of Pediatric Drug Development.

So I think the first order of business is for us to go around the room
and introduce ourselves. Let\'s start with Ben.

DR. WILFOND: I\'m Ben Wilfond, a pediatric pulmonologist with the
National Human Genome Research Institute in the Department of Clinical
Bioethics. And I\'m here as ‑‑ I\'m not quite sure what exactly I am.

(Laughter.)

DR. CHESNEY: It\'s a good way to start.

DR. MOFENSON: I\'m Lynne Mofenson. I work in the Pediatric, Adolescent
and Maternal AIDS Branch at the National Institute of Child Health and
Human Development, and I\'m here to talk to you about perinatal
transmission this morning.

DR. SPIELBERG: I\'m Steve Spielberg, Vice President for Pediatric Drug
Development at Johnson & Johnson, representing PhRMA.

DR. GLODE: I\'m Mimi Glode and I\'m a pediatric infectious disease
doctor at the University of Colorado and Children\'s Hospital, Denver.

DR. RODVOLD: I\'m Keith Rodvold. I\'m a clinical pharmacist at the
University of Illinois in Chicago, Colleges of Pharmacy and Medicine.

DR. FLETCHER: I\'m Courtney Fletcher. I\'m Professor and Chairman of the
Department of Clinical Pharmacy at the University of Colorado Health
Sciences Center.

DR. ENGLUND: I\'m Janet Englund, Department of Pediatrics, University of
Washington in Seattle.

DR. WOOD: I\'m Lauren Wood. I\'m a senior clinical investigator in the
HIV and AIDS Malignancy Branch, NCI.

DR. SANTANA: I\'m Victor Santana. I\'m a pediatric oncologist at the
University of Tennessee and St. Jude\'s Children\'s Research Hospital in
Memphis, Tennessee.

DR. NELSON: Robert Nelson. I\'m in pediatric critical care medicine in
the Department of Anesthesia and Critical Care Medicine at Children\'s
Hospital, Philadelphia.

MR. PEREZ: Tom Perez, Executive Secretary to this meeting.

DR. CHESNEY: Joan Chesney. I\'m a pediatric infectious disease person at
the University of Tennessee in Memphis, and also more recently at St.
Jude\'s.

DR. GORMAN: Rich Gorman in private practice of pediatrics in Ellicott
City, Maryland and presently the Chair of the American Academy of
Pediatrics\' Committee on Drugs.

DR. HUDAK: Mark Hudak. I\'m a neonatologist at the University of Florida
at Jacksonville.

DR. FINK: Bob Fink, pediatric pulmonologist at Wright State University
and Children\'s Medical Center in Dayton, Ohio.

DR. CHADWICK: Ellen Chadwick in the Division of Pediatric Infectious
Diseases at Northwestern University in Chicago.

DR. DANFORD: I\'m Dave Danford. I\'m a pediatric cardiologist in the
Joint Section of Cardiology, University of Nebraska Medical Center and
Creighton in Omaha.

DR. SEVER: I\'m John Sever. I\'m at the Children\'s National Medical
Center here in Washington, D.C. I\'m a co-investigator on the AIDS
Clinical Trials Group there and I\'m chairing three IRBs.

DR. FOST: Norm Fost, pediatrician at the University of Wisconsin, head
of the bioethics program and chair of just one IRB there.

(Laughter.)

DR. BAYLOR: Melisse Baylor, medical reviewer, FDA.

DR. LEWIS: Linda Lewis, medical officer, FDA.

DR. DIANNE MURPHY: Dianne Murphy. I\'m the Director of the newly formed
Office of Pediatric Therapeutics and the Office Director for
Counter-Terrorism and Drug Development, as Joan noted. Thank you.

DR. CHESNEY: Tom Perez, our Executive Secretary, will read the meeting
statement.

MR. PEREZ: Thank you.

The following announcement addresses the issue of conflict of interest
with respect to this meeting and is made a part of the record to
preclude even the appearance of such at this meeting.

The Food and Drug Administration has granted waivers to the following
special government employees which permits them to participate in
today\'s discussion: Drs. Joan Chesney, Robert Fink, Keith Rodvold,
Ellen Chadwick.

A copy of the waiver statements may be obtained by submitting a written
request to the agency\'s Freedom of Information Office, room 12A-30 of
the Parklawn Building.

In addition, we would like to note that Drs. Robert Nelson, Victor
Santana, David Danford, Richard Gorman, Mark Hudak, Mary Glode, Lauren
Wood, Jan Englund, Courtney Fletcher, John Sever, and Jeffrey Botkin did
not report any financial interests in the products or firms that could
potentially be affected by the subcommittee\'s discussions. Therefore,
they do not require a waiver to permit their participation in today\'s
meeting.

Further, Dr. Victor Santana and Dr. Courtney Fletcher reported financial
interests in the pharmaceutical companies covered under C.F.R.
2640.202(b)(2) de minimis exemption.

The topics of today\'s meeting are issues of broad applicability. Unlike
issues before a committee in which a particular product is discussed,
issues of broader applicability involve many industrial sponsors and
academic institutions.

The committee participants have been screened for their financial
interests as they may apply to the general topic at hand. Because
general topics impact so many institutions, it is not prudent to recite
all potential conflicts of interest as they apply to each participant.

We would also like to note for the record that Dr. Steven Spielberg is
participating in this meeting as an acting industry representative,
acting on behalf of regulated industry. Dr. Spielberg reports that he is
a full-time employee of Johnson & Johnson and also owns stock in the
firm.

With respect to other invited guest speakers, Dr. Lynne Mofenson and Dr.
Benjamin Wilfond, employees of the National Institutes of Health, have
been screened for conflicts of interest and have been cleared to
participate in today\'s meeting.

FDA acknowledges that there may be potential conflicts of interest, but
because of the general nature of the discussion before the committee,
these potential conflicts are mitigated.

In the event that the discussions involve any other products or firms
not already on the agenda for which FDA participants have a financial
interest, the participants\' involvement and their exclusion will be
noted for the record.

With respect to all other participants, we ask in the interest of
fairness that they address any current or previous financial involvement
with any firm whose product they may wish to comment upon.

Thank you.

DR. CHESNEY: Thank you.

I wanted in advance to thank all of the speakers for the day and the FDA
for all their time and effort in preparing for today\'s meeting. It\'s
really overwhelming when you think that it\'s not just sending us the
materials, but preparing the Federal Register notice, being sure we are
all identified in Tom\'s statement appropriately, meeting all the
regulatory issues, and keeping us all in touch. It\'s really a huge
effort and we\'re really very appreciative of that.

Our first speaker is Dianne Murphy, and again, at the risk of repetition
and for those of us who don\'t really understand the FDA structure,
Dianne is now officially the Director of the Office of Counter-Terrorism
and Pediatric Drug Development in the Center for Drug Evaluation and
Research and Director of the Office of Pediatric Therapeutics within the
International Activities and Strategic Initiatives in the FDA
Commissioner\'s Office. So she has two very official sounding titles.
Dianne.

DR. DIANNE MURPHY: We try to keep it that way.

Again, I wanted to thank everybody for being here, welcome you,
particularly those who came from more hospitable, warmer climes.

I also wanted to make an introduction that we did not have and that\'s
Debbie Birnkrant. Debbie is the Division Director, the Division of
Antiviral Drug Products, and it is that division which has asked you all
to come here today for the first half of the day because they had a very
important question, as you can see.

I was telling Lynne this reminds me of many years ago when we were
discussing 076. Ellen Cooper was the division director then, and there
were adamant and sincere thoughts, feelings, and opinions on both sides
of whether that study should go forward.

One of the adamant opinions was that it should not go forward because of
the exposure of uninfected infants at a time when the transmission rate
was much higher. As you know, it was one of the success stories in this
arena.

I think that we are now coming back with the same question in a very
different context. The division has had numerous conversations,
discussions, and thoughts about what they should be doing not only from
the scientific and the ethical perspective, but also from the
perspective of should FDA use or continue to use the tool that Congress
has given us called exclusivity in which a company obtains an additional
six months of marketing. Should we continue to use that tool in this
arena?

This committee does not get the simple stuff like here\'s a product,
here are the studies that were done, should we approve it or not. You
guys get some really difficult scientific questions, groundbreaking
questions really, about does this disease even occur in kids. Should we
be marketing drugs to these children of different types? I\'m talking
about prior questions you guys have addressed. What kind of studies
should we be doing? Is it ethical to do these kind of studies? In every
meeting that you all have had you have had to deal with not only a
scientific question, but also an ethical question.

Today is no different. We look forward to your deliberation and, believe
me, it will be very important in how we proceed as to what you say
today. Thank you very much.

DR. CHESNEY: Thank you, Dr. Murphy.

Our first speaker is Dr. Mofenson. I should say Dr. Cummins has prepared
very nice introductions for everybody for me. She is a board certified
pediatrician with special training in adult and pediatric infectious
disease. She joined the Pediatric, Adolescent and Maternal AIDS Branch
at the NICHD in 1989 as Associate Branch Chief for Clinical Research and
became Chief of the branch in 2002. She\'s been involved in many
studies, of which we\'re all well aware. She\'s chair of the Department
of Health and Human Services Public Health Service Task Force that makes
guidelines for the treatment of HIV-infected pregnant women and
participated in the development of the recent WHO antiretroviral
treatment guidelines for resource-limited settings.

Dr. Mofenson will briefly update us on the state of the art of perinatal
HIV transmission.

DR. MOFENSON: Good morning. I\'ve been asked to provide you with an
overview and update on prevention of mother-to-child HIV transmission
both in the U.S. and globally.

What I\'m going to do first is talk a little bit about perinatal
transmission in the United States and in particular talk about the
mechanisms by which AZT is effective in reducing transmission in 076,
risk factors for transmission in this new era of antiretrovirals,
transmission that we\'re seeing now in the post-076 era, and challenges
that we have.

Then I\'m going to talk about perinatal transmission on a global basis,
giving you a short and rapid overview of the short-course antiretroviral
prophylaxis trial results, relevance to the U.S., and end with
challenges in that area as well.

So, first, the United States. In the U.S., about 6,000 to 7,000
HIV-infected women give birth annually. Prior to 1994, transmission was
approximately 25 percent, and thus we had 1,500 to 1,750 infants newly
infected with HIV born every year before 1994. And more than 16,000
HIV-infected children have been born in the U.S. since the beginning of
the epidemic.

Now, in 1994, there was a dramatic change to the landscape of perinatal
HIV in the United States, secondary to the results of PACTG 076. Now,
this regimen was designed to target multiple potential time points of
transmission because in 1987, when the trial was first designed, we
really didn\'t know when the large proportion of transmission was
occurring.

Thus, AZT was given from 14 to 34 weeks of gestation to start for the
rest of pregnancy to target transmission occurring in utero after the
first trimester. It was given intravenously during labor and delivery to
target transmission occurring during the intrapartum period, and then it
was given to the infant for 6 weeks postpartum to target transmission
that might be occurring through infected cells or free virus that had
entered infant either through swallowing of infectious maternal genital
secretions during the process of birth or through blood-to-blood
transfusion during microtransfusions with uterine contractions.

This regimen resulted in a 67 percent reduction in the risk of
transmission, from 26 percent in placebo to 8 percent with AZT.

So I think an important question for you to discuss and think through is
what were the mechanisms by which AZT lowered perinatal HIV transmission
since you are discussing issues around neonatal drug testing.

Well, effect on viral load may be one part, but in PACTG 076, change in
HIV RNA accounted for only 17 percent of the observed efficacy of 076 of
AZT. I\'ll show you that on the next slide.

Two other important mechanisms through which AZT reduces transmission
include pre-exposure prophylaxis of the baby, and this is through
transplacental passage of the AZT given intravenously to the mother to
achieve levels in the baby during the birth process capable of being
virucidal, and post-exposure prophylaxis of the infant through continued
administration of AZT after birth.

This slide just gives you some of the data from 076. The mean entry RNA
in these women was relatively low, about 5,600. This was a relatively
healthy group of women who enrolled. The median change from entry to
delivery in RNA was only .28 log, and the proportion of AZT efficacy
explained by HIV RNA levels at delivery was only 11 percent and the
change from entry to delivery only 17 percent.

Now, additional evidence that AZT works by more than just lowering viral
load is the fact that AZT lowers transmission even in HIV-infected women
who have a very low viral load. These are data from a meta-analysis of
seven prospective cohort studies and clinical trials by John Ioannidis
and colleagues, and he looked at 44 cases of transmission among about
1,200 women, all of whom had delivery HIV RNA under 1,000.

Transmission differed by receipt of AZT. In mothers receiving AZT,
transmission was only 1 percent. In mothers not receiving AZT,
transmission was 9.8 percent. And on a multivariate analysis that
adjusted for maternal CD4 count, mode of delivery, and infant birth
weight, AZT still independently reduced transmission. And these data
illustrate the importance of infant pre- and post-exposure prophylaxis
in addition to lowering maternal viral load as a mechanism of
prevention, particularly in women with low viral load.

The importance of the infant pre- and post-exposure component of 076 can
also be illustrated if you look at infants who are born to mothers who
received different components of the regimen. These are data from a
population-based study in New York State by Nancy Wade and colleagues,
and you can see when all three components, antepartum, intrapartum, and
postpartum, of 076 were received, transmission was very low, 6 percent.
But even when the mother did not receive antepartum therapy and only
intrapartum and postpartum therapy was given or postpartum therapy alone
was given, but started within 24 hours, transmission rates were still
low, 10 and 9 percent, compared to those who started after 48 hours or
who had no AZT. Thus, even when no maternal AZT is received, infant AZT
started within 24 hours reduces transmission.

Why might pre- and post-exposure prophylaxis be important? Well, we now
know that the amount of cell-free and cell-associated HIV found in the
cervicovaginal canal is associated with transmission. I\'ve given you
two illustrative studies.

The first one is from a short-course AZT trial in Thailand I\'ll talk a
little bit more about later. They looked at quantifying HIV RNA in
cervicovaginal lavage and found that the presence of RNA was associated
with a 3.4-fold increase in the risk of transmission, and this effect
was independent of plasma RNA and was actually greatest when plasma RNA
was low, and the post-exposure prophylaxis component can become more
obvious. Antepartum AZT was associated with a median .8 log decrease in
RNA in CVL.

Ruth Tuomala and colleagues in the Women and Infants Transmission Study
looked at cell-associated HIV DNA in cervicovaginal lavage in women who
were receiving antiretroviral and found that detection of DNA was
associated with transmission, and for every 1 log increase in HIV DNA in
CVL there was a 2.3-fold increase in the risk of transmission.

Now, why would this be important? Well, the infant exposure to HIV in
vaginal secretions and the swallowing of this HIV both in cells as well
as free virus likely infects the baby through the intestinal mucosa of
the infant either by infection by cell-free virus going to lymphocytes
in the lamina propria, or through cell-associated virus again going
through to cells in the lamina propria, or virus going through
specialized M cells that bring it more directly to cells in the Peyer\'s
patch.

These are data from the PETRA study I\'m going to talk a little bit more
about later. This is presented to you to illustrate that pre-exposure
prophylaxis of the infant without post-exposure prophylaxis is not
effective. This study looked at a three-part regimen, short course
prenatal, intrapartum, and 1 week postpartum; a two-part regimen,
intrapartum and postpartum. Both of these regimens were effective with
the three-part regimen being most effective, the two-part regimen being
next effective. But the intrapartum regimen alone, which is giving
pre-exposure without post-exposure prophylaxis, was ineffective.

I\'d like to now turn to risk factors for transmission now in women and
infants in the post-076 era. Probably one of the most important risk
factors is delivery plasma RNA level. These are data from the Women and
Infants Transmission Study, a prospective cohort study. And you can see
a clear association between the level of RNA in the plasma of the
infected mother and the risk of transmission to the infant, ranging from
only 1 percent in women with undetectable virus under 400 up to 32
percent in women with high viral loads over 100,000.

As one might expect then, if low viral load is associated with lower
risk of transmission, more potent antiretroviral regimens in the mother
that are capable of significantly reducing their viral load is also
associated with lower perinatal transmission. And these are again data
from the Women and Infants Transmission Study, and you can see that as
the potency of antiretrovirals increases, the risk of transmission
decreases 8 percent with the 076 regimen, 4 percent with the dual NRTIs,
and only 1 percent with protease inhibitors.

Now, importantly these two factors are independent. This is a somewhat
complicated slide. Let me work you through it. This shows percent of
transmission. This x axis here shows you maternal plasma HIV RNA at
delivery, and here you see the type of maternal antiretroviral therapy
which increases in complexity. So if you first look down across HIV RNA
levels, you can see that in most of these categories of treatment you
can see a clear relationship between the level of RNA and the risk of
transmission, high transmission when RNA is high, low transmission when
it\'s low. But interestingly, if you now look within an RNA strata going
this way, you can see also that with increasing complexity of therapy,
you see a decrease in transmission even in women who have the same viral
load.

Elective cesarean delivery. Mode of delivery is another important risk
factor even in women receiving antiretroviral therapy. These are data
from the International Perinatal HIV Group which was a meta-analysis of
about 8,500 women from 15 different cohorts, and you can see that with
elective cesarean delivery without AZT, transmission is 18 percent
compared to 19 percent with other modes of delivery. When you\'re
receiving the 076 AZT, you lower transmission in both groups, but there
is an additive effect of elective C-section. So transmission is 2
percent with elective section and 7 percent without elective section. So
the addition of an intrapartum intervention further reduces perinatal
transmission even in the face of AZT prophylaxis.

I want to talk a little bit about what happened in the U.S. following
the results of 076. In February 1994, the results of this trial were
announced pre-publication, and within six months, the U.S. Public Health
Service had issued guidelines for use of AZT to prevent transmission.
And about a year later, they issued guidelines for prenatal HIV
counseling and testing recommending universal HIV counseling and testing
in the U.S. These guidelines are periodically updated, with the last
update of the prophylaxis guidelines being just a few months ago in
November 2002.

So what are the current Public Health Service guidelines for prevention
of mother-to-child transmission?

Well, when women have plasma HIV RNA levels over 1,000, the use of
highly active antiretroviral therapy, usually two NRTIs and a protease
inhibitor is recommended, as well as elective cesarean delivery if the
mother remains greater than 1,000 copies near delivery.

For women with plasma RNA 1,000 copies or less, the use of either HAART
or in this case the use of AZT monotherapy as in the 076 regimen is
recommended.

For women with no treatment prior to labor ‑‑ and this is a significant
minority of HIV-infected women. 15 to 20 percent of HIV-infected women
lack prenatal care, particularly those who are illicit drug users. There
are a variety of regimens recommended, in this case
intrapartum/postpartum regimens, either AZT alone, AZT/3TC, nevirapine,
or AZT/nevirapine. And near the end, I\'ll go through the trials that
have the evidence for this.

And then there is the situation where the mother has neither antenatal
or intrapartum therapy and therefore you only have post-exposure
prophylaxis open to you, and in this case infant prophylaxis for 6 weeks
with either a combination regimen is recommended for nosocomial
post-exposure prophylaxis or with AZT alone.

This is just to show you some data about what we\'re seeing in the U.S.
in terms of antiretroviral prophylaxis. These are data from PACTG sites
between 1998 and 2000 from an observational study that we\'re doing, and
the main message I want you to get here is that the vast majority of
women, 99 percent, are receiving some kind of therapy during pregnancy,
and the vast majority, 78 percent, are receiving combination therapy
primarily with protease inhibitors although there are a variety of other
types of regimens being received.

This is data also to show you the increasing rate of elective cesarean
delivery among women in the United States from the Pediatric Spectrum of
Disease project of the CDC. You can see that rates were relatively
stable between \'94 and \'97, a slight increase in \'98, but then in
1999 when the international perinatal meta-analysis was published, as
well as the clinical trial became available, rates jumped to over 40
percent and are nearing 50 percent now.

This is really the punch line. What have we seen in the United States
with this? We\'ve seen a dramatic decrease in the risk of transmission.
These are data from a variety of different studies and clinical trials
that I\'ve combined to show this decrease, rates of 25 percent from the
Women and Infants Transmission Study in 1993, down to 8 percent with
PACTG 0786. In another clinical trial 185 where all the women were
receiving the 076 regimen, transmission was 5 percent. In 1999,
beginning to see combination therapy used, 3 percent, and 2001 and 2002,
transmission down to 1.5 percent when most women are receiving
combination therapy.

Along with this, we\'ve seen a significant decrease in perinatally
acquired AIDS as one might expect. You can see the increase in cases
over time until about 1994. Here the results of 076 were announced, and
soon after, the U.S. Public Health Service made their recommendations.
And you can see an 81 percent decline in the rate of pediatric AIDS from
1994 to 2000.

So in summary, we\'ve made great progress in the U.S. in reducing
transmission. It\'s currently under 2 percent for women who are in
prenatal care. The number of infected infants born every year has
decreased from about 1,500 to 2,000 before 1994 to an estimated 300 to
400 currently, and this reduction has been achieved through enhanced
prenatal HIV counseling and testing, recognition of the importance of
viral load, and the increased use of HAART by pregnant women, and an
increase in elective cesarean delivery.

However, we shouldn\'t be too complacent. Many challenges still remain.
There are significant barriers to eliminating perinatal HIV in the
United States. One of the most predominant is continued HIV transmission
to women, particularly adolescent women who have high rates of
unintended pregnancy. I already talked a little bit about lack of
perinatal care, particularly in women who are illicit drug users, and a
significant minority of HIV-infected women lack prenatal care. Failure
to identify HIV infection during pregnancy and antiretroviral drug
resistance, which I\'d like to take a minute or two to talk about in a
little bit more detail.

The frequency of antiretroviral drug resistance mutations in virus
identified among newly infected persons in the U.S. and Canada is
increasing. A study in San Francisco compared the rate of resistance,
1996-1997 to 2000 and 2001, and found about a quarter of patients had
resistance to nucleoside analogs. It didn\'t really change. The rate of
resistance to non-nucleosides increased from 0 to 13 percent; to
protease inhibitors, 3 to 8 percent. And this resistance appeared to
potentially be clinically important.

Additionally, studies from 10 cities in the U.S. and Canada comparing
\'95-\'98 to \'98 to 2000 found an increase in any drug resistance from
8 to 23 percent and in multi-drug resistance from 4 to 10 percent.

We\'re also seeing that more HIV-infected pregnant women are
antiretroviral-experienced and have drug-resistant virus. These are data
on resistance from women in PACTG 316 which was a study where women were
receiving primarily combination therapy and it was evaluating whether
single-dose nevirapine offered any added benefit. You can see that 44
percent of these women at delivery had the M184 mutation consistent with
resistance to 3TC. 8 percent had resistance to AZT; 2 percent to NNRTIs,
although these women had not received non-nucleosides before; and 9
percent had primary protease inhibitor-resistant virus.

What is the impact of resistance on prevention of transmission? Well, I
think that that\'s still very debated but there are some studies that
suggest that there may be a significant impact. We did a study, PACTG
185 I talked about before. All of the women were receiving AZT, and we
had 24 transmissions in this study. The transmission rate was 5 percent.
And we did a case-control study comparing transmitters to controls, and
you can see that at delivery AZT resistance was found in 25 percent of
women who transmitted versus 11 percent of non-transmitters. This was
not statistically significant. Small numbers. And any nucleoside analog
resistance, 46 percent in transmitters, 25 percent in controls.

Additionally Seth Welles and colleagues in the Women and Infants
Transmission Study did a case-control study. They had about a quarter of
their women having prevalent AZT resistance, and in a multivariate
analysis, genotypic AZT resistance was associated with a 5-fold
increased risk of transmission.

At present I think most cases of antiretroviral failure where you have
transmission despite maternal prophylaxis are probably not due to drug
resistance, but this may change as resistance becomes more frequent in
the U.S.

I want to then turn to the global picture. Globally over 2 million
HIV-infected women give birth annually, most of these in resource-poor
countries where the 076 regimen is too complex and expensive to use.
Transmission rates in breastfeeding women who have not received
prophylaxis range between 25 to 40 percent, and currently about 2,000
children become infected every day globally. And an estimated 3.2
million children are living with HIV.

This slide is to illustrate for you the importance of breastfeeding
postnatal transmission in resource-limited countries. The colors show
you the blocking of the proportion of infections occurring at different
time points. About 20 percent of transmission occurs in utero, with a
majority of that probably occurring late in utero, about 40 to 50
percent during labor and delivery, and you can see a full 40 percent
occurring both early and late postpartum through breast milk
transmission. So in a breastfeeding population, breastfeeding postnatal
transmission is extremely important.

Following 076, there was clearly a need to develop shorter, less
expensive regimens that are more applicable to resource-limited
settings. Studies first looked at modifying AZT-alone regimens to see
whether shorter regimens would be effective. They then also explored
whether short-course combination regimens might be better than AZT
alone. And they also looked at whether similar efficacy to combination
therapy could be achieved with alternative drugs in what might be
simpler regimens.

This is just a schematic, and I just put this up here to illustrate to
you the types of questions that were asked in the trials that have
currently been completed. These trials focused on prevention of in utero
and intrapartum transmission. This up here is the 076 regimen, starting
at 14 weeks, 6 weeks to the baby, and the yellow is antepartum regimens.
And you can see the questions being asked were what is the minimum
duration of antepartum therapy needed, and is it needed at all, a
question whether intrapartum therapy alone might be effective. Then a
variety of different postpartum durations were looked at, and the
questions were what\'s the minimum duration and is it needed at all.

I\'m going to give you the punch lines first to the results of the
trials. Short-course AZT prophylaxis is effective, although longer
antenatal therapy starting at 28 weeks is more effective than shorter
antenatal therapy starting at 36 weeks, and that shows that some portion
of antenatal transmission is occurring between 28 and 36 weeks. And
efficacy of prophylaxis is diminished by breastfeeding but still
persists at 24 months, at least with the short-course AZT regimens.

This illustrates for you two trials that looked at the same regimen.
They looked at AZT starting at 36 weeks and given intrapartum, no infant
regimen at all. This is first looked at in Thailand in a formula-feeding
population with an efficacy at 6 and 24 months of 50 percent. You take
the same antiretroviral regimen, you put it into a breastfeeding
population in Africa, and you see there is still efficacy but it is
significantly diminished: 37 percent at six months compared to 50 and
down to 26 percent at 24 months. Still statistically significant, but
clearly less than 50 percent.

Another study in formula-feeding infants tried to assess whether the
duration of antepartum or postpartum therapy was important. This looked
at an 076-like regimen, started at 28 weeks, and given for 6 weeks to
the baby, and then looked at a very short regimen starting at 36 weeks
and 3 days to the baby and the different variations in between. They
found that the most effective regimen, which is not surprising, was the
longer regimen, transmission of 4 percent compared to 11 percent in the
short-short regimen. With the variance, you see that the transmission
rate was intermediate with those who had long antepartum therapy being
more like the long-long regimen, those with short antepartum therapy
being more like the short-short regimen. Indeed, when they looked at the
in utero transmission in this study and they compared long and short
antepartum therapy, they found a significant difference in that longer
antepartum therapy was associated with a transmission rate in utero of
1.6 percent compared to 5.1 percent with short antepartum therapy.

Now we move to the short-course combination regimens. After short-course
AZT was found to be effective, researchers then asked whether
short-course combination regimens might be more effective than AZT
alone. AZT/3TC prophylaxis does appear to be more effective than AZT
alone, and a three-part regimen appears more effective than a two-part
intrapartum/postpartum regimen. As we talked about earlier, intrapartum
only is not effective, showing the importance of this post-exposure
prophylaxis component, particularly if the mothers do not receive
antenatal care.

And in this particular AZT/3TC regimen, efficacy did not persist at 18
months. This first looks at the combination of AZT/3TC in formula-fed
infants. This is a study in France. They took the 076 regimen and added
3TC to the mother starting at 32 weeks and also added 3TC to the baby
for 6 weeks. So the baby got AZT and 3TC. Transmission was 1.6 percent
compared to their historical control of 6.8 percent.

A study in Thailand took their standard short-course regimen, 36 weeks
and 4 weeks to the baby, added 3TC to the mother antepartum/intrapartum,
and found a transmission rate of 2.8 percent compared to a historical
control of short-course AZT alone of 12 percent.

This is the PETRA study I talked about before. This is AZT/3TC,
three-part regimen most effective; intrapartum/postpartum also
effective; intrapartum-only not effective. But you see at 18 months in a
breastfeeding population a real severe diminishing of the efficacy of
this regimen.

How about alternative prophylaxis regimens? Researchers then asked
whether alternative drugs that had some significantly different
properties like nevirapine, long half-life, very good penetration into
tissues, might provide efficacy similar to the short combination
regimens. The bullet point is that when only intrapartum/postpartum
prophylaxis is given, single-dose nevirapine is superior to
intrapartum/postpartum AZT alone and similar to intrapartum/postpartum
AZT/3TC. Efficacy is diminished by breastfeeding, but unlike the PETRA
study, nevirapine appears to retain significant efficacy at 18 months in
breastfeeding populations. The addition of single-dose nevirapine to the
mother and baby to short-course AZT appears to improve efficacy, but
adding it to standard regimens in the U.S. does not offer benefit.

Now, to just show you these studies that support those statements. This
is the HIVNET 012 study. This compared a single dose of nevirapine given
to the mother at the onset of labor to a single dose of nevirapine given
to the baby at about 72 hours, and it compared it to an ultra-short
regimen of AZT/3TC given orally intrapartum and for 1 week to the baby.
The key point here is that the nevirapine regimen was significantly more
effective than ultra-short AZT, efficacy 47 percent at 14 to 16 weeks
and still significant, 41 percent at 18 months.

Well, the next question would be, now we\'ve got two
intrapartum/postpartum regimens, single dose nevirapine and AZT/3TC. Is
one better than the other?

The same trial, which was actually just published this week in the
Journal of Infectious Disease, compared the 102 regimen, a variant of it
‑‑ they gave two doses to the mom instead of one ‑‑ to the AZT/3TC PETRA
regimen, and the end result here was that the transmission rates in two
groups, 12.3 percent with nevirapine, 9.3 percent with AZT/3TC
intrapartum/postpartum, are not significantly different. So similar
efficacy.

The next question is whether the addition of single-dose nevirapine to
the proven effective short-course AZT regimens might improve efficacy.
Now we\'re beginning to move to studies that are still ongoing.

This is a study in a formula-fed population in Thailand. They looked at
a baseline short-course AZT regimen and added single-dose maternal and
infant nevirapine and single-dose maternal nevirapine only. At the first
interim analysis, the placebo arm, the AZT-alone arm, was discontinued
because transmission was significantly higher than in this arm. So the
study is still ongoing, and I don\'t have the actual transmission rates
to give you.

In a study in the Ivory Coast, this was an open-label study where we
again had short-course AZT. Single-dose nevirapine to the mom and baby
was given. Transmission was only 7 percent at 3 months compared to 13
percent with a historical control.

Now, nevirapine appears to add efficacy to AZT alone, but what about to
the standard regimens that we\'re receiving in the U.S. now, most of
which is combination? And this was addressed in the study, PACTG 316,
conducted in the U.S., in France, Brazil, and the Bahamas, that looked
at women receiving standard therapy during pregnancy, intravenous AZT
during labor, and AZT to the infant, and they were randomized to
single-dose nevirapine to the mom and baby or placebo. Transmission
rates were remarkably low, 1.4 and 1.6 percent, but not significantly
different.

Infant prophylaxis. Now, many women may not present until labor. In the
U.S. I talked about 15 percent of HIV-infected women do not have
prenatal care. In resource-limited settings, it is a much higher
percentage of women who do not present to the health care system until
they are actually in labor. Therefore, they can\'t receive antepartum
therapy.

Epidemiologic data suggests that AZT for 6 weeks after birth reduces
transmission. That\'s the Wade data I already showed you. And the Wade
data also showed that infant prophylaxis must begin within 24 to 48
hours after birth if it\'s going to be effective when the mother has not
received antepartum/intrapartum drug.

Preliminary data again from studies that are still ongoing show that
single-dose nevirapine given to the infant may have similar efficacy to
AZT, but that single-dose nevirapine plus AZT may have better efficacy
than nevirapine alone.

And these are the two studies that have shown that. This is a study that
compared single-dose newborn nevirapine only to 6 weeks of AZT, found
similar transmission rates at 6 weeks. This study is still ongoing.
There was a lot of lost to follow-up, so I don\'t know that we can draw
any definitive conclusions.

And this study here I want you just to concentrate on the top part. Here
they compared newborn nevirapine, single dose alone, to single-dose
nevirapine plus 1 week of AZT, and found that the combination had a
significantly lower rate of transmission, 14 versus 22 percent.

In the U.S., we use the standard 6 weeks AZT, but the transmission rate
even with 6 weeks AZT, is still relatively unacceptably high, 10-12
percent. So we\'re currently doing a study in Brazil and the U.S.
that\'s going to look at whether combining 6 weeks of AZT with
additional drugs might be more effective in reducing transmission in
this circumstance. And it\'s comparing 6 weeks of AZT, 6 weeks of AZT
with three doses of nevirapine, and 6 weeks of AZT with three doses of
3TC and nelfinavir. This study should be enrolling in April.

To finally move to what is currently planned in terms of international
perinatal trials, clearly the largest problem in the resource-limited
setting now is how do we reduce postnatal breast milk HIV transmission
in areas where formula feeding is not safe, is not sustainable.

This is the design of ongoing infant prophylaxis studies. Again, this is
just a schematic for you to look at. Whereas before with our completed
studies most focused over here on antepartum duration, now we see
they\'re focused over here on postpartum duration in the infant.
Questions being asked include what\'s the optimal duration of antepartum
therapy. Do you need it? And postpartum, a number of questions are being
asked. What\'s the optimal duration of prophylaxis of a breastfeeding
baby? Will it work if it\'s given alone? What drugs should you give? Is
combination better? What about exclusive breastfeeding?

This just gives you a flavor of the type of drugs that are being looked
at antepartum/intrapartum and focus on the infant postpartum here.
Duration varies from 1 week, 6 weeks, 14 weeks, to 6 months looking at a
variety of drugs, AZT, nevirapine, 3TC, and a number of different
combinations.

Additionally, probably most importantly, a number of studies are looking
at maternal prophylaxis during breastfeeding where the mothers are
receiving highly active antiretroviral therapy. These studies are all
very similar. They start HAART at 34 to 36 weeks, and they give 6 months
of HAART to the breastfeeding mother. Some of these are open-label and
some of them are comparative.

So in terms of global perinatal transmission, shorter, less expensive
regimens than 076 have been found to be very effective in reducing in
utero and intrapartum transmission by 41 to 63 percent. Although
breastfeeding decreases overall efficacy, most of these trials still
show a significant decrement at 18 to 24 months. However, we\'ve only
lowered transmission in these populations to what we saw in the U.S.
pre-076. We\'ve lowered it to 25 percent instead of 40 percent.

Thus new approaches, and importantly including infant and/or maternal
prophylaxis that are targeted against reducing postnatal breast milk
transmission are clearly needed.

And finally, implementation of what we know are effective regimens is
now key in developing countries.

Thank you very much.

(Applause.)

DR. CHESNEY: Thank you very much. That was superb. Just as one had a
question, you answered it.

Dr. John Sever is going to speak to us next. We are scheduled to have
questions on the presentations at the end of the three presentations.

Dr. Sever has had a long and distinguished academic and research career
in pediatrics and pediatric infectious diseases with a special focus on
pediatric HIV and other perinatal infections.

Currently he\'s Professor of Pediatric Medicine and Infectious Diseases
at Children\'s National Medical Center and Professor of Pediatrics,
OB-GYN, Microbiology, and Immunology at George Washington University
School of Medicine. Prior to this, he was Chairman of the Department of
Pediatrics at George Washington University School of Medicine and Vice
President for Medical and Academic Affairs at Children\'s Hospital
National Medical Center.

He\'s also an associate investigator in the Washington Regional
Consortium, Pediatric AIDS Clinical Trials Unit for the NIH.

And Dr. Sever has published extensively with over 500 publications.

He will address the ethical issues that arise when conducting neonatal
research.

DR. SEVER: Thank you very much. It\'s a pleasure to be here this morning
to discuss some of the ethical issues in the area of concern here.

I\'d like to bring forward some of the issues which I think are
important to keep in mind for you to consider as these discussions
proceed today.

First, I\'d like to refer you to a couple of references. One I think is
particularly worthwhile. Those of you who are here on the panel have a
copy in the FDA briefing document. It\'s the reference to the American
Academy Policy Statement on the Guidelines for Ethical Conduct of
Studies to Evaluate Drugs in Pediatric Populations. That does a very
thorough job of discussing some of the important things in pediatric
studies in general and I think is particularly useful for you to review.
Again, it is in the briefing material that you have in your package.

Another reference, of course, is the Code of Federal Regulations. This
one, Title 45, part 46, subpart D, deals specifically with pediatric
studies. There\'s a parallel document for the FDA. This details the
issues which are perhaps the minimums that we have to consider in
relating studies to newborns and pediatrics specifically and provides us
with general guidance that\'s used by the institutional review boards in
considering pediatric protocols.

Now, I\'d like to take up some of the principles that are guidance for
us in general in looking at areas of research and specifically how they
apply to pediatrics and newborns and HIV in newborns.

First, of course, is respect for persons. This deals with the
participants voluntarily consent to participate in research, that you
obtain an informed consent, and that there\'s privacy and
confidentiality.

You can see immediately, of course, in pediatric studies we\'re under
the constraints that the participant cannot voluntarily consent to the
research, and we have to then determine that we will have to obtain
consent from some reasonable surrogate for that individual. The parent
or the legally appointed guardian has to be the one that would be able
to then consent.

Usually in pediatrics we also require an assent, and that is for
children over 7. We look to the child also to participate in the
consenting process. Here again in studies for neonatal investigations
that\'s also impossible.

So two of the main issues that we have to consider is this respect for
persons and we have to be particularly careful in our electing to
proceed in studies to protect the child in that consenting process.

Now, the second major area is beneficence which concerns the risks for
research are justified by potential benefits to the individual or
society. The study is designed so risks are minimized and conflicts of
interest are managed adequately.

Of course, in many of these studies for pediatric patients, they\'re
early studies. They\'re phase I studies, phase II studies, so we may not
know what the risks and benefits are particularly for children in that
age group. That has to be something that you have to keep in mind. We
don\'t know the benefits because although we may have some indication
from other studies what the benefits are in adults, whether that same
benefit will be present for the issue that you\'re trying to accomplish,
such as a lack of transmission of infection as opposed to treatment of
infection. And the risks to the child, of course, are often unique and
serious.

The last main area we have is justice and that vulnerable subjects are
not targeted for convenience and people who are likely to benefit from
research participation are not systematically excluded. That means
looking carefully at the populations we study and how they match up with
the populations at risk and the need for these studies. Do we go to
other populations simply because there are more infected patients and
it\'s easier to complete your study, or do we do it because of
consideration for the true need for that type of a study?

Now, taking this into a greater, more specific area, I\'d like you to
consider neonatal research which is what I was asked to talk about and
specifically neonatal HIV research. Here under respect for persons, we
have to look at the issue of voluntary consent. Again, we have to use a
parent or a guardian.

The concerns we often are undertaking are is there a good understanding
of what this means to the child, as well as to the mother.

Are we communicating that adequately by the consent process? Often the
consents get very long and detailed because they have to be to get in
all of the issues about risks and potential benefits. But can the
individual really understand the issues? We find, for example, in
dealing with pregnant women who are HIV-infected that they\'re
particularly willing to be compliant while they\'re pregnant for the
benefit of their child, but what about the continued issue of their
understanding about the drugs and their potential toxicities which has
to be communicated?

Their ability to cope becomes important. In so many of these instances,
as you know, of course the mother has HIV and the child has HIV, and if
that\'s the total family, the issues of coping with the mother taking
the medicine she needs, getting the appointments she needs, as well as
getting that drug to the child at the time that the child needs it,
getting the visits that the child needs to have become a real problem in
coping with being able to be employed, as well as taking care of these
issues. And if the mother isn\'t really present ‑‑ the child is being
taken care of by another individual in the family ‑‑ the ability for
that regime to be administered and to be followed often becomes very
difficult.

And then the motive of the individual. I will discuss that a little bit
more, but I think it\'s important to understand why the parent or
guardian would want to participate in this study. Why would they want to
have their child receive this drug if we don\'t know much about the drug
and its possible toxicities? Are they altruistic and interested in that,
or are there other motives present which are understandable but must be
recognized?

We look at these phase I studies. And this is often a problem in
pediatrics. Is there going to be direct benefit in a phase I study? And
if not, is the benefit important and how must we approach that? In most
phase I studies that have been followed ‑‑ and I\'ve been discussing
this with Dr. Nelson because we get involved in this in our oncology
phase I studies too ‑‑ it\'s unlikely that the child will benefit.
Estimates have been made that in adult studies it\'s somewhere around a
5 percent chance that in a phase I study you\'ll have any benefit
whatsoever, and that takes into account even no observable clinical
benefit but some laboratory type benefit.

Now, it\'s said that perhaps you have a 10 percent chance in children
because you\'re using drugs that hopefully have had some evaluation in
adults. But increasingly we\'re seeing drugs that have had little or no
evaluation in adults and have not had evaluation certainly for some of
the issues that you may be applying them in the pediatric patients or
the transmission of infection.

Is better care an important issue and is that important in the decision
to volunteer, as well as the benefit of the study? Frequently patients
will tell us they volunteered because they know it\'s better
surroundings and they can see the same doctor every time when they
participate in a clinical trial, whereas that rotation ‑‑ and there will
be fellows and residents they\'ll be seeing ‑‑ does not pertain if
they\'re not in the clinical trial.

Is there a certain assistance that\'s participating in this decision
making in their effort to participate? Will they receive some
compensation for it? Yes, we\'ll compensate them for their travel and
perhaps for their time away from work, but is that the important factor
that\'s motivating them to participate?

Is the social support and aid, the fact that they\'re going to have a
lot more social workers around them and available to them in our
settings, important to them and, therefore, that\'s why they\'re going
to participate?

And for some individuals, the important thing appears to be that they
get food and formula and diapers free if they participate, and I think
we have to be careful about understanding that motive in balancing that
against the situation that we\'re giving to the family.

Other things, of course, come up. What about the inconvenience? And the
inconvenience becomes very large. Frequently we are providing the
subsidy for taxi travel in order to make it convenient for the
individual to come.

The time away from their work and the fact that their visits and their
time away, in addition to their own visits and time away, becomes really
important. So obviously we all try to combine those together to make it
a joint visit.

But the concern often is that their work or their fellow workers will
learn of their diagnosis by the fact that they\'re away so much or
they\'re being called. The way the calls are made to their offices to
tell them about canceled appointments or changes become very important
so that they can keep their privacy about their own diagnosis, as well
as about their child. Very often, of course, they do not want the
child\'s father to know the diagnosis, and that adds to the
complications.

The travel, the extensive use of medications is an inconvenience. Side
effects for the medications, both to the mother and to her child,
certainly are important.

Then any additional costs that we don\'t cover that are necessary to be
paid for become an important issue for the consenting and for retaining
their interest and participation in ongoing studies.

Well, in beneficence then we would like to have as much background
information, first of all, as we can from laboratory studies, from
animal studies, and from adult studies. This gives us the greatest
amount of it, if we have all three, as we enter into our first phase I
pediatric studies.

But we may not have the information we need or it may not be appropriate
for the age group that we\'re dealing with, particularly if our
questions are not exactly the same as those in adults. Obviously,
prevention of transmission is different from treatment studies.

Then the risks that are involved, of course, as Dr. Mofenson has pointed
out, are that most of the patients are not infected so that if we\'re
doing studies in pregnant women in this country, we have to realize that
only about 2 percent of the children will be actually infected and 98
percent will be exposed to these drugs with really no benefit to them.

Also in the immediate newborn period, again dealing with the neonatal
period, the diagnosis may not be made until several weeks have passed so
that if you\'re going to initiate a study and you feel you must initiate
it in the immediate newborn period, you may not know again whether that
child is infected. I think here is a role for intensive evaluation of
the rapid tests in making the diagnosis in newborns and documenting it
at birth whenever possible and selecting on that basis.

But there may be particular toxicities in newborns. They have different
metabolism. The studies of drug levels in the newborns would be
important to document, and now, fortunately with tandem mass SPECT,
we\'re able to do that a lot better, getting rapid drug levels in
children, which we\'re doing in our studies at the Children\'s Hospital
here in Washington. They have different metabolism.

Also you may have long-term effects which you don\'t appreciate in
studies done in adults. Certainly the effects on growth and development
of the child we have to monitor and we won\'t find out for a long period
of time whether there has been a detrimental effect on growth and
development or mental development. Neurological findings are not going
to be apparent as readily in relation to these children being exposed
very early in life and what might occur many years later.

And then the effect of maternal treatment. How does that affect the
child, the drug effects themselves, as well as the development of
resistance which may be occurring in the mother, and therefore the
effect on the treatment of the child has to be consider.

Some of the benefits, of course, could be the better suppression of
infection, lower risk of transmission, perhaps less side effects if we
choose the drugs appropriately and then are able to use drugs with less
side effects.

Easier to administer, very important in children obviously. The
mixtures, some of them that have been developed over the years, have
been just terrible tasting, atrocious. Some of them taste like kerosene
and the children won\'t take it. They\'ll spit it out. So drugs that are
easier to administer, more palatable drugs, become important for us to
have available and to be thinking about in terms of benefits.

Again, some of the benefits are better medical care because they are
participating in these studies, social support for the family, and
benefit to other children as an indirect benefit in the long run.

Now, as to justice, again these are vulnerable subjects. They\'re
newborns and they shouldn\'t be targeted for convenience. They don\'t
have either consent or assent, and so not only do we have to ask the
parent or the legal guardian to be concerned about this, but we have to
ask the investigators and those of us who are reviewing the protocols in
general to be sure that we\'re protecting the child as appropriately as
we can.

There\'s a question about general availability, the location of the
center. There are these centers which do studies and then there are
other areas of the country where there are usually less HIV-infected
patients that may not have centers. Those locations still have these
HIV-infected children and they may or may not be able, therefore, to
participate in studies because they are in a low incidence area and
there are no centers in that particular area.

We have to be very careful about our recruitment procedures, be very
conscious of the way that we induce patients or discuss with patients
their participation and the benefits. While there is the constant pull
for increasing accrual in protocols because the study wants to get it
done, we still have to be careful about ensuring that the recruitment is
reasonable.

Now, the IRB has to look at protocols and consider them, first of all,
that they may be not more than minimal risk and they may, therefore,
number one, have a direct benefit or they may have no direct benefit.
And if the IRB determines that it is not more than minimal risk, in that
category it has the authority to approve or disapprove that study.

But some of the studies have some risk. Are bone marrows going to be
required? Are other procedures going to be required that would not
normally occur in these children? One has to then decide is this a study
that\'s a minor increase over minimal risk where there is either a
direct benefit or no direct benefit.

The IRB can approve that level, but the decision there is a difficult
one often. There is not good guidance in the decision as to what is a
minor increase over minimal risk. So what one IRB decides is a minor
increase over minimal risk and another one decides is not acceptable
will differ. We ourselves go through that frequently. So that\'s a hard
decision to make. Is this particular drug study a minor increase over
minimal risk and therefore something that we can approve or not?

If it\'s more than minimal risk and you can feel quite sure that there
is direct benefit, the potential for direct benefit is reasonable, then
the IRB can approve it.

However, if the study involves more than minimal risk and there is no
evidence of direct benefit but the IRB continues to feel that the study
is worthwhile doing, this can be referred to HHS for a panel decision.
That\'s a much longer route and more complicated. So this decision point
between a minor increase over minimal risk for no direct benefit study
and a more than minimal risk for no direct benefit study becomes very
important and puts us into a different area. But studies can be done if
there\'s more than minimal risk and no anticipated direct benefit if the
IRB supports it and sends it on for this panel and if the panel supports
it.

So in conclusion then, I\'ve summarized some of the things that I think
are important for us to consider when we look at these protocols. Some
of the benefits certainly have been demonstrated by 076 and other
studies, but now we\'re down to the point where we only have 2 percent
infection rates, and as we realize from the start, this then puts both a
difficulty in conducting the studies and a difficulty in considering the
risks which we are taking and the child is taking as a result of
participating in this study.

Again, I would suggest that if we had an emphasis on the support of the
use of rapid tests in the immediate newborn period, that would help us a
great deal to at least identify at that point the infected child
immediately rather than a month later or so.

The use of foreign studies is certainly important because of the
availability of more infected patients to participate in those studies,
but the information from many of those studies using shortened regimes
and less effective protocols, as we know, may not be applicable to the
information we need to try to get down to 0 infected children in this
country.

Thank you.

(Applause.)

DR. CHESNEY: Thank you very much, Dr. Sever.

The next individual to present to us is Dr. Linda Lewis who is a board
certified pediatrician with subspecialty training and board
certification in pediatric infectious disease. She\'s been with the FDA
since July of 1999 and is a medical officer with the Division of
Antiviral Drug Products.

Prior to joining the FDA, she was a senior clinical investigator at the
Pediatric Branch of the NCI where she supervised phase I and II clinical
trials of antiretroviral drugs in children. She also has served as a
pediatric ID consultant for the DuPont Hospital in Wilmington, Delaware
and was a medical consultant to the Delaware pediatric HIV program.

Dr. Lewis is going to present to us the FDA perspective regarding the
need for reevaluation of antiretroviral drug development in neonates,
and she will close with a presentation of the questions for our
consideration today.

Dr. Lewis.

DR. LEWIS: Thanks, Dr. Chesney.

As Dr. Chesney says, I have been on pretty much every side of this
debate over the last many years, but I am here today on behalf of the
Division of Antiviral Drugs and would like to thank the committee and
all of the other people who are in attendance for participating in this
meeting.

We would like to obtain from this meeting advice on the best approach to
drug development for all pediatric populations. You\'ve just heard a
very concise description of where we stand with perinatal transmission
programs both in the U.S. and globally and some thoughts on the ethical
issues that are involved in performing studies in neonates.

We\'re here today to ask specifically for advice regarding the
development of HIV drugs in neonates, that is, infants from birth to
about 4 weeks of age. During the next few minutes, I would like to
present some of the issues that have been brought to the Division of
Antiviral Drugs that have led us to ask for this reevaluation of our
standard request for studies in this age group.

I\'ll begin my presentation with a description of the written request as
a mechanism for requesting pediatric studies. I\'ll present our current
standard request issued to sponsors of HIV drugs. After that, I will
present some of the issues that have been raised regarding the
feasibility of conducting HIV drug development studies in the neonatal
age group. Many of these concerns have been brought to us by our
pharmaceutical sponsors. The next several slides will provide a little
more detail on each of these topics.

First, a description of the written request for pediatric studies. Those
of you who are on the Pediatric Subcommittee have heard a little bit
more about written requests and pediatric exclusivity than some of our
guests who participate in the Antiviral Advisory Committee.

The Best Pharmaceuticals for Children Act of 2002 reauthorizes the
exclusivity provision that grants sponsors six months of market
exclusivity for conducting pediatric studies as outlined in a written
request. This legal provision was originally passed in 1997 as part of
the FDA Modernization Act and has been instrumental in providing
pediatric data on many drugs.

A written request comes in the form of a letter sent by the FDA to the
sponsor describing the studies that must be done, the number of patients
who must be studied, and the time frame for completion of these studies
in order for the drug to be eligible for pediatric exclusivity. The FDA
requests studies in a written request that we believe will provide a
public health benefit. That\'s one of the keys in the legislation.
Agreement to conduct these studies as outlined in the written request is
entirely voluntary on the part of the sponsor. The incentive to perform
these studies is the potential financial benefit provided by six months
of patent protection.

In order to provide a consistent approach to pediatric drug development,
the Division of Antiviral Drugs developed a standard written request for
HIV drugs. A copy of our written request template for antiretroviral
drugs was included in the briefing package that was sent to all of the
committee members.

In general, a written request is issued when enough data is available in
adults to indicate a drug\'s potential efficacy and preliminary safety
profile. This is usually occurring during phase II or phase III of drug
development or occasionally after an accelerated approval. The Division
of Antiviral Drugs has issued 20 written requests for HIV drugs that are
either approved or already in development.

To date, five of our drugs have been granted pediatric exclusivity, and
these include abacavir, lamivudine, didanosine, stavudine, and
nevirapine.

You might notice that zidovudine, which is our original first
antiretroviral drug, is not on this list, and that\'s because most of
the pediatric data that was required during those studies had been
submitted to the FDA and reviewed prior to the initiation of this
program.

As I stated, the division has developed a standard template for
antiretroviral drug written requests, and this slide really gives pretty
much the exact wording that is included in our template. We identify the
type of studies that are requested and these include multiple dose, PK,
safety and activity studies of drug X in combination with other
antiretroviral agents in HIV-infected pediatric patients. These studies
are designed to support the use of the drug in HIV treatment regimens
for children. We do not generally require that the sponsors perform
randomized, controlled phase III studies in children if there are
adequate data confirming the drug\'s efficacy in HIV-infected adults.

We also request multiple dose, PK, and safety studies of drug X in
HIV-exposed neonates, and by that we mean neonates born to HIV-infected
mothers. These studies are designed primarily to identify the PK profile
and some safety data in this age group and not to show the efficacy of a
treatment or prophylaxis regimen.

The template also identifies the age group in which studies will be
performed. These are HIV-infected pediatric patients from 1 month to
adolescence and HIV-exposed neonates.

These patient groups were originally designated to allow the inclusion
of the larger population of neonates whose HIV status had not yet been
determined at a time when the rate of perinatal transmission was
significantly higher in this country and other countries where most of
the research was being performed.

Over the last year, a number of issues regarding the development of HIV
drugs in neonates have been raised. Sponsors have voiced concerns
regarding the feasibility of conducting studies in neonates and some
have been asked to be released from their commitment to study drugs in
this age group and to have their written requests amended. Amending a
written request would allow a sponsor to be granted the six months of
exclusivity for that drug without performing the neonatal study
component.

Some of their concerns include the size of the population available for
study, the characteristics of this population available to be studied,
the ethics of including uninfected neonates in clinical studies, and the
ability of parents to understand and give informed consent during the
first few weeks of an infant\'s life.

Lynne has given you a very good overview of the size of the population
involved in the U.S., but just to recap a little bit, it is estimated
that 300 to 400 HIV-infected infants are born annually in the U.S. It is
now standard practice for infants born to mothers with known HIV
infection to receive prophylaxis through 6 weeks of age or until a
definitive diagnosis can be made, whichever comes first. Current
pediatric guidelines recommend treatment for HIV-infected infants less
than 1 year of age.

Diagnosis of HIV infection in the neonate can clearly be made by 4 weeks
of age using the Public Health Service\'s recommended testing schedule.
In practical terms, although many centers who are familiar with HIV have
gotten much better at identifying infants early, it is not always
possible to identify a newborn as HIV-infected prior to leaving the
hospital and is not always possible to confirm early positive test
results with a second confirmatory test before the infant is 4 weeks of
age. Consequently, the number of infants diagnosed with HIV infection
and presenting for treatment during that time is relatively small.

The total number of infants born to HIV-infected women in the U.S. is a
little more difficult to determine. Reporting of HIV infection is not
required in all states and there is no linking of infection status to
pregnancy in the states that do require reporting. The CDC HIV/AIDS
Surveillance Report identifies approximately 50,000 women reported to
have HIV infection through December of 2001. That\'s the last time
period for which appropriate statistics have been compiled. This number
includes women only from the jurisdictions that require reporting, but
does include all female patients greater than 13 years of age.

We know that rapid HIV testing of women in labor whose HIV status is not
yet determined are being evaluated and it is hoped that these studies
will provide the identity of more women and infants who are at risk, but
it is not clear how the identification of these infants will impact on
neonatal studies.

We know that studies have shown that in the U.S. and other countries
using current HIV treatment regimens, the rate of perinatal transmission
is less than 2 percent in pregnant women receiving appropriate HIV
treatment. If you calculate backwards from the estimated number of
HIV-infected infants who are born, you can come up with a number of
thousands of HIV-infected women delivering infants in the U.S. each
year. These estimates range from the 6,000 or 7,000 that Lynne says up
to 12,000 or 15,000 in other estimates.

Worldwide the size of the population potentially available for study is
quite different. It has been estimated that 600,000 to 800,000 infected
infants are born annually worldwide. Compared to the number estimated in
the U.S., the population of infants born to HIV-infected women outside
the U.S. is tremendously larger. As we all know, these women and infants
reside predominantly in resource-limited countries. Rates of
transmission are decreasing in some of these countries but not in
others, and certainly treatment of HIV-infected children remains much
less common in resource-limited countries than in the U.S.

Clearly there have been studies successfully conducted in neonates. Four
of the five drugs that have already received pediatric exclusivity were
evaluated in infants less than 4 weeks of age. Also, the Pediatric AIDS
Clinical Trial Group has been instrumental in performing studies in this
age group by enrolling pregnant women in clinical trials and following
them and their infants through the postpartum period. I have a couple of
examples listed here of neonatal studies that were reported last year at
the 9th Conference on Retroviruses and Opportunistic Infections.

PACTG 354 evaluated ritonavir in pregnant women and their infants and
enrolled from November 1997 to November of 2000. This study enrolled 7
pregnant women. There were cord blood drug levels available in 4 infants
and full PK assessment in 3.

PACTG 353 evaluated nelfinavir in pregnant women and their infants and
enrolled from December 1997 to November of 2001. Cohort I of this study
enrolled 10 mother-infant pairs and determined that the dose of
nelfinavir being studied in the neonate did not provide adequate drug
levels. Cohort II enrolled 23 pregnant women. Cord blood levels were
available in 16 infants and full PK assessments were available in 10
neonates.

These studies and others provide valuable information about how to use
the HIV drugs in neonates, but they also point out the pros and cons of
conducting studies in young infants. These studies require years to
enroll very small numbers of mother-infant pairs, and even in these
well-conducted studies, only about half of the neonates remained on
study and completed the pediatric PK portion of the study.

However, both of these studies pointed out that the initial doses of
ritonavir and nelfinavir that were being studied resulted in inadequate
drug exposure. This confirms that appropriate dosing of at least some
antiretroviral drugs in neonates cannot be predicted accurately on the
basis of PK modeling or dosing in older children.

In terms of the characteristics of the population available for study,
we know that the vast majority of infants born to HIV-infected women in
the U.S. and increasingly in other countries as well will be uninfected.
Their HIV status may not be confirmed for 2 to 4 or even 6 weeks.
Therefore, most of the HIV-exposed neonates available for research
studies will be uninfected. Because they are not infected, most of the
HIV-exposed neonates enrolled in drug studies are unlikely to derive
direct benefit from participation in these studies.

Is the risk/benefit assessment in this subpopulation of HIV-exposed
infants, those whose HIV infection status has not yet been determined,
different when the rate of transmission is less than 2 percent compared
to 20 percent or compared to 10 percent?

In the case of HIV drug development, the major concern expressed by our
sponsors involves the ethics of studying this population of uninfected
infants. Uninfected neonates enrolled in clinical studies would be
subjected to the risk of drug exposure and study procedures without the
potential to directly benefit from the knowledge obtained. We know in
many of our studies HIV drug PK assessment often requires multiple blood
samples. Many of our newer drugs are not amenable to single-dose PK and
require multiple days of dosing for accurate assessment and steady state
levels.

Also, many of our drugs have significant potential for toxicity,
including bone marrow suppression, hepatitis, hyperlipidemia,
mitochondrial toxicity, and hypersensitivity reactions. Some of these
events have been seen not only in adults and children who are receiving
the drugs in HIV treatment regimens but also in HIV-negative adults who
were receiving the drugs as part of post-exposure prophylaxis.

In 1999, the Ethics Working Group of the Pediatric Advisory Subcommittee
recommended that the FDA adopt the principles described in subpart D of
the Code of Federal Regulations, as Dr. Sever alluded to. This section
provides for additional protections for children involved as subjects in
research. At that time, the Pediatric Subcommittee strongly suggested
that children enrolled in clinical trials should have or be susceptible
to the disease under study.

In the case of HIV drug development, this concept has been interpreted
and discussed broadly. HIV-exposed infants were believed to be at
sufficient risk for a uniformly fatal disease to warrant their inclusion
in drug studies. This concept was discussed at length prior to the
initiation of study PACTG 076, the first study that proved the value of
prophylaxis for perinatal transmission. That study represented the first
example of a proposed protocol being discussed at an advisory committee,
and as you have heard from the previous speakers, it engendered a lot of
debate on both sides of the question.

At the time of that discussion, the rate of perinatal transmission in
the United States was between 20 and 25 percent. Clearly now if infants
are not likely to derive direct benefit, we must agree that the benefit
to the public health still outweighs the potential risk to an individual
neonate who does not require HIV treatment.

Last, the FDA works to encourage ethical conduct of studies through
protocol reviews and other communications with sponsors and convening
advisory committees like this one. But study sites are required to
report to an institutional review board, and that IRB is the final judge
of a study\'s acceptability to the local community. IRBs at different
institutions in different communities may not agree on what is ethical
and acceptable.

Finally, some concern has been raised by our sponsors regarding the
ability of parents to provide informed consent. We know that parents of
newborn infants are very protective regarding painful procedures. As in
the PACTG studies, they may initially enroll in a study but later
withdraw their infant before the study can be completed. We know that
parents of HIV-exposed infants may be very anxious over the unknown HIV
status of their infant until the diagnosis can be confirmed. Similarly,
parents may express feelings of guilt regarding the possibility of
infecting their child with a potentially fatal infection.

However, those of us who have worked with parents in this setting
acknowledge these issues but have learned never to underestimate the
ability of parents to assimilate information and make difficult
decisions.

In summary, the Division of Antiviral Drugs has tried to encourage the
study of neonates as part of antiretroviral drug development through the
incentive mechanism of the written request and pediatric exclusivity.
The sponsors who have completed studies or agreed to conduct studies
should be commended.

However, we believe that the issues raised by some of our sponsors
regarding the study of neonates are legitimate and are worthy of
bringing to public discussion because of the changes that have been
brought about by improved perinatal prophylaxis. We would like the
advisory committee to consider the risks and benefits of antiretroviral
drug studies in this age group, especially in uninfected neonates, and
whether we in the Division of Antiviral Drugs should amend our request
for sponsors to perform clinical trials in this youngest age group. We
recognize that this is an area of great interest to many individuals and
groups and we doubt that this is the last discussion we\'ll have on this
topic.

Thank you.

(Applause.)

DR. CHESNEY: Dr. Lewis, did you want to introduce us to the questions or
can we pick that up?

DR. LEWIS: I can either do that now or later.

DR. CHESNEY: Maybe we could do it later after we do the questions for
the presenters.

So the floor is open. Dr. Nelson.

DR. NELSON: A question for Dr. Mofenson. Thank you for your clear
presentation.

You emphasized efficacy. I\'m wondering if you could briefly comment on
safety, in particular two questions. Do you anticipate the safety
profile would follow drug class, and can you extrapolate safety from
preclinical or from older children and adult studies to this population?

DR. MOFENSON: That\'s about another half an hour talk. Let me first
address safety of neonatal prophylaxis as used in prophylaxis regimens
as opposed for treatment, and I can provide you an article recently
published in JAIDS. Is it in here? Okay, good.

I think that the data show for the prophylactic regimens we\'re
currently using, that toxicity is minimal and transient with probably
AZT having the most toxicity, bone marrow toxicity, with anemia being
more frequent in infants receiving AZT.

The issue of long-term toxicity is more difficult to address. Data from
our studies of long-term follow-up have followed children from 076
through maybe 10 years of age and not found any problems to date. But
the French have reported a mitochondrial toxicity syndrome associated
with lactic acidosis and some neurological disorders in a small number
of children. I estimate, based on reading their articles, that the
incidence of this would be about .5 to .7 percent, if I remember my
calculations correctly.

Following the presentation by the French of their 7 children who had
those disorders, 2 of whom died, we did an in-depth analysis of our
database of children in the U.S., including data from the CDC and all of
our clinical trials, over 16,000 uninfected infants followed since the
early years through 2000. We did not identify any deaths similar to the
deaths reported by the French.

There has been a study of uninfected babies within the PACT study, which
is a CDC natural history study, and they looked at their uninfected
infants for the prevalence of disorders that the French described and
did not find those. That\'s been published.

I know from the European collaborative study, not published, but through
verbal conversations, that they have also not seen this event.

So is it real? Is it not real? I think that it may be real. I think that
it is very rare and in my view doesn\'t outweigh the potential benefit
to the infant in terms of prevention of transmission.

Can you extrapolate? Well, I guess I was just trying to think whether
the mitochondrial toxicity with in utero exposure could be extrapolated.
We haven\'t seen any toxicity in newborns and children that haven\'t
also been reported in adults is what I would say to date.

DR. NELSON: And then the final thought is if resistance in future is one
of the issues that will have to be addressed, would you anticipate
seeing different toxicity profiles as you move from drug class to drug
class so that the data you\'ve got now may or may not be relevant to
that?

DR. MOFENSON: Well, we have data in neonates on all three of the major
drug classes, the NRTIs, the NNRTIs, and the protease inhibitors, not
all drugs in all classes, but we have data on all of those and haven\'t
seen anything unusual.

There are two new classes, the nucleotide tenofavir, which has not been
tested in newborns yet, and the T20 fusion inhibitors have not been
tested in newborns yet.

But we haven\'t seen anything surprising in terms of the three classes
that we use most frequently. Linda talked about the protease inhibitor
ones. Nevirapine had a phase I study prior to the HIVNET 012, and AZT
and 3TC and ddI and d4T have all been studied in neonates.

DR. CHESNEY: Dr. Mofenson, could you comment for us on the accuracy of
diagnosis in the first 24 hours, the current state of the art?

DR. MOFENSON: Yes. I think that you can diagnose at birth the kids who
are infected in utero. So it depends on the proportion of children
infected in utero. Probably that\'s around 20 percent, so that means 80
percent of infants will potentially be infected but not have a positive
culture at birth.

This may change as we see women receiving antiretroviral therapy for
prolonged periods during pregnancy. In 316, the most recent perinatal
trial, about 40 percent or so, I think, of the kids who were infected
were positive at birth. So you may see a change as you have more
effective intrapartum interventions put in, but I\'d say most people
would say 20 percent or so positive at birth.

DR. CHESNEY: Would there be any reason to think that if a mother had
received prepartum and intrapartum therapy, that the test may not turn
positive within the first 24 hours?

DR. MOFENSON: There have been studies with AZT and there doesn\'t appear
to be any problem with AZT monotherapy. With the other drugs and in
particular with combination drugs now we\'re talking about being given
to the newborn, I don\'t know. There haven\'t been that many studies of
diagnostic tests in newborns who have received more than just AZT. AZT
alone doesn\'t appear to affect.

Let me just comment. If you\'re using DNA PCR, one might not think that
you\'d see a delay, and that\'s because even adults who are undetectable
for many years, in terms of plasma RNA, still have positive DNA. And in
children who have received treatment starting at 3 months of age or more
and have been RNA negative and have seroreverted, they still are DNA PCR
positive. So if you\'re looking at the virus in the cell, you may still
be accurate.

DR. CHESNEY: Thank you.

Dr. Fink and then Dr. Danford.

DR. FINK: One comment and one question. The comment is, as the
presentations went on, I was confused. Although it\'s medically correct
the use of the term \"prophylaxis\" versus \"prevention\" of
transmission, particularly to IRBs and lay individuals, I think it would
be very helpful to talk about prevention of transmission because this
really to me doesn\'t seem to fit prophylaxis in terms of talking about
neonatal treatment.

But my question is, as we look at PK data and discuss studies in
neonates, what is going to be the effect of the issue that we have
mothers who have received vastly different amounts of prenatal
antiretroviral therapy and how will this allow you to interpret PK data
in neonates, some of whom may have been exposed to multiple drugs
prenatally and some of whom have been exposed to no antiretroviral drugs
prenatally?

DR. LEWIS: That\'s a very difficult issue for some drugs but not for
others. Not all of these drugs cross the placenta well. In the studies
that I outlined, the PACTG studies, what we found is that the protease
inhibitors really don\'t cross the placenta in identifiable amounts.
There may be some effect, but it is likely to be minimal.

Drugs like AZT and nevirapine and probably some of the other nucleoside
reverse transcriptase inhibitors do cross the placenta in varying
degrees, sometimes widely variable. But that was the purpose of looking
at cord blood levels in many of those infants as well as then doing
direct PK analysis on the infants.

DR. FINK: But isn\'t it possible or likely that even prenatal exposure
to AZT may alter postnatal metabolism of a protease inhibitor?

DR. LEWIS: No. Those drugs do not interact. So some of the protease
inhibitors interact with each other, and that\'s why if you\'re going to
look at mother-infant pairs, it makes the most sense to look at the same
drugs in the mother and the infant so you don\'t have too much conflict
or too much interaction. But again, most of these drugs, the newer
drugs, don\'t cross the placenta in substantial quantities.

DR. MOFENSON: Just a comment as to how we studied this with nevirapine,
which has a plasma cord blood ratio of about 1, was we first studied
nevirapine in the mother and did not give drug to the baby, looked at
the fade-out pharmacokinetics in the baby to determine when giving
another dose of nevirapine would be warranted. So that is how that was
done. And the half-life of nevirapine was prolonged. In the cord blood,
it was prolonged in the baby, and we didn\'t have to give a second dose
until 72 hours.

DR. CHESNEY: Dr. Danford.

DR. DANFORD: Before we have to face the question of whether it\'s
ethically permissible to enroll neonates who are not actively infected
to study the pharmacokinetics of these drugs, I think an important
question is, would the study of such groups be scientifically valid? Are
uninfected neonates known to be or thought to be the same in their
pharmacokinetic handling of these drugs as infected infants? And I\'d be
interested in comments about whether this is known by any data that we
already have or if there is scientific reason to believe these
populations are different.

DR. MOFENSON: The data we have from earlier studies, such as AZT and
nevirapine, showed no differences in metabolism between infected and
uninfected babies. So I don\'t anticipate that\'s an issue.

DR. LEWIS: Just as an addition, most of the neonates who are born to
HIV-infected mothers are born healthy, so they have no real identifiable
abnormalities of renal or liver function. Occasionally there is a sick
infant or a premature infant, and then all of the metabolic processes
that go along with extreme prematurity are in play and that\'s a
different group entirely. But in terms of most neonates, they\'re mostly
indistinguishable whether they\'re infected or non-infected.

DR. CHESNEY: Dr. Wilfond.

DR. WILFOND: Yes. I had two questions for Dr. Mofenson. The first was a
clarification. While people were making the distinction between
HIV-infected and not infected, my impression was the recommendations are
for the treatments for HIV-exposed patients. And my question for you is
whether before there ever would be a change in the clinical
recommendations for those HIV-exposed patients, would PK data ever be
sufficient or wouldn\'t you want data about efficacy before using a new
drug in those children?

DR. MOFENSON: You\'re correct that the U.S. Public Health Service
recommendations for neonatal treatment are for HIV-exposed infants
because you won\'t have their diagnosis.

Back in 1994, when we had the first Public Health Service meeting,
people without any data but with natural history epidemiologic data felt
that even though we didn\'t have efficacy data for
intrapartum/postpartum or postpartum only AZT ‑‑ we didn\'t know for
sure that that was effective ‑‑ that they felt that there was suggestive
enough evidence to go ahead and make those recommendations. So even in
1994, those recommendations were made and that was way before we had the
studies showing intrapartum/postpartum efficacy.

The second meeting of the group was 1998, and there was extensive
discussion in the recommendations for the intrapartum/postpartum when
the mom hasn\'t received antepartum therapy or when the mom hasn\'t
received antepartum/intrapartum therapy. So here you\'re dealing with
pre-exposure and post-exposure prophylaxis or only post-exposure
prophylaxis.

And we have to remember that the 2 percent transmission rate is only for
those mothers who are in antenatal care early, get HAART treatment,
perhaps elective cesarean delivery. 15 percent of HIV-infected women are
not seen until labor, and those women have a transmission rate even with
intrapartum/postpartum or only postpartum prophylaxis of over 10
percent. So it\'s a very different situation.

There was extensive discussion in the group about whether to recommend
anything other than AZT, and the clinicians and obstetricians and
pediatricians and experts that were part of that group felt the data
from nosocomial prophylaxis where they recommend two to three drugs for
prophylaxis was enough to put combination therapy of the baby into the
guidelines with the comment that we don\'t have a lot of data on
pharmacokinetics and safety of these drugs in the baby. We now have an
increased amount of information on that based on the studies that Linda
has talked about.

So I would say that having efficacy data for use of the drugs
postnatally on every drug that gets used postnatally probably will never
happen, and that if we have pharmacokinetic and safety data, that would
probably be enough.

I think maybe the pediatricians in the group who care for HIV can
comment as to whether they use combination antiretrovirals in neonates
in selected circumstances. It\'s my feeling that many HIV experts do do
that. I see nods over here.

DR. LEWIS: Just a regulatory comment. We in the Division of Antiviral
Drugs, because of primarily numbers and the feeling that there would
never be controlled clinical efficacy trials in young infants,
determined many years ago that we would accept the efficacy of a drug in
an adult population as proof of concept that there would be efficacy in
the pediatric population because the virus isn\'t any different.

DR. CHESNEY: Dr. Mofenson, I had one more burning question and then Dr.
Fletcher has a question.

I wonder if you would give us your take. Because you\'ve, I think,
participated in trials in other countries, given the diminishing
population in our country, what are your thoughts about doing these
studies? Say we were to advise continuing these studies in neonates.
What are the issues involved in doing these in other countries?

DR. MOFENSON: Well, the HIVNET 012 study had, as a prelude to it, a
phase I study of nevirapine in pregnant women and neonates in Uganda. We
did the study first in the U.S. That was PACTG 250, the study that I
talked about where you gave it to the mom first and then to the baby.
And then that study was repeated in Africa because the Ugandans wanted
data in their own population. The pharmacokinetics were basically the
same.

I think that there are reasons to want to do those phase I studies in
resource-limited settings because the children there may have
co-existing conditions that are not necessarily present in U.S.
children. There may be a higher incidence of anemia, for example. So
there may be more potential for toxicity in children in resource-limited
settings. Having said that, we have not seen that to date.

So I think that there are strong reasons for doing the studies there as
well because the issue in resource-limited settings, as I tried to
emphasize, is postnatal transmission. That\'s the issue, breastfeeding
transmission. How can we make breastfeeding transmission safer? And if
one way you\'re going to do that is by doing infant prophylaxis with
drugs for 6 months, you have to have the data on pharmacokinetics and
safety. So I personally feel it is essential to continue to gather that
data because that\'s going to be the only way that we\'re going to be
able to prevent postnatal transmission.

DR. CHESNEY: Thank you.

Dr. Fletcher.

DR. FLETCHER: My question is really for Dr. Lewis, and it really just
follows Lynne\'s last point. It\'s like one of these \"what if\"
questions. So if the FDA is going to contemplate changing the requests
to obtain neonatal data, what is the alternative given the scenario that
Lynne just identified that in this country there will certainly be
infants, newborns that receive these agents and in other countries there
will clearly be infants, newborns that receive these drugs? So if
relaxing the rule is on the table, is there some alternative
contemplated?

DR. LEWIS: Well, that\'s one of the reasons why we wanted you guys to
come.

But there are certainly other options. Organizations like the PACTG
would certainly be encouraged to continue doing studies that they felt
were of benefit globally.

The written request, as I said, is a voluntary mechanism. We can
continue to ask sponsors to provide those studies and they can choose
not to do it because they may say that the potential financial benefit
does not compensate them for the cost and difficulty of doing those
studies.

The written request has been our best incentive. We don\'t have much in
the way of requirements.

We could make some of these studies phase IV commitments. Again, those
are being tracked a little more closely now than they were in past
years, but there\'s very little enforcement for making sure that the
companies actually complete their phase IV commitment studies. So we
know that if we don\'t have the data for use in the U.S. population, we
clearly won\'t have it for use in the global population either. So it is
a very difficult process.

DR. DIANNE MURPHY: And I just want to point out one thing too from a
regulatory point of view. I\'m sure many of you are aware of this, but
for some of those who are not on the Pediatric Advisory Subcommittee,
the pediatric rule, as you know, has been enjoined. So that is a tool
which we no longer have in which we could require a company that came in
with a product ‑‑ that was, the disease occurred in adults. We could
require them to study it in children and we are now enjoined not to do
that. So that mechanism is not available to us.

DR. CHESNEY: Could I just clarify timing? I\'m aiming for us to go on
our break in about 10 minutes. Although I don\'t know if we have anybody
who wishes to speak at the open public hearing, we do have a number of
people well-known to all of you, who have written letters who were not
able to attend, and I wanted to be sure we had an opportunity to read
some of those into the record before we begin our discussion of the
questions at 10:50. So I just wanted to give you an idea of where we
were at.

I think Dr. Nelson and Dr. Gorman both have questions. Dr. Nelson.

DR. NELSON: Back to pharmacokinetics. At what age in the first, say, 6
months of life do you begin to see a shift in the metabolism? What I\'m
leading up to is if we have a problem doing PK data in someone who is
not infected, would it scientifically still be valid to wait until we
were able to demonstrate or prove infection before doing that PK study,
say, at 1 month of age or 3 weeks?

DR. MOFENSON: Probably Courtney should answer this. Let me give you my
feeling and then Courtney should answer this because he\'s the
pharmacologist in the PACTG.

I think it depends on the drug. A renally excreted drug is different
than a liver-metabolized drug.

I think that we don\'t have a lot of data sequentially on a drug from
birth going all the way up. Usually what we\'ve got is neonatal data and
then ‑‑ I don\'t know ‑‑ 2-month, 3-month data, and there\'s this big
blank period in between. For some drugs, there\'s a big difference
between neonatal data and 3 months. So I think you need that data in
between.

But, Courtney, you\'re the expert.

DR. FLETCHER: I\'d probably like to see if I can\'t pass it to Dr.
Spielberg.

(Laughter.)

DR. FLETCHER: But I think Lynne is right. It really is drug-dependent.
There are changes that happen certainly over the first 3, if not into
the first 6 months. I think AZT again has been one of the better studied
drugs with PK within the first week that was showing half-lives of 14
hours. Within 2 weeks, it was down to about half of that. By 3 months,
it really began to approach adult half-lives which are in the 1 to 1.5
range. They may have still been about 3.

The non-nucleoside drugs and the protease inhibitors have really been
less intensively studied. I think as a general rule, the half-lives in
the neonates are longer and then approach adulthood in some varying time
after that.

DR. MOFENSON: One comment is that for a drug like nelfinavir, for
example, the original neonatal doses were based on extrapolating from
children under 12 months but that were older, and it was wrong. Way
wrong. I mean, we had to really double the dose on a milligram per
kilogram basis to get adequate levels in neonates.

DR. SPIELBERG: I think the bottom line of what\'s been said is it
depends and that\'s why you need data. That\'s the bottom line to the
whole thing. There are drugs where a babe at a week is a very different
biologic organism than a babe at 1 day of age. There are drugs where it
really doesn\'t matter very much, and it depends on the mechanism of
clearance and it depends on the nature of the compound.

Given that we\'re going to be seeing new compounds with varying
different structures and varying different pathways of clearance,
varying different metabolism by different cytochromes and other
pathways, the bottom line is, if you\'re going to do it rationally and
if you\'re going to provide adequate coverage of the organism and safety
for the patient, you\'ve got to have the data.

DR. CHESNEY: Thank you.

Dr. Gorman has been waiting patiently over here.

DR. GORMAN: I\'m not sure who the question is for, but how comfortable
are we with the non-treated transmission rates in terms of placebo
treatments? Are those 20 to 25 percent numbers stable over long periods
of time, or are those numbers that we generated over a brief of time and
now have little confidence in?

DR. MOFENSON: Do you mean the comment that the transmission rates in the
U.S. are 25 percent? You think maybe they might be different?

DR. GORMAN: I\'m asking how comfortable you are.

DR. MOFENSON: Well, I think that even back in the early \'90s we saw
differences between the U.S. and Europe, 25 percent here pretty
consistently, 15 percent or so in Europe. This may have been due to
differences in elective cesarean delivery between the countries.

What I\'m not comfortable with is extrapolating from one country to
another. If you took what happened in the United Kingdom, it was not the
same as the U.S. which is not the same as Africa. Ideally you would have
placebo controls for all of the trials. That\'s ethically not possible
anymore.

DR. GORMAN: You\'ve anticipated my second question which was, if all
mothers who were HIV-positive had elective cesarean sections, what
impact would you postulate on the transmission rate?

DR. MOFENSON: Based on the studies without antiretroviral prophylaxis,
it\'s 10 to 12 percent.

DR. GORMAN: And the third question that I have is, is the interruption
of transmission from mother to child independent or dependent upon the
continued treatment of the mother after delivery?

DR. MOFENSON: In the U.S. with our regimens, no, because the mothers
don\'t breastfeed. The place where treatment of the mother postpartum
may be important is in breastfeeding.

DR. GORMAN: Well, then I\'ll make my question more specific. With
breastfeeding mothers, is the transmission rate independent or dependent
upon continued treatment of the mother?

DR. MOFENSON: We don\'t know. That\'s why the trials I showed you are
being done. I don\'t know.

DR. GORMAN: Those trials looked like they were addressing, at least in
this arena, only the treatment of the infant. Is that an assumption on
my part that\'s incorrect?

DR. MOFENSON: Yes. I showed two slides. One was the slides of the schema
for infant prophylaxis, and the last schema slide was maternal HAART
treatment.

DR. CHESNEY: Dr. Gorman, do you have fourth and fifth questions?

(Laughter.)

DR. GORMAN: Thank you very much, but no.

DR. CHESNEY: I think we\'ll take one more question and try to get back
on track. Dr. Spielberg, I think you had your hand up first.

DR. SPIELBERG: Just a couple of comments. I think in the ideal world,
those of us who worked hard on the Best Pharmaceuticals for Children Act
went at it conceptually from the point of view that the incentives would
really be a driver to do important public health studies. I\'m
encouraged that in fact the act has driven the development of many
compounds so far in the HIV arena because, in fact, most of these drugs
are not blockbusters. In fact, the issues of finances here do become
tight. And I\'m encouraged that the mechanism has worked.

I think what we\'re struggling with here is that the public health
issues really do vary internationally and U.S.-wise. I would posit that
all of us have a major vested interest in public health issues
internationally because it\'s going to come back as an international
issue to bite us if we do not, indeed, take into consideration the needs
of kids internationally. And that\'s why the ICH effort and the efforts
to move ICH out of, if you will, the first world into the rest of the
world. We are all part of the same world.

It strikes me from what Dr. Mofenson has said that the numbers of
patients internationally are still staggering. They will remain
staggering because of some of the issues we\'re dealing with with
breastfeeding and transmission by other mechanisms, which makes it
incumbent on all of us to understand how some of these drugs in fact are
handled pharmacokinetically and safety-wise in the neonate.

And that\'s also in the U.S. public health interest because of the issue
of emergence of resistant organisms. We are going to face this in our
own situation here, and we have to figure out a way of doing the studies
to get the information.

I\'m encouraged by the safety that\'s been discussed here. We\'re not
dealing with URIs or ear infections. We\'re dealing with a fatal
disease. As such, the incidence and prevalence of the kinds of side
effects that have been described, although very real and we have to take
them into consideration in the newborn, appear to be reasonable, given
the risks.

And I would also posit that the risks, when you\'re talking about 25 and
40 percent remaining risks for babies and large numbers in the rest of
the world, that the risk/benefit of doing those studies in a
distributive justice sense in those populations, if the drugs are made
available to those populations subsequently ‑‑ and that\'s one of the
criteria, but if that\'s the case, then the risk/benefit in those
populations becomes very different than the risk/benefit of waiting to
get diagnosis in the kids here. If you already have a 40 percent risk of
having a fatal disease, we\'re back to where we started with 076.

DR. CHESNEY: Thank you, Dr. Spielberg.

I think we could take a 15-minute break and we\'ll reconvene at 10:38.

(Recess.)

DR. CHESNEY: I think we\'re ready to start the open public hearing, if
everybody could find their seats please. I\'d like to start the open
public hearing by reading into the record four letters that were
e-mailed to the FDA based on today\'s discussion. We\'ll finish up with
Dr. Jim Oleske who was able to come to the meeting.

The first letter is from Margie Rogillio, and she writes:

\"Hi, I am a foster and adoptive mom and have so far lost six babies to
this virus. And I currently have a foster child in end stage renal
disease, and on dialysis at home daily, from HIV nephropathy. I am also
a member of the Pediatric Community Constituency Group of the PACTG and
a member of the CAB at my local site.

\"It is so important to continue to develop medications that are
effective and safe for our babies. Yes, the rates are down due to 076,
but the truth is many women do not get prenatal care and are still
having babies born with or exposed to HIV. It is very disheartening now
with the focus on adolescents and international ‑‑ not that these are
not important ‑‑ money that was being used to help American infants is
now being re-routed to these populations and there is no increase in
funding. So we are losing money to fund studies for our kids.

\"I think in some cases information extrapolated from the United States
studies could be used internationally, but I am concerned about the
reverse. We live in a very different way from the rest of the world.

\"I know these babies are being born here because they come into my
home. I would like to plead that we keep our children, our babies, in
focus.

\"Thanks.\"

The second letter is from Dr. Philip Walson, a professor of pediatrics
at the University of Cincinnati who is Director of the Clinical
Pharmacology Division and Clinical Trials Office. He says:

\"This brief note is in response to the announcement of the upcoming FDA
advisory committee meeting to discuss studies of anti-HIV drugs in
infants. Unfortunately, I cannot attend the meeting, but I wanted to
provide some comments.

\"Clearly studies are needed and could be done in HIV-infected infants
both in the United States and abroad. However, children whose mothers
were given HIV drugs could provide subjects for useful PK/dosing
information with little or no risk. Important dosing information could
be obtained by merely doing population PK studies on children who were
exposed only while in utero and even if not given additional medication
after delivery.

\"Such children will have blood drawn for HIV infection status and for
other routine lab testing. If collected and analyzed correctly, these
samples would provide much of the PK/dosing data necessary to dose
infants who need postnatal treatment. Such studies would be ethically,
financially, and practically fairly easy to do. Studies in children are
clearly preferable to the only alternative, that is, the continued
unregulated and uninformed use of anti-HIV drugs in such children.\"

The next letter is from Dorothy Shaw.

\"To Whom it May Concern:

\"As a parent of an HIV-infected child, I believe studies on new HIV
meds for use in neonates should be limited to those that have proven
safe and effective and useful in older children and older babies. I do
not believe every drug needs to be studied in newborns since there are
effective drugs currently available. As we discover meds that do not
have side effects of the current meds, or have improved results, we must
first find them to be safe and effective in older babies and children,
then they should\" ‑‑ in bold ‑‑ \"be tested in neonates. Since we do
not have adequate numbers of neonates in the U.S., studies can be done
with newborns throughout the world, where the numbers of HIV-infected
newborns is not diminished. Studies must be carried out with the same
ethical considerations, et cetera, as they would have been designed for
U.S. newborns. The results of such studies would translate for use in
newborns in the United States as well as throughout the world.

\"Thank you for the opportunity to put in my two cents.\"

And the last is from Robert Reinhard. \"I am not able to attend the
March 3 meeting to discuss the announced issues. However, please
consider these e-mailed comments on one of the three questions announced
in your notice.\" And the question is, \"If studies are conducted in
resource-poor countries, where perinatal transmission rates are still
unacceptably high, can the results be extrapolated to the U.S.
population?\"

And his comment. \"Although the announcement was intended to be brief,
it did lay out many factors affecting this drug development initiative,
including the use of current guidelines for study and considerations of
minimal risk towards populations. Specifically, the announcement
mentions \'current guidelines endorsed by the American Academy of
Pediatrics, NIH and FDA, stating that infants who are unlikely to
directly benefit from research should not be exposed to greater than
minimal risk, and suggest that exposure of uninfected infants to
antiretroviral drugs constitutes a greater than minimal risk.\'

\"On the other hand, the announcement appears to be silent on ethical
issues involved in exposing and testing drugs in populations in
resource-poor countries who might directly benefit from such research
but only for the announced purposes of extrapolating results to U.S.
populations. Such a plan could only be pursued if, first and foremost,
the benefits were secured and committed to the populations where the
testing took place. Any plan to initiate such tests in resource-poor
countries would have to recognize and resolve in advance the formidable
problems associated with paying for and distributing the benefits of the
research to the local populations broadly and successfully. Otherwise
such testing would be exploitative. During your discussions and further
announcements on this initiative, please make sure to include public
awareness of the ethical issues involved in conducting clinical trials
in resource-poor countries.

\"Thank you.\"

Dr. Oleske. I think we all know who you are, but maybe you could give
just a few sentences of introduction.

DR. OLESKE: I\'m Jim Oleske. I\'m a pediatrician from Newark, New
Jersey. I guess I came to this because I\'m the Chair with Gwen Scott of
the Pediatric Antiretroviral Treatment Guidelines and an active
participant in clinical trials for a number of years.

Interestingly, I just got back from South Africa where we spent a week
and a day implementing the MCCT Plus program which is, in fact, trying
to get treatment early to both infected women and their family members.

I have some very strong feelings on the need to provide appropriate
dosing and experience with drugs that have not been studied in children.
I think that we need to, as Lynne very eloquently pointed out, have the
responsibility and the obligation to provide reasonable studies on such
drugs as they become available in adult populations.

As I told people in the very beginning, infants and children die of this
disease much quicker than adults, and access to newer drugs are
critical. Now, we\'re talking more about in the first 4 weeks of life,
and I\'d like to address that.

In the outline it says that 300 or so children are born infected. But
there\'s not 300 children born infected. There are 6,000 children who
are exposed to antiretroviral drugs possibly, but certainly exposed to
the virus every year in the United States. From that 6,000, maybe 300
children become truly infected. But in the first 4 weeks of life, we
don\'t know which one is which. And I don\'t think even with our best
technologies we\'ll really be able to say someone is absolutely negative
or absolutely positive in that critical period of time when in fact
treatment started and initiated early may prevent lifelong infection
with a uniformly fatal disease. I don\'t know of anybody who lives
through AIDS. I\'m always proud to tell people that I have older
children. In fact, my happiest moment last week was when one of my
patients, who was perinatally infected, said she got accepted to medical
school. But the bottom line is that\'s the exception and certainly not
the rule.

So I would just like to say that we need to do PK data in the first 4
weeks of life on HIV-exposed infants. But in general ‑‑ and I will admit
this ‑‑ most of the studies are not going to be begun until infants are
4 to 6 weeks after a presumptive diagnosis of infection can then be
made. We need to study, though, that pool of 6,000 exposed and we need
to effectively treat the 300 that remain infected with HIV.

In the United States we do have the advantage of not breastfeeding. That
is not available to the rest of the world.

We could all come up with randomized clinical trials, and in my written
statement, I included that and what we could do to study this problem.
But it starts with having, in selected, small numbers of infants in the
first 4 weeks of life, appropriate PK data and safety data on new drugs
for antiretroviral use. As resistance develops, we could have other
waves of children not sensitive to the drugs that we now feel
comfortable in using. So I would make the plea that we need this kind of
safety data.

I also feel that the U.S. cohort of exposed infants is certainly not
like the exposed cohorts I have seen in the developing world. I think
that it\'s certainly ethical and appropriate to do studies in those
children. I don\'t think that data translates directly back to the
United States.

I agree with the last-read statement about the vital importance of doing
ethical clinical trials whether it\'s in the United States or whether
we\'re partnering it in the developing world. We have that obligation to
be ethical no matter where we do our studies.

However, I don\'t think the studies done in the developing world will be
easily transferrable to the U.S., and therefore, I think we are left
with the challenge of how do we identify, talk with women so that they
are giving their permission in a knowing way, not at the time of labor,
to study these drugs. I think if we do a good job, reach out to these
women, present them the risks and benefits of studying new drugs, I
think they would be included in clinical trials and we could develop
enough information to have access in the future to these newer
antiretroviral drugs being developed.

Thank you very much.

DR. CHESNEY: Thank you.

I think we\'ll move on to the questions. Dr. Lewis, did you want to
present them to us at this point? You could read them, or I don\'t know
if you have them as an overhead. We all have a copy.

DR. LEWIS: These will just make them a little prettier.

What I\'d like to say is the original questions that went out in the
committee\'s backgrounder, as we read over them many, many times, we
came to some subtle changes in the wording that we thought really got to
the crux of the issues we were trying to bring up a little bit better
than the way we had originally worded them and sent them out to you. The
concepts are very similar, but we put them in a little bit different
order.

What I\'ll do is I\'ll just go through all of these questions and then
I\'m going to sit down and let you guys hash out what you think the best
answers are for some of these. We understand that we may not come to
definitive answers today, but the discussion itself may help us a lot in
determining where to go next.

So we started with really the biggest question. Given that an estimated
300 to 400 HIV-infected infants are born annually in the U.S., that some
of these infants are diagnosed after the first months of life, and that
it is difficult to enroll neonates in studies in general, are there too
few HIV-infected infants born each year in the U.S. or is there now not
enough public health benefit to justify requesting studies in neonates?

The second question. Since neonates born to HIV-infected mothers may be
tested for HIV infection in the first 48 hours and again at 4 weeks,
HIV-infected infants can be diagnosed within the first month of life.
Should only HIV-infected neonates be studied?

If an HIV-exposed population is to be studied, please discuss the
risk/benefit assessment for HIV-exposed neonates who might be enrolled
in a clinical trial. We mean the infants whose status is not yet
determined with the rates of transmission that are variable in the U.S.
and other countries, whether mothers have had prenatal care or not.

The second part of that question. If studies are to be conducted in
resource-poor countries where the rate of underlying diseases,
malnutrition, infant mortality, and pharmacogenetics may differ
substantially from the U.S., can we extrapolate these results from these
studies to the U.S. population?

And our last question. Should we continue to request pharmacokinetic and
safety studies for every antiretroviral drug under development, which is
our current policy? If not, what criteria would you suggest for deciding
which drugs should be studied in the neonate? New classes of drugs,
different resistance profiles, specific safety issues, or
pharmacokinetic parameters?

DR. CHESNEY: Thank you.

So our first question is are there too few HIV-infected infants born
each year in the United States or too little public health benefit to
justify requesting studies in neonates. And the floor is open for
discussion. Dr. Fost.

DR. FOST: Well, I\'ll start off. First of all, it\'s not really the
province of this committee, but it is an odd allocation of limited
health care resources to be pouring so much into a problem that affects
300 children. Every one of them has a name and a face and Jim Oleske
knows them better than I, but for every one of those, there are 3,000
abused children, more of whom will die than these 300 and many of whom
will be permanently disabled and so on. And the amount of Federal
resources we\'re putting into research and prevention on that is trivial
in comparison. That\'s not the FDA\'s responsibility, but it\'s one
reason to be studying this problem, that is the neonatal problem, in the
place where it is truly an epidemic where every hour there are 300
children, almost, born with this problem.

But it seems to me there are other compelling reasons for studying this
abroad rather than here, and the points have already been made, but just
to reiterate them.

The risk/benefit ratio for a child in the third world who has this
problem is just much greater. That is, whatever the toxicity of the
drugs are, they\'re nothing compared to the risk of getting nothing, and
that is, the potential benefits of getting postnatal treatment are just
so much higher. And we haven\'t heard that the toxicity is likely to be
profound enough in frequency or severity to outweigh that potential
benefit.

The ethical issues would be the same as here, that is, a satisfactory
risk/benefit ratio to that child. That\'s at the center of doing
ethically responsible drug studies, and it would be much more favorable
for those children.

Obviously, the high standards of consent and IRB review and so on should
be followed.

Now, whether or not they\'re extrapolatable to the U.S. I\'ll leave to
the scientists to comment on. Presumably not or for many reasons might
not be. But that to me is not a reason not to do them for their own
sake.

So it seems to me there\'s lots to be said from a justice standpoint,
but also from an ethical standpoint to be doing these studies where
they\'re needed and where the benefit will be the greatest.

DR. CHESNEY: Dr. Englund.

DR. ENGLUND: Well, I would just like to comment a little on the
risk/benefit ratio. By saying that there\'s an estimated 300 to 400
HIV-infected children born a year really doesn\'t take into account who
these children are being born to. These children are being born to our
women who don\'t have treatment, who never show up to clinic. They\'re
now being born to our teenagers who themselves were perinatally infected
‑‑ many of them or some of them. So we\'re seeing second generation HIV.
I think we have a differential risk ratio depending on who the mother
is, and I think we need to take that risk ratio into account when we\'re
talking about risk/benefit.

I also would like to say that I think we can do some extrapolating from
some of the foreign studies also, but as a former investigator in ACTG,
we have been wrong too many times about the doses to not have to look
closer at the doses. But I do think there are subpopulations within the
United States that we can try to use but they\'re very difficult to
capture.

DR. CHESNEY: Dr. Nelson.

DR. NELSON: I think we need to start off by being clear about a
distinction between HIV-infected infants and HIV-exposed infants, and I
think we\'re bouncing back and forth in the conversation between those
two groups. My understanding here is the purpose is to talk about
HIV-exposed infants.

If you think about that at-risk population, if you take the data of 2
percent prevention versus what I heard was 10 percent where women would
be untreated coming into labor and delivery ‑‑ I don\'t see our
statistician around the table. But I took out my chi-square program and
spent the time to try and calculate sample sizes. If you even provide
for a generous, say, 4 percent difference ‑‑ in other words, if you
accept a 2 percent increase if you\'re trying to look in the efficacy
arena ‑‑ you need 1,200 infants to answer that question. And if you then
go abroad because there are more of them, to go from 10 to 12 percent,
you need 4,000. So the sample size for any efficacy study when you\'re
down in the 2 to 10 percent range is considerable regardless of
location. But there may, in fact, be enough abroad.

When you then get into the PK data, since that gets down to question 3,
I\'ll wait to comment on what I think are PK and safety data, but as
part of this conversation, I think there\'s some confusion about
infected versus exposed. And if we\'re talking about treating
HIV-infected infants and studying them, then the issue gets back to the
diagnostic criteria and the ease with which we can make that diagnosis
and we shouldn\'t think that we\'re treating HIV-infected infants by
treating the other 98 at the same time.

DR. CHESNEY: Can I just make a comment? We keep hearing about the 300 to
400 who are infected, but I think we\'ve also heard that you can\'t make
the diagnosis, particularly for those infected intrapartum. You can\'t
know that they\'re infected in the first 28 days of life. Is that a
correct statement? Dr. Mofenson.

DR. MOFENSON: It depends on what test you\'re using. I\'m trying to
remember. There was a meta-analysis of DNA PCR, and 20 percent positive
at birth and then you end up in the 90 percentage by 3 to 4 weeks. So
you can diagnose most infected children or at least early diagnosis.
Ellen?

DR. CHADWICK: And by 2 weeks, you can diagnose well upwards of 70
percent. So if you time your testing appropriately, you can make that
diagnosis. It\'s just a question of how frequently you can get the baby
in for repeat blood draws, et cetera.

DR. CHESNEY: Dr. Wilfond.

DR. WILFOND: Even though some people can be identified earlier, as I
understand it from hearing the conversation, the clinical question is
what do you do for people who are HIV-exposed. The impression I got was
that those individuals are continued on therapy for at least 6 weeks
before stopping. So regardless of whether somebody is identified with
HIV, the clinical question still remains.

The question that I would like to ask ‑‑ it\'s probably more a
clarification than a comment. I have the impression that the types of
studies that are being described are essentially add-on studies. In
other words, somebody is receiving AZT or some other intervention and
then an additional drug would be used for a PK study.

But I also heard from Dr. Lewis that in general most people are quite
comfortable stipulating efficacy of drugs based upon other information.
If that\'s the case, it would seem that treating an HIV-exposed
individual with a new drug instead of the standard drug would provide
efficacy, since that\'s being stipulated, and then you could still do
your PK studies on that population. It seems like that would be a very
reasonable way to proceed.

DR. LEWIS: To answer that clarification, there is actually a difference
between treatment studies and prophylaxis or prevention of transmission
studies. As we\'ve heard, trying to get the numbers available for a
study that will prove that a drug prevents perinatal transmission are
quite large. Those studies are not part of our requirement. Because they
are so large and they are very difficult to conduct, we have not used
those as part of these written request mechanisms because clearly not
all drug products can be studied in populations of infants that are that
large.

The treatment studies ‑‑ so an infant is identified as HIV-infected
somewhere 2, 3, 6 weeks of age. Then those infants go on a standard
treatment regimen, and for those drugs generally we accept efficacy data
from adults as correlating with antiviral efficacy data in children.

So efficacy studies are proven differently from perinatal transmission
studies. What we really expect the companies to perform as part of their
written request is a PK and safety profile on some subset of the
population in that age group.

DR. CHESNEY: Dr. Fink.

DR. FINK: It raises a dilemma that I\'m beginning to feel, which is in
the United States, if we\'re talking about prevention of transmission,
then in that group of patients, safety becomes a key issue, particularly
as Dr. Sever raised the issues of growth development and mental outcome.
It is terribly hard to follow those infants for 5 years in the United
States with all of the resources we have available. I would think it
would be nearly impossible to get long-term safety data from foreign
studies.

DR. LEWIS: That is correct. And what we have tried to do is get safety
data over a period of at least 6 to 12 months in the population being
studied. But remember, in these populations, the length of treatment is
generally fairly short, anywhere from a few doses, a couple of weeks; in
the longer ones, maybe up to 4 to 6 weeks.

DR. FINK: But in the U.S., it would seem the key issue is potentially
the HIV-exposed infants. We want to minimize their exposure to toxic
drugs, and we\'re not going to know that long-term toxicity from foreign
studies. Those studies I would think would have to be done in the U.S.

DR. LEWIS: That\'s correct.

DR. CHESNEY: I think Dr. Chadwick, then Dr. Gorman, and then Dr. Nelson.

DR. CHADWICK: Just sort of a real world look at what we\'re seeing in
the clinics. I\'m in a university setting where we have a close
relationship with our OB group, and I\'m in a freestanding children\'s
hospital. I think a lot of the HIV centers around the country are
similar to this.

In those settings, the OB groups that are on top of the women that are
providing the prenatal care are, by and large, not delivering infected
women. It\'s the women that come in off the street, the patients that
Dr. Mofenson was mentioning, up to 15 percent of women who are not
getting prenatal care that are either walking into the university
settings or, more worrisomely, in the community that we have to try to
find those patients and then among those babies born to the women that
are most likely to be delivering infected infants, studying those
infants, doing the PK, making sure that we have drugs available that we
know the appropriate dose to treat the babies for the time down the road
when the current perinatal prophylaxis drugs will no longer be effective
because there\'s widespread resistance. So I think the treatment at hand
at this point is to make early identification of the infected babies,
study those babies, and then have that data available for prevention
studies in the future.

DR. CHESNEY: Dr. Gorman.

DR. GORMAN: In discussing these questions, are we discussing
interruption of transmission or prophylaxis, or are we just discussing
the need for pharmacokinetic and safety data on a certain number of
neonates?

DR. LEWIS: We\'re really interested in primarily the pharmacokinetic and
safety data on a more limited number of infants.

DR. GORMAN: And is the number that you\'re requiring the number that is
listed on page 3 of the proposed things? So we\'re talking about 8
neonates?

DR. LEWIS: Yes. We asked our pharmacologists what the minimum number was
that they felt they could derive an adequate PK profile in a drug that
didn\'t have extensive variability, and that was their answer, that if
they could get 8 babies.

DR. GORMAN: And do you want a potentially larger number for the safety
studies?

DR. LEWIS: Yes. This is all dependent on the specifics of the drug being
tested. If there\'s a large amount of variability in pharmacokinetics
that we know in adults or older children, we would pretty much
anticipate that that might be true in very young infants also, maybe
even more so. So we would need more PK data. If we had particular safety
concerns based on the adult or pediatric data, we would want a larger
number of infants to be tested.

But again, these are relatively short-term studies. So the real safety
data that you see with long-term administration of treatment regimens
you may not find. You are certainly unlikely to find it within the
neonatal period because by the time the kids get that much treatment,
they\'re no longer neonates. So it\'s a little bit different safety
assessment.

DR. CHESNEY: Dr. Nelson and then Dr. Glode.

DR. NELSON: Some of these questions I think overlap, but let me make my
comment and it may also come back up in talking about pharmacokinetic
and safety.

But if you are looking specifically at the issue of HIV-exposed infants,
one of the problems that you then have to address is what sufficient
safety data do you need before you\'re willing then to expose those
infants, which is a very different risk/benefit calculus than if
they\'re proven HIV-infected and then you get the 20 percent versus 70
percent over the first 3-4 weeks.

The other problem you get into is asking what condition are you
treating. Even if you limit yourself to pharmacokinetic data, if you\'re
not limiting yourself to pharmacokinetic data in the infected
population, I would assume that you would have to have some reasonable
perspective of expecting to use that drug in prevention of transmission
to justify doing the pharmacokinetics in that population. So then you\'d
have to make an argument about resistance and whether that\'s coming up
or about ease of use, which is partly why the nevirapine and other
studies have been used.

So there would have to be a justification for that drug. It wouldn\'t
just be a justification to have PK data in that population in order to
be able to then use it in a treatment setting if in fact you\'re
studying uninfected infants. I think that made sense.

DR. CHESNEY: Just incredible sense.

Dr. Glode.

DR. GLODE: I was not part of the ethical discussions around 076, but at
that point obviously there were exposed infants and 80 percent of those
infants were not going to be infected, but 20 percent were. And there
the risk/benefit seemed on the whole I guess to favor that study.

So I just wondered if people who were part of that discussion at that
time sort of said, well, if it was 95/5, then we wouldn\'t do it because
now, if you have 6,000 to 7,000 exposed infants and you estimate, taking
all those different groups you talked about, the people who do have
prenatal care and the people who don\'t, unless you subdivide that
group, it\'s overall 5 percent. So if 95 percent of the babies are not
going to be infected but 5 percent are, then again one has to look at
the potential safety issue and ask if that\'s ethically appropriate.

Did those discussions go on of 80/20 versus 90/10? If it was 90/10, we
wouldn\'t do it, but if it\'s 80/20, we would. I don\'t know how one
decides what the breakpoint is. I guess it depends on the presumed
toxicities.

DR. CHESNEY: Dr. Lewis.

DR. LEWIS: Well, I remember some of those discussions because I worked
across the street. I think Lynne was probably involved in some of those
discussions also. I don\'t remember there being a discussion of varying
things, but there was discussion that the rates in different countries
were different. So the French studies seemed to have a somewhat lower
transmission rate than the U.S. seroprevalence data, and it was felt
that the 076 study might provide benefit in both of those scenarios.

So, Lynne, do you remember any other specifics along that line? It was a
long time ago.

(Laughter.)

DR. MOFENSON: Yes. I guess a comment would be, what about other
conditions that are low in frequency and perinatally transmitted,
Chagas\' disease, trypanosomes, CMV, HSV? If we say that 2 percent or 10
percent is too low to test drugs for prevention of HIV, what does it
mean for prevention of these other diseases that also have low
frequency? What it basically means is that you can\'t prevent
transmission of multiple infectious agents, not just HIV, if you decide
that there\'s a percentage below which you\'re not going to test.

DR. CHESNEY: Dr. Hudak and then Dr. Nelson.

DR. HUDAK: I agree. I\'ve been listening to the discussion about this
possible breakpoint in terms of the risk/benefit analysis, and I think
possibly back in the 1980s when there was so little information known
about the possible toxicities of these agents in newborns and infants,
that certainly factored into the equation. We have a lot more
information now and are a lot more reassured about, at least in the
classes of drugs that have been studied, minimal toxicity in neonates,
in children.

From my perspective I think that this is a potentially fatal disease and
the difference between a 2 percent versus a 20 percent is the same. I
can\'t personally calculate a different risk/benefit ratio on what we
know based on 2 percent or 20 percent. So whether it\'s a 90/10 or 2/98
or a .1/99.9, I\'m not sure that you can set a set point there on that.
Certainly 2 percent is a significant rate.

The other thing that I would like to echo is Dr. Spielberg\'s comment
that this is in fact really a global problem. In this country, as Dr.
Fost said, it\'s really fairly minimal number-wise compared to a lot of
different pressing issues we have with child health and neonatal health.

On the other hand, I do think it is important and ethical to get the
best information we can get in this country for the dosing among the
HIV-exposed babies because that\'s going to be the basis for doing
larger studies in third world countries. I think it\'s easier to do
here, and we have to make sure that the studies we do in other areas are
the best studies we can do.

And we haven\'t even touched on the larger issue in terms of perinatal
transmission in several countries where the breastfeeding makes it such
a difficult problem and that clearly there would be a need for a lot
more different classes of drugs, potentially a lot more drug dosing if
breastfeeding continues and can\'t be abated completely like in this
country.

DR. CHESNEY: Thank you. I think we\'re getting close to maybe being able
to vote on this one, but I have Dr. Murphy, Dr. Nelson, and I think Dr.
Chadwick had her hand up.

DR. DIANNE MURPHY: I was saying if one could go back and look at the
transcripts of those advisory committee meetings, I do want to reiterate
what others have said here is that the safety was really an issue of the
long-term safety. I do think we have to then come right back to where we
started from which is here you have successful treatments and if you\'re
going to do studies for PK in that risk/benefit ratio, you still have
molecules that may be less known that you\'re going to be putting into
this population. The question is, should we be putting it into the
uninfected versus only those patients in which we do have a diagnosis?

Thank you.

DR. CHESNEY: Dr. Nelson.

DR. NELSON: Actually my comment I think reinforces Dianne\'s last
comment. I don\'t think the issue is the 2 percent versus 10 percent
versus 20 percent. Now that you have a track record with AZT, with
nevirapine, or whatever ‑‑ and I\'m not sure what PACTG 247 or 316 is
necessarily ‑‑ what regimen, but whatever regimen is getting you below 2
percent, you\'ve got a track record with that. The risk that needs to be
considered is the new drug against that track record, not the 2 percent
versus the 15 percent. If there\'s really no immediate justification for
adding a new drug into the prevention of transmission portfolio, then
that\'s the question in my mind. What evidence do you need to where you
think it\'s justified to enter a new drug into the prevention of
transmission portfolio, not entering a new drug into the treatment
portfolio, and what safety would have to be established before you\'d be
willing to do that against the track record of existing agents?

DR. CHESNEY: Dr. Chadwick.

DR. CHADWICK: But I think that comes back to the basic issue which is I
think we have to be very clear about who we\'re testing the drugs in and
that we have to start in the infected babies so that we have doses
available, we know that they\'re safe in the infected babies. Clearly
those are infants that have a need. We will not be able to do an
efficacy study or, I would submit, even a safety study in this country
looking specifically at prevention. So we just have to know how to use
these drugs to treat. There\'s no reason to believe that we\'re going to
use them very differently if we come to the point that we will need to
use them for prevention. So we start out looking at the infected babies
for the new drugs and not try to address prevention issues until we have
the data in babies that truly need the drugs.

DR. CHESNEY: I think Dr. Walson\'s comment about being able to study it
if it\'s given to the mother in the first couple of days after birth was
also an intriguing one.

Dr. Wood?

DR. WOOD: Just several comments regarding the assessment of risk/benefit
because we are dealing with, as Dr. Nelson has highlighted, two distinct
populations, those infants who are HIV-exposed and then those infants
who are ultimately determined to be HIV-infected. So our assessment I
believe is not dependent upon the background transmission rates, but
truly the first component of the risk/benefit assessment is whether or
not they\'re exposed. So by definition, all infants who are HIV-exposed
have the potential to have direct benefit because they\'re exposed to a
life-threatening illness.

The second component of the risk/benefit is dependent upon whether or
not they are truly HIV-infected, and that is dependent upon when you can
actually determine their HIV infection status. I actually think that
based on the data that Lynne has so elegantly summarized, we clearly
know that prepartum, intrapartum, there is clearly evidence that
antiretroviral exposure results in a reduction of transmission. And
given that that exposure exists and that the infant\'s status is
unknown, that\'s an acceptable risk/benefit ratio. Once you get to the
point where an infant is born and you don\'t know their infection
status, once that\'s determined, that would then alter the risk/benefit
ratio because if you knew that an infant was truly uninfected, you want
to minimize their risks by being exposed to antiretroviral drugs.

And I think that\'s just an issue that is a gradation of risk/benefit
that\'s dependent upon whether or not you know the infant\'s HIV
infection status. It can be known within the first 4 weeks depending
upon the setting, but in other situations it can\'t be known. And I
would believe that as long as the infant\'s status is not known, if
it\'s not determined whether or not they\'re infected, then the
risk/benefit assessment needs to be based on the fact that they truly
are exposed to HIV, which is a life-threatening illness.

The separate issue is regarding the public health benefit of doing PK
data and doing these studies in the United States, as well as globally
in resource-poor countries. I think everyone has iterated that we
clearly have derived critical information from these studies about
dosing in neonates. I think there\'s no question that there is clearly a
need to obtain PK data in this neonatal population. I also think that
Dr. Spielberg highlighted that the written rule has had the desired
effect that we wanted, which was to actually obtain PK data in this
population, and then because of the emerging issues of resistance and
heavy treatment experience, as well as those children who are aging out
and now having second generation infection, there\'s a scientific
mandate to continue to study these drugs in this country.

DR. CHESNEY: Could I ask, Dr. Chadwick, your suggestion that the new
drugs only be studied initially in infected infants would mean that the
earliest age they could ‑‑ well, that\'s probably not true. You could
find some who were infected at birth, but you said it would be 70
percent at 3 weeks. And then we heard that the metabolism might be
different in the newborn compared to an infant over 2 weeks. So does
that change your thinking at all, or do you still think we should just
study it in infected infants initially?

DR. CHADWICK: Well, I think that\'s the safest way to proceed. I think
the uninfected or the exposed babies ‑‑ I should say exposed ‑‑ the only
ones I would really think would be justified to do intensive PKs on, if
that, would be the women who were most likely to be transmitting. In
other words, if I had a treated woman who had an undetectable viral load
before delivery, that\'s not a baby I would even think about studying.
If I had a woman that came in with perhaps an unable-to-be-controlled
virus, then I\'d think about that baby. So there\'s only a small
population of exposed infants I would think about trying to do some of
these intensive studies in.

But there are babies out there and there are babies that are
intrauterinely infected. 20 percent of infected babies are going to be
intrauterinely. 2 weeks is when we have at least 70 percent sensitivity
of getting a DNA PCR positive. So there are different time points within
that first month that the babies are available. It\'s just you have to
be coordinated and very attentive to find those babies.

DR. CHESNEY: Dr. Mofenson, I don\'t want to put you on the spot, but I
will. Do you agree with that position?

DR. MOFENSON: I\'m not exactly sure which position Ellen is discussing
because she said two different things. One is test in infected babies,
and the other one is, well, but maybe in babies who may be at higher
risk, I might test in those children. It comes back to the percentages
that we were talking about before. So you end up confused.

If you have a mother come in and she\'s had no prenatal care and you
diagnose her during labor, but you don\'t have the chance to give her
drug, her baby has a 25 percent risk of being infected, maybe more if
she has a high viral load because the baby has gotten no pre-exposure
prophylaxis, no post-exposure prophylaxis. That\'s a very high risk
baby. It\'s just like back when we were doing 076. So I think that, yes,
we need to have the data.

I think agree more with the concept that Lauren was coming out with,
that you have an HIV-exposed child. That child is at risk as opposed to
making percentages different.

Does that kind of answer?

DR. CHESNEY: Dr. Fletcher, I think you\'ve been waiting, and then Dr.
Rodvold and then Dr. Spielberg.

DR. FLETCHER: Well, in a word to this question, my answer would be no,
and two comments.

Someone from the FDA should correct me if I get this wrong, but my
understanding in the application for the antiretroviral agent Kaletra ‑‑
that\'s a combination product of lopinavir/ritonavir ‑‑ that the
pharmaceutical sponsor provided pediatric pharmacokinetic data from a
study in South Africa. And if that\'s true, if I\'ve got that right,
then the company has indicated that they\'re interested in doing
pediatric studies, that they can do them in a foreign country, and that
we are willing to accept those data.

And so if that\'s all true, then I think this question about seeing too
few born in the U.S. is probably now narrower than it really is if
we\'re already willing to accept pediatric data from outside of the
United States. Thus, we\'re probably not talking about 300 infected
infants, but a much, much larger group of infected infants if we\'re
just going to constrain it to infected infants.

And then the second comment that I would make. The drugs we may want to
study might be ones that are not candidates for looking at prevention of
transmission, and the drug that comes to mind here is efavirenz, so a
drug that\'s been deemed to not have a safety profile suitable to be
given to pregnant women, but in HIV-infected children has to been shown
to be an incredibly efficacious agent. And here is a drug now where we
still don\'t have data in infants that are less than 4 weeks of age. And
I think it\'s one of the real important gaps in knowledge with this drug
that has otherwise been shown to be incredibly safe and effective in
children.

DR. CHESNEY: Dr. Rodvold.

DR. RODVOLD: With that, I also would make the comment that reading the
document that you sent back to the sponsors that this seems awful rigid
in the pharmacokinetic design of these studies. You have not really
loosened up the design to allow easier sampling. You\'re kind of looking
for full runs at steady state versus using the state of the art
population analysis type techniques where you could take someone from a
single dose to a second dose, a fifth dose, a 20th dose, whatever. That
way, while you increase your numbers, you increase your number of
subjects that have to be studied, you decrease the number of samples
that have to be studied, which is a complaint from the industry because
you can\'t collect all these samples. You have a blood limit issue going
on. So you then take out those variables that may be inhibiting them
from wanting to proceed in these studies.

The other advantage of doing population analysis is that you could do
multiple other things. You can account for intra- and inter-patient
variability and you could also study continuum. If a patient was coming
in and put into a trial, anyplace in the trial ‑‑ let\'s say at 2 weeks
of birth ‑‑ and they were shown to be infected, they could stay in the
trial the whole time because you could sample them at various times and
add it into the population analysis versus doing a study only at day 3
or day 4. So thus, those that drop out because they\'re not infected get
studied, but those that are infected get in as well, and they can come
in and come out of the study at anytime and anyplace and you can study
throughout the continuum in age as well as throughout the continuum of
the disease.

The other issue I\'d add to that is that then you can mix and match
populations. You can take international data and you can take data from
the United States and you could compare them because you could tag them
as a variable. But at the end of the day, you\'d still have a group of
patients that have been PK-studied. Then you could separate from there,
and you can continue to build these files to be able to continue to
study the pharmacokinetics both within the industry, in the agency, and
study groups such as Courtney does.

So I would think that at least the current design that\'s in this letter
is limiting what potentially can really be done that\'s state of the art
today which you do require in a lot of the other studies and were
implementing in pregnancy in other types of populations outside of this
by FDA sponsors.

DR. LEWIS: Could I respond to that? First to Courtney\'s comment about
the Kaletra study, that was actually not a study done in South Africa
alone. It was a multi-site, multi-national study. About 20 percent of
the patients in that study came from South Africa. So there was in that
study quite a nice mixture of patients from a variety of sites within
North America and outside of the U.S. in international sites that had
varying levels of sophistication of their infrastructure and general
treatment guidelines.

In terms of international studies, the FDA ‑‑ and now I think this is
passed on from legislation ‑‑ accepts any study that is done in an
international site as long as it can be shown that that study meets the
standards of a study that would have been done in the United States. So
it has to meet good research practice standards, and they are subject to
audit just like any study that\'s done within the U.S.

Responding to the comment about the way the written requests are
written, these are, as you might consider, somewhat legal documents. We
are constrained by the way the law was written in how we can write what
we want the companies to do. But what generally happens is that we will
get a request from a company saying, okay, we\'re ready to start our
pediatric development program. We know the general guidelines that you
want. Basically what we want is PK data in everybody, all ages, safety
data in pretty much all ages, and a little more evidence of activity,
although not a defined efficacy trial, in infected children.

So we could, in fact, work in other study designs. Population
pharmacokinetics have been proposed in some cases, but it\'s hard to do
population pharmacokinetics if you only enroll 7 patients. So we are
amenable to those things, but we sort of start from the standard and go
from there.

DR. CHESNEY: I have Dr. Spielberg, Dr. Wilfond, and Dr. Englund.

DR. SPIELBERG: A couple of other PK issues following up on that. We\'ve
already heard that not all drugs really achieve significant
concentrations in the newborn by transplacental routes. So depending on
the nature of the drug, taking advantage of that will not necessarily
really get us the answer from any drugs.

The second issue is that data at a month really are still not
necessarily going to help us with data on how to rationally and safely
use the drug at day one. So one way or another, we\'re going to have to
do neonatal studies if we are going to choose to use that medicine in
the neonate.

The third issue is ‑‑ and I think Dr. Rodvold said it very nicely ‑‑ we
should really be trying to get as much comparative data as we possibly
can among different populations. We already heard from Dr. Mofenson that
at least to date for the limited amount of data, we\'re not seeing huge
differences, say, between babes in Africa versus here, despite
infestations and protein calorie malnutrition and all the other things.
But there may be situations where in fact they are different. And the
more data that we\'re able to accumulate from international studies to
be able to say, yes, we can extrapolate here or no, we can\'t
extrapolate there is going to be important.

And the final issue again gets back to some of the essential differences
in the disease internationally. We\'re dealing with a situation here
where primarily, in terms of prophylaxis or treatment, exposure is in
utero/intrapartum. In the rest of the world we have ongoing exposure.
And to me that changes the whole nature of what we\'re talking about in
terms of prophylaxis and of treatment because we have to, in fact,
intervene right at the beginning and we have to continue that
intervention or we\'re running the risk of what? 40 percent? Those
numbers are already getting staggering. So we\'re both in a treatment
and in a prophylaxis mode in the rest of the world where breastfeeding
is going on.

One can talk about all sorts of other strategies of bottle-feeding or
whatever, but basically we\'re a long way from being able to deal with
those issues and we\'re still going to have to rate babes in whom
ongoing exposure is an enormous risk. And you have to start those babes
on therapy very early on, and you have to know that the dose is going to
be in the neonate as well as at a month. So the disease process, the
nature of the disease bespeaks a rather different paradigm in those
countries.

If we are, indeed, going to serve those populations, that information,
as long as we have the extrapolation information from one population to
another, becomes very applicable. I\'d rather have developmental data in
newborns from children in the rest of the world to look at potential
treatment regimens at day one here than I would children anywhere
treated at day 30 because we\'re going to need those neonatal data.

So basically I think it\'s an issue of taking advantage in an ethical
way of all the differences in disease processes and get those data
applied to all children, be it a therapeutic regimen or a prophylactic
regimen, and just with the cautionary note that taking advantage of
maternal treatment may not be as useful as it really might seem because,
again, of some major differences in placental transport of the drugs.

DR. CHESNEY: Thank you for pointing that out.

Dr. Wilfond and then Dr. Englund.

DR. WILFOND: I\'d like to sort of take Skip Nelson\'s comment from
earlier on and address it towards how the written request might be
written. Skip seemed to make a distinction that I think is very
appropriate regarding what the purpose of the study is and the goal of
the study and the intention of the study. So if the purpose is to use a
drug in HIV-infected individuals, then that\'s the appropriate group to
study. Only if the intention and desire would be to use the drug in
HIV-exposed, because of some of the characteristics such as a better
safety profile or better dosing, would it make sense to do that.

The problem, though, is that the written request doesn\'t distinguish
between those two objectives, and so if the written request could
somehow distinguish between when it was desired to use it in a
prevention setting, then it would make sense to do those PK studies, but
it perhaps wouldn\'t make sense if that wasn\'t the case.

DR. CHESNEY: Thank you.

Dr. Englund.

DR. ENGLUND: I just wanted to reiterate that I think the international
setting is very important, but perhaps to the manufacturers, the
international setting is not where they\'re going to be emphasizing
their resources. Certainly these drugs are going to have a limited
marketplace in pregnant women and in newborn babies.

But with the increasing development of resistance, which is really
changing the total practices of how we deal with our patients, we know
in our pregnant women what drugs they are resistant to if they come for
care before they ever show up. And we have a need sometimes to use drugs
such as tenofavir or some other drugs that aren\'t approved for kids
because it is one of the few drugs or only drug we have available to us,
and yet we don\'t know at all how to use it.

So I think in the context of the U.S., we need to emphasize resistance
and put it in the context of some of these children are going to be
getting it anyway, and yet they\'re not going to be getting perhaps the
right dose, add that to the population-based pharmacokinetics, and put
that into the equation. I think it\'s very important to think about
developing countries, but for the purpose of the FDA, I think it\'s even
more important to think that the drugs are going to be misused in
American kids.

DR. CHESNEY: The whole purpose of the Pediatric Drug Advisory Committee.

Does anybody else have anything? Dr. Sever.

DR. SEVER: I think that we\'ve been coming around to a discussion of
international settings and U.S. settings and using comparative data from
those which seems to be valuable and important. We\'ve not resolved in
this discussion so far whether we should limit the studies to children
who are infected. Certainly that would be the most desirable, but the
reality is if the data is needed in the first few days of life, that
would be almost impossible to accomplish. You\'d have to limit yourself
to those at most 20 percent of children who are infected in utero who
themselves might be a slightly different subpopulation. But I think the
emphasis should be then on studies done very early within the first few
days after birth and including international and U.S. sites.

DR. CHESNEY: Dr. Mofenson.

DR. MOFENSON: Just a comment about infected children and being able to
diagnose them early. We\'re talking as if the day you draw the test, you
get that test result back.

(Laughter.)

DR. MOFENSON: That\'s not true. You test a child at 2 weeks. You get the
result back; it\'s 3 weeks or 4 weeks. You test a kid at birth; you get
the result back in a week. So it doesn\'t really help you in terms of
making decisions during that early time period.

DR. CHESNEY: Maybe Dr. Nelson\'s comment, and then let\'s think about
voting on this first question.

DR. NELSON: Well, I guess what I\'ve heard from a number of different
speakers is whether there\'s a way that you can enrich the HIV-exposed
population to where you\'re then linking the exposure to a drug whose
safety profile may not be as well traveled as AZT and some of the other
ones to where there\'s a justification for using it whether it\'s
picking based on risk factors, based on resistance of the mother\'s
virus or the like. But enrichment might be a way to go rather than just
saying HIV-exposed, all comers.

DR. LEWIS: I think that we could perhaps amend this question to include
if you felt there was a smaller subpopulation of exposed infants that
could be studied to consider that in your voting.

DR. DIANNE MURPHY: I wanted to make it clear to the committee too that
we\'re asking you to give us what you think would be the best way to go
about this, and we can change the written request to reflect that. So
you don\'t need to be limited to what we\'ve done in the past or
whatever. As Linda said, if this isn\'t the way to answer the question,
fine, don\'t answer it that way.

DR. CHESNEY: The question is are there too few HIV-infected infants born
each year in the U.S. or too little public health benefit to justify
requesting studies in neonates.

We\'ll start and go around to all the voting members, and please tell us
yes or no, and if you feel a need to qualify it, do so. Dr. Glode,
we\'ll start with you.

DR. GLODE: No. I think the studies should be done.

DR. CHESNEY: Dr. Rodvold.

DR. RODVOLD: No. I think the studies should be done.

DR. CHESNEY: Dr. Fletcher.

DR. FLETCHER: No. The studies should be done. I would certainly accept
modification, not just U.S. but international, and I think others
probably a little bit better than I could insert language to expand from
\"infected\" to \"exposed, high risk.\"

DR. CHESNEY: Dr. Englund.

DR. ENGLUND: I agree with Dr. Fletcher, with those caveats.

DR. CHESNEY: Dr. Wood.

DR. WOOD: No, and I concur with Courtney.

DR. CHESNEY: Dr. Santana.

DR. SANTANA: No, with the caveat that I think like Dr. Nelson suggested
that some strategies should be built into this to allow for enrichment
of special populations of subjects that could potentially be identified
beforehand like one of the risk categories that I heard across the hall
there was a high-risk adolescent who\'s had no prenatal care who comes
in and we know nothing about. That potentially could be a population
that because of the history, you suspect that there\'s a high
transmission rate. That would be a population that you could enrich to
get the studies done in a very safe way.

DR. CHESNEY: Dr. Nelson.

DR. NELSON: Since I\'ve peaked at 2 and 3 and see that we\'ll get to
deal with HIV-exposed under those two questions, answering this one the
way it\'s worded, \"HIV-infected,\" I don\'t see any reason to treat
infants in the U.S. differently than abroad apart from some of the
feasibility issues in just conducting a trial. But on the face of it,
then I would say there should be studies done both in the United States
and abroad, conducted according to the same ethical and research
standards.

DR. CHESNEY: Chesney agrees with Dr. Nelson and Dr. Fletcher.

Dr. Gorman.

DR. GORMAN: No.

DR. CHESNEY: Dr. Hudak.

DR. HUDAK: I think no, but I\'m going to speak up for the 2 percent
rather than enriched because if I\'m a part of the 2 percent minority,
I\'d like to be available for that type of study myself.

DR. CHESNEY: Dr. Fink.

DR. FINK: No.

DR. CHESNEY: Dr. Chadwick.

DR. CHADWICK: No, and I agree with Drs. Fletcher and Nelson.

DR. CHESNEY: Dr. Danford.

DR. DANFORD: No, and I agree with the enriched population study notions
that have been put forward as maybe a potential way to deal with the
problem.

DR. CHESNEY: Dr. Fost.

DR. FOST: Well, emphasizing that this question is just about known
HIV-infected infants, no. I mean, that is, studies should be done on
known infected infants.

DR. CHESNEY: Oh, I\'m sorry. Dr. Sever, I didn\'t realize you were also
a voting member.

DR. SEVER: No. Again, we\'re either with high risk for infection or
infected infants. I\'m not sure what the wording is now that we\'re
voting on, but there it says infected, so it would be definitely no.

DR. CHESNEY: I think that we\'re all under the impression that these are
infants known to be infected with this question.

The second question.

DR. LEWIS: The second question actually has another part on the next
slide, but we\'ll get to that a little later.

DR. CHESNEY: Since neonates born to HIV-infected mothers may be tested
in the first 48 hours ‑‑ but we\'ve heard the result may not be
available for a week ‑‑ and at 4 weeks, HIV-infected infants can be
diagnosed within the first month of life if you have a fast lab.

(Laughter.)

DR. CHESNEY: So the first question is, should only HIV-infected neonates
be studied? And the second question, if an HIV-exposed population is to
be studied ‑‑ so now we get down to Dr. Nelson\'s differentiation ‑‑
discuss the risk/benefit assessment for exposed neonates who might be
enrolled. And the third part, if studies are conducted in resource-poor
countries, can we extrapolate results from these studies to the U.S.
population?

So, the first question, should only HIV-infected neonates be studied?
Comments. Dr. Danford.

DR. DANFORD: It would seem clear that the answer to that is no because
the information that we need to get is in a time frame during which we
would not have the information about whether they\'re actually infected.
I can\'t see a way around that unless there\'s more science out there
that we haven\'t heard yet.

DR. LEWIS: I think this question was intended actually to capture that
specific population that had already been diagnosed early. So that was
really the somewhat different aspect of this particular bullet.

DR. CHESNEY: So what we would vote on is should only HIV-infected
neonates picked up early in the first couple of weeks be studied. Any
other comments, or do we feel ready to vote on this? Dr. Englund.

DR. ENGLUND: I just want to say one thing. That is going to be a really
hard population to get, I mean, really hard.

DR. CHESNEY: I think we\'re ready to vote. Shall we start the other way
around? Dr. Fost. Should only HIV-infected neonates picked up early in
the first month be studied?

DR. FOST: Well, first, I\'m not sure we\'ve had enough discussion on
this. But if pressured, I\'d go back to Dr. Chadwick\'s comment first,
that we\'re assuming we\'re talking about drugs that have first been
studied in known infected infants for which a safety and efficacy
profile has been established, admittedly a little bit older than
immediate neonatal.

Given that, I think it\'s appropriate to study a drug that meets that
description in an exposed infant if there was nothing else available,
number one, assuming the infant doesn\'t otherwise have access to known
effective treatment and that might be in a third world population or in
a non-U.S. population. But for a U.S. child who has access to drugs of
known safety, then I would have problems about justifying a new drug in
such a child. So to me there\'s a difference between whether you\'re
talking about a population that already has access to known effective
treatment or not.

DR. CHESNEY: Well, that\'s an important point, a very important point.
Any comments? Dr. Mofenson.

DR. MOFENSON: Yes. You can no longer do a study where there\'s no known
effective treatment. If you go to Africa to do a study, as a baseline
you have to be providing some effective prevention regimen. Usually
it\'s single-dose nevirapine. So the studies now all involve single-dose
nevirapine versus either something else or something plus.

DR. FOST: No, but at the time the nevirapine studies were done in Africa
and in Thailand, there was known effective treatment. There was 076. It
just wasn\'t available.

DR. MOFENSON: No, that\'s not true. That\'s true for the Thai study, but
the moment that the Thai study became available, the placebo arms in
every single trial done across the world dropped the placebo arm. The
HIVNET 012 originally had a placebo. It became a comparative trial to
short-course AZT.

DR. CHESNEY: So all studies now are comparative and adding on, not
replacing.

DR. MOFENSON: Some studies are looking at replacing but most are looking
at adding on. Some are looking at different regimens like the SAINT
study I talked about compared single-dose nevirapine to
intrapartum/postpartum AZT/3TC.

DR. CHESNEY: Dr. Nelson.

DR. NELSON: Just for procedural simplicity, if the answer to question 1
is no, then question 2 needs to be answered. I\'m just wondering if
instead of going around and answering 1 and then answering 2 separately,
if you\'d just prefer each person to answer 1 and 2 together, as Norm
effectively I think did.

DR. CHESNEY: Norm, I have one question about your first statement. Did
you say if the drugs had been tested in older children, then it would be
all right to give these very early diagnosed infants ‑‑ or did I make
that up?

DR. FOST: Well, it seems to me it\'s desirable to do it in the sequence
that Dr. Chadwick said, that is, to first give drugs to known infected,
let\'s say 1-month-old infants. Presumably we\'ll know efficacy before
that point, but then we\'ll know safety at least in little babies,
admitting that a 1-day-old is not a 4-week-old. But at least we\'ll know
that there\'s no previously unsuspected toxicity, at least short term to
medium term. So that should be a prerequisite to doing a study in an
exposed 1-day, less than 1-week infant. Is that your question?

DR. CHESNEY: Yes, because that\'s not an issue that we\'ve really
discussed or that\'s been put on the table. So I think that\'s
important.

Dr. Fink.

DR. FINK: This may be a stupid question to some of the people, but
we\'ve heard that you can diagnose HIV-infected infants at 2 weeks of
age by DNA PCR. How old does an infant have to be testing negative to be
sure that they are not HIV-infected?

DR. LEWIS: Lynne, do you want me to handle that or do you want me to
dive in?

(Laughter.)

DR. LEWIS: There should be at least one negative test after the age of 4
months? After 1 month and after 4 months.

DR. MOFENSON: Yes. According to the CDC guidelines for PCP prophylaxis,
all babies born to HIV-infected women get put on trimethoprim-sulfa at
birth. You stop after you have a presumptive uninfection status, which
is after two negative tests, one at greater than 1 month and one at
greater than 4 months.

It\'s a good point because you\'re talking about infection as well, and
we usually want a confirmatory test before you definitively call a child
infected. So it\'s not just one test, it\'s two tests.

DR. FINK: Well, the other thing is where it says in the question should
only HIV-infected neonates be studied, I guess I would feel that other
neonates who are HIV-exposed would also be eligible for study until such
time that they were proved to be uninfected.

DR. CHESNEY: I think that\'s part 2 of this question.

Could I ask Dr. Lewis, should we work under the assumption that what
Norm said is correct, that these drugs would have been studied, or do
you want an answer on that before you gave them to 1-week-old infants?

DR. LEWIS: No. These drugs are almost always studied in older children
first, and before that, they\'re studied in adults. So there really is a
progression downward of the age group in general practice. I think if a
company came in and said we have this great data that we think a drug
might be really effective in this setting that would require testing in
newborns before fleshing out the other safety profiles, I think we would
have to consider that very, very carefully, but in general all of these
drugs are studied in adults, older children, younger children, and then
in the youngest age group.

DR. CHESNEY: Dr. Nelson.

DR. NELSON: I need to follow up on the testing and make sure I\'m not
confused. I assume the CDC recommendations are doing HIV RNA not the
DNA?

DR. MOFENSON: No. DNA.

DR. NELSON: So the 20 percent sensitivity at birth in these 70 percent
at 2 weeks and then the flip false negative. So that would be the false
negative initially or the sensitivity and then at 1 month and 4 months
would be I guess the false positive.

DR. LEWIS: It\'s really more the pathophysiology of being able to
identify the infection in that age period more than the sensitivity of
the assay itself. If you spike specimens, the assays are sensitive, but
depending on the timing of infection of that infant, if the infant was
infected in utero, then there is sufficient viremia that you can
identify in the neonate at the time of birth. If the infant is infected
at the time of delivery from exposure to blood and amniotic fluid and
the like, then that infant may not have identifiable viral DNA present
until a couple of weeks later.

DR. NELSON: So I guess if you went two different directions, one is if
you require test studies in only HIV-infected neonates, you could
require it only in DNA PCR positive infants in this 20 percent or 70
percent sensitivity, and is this tail where you have to go long enough
just the other 30 percent that you have to follow out? I guess I\'m
getting a little confused about how you could use this test to see
who\'s in or who\'s out of that particular population.

DR. MOFENSON: Yes. I understand why you\'re confused because most of us
are confused too. The CDC hasn\'t yet changed its definition of
\"uninfection.\" That\'s what you\'re talking about. How do you define
someone who is uninfected? And it\'s more conservative because there is
that tail that may not have a positive DNA PCR until a month or 2 months
or 4 months. I know of one child in one of our trials who never had a
positive DNA PCR. The only way we picked up their infection was they
were persistently antibody positive at 18 months. So they\'re trying to
avoid that tail.

DR. CHESNEY: Dr. Spielberg.

DR. SPIELBERG: Can I ask the question in a little bit different way? We
now routinely treat these newborns under the presumption that in fact
they are infected. That\'s why we\'re using the drug. So in a treatment
paradigm, given that we don\'t fully understand the diagnosis, we are
treating them with medicines as we speak. Whether we call it prophylaxis
or whether we call it treatment, they are nonetheless being treated
under the assumption that they are infected, and that what we\'re doing
with these medicines is either preventing the infection from \"taking
hold\" or that even if the infection does take hold, they are on
treatment from the beginning. So they are already getting drug.

The question to me is, if you are already treating the babies either in
a prophylactic or in a treatment modality on the assumption that they
are at risk for having been infected in utero or intrapartum, the
ethical question then comes, given that we\'re already treating them,
what the ethics of giving a single dose of a medicine for a
pharmacokinetic study, which might be used in this patient population
subsequently with the development of resistance or in fact might be used
in this individual patient for therapeutics later on ‑‑ what the ethics
of that single-dose PK study, with all the other caveats that Norm
talked about in terms of safety in adults, safety in older kids, et
cetera ‑‑ to be able to get that information in patients who we are
already treating.

DR. MOFENSON: No. I think there\'s a difference because appropriate
treatment would be triple therapy usually with a protease inhibitor, and
the baseline prophylaxis is AZT alone. So it\'s very different. If you
have a child in whom you have confirmed HIV infection by age 4 months,
you change them from AZT to standard combination therapy. So I don\'t
think we can talk that we\'re providing treatment. That\'s why I like to
use the word \"prophylaxis\" for that first 6 months and treatment for
‑‑

DR. ENGLUND: 6 weeks.

DR. MOFENSON: 6 weeks. Thank you. I\'m thinking breastfeeding.

DR. SPIELBERG: But it is nonetheless treatment based on the presumption
that the baby has been exposed to virus or we wouldn\'t treat them at
all. Right?

DR. MOFENSON: It\'s prophylaxis.

DR. SPIELBERG: No. It\'s prophylaxis but it\'s based on the assumption
that they\'ve been exposed because if we didn\'t assume that they were
exposed, we wouldn\'t be treating them. And that next baby a year later
might be in the same position but, because of changes in resistance in
the population, may need a new drug for that same treatment modality,
the same prophylactic treatment modality. We\'re putting them on an
agent. Right?

DR. MOFENSON: Yes.

DR. SPIELBERG: So I suppose the question still comes down, given that
we\'re already treating the babes, what is the ethics of adding on a
drug for only single-dose PK so that we know the pharmacokinetics of
that drug in that patient population. Is it acceptable or not? That\'s
sort of the question.

DR. LEWIS: The trouble is many of our drugs are not amenable to
single-dose PK because they don\'t achieve steady state levels. Maybe
Courtney can comment on this a little bit further, but generally,
particularly for the protease inhibitors with hepatic metabolism, a
single dose does not give us accurate information.

DR. CHESNEY: Dr. Chadwick, did you want to add?

DR. CHADWICK: No.

DR. CHESNEY: Looking at the time and trying to figure out if we can
maybe vote on the first two, as Dr. Nelson said, but let\'s hear from
Dr. Fletcher and Dr. Wilfond and then maybe see if we can vote on a
combination of the first two.

DR. FLETCHER: I\'ll try to keep this short. To the point about the
single dose versus multiple dose, it seems it\'s maybe a little bit more
question 3.

But I guess I would raise the question as to whether we can do what Dr.
Spielberg suggested and have single-dose studies. Do we have to give
multiple-dose studies to get to steady state to get useful information
in these children? And more and more I\'m thinking, no, we don\'t.

If we were to approach this as if this is a first-time drug in humans
and we knew nothing about it, what would we do ‑‑ and Dr. Rodvold and I
were talking about this ‑‑ we\'d give a single dose. And perhaps maybe
we ought to approach this population somewhat like that, like we don\'t
know what the PK are because every time we studied it, we\'ve been
surprised. They\'ve never predicted what we thought they were going to
be, and maybe we ought to think about this in a single-dose context.

And then there are two issues: the long half-life drugs to steady state
and the drugs that have their own auto-induction. But maybe I\'ll just
stop and we can talk more about that when we get to question 3.

DR. SPIELBERG: If we already have those data in older kids, we should be
able to design things that will give us the key, critical basic
information from a single dose.

DR. CHESNEY: Dr. Wilfond.

DR. WILFOND: My question is sort of the analog of Dr. Spielberg\'s
question. Even if we need to do multiple-dose studies, the question is,
why consider substituting a new drug for the standard drug as a way of
answering that if we believe that efficacy is likely to be present?

DR. CHESNEY: Dr. Fost.

DR. FOST: Is someone going to answer Ben\'s question, or is that just a
comment?

DR. CHESNEY: I thought you were.

DR. FOST: Let me be clear on what this question is about. Are we talking
about infants born to mothers who were not treated? Is that the
population we\'re talking about?

DR. MOFENSON: No.

DR. FOST: Not necessarily. We\'re talking about mothers who were
treated.

DR. CHESNEY: May or may not have been.

DR. FOST: And so we\'re talking about an infant whose mother may have
been treated with a presumably effective regimen in which the infant
would be scheduled to be continued on a known effective regimen. And we
got a new drug that we\'re considering adding on or replacing the known
effective regimen?

DR. SPIELBERG: Single-dose add-on.

DR. FOST: For treatment or just for a PK study? Just for a PK study
while the infant is getting the other known effective regimen. All
right.

DR. CHESNEY: Dr. Wilfond, did you want an answer to your question?

DR. WILFOND: Yes. Even what Norm asked, that\'s what\'s confusing me in
the sense that my question was, instead of doing a single-dose add-on
PK, if we had presumptive views about efficacy, wouldn\'t it make sense
then just not to do a single-dose PK, but just to substitute this new
drug instead of one of the standard drugs.

DR. SPIELBERG: If you got the PK wrong, you wouldn\'t have that data
back and you\'d be treating that baby with the wrong dose that whole
period of time. That\'s the whole rationale in pediatrics of getting
that single dose before plunging into the trial.

DR. WOOD: And I\'d also like to raise that if you did a substitution and
you found out that there wasn\'t efficacy, then that infant that was
exposed was denied an established standard treatment. So I think it
would always have to be an add-on whether it\'s single-dose or
multiple-dose based on what we currently know is effective for
prophylaxis of exposed infants.

I\'d also like to add that when you\'re looking at the risk/benefit
ratio ‑‑ and I think this goes again to question 1 and question 2 ‑‑ is
that everyone agrees that antiretroviral exposure is clearly more than
minimal risk. And then if you break it down into what Dr. Sever
highlighted during his presentation, it\'s is there evidence for a
direct benefit. Well, the direct benefit applies to all infants whether
they are exposed or infected because there is potential for direct
benefit to them because they are exposed.

The issue of no direct benefit really is conditional and dependent upon
whether or not they truly are infected or only exposed, and that again
is dependent upon the time period in which you can make that
determination that they truly are infected and, maybe even more
importantly, that they truly are not infected.

DR. FOST: Excuse me. If we\'re talking about a single-dose PK study,
we\'re not talking about any direct medical benefit. So there\'s no
direct benefit for the sort of studies we\'re talking about. We\'re
talking about a non-therapeutic, single-dose PK study.

DR. FINK: Previously we\'ve held that if a child had a seizure disorder,
that a single dose of a new seizure drug to determine PK, even though
they would not have that drug available to treat their seizures, had the
potential of direct benefit in the future. And I would maintain this is
the very same situation.

DR. FOST: Well, if you\'re talking about what? An intravenous drug to
stop a seizure, possibly.

DR. FINK: No, no, no. An oral drug.

DR. FOST: Is there a claim here? I\'m confused again. Is there a claim
here that a single-dose PK study might have clinical benefit for these
infants?

DR. WOOD: That\'s the thing that\'s so impressive about the nevirapine
data actually particularly in resource-poor countries, that there\'s
reduced transmission even out to 18 months based on a single dose.

DR. FOST: Okay, thank you.

DR. CHESNEY: Dr. Nelson, one more comment and then I\'d like to see if
we can\'t vote on it.

DR. NELSON: I can\'t resist the IRB comment. Even if you decide to
approve this under 5052, which is the prospect of direct benefit, or
5053, which is the minor increase over minimal risk, the prospect of
direct benefit still requires that the risks and benefits are
commensurate with the other alternatives. And so you still end up in
Norm\'s position that you have to have sufficient safety data to make
sure that in fact the new treatment is no different than what you would
have been doing in the past, whether it\'s AZT, whether it\'s AZT plus
single-dose nevirapine. You can\'t use the benefit to just justify any
risk. It needs to be comparable to the alternatives either inside or
outside of the trial.

DR. CHESNEY: And presumably there would be safety data from older
children.

Maybe we could make another try at these two. I think the real question,
leaving out all the assessment for after lunch ‑‑ maybe we can vote on
the issue of whether people think only known HIV-infected neonates
should be studied or should the HIV-exposed population also be studied.
Can we try that, Norm?

DR. FOST: With the previous caveat, that we\'re talking about drugs that
are studied in not just older adults and children but known infected
infants, it seems to me it would be in the interest of an HIV-exposed
infant to be part of a ‑‑ or at least there\'s a prospect of reasonable
benefit that would warrant being in a trial, a single-dose PK trial,
with a drug that was of known efficacy and was of known safety
admittedly. So it seems to me it\'s appropriate to study HIV-exposed
infants, that it is in the interest of such infants to be in such
studies given those caveats.

DR. CHESNEY: Thank you.

Dr. Sever.

DR. SEVER: To answer the first question, should only HIV-infected
neonates be studied, I would put that as no.

And for the second question about the risk/benefit, you\'d have to have
that data from other studies done in older children.

DR. CHESNEY: Dr. Danford.

DR. DANFORD: The first question, should only HIV-infected neonates be
studied, the answer is no with the caveat that should the time come when
instant diagnosis is available right at birth, then I reserve the right
to change my mind about that.

I think that a rational mother, informed to the issues that we were
informed of today, would be capable making a decision saying that yes, I
would enroll my exposed but not definitely infected infant in the sorts
of studies we\'re talking about, and so I think risk/benefit would be
favorable for going forward with these trials in the exposed population.

DR. CHESNEY: Tom is wondering if that\'s a yes or a no or a
fence-straddle?

(Laughter.)

DR. DANFORD: Question 1, no. Question 2 was a please discuss. That\'s
what it says up there, so I discussed it.

(Laughter.)

DR. DANFORD: Yes, go ahead with the studies in the exposed population.

DR. CHESNEY: I probably wasn\'t very clear, but I thought maybe we could
review the risk/benefit assessment when we came back from lunch. I
realize that might influence your vote.

Dr. Chadwick.

DR. CHADWICK: I think that the answer to the first question should be
no.

And in the second question, I think that we can justify studying exposed
infants if they are considered to be high-risk exposed children in this
country. In developing countries, that\'s a different issue.

DR. CHESNEY: Dr. Fink.

DR. FINK: I guess I would have to say I think no to the first question,
but I would probably fudge that a little bit by saying multi-dose trials
should only be in HIV-infected infants.

And that would sort of be my answer to the second, that a single-dose
trial would be ethical in HIV-exposed infants but not a multi-dose trial
so that an HIV-infected infant could be either in a single-dose or
multi-dose PK trial. An HIV-exposed infant could only be in a
single-dose trial.

DR. CHESNEY: This is good. We\'re getting some of the risk/benefit
assessment we can do after lunch.

Dr. Hudak.

DR. HUDAK: I would say the answer to the first question is no, and with
respect to the second question, I think that given adequate efficacy and
safety data in older populations, I would say all HIV-exposed infants
should be offered the opportunity to participate rather than a high-risk
group.

DR. CHESNEY: Dr. Gorman.

DR. GORMAN: The answer to the first question is no, and I will echo some
of the other comments that there are hopefully ethical researchers and
well-peopled and intentioned IRBs that will make sure that the design of
those studies will continue to be ethically as well as clinically
efficacious.

In terms of the second question, if the HIV-exposed population is
studied, I would think that anything that increased the risk of
transmission would therefore increase the benefit of the infant in the
study. So the presence or absence of maternal therapy, the mode of
delivery, and the choice of postpartum feeding mechanisms would all be
issues that would be in that particular risk/benefit.

And a second issue that I would want to raise is if the mother\'s
infective agent is known, whether or not it is resistant to known
therapies would also be a thing that would significantly influence my
risk/benefit assessment.

DR. CHESNEY: Dr. Chesney agrees with Dr. Gorman.

Dr. Nelson.

DR. NELSON: The answer to the first question is no.

In answering the second question, I want to just make sure that people
don\'t use the fact that a neonate who is exposed may become infected to
justify exposure to risk that would only be acceptable if you\'re
infected, and that\'s where I find this logic very important to keep
separate. Someone may be infected, but it then needs to consider that
risk against known prevention strategies at this point, which gets into
whether that single-dose nevirapine or AZT or the like, with the caveat
that there may then be enriched exposed populations, whether that\'s
based on maternal known resistance or other factors that are determined,
where you might justify a higher risk of drug exposure because of those
factors that have led that population to be defined at an increased risk
of becoming infected.

DR. CHESNEY: Dr. Santana.

DR. SANTANA: No to the first one and concur with Skip. I think a major
issue here is knowing what the alternatives are and clearly having as
much information in other age groups that could help guide the decision
of how to apply that to this neonatal group.

DR. CHESNEY: Dr. Wood.

DR. WOOD: No to the first question.

Yes to the second question regarding HIV-exposed infants with the
caveats that have already been mentioned.

However, I would also like to raise the issue in terms of assessment of
transmission risk. While clearly there are correlations between
treatment and viral load with risk of transmission, we all know and are
aware of the fact that there are women with undetectable viral loads who
transmit to their children who have been extensively on highly active
antiretroviral treatment for many years. So I put that out because from
a neonate\'s perspective, there\'s no such thing a percentage of
transmission risk. Either I get infected as a neonate or I don\'t. And
as a neonate, I would like to be given the maximum benefit to prevent
getting infected. So that\'s my caveat.

DR. CHESNEY: Dr. Englund.

DR. ENGLUND: The first question is no.

And the second question is yes, we should study the HIV-exposed infants,
and I think we need to have our clinicians design studies that are going
to be acceptable in the different populations in which you do the
studies.

DR. CHESNEY: Dr. Fletcher.

DR. FLETCHER: To the first question, no.

To the second, yes, exposed should be studied with the caveats of Drs.
Gorman, Nelson, and Wood.

(Laughter.)

DR. CHESNEY: Dr. Rodvold.

DR. RODVOLD: No to the first question, and yes to the second question,
just like what Courtney stated.

DR. CHESNEY: We\'re now referring back to about five people.

(Laughter.)

DR. CHESNEY: Dr. Glode.

DR. GLODE: No to the first question.

And yes, I think the HIV-exposed population should be studied. I\'m not
so enthusiastic about enriching population studies myself because it
looks to me like if you do it perfectly, you still have a 2 percent
risk. So you enrich it to what? Enrich it to a 5 percent risk and then
it\'s okay? So it depends on how toxic you think these medications are
or what the evidence is that they\'re highly toxic. That\'s what I would
use to sway that, but right now I would think all HIV-exposed babies
should be eligible to be studied.

DR. CHESNEY: Dr. Fost, the first part of your answer was no. Is that
correct?

DR. FOST: Correct.

DR. CHESNEY: Thank you.

We were originally scheduled to have an hour for lunch, but if you
wouldn\'t mind, could we still come back at 1 o\'clock? I think for
those of us at the table, they are bringing sandwiches, for which we\'re
very grateful, but we also all have planes to catch. So if you don\'t
mind, let\'s start again at 1 o\'clock. Thank you.

(Whereupon, at 12:20 p.m., the subcommittee was recessed, to reconvene
at 1:00 p.m., this same day.)

AFTERNOON SESSION

(1:05 p.m.)

DR. CHESNEY: When we finished before lunch, it was unanimous that
everybody agreed that not just HIV-infected neonates should be studied.

And then we got to the second part, and I think most people agreed that
the HIV-exposed population should be studied, but everybody had
different caveats in terms of risk/benefit assessment. I thought maybe
we could give them a little bit more guidance.

What I wrote down from what you all said was that the drugs had to have
been previously studied in older children and demonstrated to be safe.
We were talking potentially about single-dose only pharmacokinetic
studies.

We had to have some estimate of the resistance I don\'t know if in the
mother or the area. I don\'t know if there is such a thing as area
resistance.

Then there was a lot of talk about whether to single out some children
as being at higher risk for transmission, and people talked about the
maternal history of having received drug or not having received it and
the maternal viral load.

Do we want to expand on that in any way? Do we want to suggest
single-dose only, or just having raised the issue, that was enough? And
do we want to talk more about narrowing down a population that would be
at higher risk for transmission, after Dr. Wood made the point that you
can have a negative viral load and have been on long-term therapy and
still transmit to your infant? Any comments in terms of this? Dr.
Englund and then Dr. Nelson.

DR. ENGLUND: I want to suggest not just single-dose only. Of course, it
depends on the agent, and there are some agents that will be perfectly
appropriate as a single dose, but we know there are others of our
antivirals that you have to give multiple times and that there\'s
accumulation like the protease inhibitors. A single dose will tell you
basically not much at all. So I think we have to be a little careful
here because it really might depend on the agent.

DR. CHESNEY: Dr. Nelson.

DR. NELSON: In many ways the answer to the question would depend upon
the details of the particular drug, the particular protocol, the safety
profile, and the population and how that population has been defined.

But I think the general principle is that the risk and benefit, if
you\'re going to argue benefit, has to be comparable to the
alternatives, which are existing treatments. And if you\'re in a
no-benefit situation, you\'re in a minor increase over minimal risk
which places you back into having sufficient data to establish safety to
where you\'re confident in that risk estimate, which gets you almost in
the same place as the other approach. I think being able to specify that
in any more detail would probably require much more specification that
we have available here.

DR. CHESNEY: Norm.

DR. FOST: Dr. Mofenson, could you just clarify for me something you said
before lunch, that some kind of treatment you think is available
everywhere in the world today? Are there populations where no treatment
is available?

DR. MOFENSON: No. I was talking about doing clinical research. There are
resource-limited countries where prophylaxis is not available, but if
you go into that country to do a study of prevention of transmission,
it\'s felt that you need to provide the minimum effective care, the
minimum effective care being single-dose nevirapine.

What\'s actually happened in the places that we\'re doing clinical
trials is that there\'s been a large effort to bring nongovernmental
organizations in to provide that level of single-dose nevirapine. So in
many of the countries, it\'s then upped the standard of care, the
standard of care being single-dose nevirapine, which wouldn\'t
necessarily be the standard of care here.

So I don\'t think that you would be able to do a study where you don\'t
offer at least single-dose nevirapine, at least in the clinical trials
groups that I\'ve worked with.

DR. FOST: Politically you mean.

DR. MOFENSON: Ethically.

DR. FOST: I would argue ethically. If there\'s a country or an area
where presently no treatment exists and doing a trial presents the offer
of treatment to hundreds or thousands or however many infants are in the
trial, assuming that it\'s a well-designed trial and the drug is
plausibly safe and so on, that\'s a potential benefit to that
population, apart from whether you offer it to the whole population of
the country.

And secondly, the agencies or the sponsors that are doing the studies
are not typically ones that either have the resources or are responsible
for providing care to the whole country. So that oft-stated premise that
you shouldn\'t do a study in a place where you\'re not going to offer
treatment I think can and should be questioned.

So, again, given that risk/benefit ratio matters, if you\'re going into
a place where there\'s presently no potential treatment, then the
benefit of being in the study, even for just exposed infants, is much
higher because the alternative is zero.

DR. CHESNEY: Dr. Lewis, could I ask a procedural issue? Do you want a
more definitive statement about the risk/benefit assessment? In other
words, do you want a vote with respect to what population might be at
high risk or have you heard enough just in the discussion to provide an
answer to this section?

DR. LEWIS: I think all of these ideas are very useful. I don\'t know
that we need to vote on each one of them, but just getting sort of the
general feeling of the group of what things could be done or how we
might alter study designs or whatever that might get to the data that
we\'re interested in, which is how to use the drugs in the very young
population, is really what we\'re after.

DR. CHESNEY: Dr. Chadwick.

DR. CHADWICK: I just want to make sure we\'re very clear about
single-dose versus multiple-dose studies. I think single-dose will get
us started for most drugs. Nevirapine is an exception because it has
such a long half-life and it did have the benefit of providing antiviral
coverage for several days. Most of our drugs don\'t do that. So
single-dose studies will get us in the ball park of what sort of dosing
range we would use to then base a multiple-drug study. I think that when
we\'re talking about these things, these are important differences that
we need to be clear about what we\'re using these medications for.

DR. CHESNEY: Dr. Mofenson.

DR. MOFENSON: Just a comment that single-dose studies are not going to
help us with the major problem in developing countries which is
breastfeeding, and there infant prophylaxis requires multiple doses. So,
for example, one of the studies that we\'re doing looking at 6 months of
nevirapine in the infant required us going back and doing a phase I
study in infants to look at different doses to be able to determine what
the appropriate dose would be for a phase III study. So it wouldn\'t
help a large part of the problem to only do a single dose.

DR. CHESNEY: Could we go on to the third part of that question, which
is, if studies are conducted in resource-poor countries, can we
extrapolate results from these studies to the U.S. population? Comments?
Dr. Nelson.

DR. NELSON: To comment on this, let me just try to expand Norm\'s
comment. I think if one goes into a setting where there may not be care
provided at this point for HIV-positive women and infants, I would hope,
Norm, you would agree that the intervention being tested should be one
that could, in fact, be provided in that setting maybe not to everyone
but it ultimately could be sustainable past the end of the trial. We
could discuss that.

But if you take that as the minimum principle that at least what we\'re
testing ought to be applicable in that population, if then you wanted to
extrapolate to the U.S., by extension then if we would not allow a
control group other than a comparative study here, you sort of end up in
a position where you\'re going to be testing against a sustainable
control group there and an intervention group that could be applicable
here. Now, that\'s separate from PK studies and the like. Anything more
specific than that I think would be mainly a scientific question about
extrapolation.

DR. FOST: Well, no, I wouldn\'t agree with your premise. Obviously,
it\'s desirable when it\'s sustainable and of benefit to the population,
but again, if you\'re an infant or a mother in a country where there\'s
no treatment and, let\'s say, Engulf and Devour comes in and wants to do
a study just because it\'s easy and convenient and cheap to do and then
they\'re going to get out and you\'re never going to see them again, but
you\'re one of the 300 or 500, or whatever the number is, kids in that
trial and you have a 50 percent or a 100 percent chance of getting
something that could of substantial benefit to you, I don\'t understand
why it\'s not in your interest to be in that study and why it\'s not in
the interest of people in that country who otherwise would have nothing,
as a study that at least offers potential benefit to a small number is
better than nothing. So this whole idea that it must be sustainable I
don\'t think is coherent.

DR. CHESNEY: Dr. Fink.

DR. FINK: I\'m not sure that it has to be sustainable, but I think the
United States has signed on to the Helsinki Protocol which very
specifically states you can\'t have a placebo group if there\'s a
generally accepted therapy. And I think we would be on really soft
international grounds or bad international grounds if we advocated doing
research that didn\'t comply with that.

DR. FOST: Time does not allow us to discuss all the elements of the
Helsinki doctrine that are violated every day by almost every
FDA-approved study in the U.S. The Helsinki doctrine is a wonderful
aspirational document, but there are a half a dozen requirements in it
that are violated on a regular basis by just routine studies in the U.S.
and elsewhere. So it\'s hardly a standard for rigorous ethical thinking
about clinical research. I think that will get us afield.

DR. CHESNEY: Dr. Gorman.

DR. GORMAN: Never being afraid to tread into dangerous water, I think ‑‑
I\'m going to try to paraphrase Skip and your comments, Norm ‑‑ we
wouldn\'t be able to extrapolate data that we felt were unethically
obtained. We have sort of taken that as a standard we\'ve applied in the
past. We may choose to change that in the future, but in the past we\'ve
chosen not to extrapolate from data that had been unethically obtained.

But if they are ethically obtained in a resource-poor country, then the
extrapolation issues then become scientific. Can we really generalize
those data or not? But if they are generalizable, then we can do it.

And just because I love the Helsinki report so much, I always use the
example of hair loss when they come up with we can\'t do a study with a
placebo control. There\'s a disease where placebo-controlled trials
would be very acceptable at the IRB I sit on.

DR. FOST: Well, obviously, the results in the developing country would
be extrapolatable to that country or countries like that or populations
like that. But the question here is whether they would be applicable to
a U.S. population. That\'s complicated and would depend on the case.

DR. CHESNEY: Dr. Santana.

DR. SANTANA: I understood the question very differently, not that this
discussion is not important. I think it\'s very important, but I
understood this question very differently. I think they\'re asking are
there patient-related variables that are so different across populations
that would lead us to not or, yes, accept the data as it exists. I guess
here, as it\'s always said, the devil is in the details. How different,
how concordant, how discordant are the populations in these
patient-specific variables that would lead you to conclude that the data
is valid or not? I could add more variables here that have nothing to do
with patients. They may have to do with compliance, issues of the
environment that would lead you to believe that the data is valid or not
valid.

So maybe the FDA can help us clarify this question. Are they
specifically asking us to comment whether these patient-specific
variables are things that they should be looking for when they look at
data from other countries to see how concordant or discordant they are
to the U.S. population.

DR. DIANNE MURPHY: I think that it is a science question, and it has to
do with a general question having to do with experience in other trials.
Have we seen differences? If we have, your input as to how you would
stratify for that or think about it. But really that would be for larger
studies. I think that is a question you\'d use as a background, if you
will, that type of information because really we\'re asking, though
we\'re not going to be doing efficacy trials, if you had that kind of
information, then how would use it or not use it, or do we have to.
Would we exclude all malnourished children? Clearly there would be a
level at which you would even in a PK study I would think. So that would
be my take.

Linda, did you have anything else that you wanted to add to that?

DR. SANTANA: But that\'s what I was getting at. If this is a science
question, then the details are very protocol-specific driven because if
you have a population that\'s malnourished, you\'re clearly going to
have as entry criteria a level of albumin or a level of something that
helps you control for that. If you control it, then the populations are
the same whether they\'re in the U.S. or whether they\'re in another
country. So I think the specifics of the detail is protocol driven, and
as long as those details are valid, I think the data can be extrapolated
and can be used.

DR. DIANNE MURPHY: I think that that\'s part of the question. The other
part of it is if you say yes, then it\'s the other issues that are going
to be around the table I think actually in question 3.

DR. CHESNEY: Dr. Spielberg, Dr. Fost, and Dr. Fink.

DR. SPIELBERG: I think there are a couple of things. The really precise,
I suppose, aspect of this question is whether ontogeny dominates over
other aspects of variability in the population and therefore
understanding neonates in one setting is extrapolatable to the changes
in clearance, the changes in distribution we\'d expect in another
population.

If you look at a lot of the experience with ICH-E5 and the variability
among ethnic and racial groups, yes, there are often differences,
although when you look at the variability within a population, that
variability often is as great as the variability between or among
populations. And as such, if you understand the mechanisms of clearance
of the drug ‑‑ and remember, these are drugs that we\'re going to be
taking into the newborn with adult experience, understanding of its
metabolism, understanding of its renal handling, we should be able to
make some kinds of general judgments about whether we\'d expect, for
example, malnutrition to have a dominant effect.

Having said all that, again we\'re always surprised by data that we
actually get, and one of the opportunities that does exist here, because
we probably will, in fact, be doing studies in several different
populations, is to really begin to develop a better database so that we
understand the effects of immaturity and of ontogeny of clearance
processes vis-a-vis all those other variables.

My guess is for a lot of processes, when we get down to newborns, if you
look at renal clearance ‑‑ and your average neonate has a clearance of
what ‑‑ I don\'t know ‑‑ 30, 40 mls or so. For an adult, that would be
overt renal failure. Right? So you\'re looking at the extremes there in
terms of where the neonate is in terms of what an adult population would
be.

My guess is ontogeny is going to be the more important variable, and to
be sure that we get the dosage right with age and development. But we
are obliged to prove that, and the more data we have for each individual
process and groups of compounds as we go through, we really should try
to iteratively get that information into everybody\'s hands.

DR. CHESNEY: Dr. Fost, Dr. Fink.

DR. FINK: Well, I think the other thing is obviously we can only
extrapolate that data to the U.S. population to the extent that what
data is available in the U.S. population allows us to make comparisons.
So extrapolation with no data in the United States really, I wouldn\'t
think, is feasible or advisable. So it\'s really dependent on how much
data we have here to reinforce the extrapolation.

DR. LEWIS: So this comes back to that multinational, multi-site study
would give us the best survey of all of these things. We don\'t know
probably all of the scientific variables that might be different between
a population in Thailand or India or South Africa or Omaha, but we do
know that they exist and if we can control for them in some way, then we
feel like we get a better handle on the population PK.

DR. CHESNEY: Dr. Fost.

DR. FOST: I take it then you\'re just asking about whether the PK data
can be extrapolated because if you gave ‑‑

DR. BAYLOR: PK and safety. They\'re not efficacy trials.

DR. FOST: Okay. But if a single-dose agent might have some efficacy and
you showed this efficacy in a third world population, that would be very
interesting and relevant. So at least that part of it is extrapolatable.

DR. LEWIS: Just one sort of example that has come up is in some of the
studies done in sites outside of the U.S. where malaria is a major
pathogen, we have to change the way we think about anemia and whether
that\'s a side effect or sort of a baseline condition. Levels of
hemoglobin that we would not tolerate in U.S. infants might be really
pretty normal in a population where malaria is quite prevalent. So these
are the things that we try to balance, but sometimes it becomes very
difficult.

DR. CHESNEY: Do you want a vote on this, or have you had enough
discussion? Move on to the next question?

DR. DIANNE MURPHY: I think this is an important enough question. We\'re
asking fundamentally a science question here. I think that we would like
to have individual comment around the table.

DR. CHESNEY: So we will start with Dr. Glode.

DR. GLODE: I would go back to a comment made earlier. I think you can\'t
extrapolate until you have some directly comparative data from U.S.
populations giving the same drug under the same conditions, and then you
can enlarge those studies presumably. But I think you have to have
direct comparative data to know if you can extrapolate.

DR. CHESNEY: Dr. Rodvold.

DR. RODVOLD: Yes. I would somewhat agree. I think the study design in
needing both sets of populations ‑‑ there\'s not much you can, even in
pharmacokinetics, say a group from South Africa versus a group from the
United States ‑‑ are they that much different or not coming into it. I
think that as you take certain compounds through by having both groups
to compare, you\'ll be able to tell whether or not you can extrapolate
data and whether or not you even need to do a study in all populations.
So I think in the beginning you can\'t say you can extrapolate, but you
need to do studies so that you can decide whether or not you can
extrapolate it. Then that may answer the question of which direction you
go in the future.

DR. CHESNEY: Dr. Fletcher.

DR. FLETCHER: I will agree with Dr. Rodvold. I think you can. I think
the degree to which you have, as Dr. Lewis mentioned, multi-site
international/U.S. protocols that have, the degree to which you can,
some standardized entry criteria such as for albumin and those type of
things, I think those studies, well-done, should be able to be
extrapolated. You would probably want to do some confirmatory testing
after that, but I think the answer is yes.

DR. CHESNEY: Dr. Englund.

DR. ENGLUND: Well, I do agree with Dr. Fletcher, but I would say if
we\'re talking about HIV-infected neonates, are we going back to the
HIV-infected neonates or not? Because I think it\'s going to be hard to
get much confirmatory evidence on infected neonates. It depends if
you\'re looking at the beginning of the question or not. How much you
can directly extrapolate with infected neonates in this country is going
to be very difficult because we don\'t have many infected neonates. If
we\'re talking about exposed neonates, yes, we can extrapolate. So it\'s
a little bit of a difficult question.

DR. CHESNEY: Dr. Wood.

DR. WOOD: I think I would have to concur with the comments raised by not
only Jan but Courtney and Keith as well, and that is that initially
early on, there are going to have to be trials conducted relevant to the
design of the specific drug that\'s being studied so that you can really
see whether or not the data is extrapolatable. I think the comments from
earlier this morning, in terms of designing those trials to take
advantage of the population pharmacokinetics that would allow for
inter-population, within-population, and even inter-individual
variability would be very useful.

DR. SANTANA: I think from the scientific point of view, when you go into
these multinational trials or groups, you know a priori a little bit
about the mechanism of action of the drug, its metabolism, potentially
what pathways are affected by that drug, and you clearly relate your
study design to those, understanding that for those you can control, and
then the data is comparable or can be extrapolated, and then there will
be many others that will come as a surprise because you cannot
anticipate.

But the latter I think makes the trial more interesting because if these
drugs are going to be used across different populations around the
world, that data is very important too. It just doesn\'t only reflect
the U.S. population, but reflects other populations that could benefit
from benefit from these drugs.

The point is that when you go into the study design, you already know a
priori some information about what potential variables you need to
control for, and you control for those as best as you can. Then in that
setting then, I think that data is valid across many different ethnic
groups and cultural populations in which the study may be conducted.

One of the issues that did not come up in this is the issue of
compliance. I advise the group to read a recent article in the Journal
of Clinical Oncology, published either in December or January, in the
last few months, that actually criticizes a lot of issues of compliance
in oncology trials even within the United States and how we think that
doing multi-hospital trials gives you the same data. Uh-uh. Even issues
of compliance are critical to extrapolating data. I know you wanted to
address the scientific questions, but I throw out the issue that
compliance also has to be clearly regulated when you start extrapolating
data.

DR. DIANNE MURPHY: We think compliance is a science question because it
impacts it so tremendously.

DR. CHESNEY: Dr. Nelson.

DR. NELSON: I guess just to point out I don\'t think I have much to add
on the science other than to identify what I hear everyone arguing, that
from a scientific point of view we should treat the populations
similarly unless we have already demonstrated or in the process of
trying to demonstrate relevant differences. To the extent that you want
to assume you should treat those populations differently for other
reasons, then you\'ll get back into some of the ethical issues that Norm
and I are going to simply finesse at this point in time. But I finesse
it indicating that there could be considerable discussion on the points
that were raised earlier, meaning the standard of care that should be
applied for that population.

DR. CHESNEY: I think they could be extrapolated under all of the
conditions that have been mentioned already.

Dr. Gorman.

DR. GORMAN: I think Dr. Santana raised the issue that I think is most
crucial. If you can identify issues and then identify them and control
for their severity in extrapolation, I think you\'ll do fine. And the
question that will be unanswerable before the studies are done is how
diversified will the pharmacogenetics and the ontogeny of those
pharmacogenetics be from population to population. And those questions
cannot be answered until the studies are done.

DR. CHESNEY: Dr. Hudak.

DR. HUDAK: I think that the answer has to be a cautious yes with
conditions, as everyone has said. I think the PK data and so forth are
more likely to be more easily extrapolatable. I think given the
differences in biology and the biological complexity of the systems,
that as you move up to safety issues and then to efficacy issues,
you\'re going to have a lot more difficulty extrapolating to our
population without having some similar type studies in this country.

And I also think, at least in the way that I look at some of the studies
that might be done in the third world, study designs that are put
together there may be very radically different in their approach to
either the transmission prevention or to actual treatment, that it might
not really, in terms of study design, be exactly applicable to what we
need to do in this country. So I think that\'s another complicating
issue.

DR. CHESNEY: Dr. Fink.

DR. FINK: I guess I would recommend cautious extrapolation with two
comments. One, a well-designed and well-done multinational trial may be
preferable to a trial performed in the United States because my second
comment would be even studies performed in the United States have been
notoriously poor in reflecting some of the pharmacogenetics of our large
minority groups, and I\'m not sure you can routinely extrapolate trials
performed in the United States to the U.S. population. And we probably
have some unique pharmacogenetic mixes in the United States that exist
nowhere else in the world.

DR. CHESNEY: Dr. Chadwick.

DR. CHADWICK: I would agree with that and just say that I think the
possibility that we can extrapolate exists, but we have to collect the
data to be certain about that.

DR. CHESNEY: Dr. Danford.

DR. DANFORD: I would say, sure, you can extrapolate results from a study
such as that. The question is how much confidence are you going to have
in them. It\'s a question that has an answer in terms of a continuum,
not a yes or no. We would have more confidence extrapolating studies of
neonates in resource-poor countries to our own population in question
than we would have extrapolating results from studies done on elderly
individuals. We would have a great deal more confidence if we could do
the study on the kid\'s twin brother. I think the resource-poor
countries where we would study neonates probably fall intermediate. So
you have to extrapolate carefully.

DR. CHESNEY: Dr. Sever.

DR. SEVER: Well, I would join the group for extrapolation with, as
everyone has said, the involvement of multi-site, multinational studies,
including patients in the United States, and then to standardize entry
on the key factors which are known about the metabolism and the
excretion of the drug so as to try to keep that as close as possible,
and then obviously evaluate the data and see if you do end up with
comparable populations.

DR. CHESNEY: Dr. Fost.

DR. FOST: Well, it gets easier as you get to the end. But I think the
word \"extrapolate\" and the word \"results\" oversimplify.

First, results. I mean, as I\'ve said, there are things you can learn
from studies in another population that would definitely be useful to a
U.S. population, not immediately translatable but extremely useful for
telling you whether you\'d want to go ahead and, for example, repeat the
study.

Extrapolate. I was going to make Dr. Fink\'s point, that is, doing a PK
study on 8 children in the U.S. with different gender, race, genetics,
and other variables doesn\'t tell you that every child who is going to
get that drug is going to behave in the same way. So any PK study always
gets you in a ball park of roughly how this drug works in this age group
or, at least, in these 8 children that you happen to study. And in
general, that will be pretty predictive of most other children, but I
don\'t think the big cut there is going to be third world versus U.S. It
will be various genetic and other variables, socioeconomic and
nutritional and racial and gender and so on. So, yes, we\'ll learn
something about the pharmacokinetics of a drug in that population, but
what population it will be applicable to in the U.S. you\'ll have to
think about carefully.

DR. CHESNEY: Thank you.

So we\'ll go on to question 3. Should we continue to request
pharmacokinetic and safety studies for every antiretroviral drug under
development? And if not, what criteria could be used to decide which
drug should be studied in the neonate?

Dr. Wood.

DR. WOOD: I think the first comment that I\'d like to raise is the
issue, as Jan and I were discussing, about every antiretroviral drug
under development. I think the caveat to that would be based on known
safety data. If there are clearly preclinical and animal model data or
adult data that would suggest that there is toxicity of this new agent
that would be particularly relevant for neonates, no, you would not want
to study it or to have them exposed to it.

I think that if we looked at the greater historical issue of just
approach regarding the principle of requiring it, the principle and the
desire is so that we would have adequate, sufficient data in populations
that we know are potentially going to be exposed to these agents.

My major concern is that if we did not continue to request
pharmacokinetic data, that we would not get the pharmacokinetic data on
these antiretroviral agents. And we know that these children potentially
ultimately might be exposed to these same drugs because they would
ultimately potentially be licensed and their mothers would be taking
them for their own health. And I think that\'s another ethical
consideration that we have to keep in mind.

DR. CHESNEY: Dr. Fletcher.

DR. FLETCHER: I agree with Dr. Wood about the drugs for which we should
request pharmacokinetic and safety data.

Here maybe I\'d just add some comments about, now, what do we request?
What might actually be required? My sense currently is ‑‑ I\'m not sure
if it\'s what the FDA is actually asking the companies to do or whether
it\'s the companies\' interpretation of what they should do. Sometimes
those things are very different.

At least what I see right now from both the Pediatric AIDS Clinical
Trials Group and the industry are multiple-dose studies to steady state,
trying to look at both safety and efficacy. So in a sense they\'re
trying to do everything when they go into this population. And I think
that means there becomes a very limited number of children that can
enroll in these studies. They are very difficult to do. They take an
incredibly long time to enroll. At least so far every one ‑‑ I hate to
make generalities because I\'m sure I\'ll be proven wrong quickly, but
at least every one I can think of, the initial starting dose that we
used to go into neonates was wrong. In other words, it was suboptimal in
terms of achieving the systemic exposure that was shown to be safe and
efficacious in adults.

So increasingly I\'ve been thinking about maybe we need some
alternatives in terms of what do we really ask for. This now gets to
this issue of single-dose studies. Should that perhaps become a
requirement? So just a few points here.

It seems to me what a single-dose PK study would do would really be
establish basic pharmacokinetic characteristics for the drug in that age
group. Some of these drugs do present some challenges for single-dose
studies. They have long half-lives. So a first dose, a single dose is
not going to tell you what concentrations look like at steady state, but
if pharmacokinetic principles hold, you should be able to extrapolate to
steady state really with a high degree of confidence.

Now, if you have drugs that are auto-inducing, which we do in these
antiretroviral agents ‑‑ so, in other words, the first dose is not going
to predict steady state. The half-life will get shorter the longer you
dose it. If we know something about the time course of that
auto-induction in adults and in older children, it seems to me that
again we can have some confidence in extrapolating that to neonates if
we know what the PK are initially from a single-dose study in neonates.

So if we can do that, then these studies are clearly easier. The designs
lend themselves to both international and U.S. sites. They probably
allow themselves a broader patient inclusion criteria, so not only
HIV-infected but probably HIV-exposed.

And then I will just come back to where I started. They do, however,
just become starting points. I think it\'s information needed just like
if you were going first dose of a brand new drug in humans. It\'s a
starting point to design a multiple-dose dosing regimen that\'s going to
be given in HIV-infected infants that then would need some type of
confirmation. Now, you\'re not going to have to learn everything.
You\'re just going to have to confirm that this multiple-dose regimen
now is achieving the types of exposures that you thought it would and
those type of things, and don\'t require intensive in-patient types of
pharmacokinetic studies.

DR. CHESNEY: Dr. Spielberg and then, Dr. Rodvold, did you have your hand
up?

DR. SPIELBERG: A couple of thoughts. When you start out, even if you
have several drugs in a class, often we have no idea which will
ultimately be an optimal drug to give to neonates. It can come down to
something as simple as which of those is going to be formulatable. So if
you start off with three drugs in a class, if you only ask it of the
drug that it turns out is unformulatable, then you\'re going to have to
ask it of the next drug, et cetera. So that\'s one thing to consider.

And some drugs will have more favorable pharmacokinetics or metabolic
profiles vis-a-vis the relative maturity or immaturity of a given
pathway in the newborn and may be more suitable for certain disease
states than other disease states.

Having said that, there are some analogies to oncology because we\'ve
got a serious, life-threatening disease, with very limited numbers of
patients, and we know that we can\'t, for example, take every drug in a
class into a COG protocol.

Victor, can you comment at all from the oncology experience how some of
the decision making about doing all drugs, doing some drugs, et cetera
is done?

DR. SANTANA: Well, I think from the experience of phase I studies in
pediatric oncology, we always request some PK data even if it\'s a
me-too drug or something like that because minor differences in
structure potentially could lead to differences in some excretion
pattern or things like that, and you only find that out if you study it.
But it\'s a graded system so that for a brand new class of drugs in
oncology we would request a lot of pharmacokinetic data or we would want
a lot of pharmacokinetic data before we moved that drug forward, whereas
if it\'s a drug that\'s another me-too drug or another derivative, we
may ask for more limited studies. So it\'s graded based on the class of
drugs, how much more information you had ahead of time, but the basic
principle is that before we move any phase I oncology drug to the phase
II or phase III setting, we want some pediatric data.

Does that answer your question?

DR. SPIELBERG: Well, do you know how the review division at FDA deals
with issuing written requests on the multiplicity of compounds out
there?

DR. SANTANA: I think they\'re better suited to answer that than I am.

DR. SPIELBERG: Some of the same analogies apply, given patient supply
and number of investigators and difficulties of doing the study and that
it\'s a life-threatening disease.

DR. DIANNE MURPHY: With the written request, in the beginning of this
process, we had to take the position that it\'s a voluntary program. You
issue it. You don\'t know who\'s going to respond. We did not feel that
our mandate was to wait and see if this company responded, then start
all over. So we did issue written requests to basically every player in
the field and have done that unless there were reasons to do otherwise.
So the position is that you do issue a written request unless there is a
reason not to do so, such as a safety issue, such as some concern in
pharmacokinetics that you want worked out before you issue a broader
written request because the need is in a bigger area and you think that
there\'s something else that needs to be done.

Or you may issue a written request ‑‑ and we\'ve done this ‑‑ where we
say we want you to do this. You have to solve this problem first, then
come back and give us the information. Then you\'ll go to the second
part of the written request, and then you have to complete the whole
written request before you can get exclusivity. We have done it that way
also.

But the crux of the question is that we have taken the stance that
children deserve as many options as adults.

DR. CHESNEY: Dr. Rodvold and then Dr. Fink.

DR. RODVOLD: Well, with that, again I\'d encourage that the design of
these studies move up more to the state of the art of the science a
little bit. I think traditionally people are looking at these as more
traditional single-dose studies. I think you\'re going to have to really
look at a prior knowledge of each of these compounds and decide whether
or not a single dose or multi-dose and using optimal sampling windows
and maximum likelihoods and be able to use that data to be able to
design the study as best you can, as well as analyze it the best you
can. I think it needs to be encouraged here. The industry I think is
equipped to do it. There are no doubts about that in my mind. And I
think the people at CDER know how to do this really well, as well as the
evaluators.

I just think that that\'s missing over here on this side of the table of
the pediatrics, and particularly in this area, I think it will really
lend itself to be able to sort out variables. That I think hasn\'t
traditionally been thought of. So I\'d encourage that be brought here
because you have it in your other statement papers for the FDA guidance
papers of how to do other studies, mainly up on the adult side. It
easily can come down to here. There are plenty of people who can do it.

DR. CHESNEY: Dr. Fink and then Dr. Nelson.

DR. FINK: I guess as this discussion goes on, I\'m getting more and more
uncomfortable with the concept of pharmacokinetics and would just like
to point out that particularly if we\'re talking about the neonate, the
marrow response in the neonate is very different from the child, and
when we\'re talking about drugs that work in an intracellular level,
I\'m not sure we couldn\'t be led badly astray by saying that similar
pharmacokinetic levels in the blood will lead to similar intracellular
efficacy. The infant, particularly the neonate, has a very
polymorphonuclear response from his marrow and many of the lymphocytes
are undetectably committed in the neonatal period as to what kind of
cellular markers they\'re going to express. And I don\'t know how to
interpret all of that, other than to say it makes me very uncomfortable
in the neonatal period that pharmacokinetic data alone on blood levels
is actually going to predict biologic response.

DR. LEWIS: Just as a response to that, there has been a lot of debate,
particularly with the nucleoside analog drugs, about exactly what is the
most useful pharmacokinetic parameter. Is it a serum level or a plasma
level or is it an intracellular level, which gets to your question. We
still don\'t have excellent technology for determining those things. So
the best estimates that we can make that correlate are target AUCs and
Cmax for plasma and serum levels in many cases. We\'re getting a little
better at some of the intracellular levels, but again, those are even
different compared to the plasma and the serum levels.

I would love to hear a comment from the pharmacologists about that.

DR. RODVOLD: Well, I think you\'d have a tough time getting the answer
to your question until we have the PK answer because the next thing that
comes hand in hand is to model the PK with the PD. So if we don\'t get
the PK answered to a beginning degree ‑‑ and I don\'t think Courtney or
I are saying definitive studies here ‑‑ you can\'t even go on to the
next step and link it to toxicity or efficacy, which is what we would
ultimately want to do.

So I keep coming back to we need to turn this back to let\'s pretend we
almost don\'t have any information. What would you do the first time in
man? A single-dose study or a really well-designed study, get some
information and get you comfortable to move up the next step and be
assured into some dosing level and then move on to collect that next
piece which is the link of efficacy and safety. But I don\'t want to
give up on that knowledge I know too. So I want to use some of that in
here at this point. But that\'s going to have to be done.

DR. FLETCHER: I absolutely agree with Keith. I should probably preface
at least all my comments in the context in which we\'re discussing this
in which the question has been raised. Should we require these data at
all? And so if that\'s the question on the table, my answer is yes, we
should require it, but I think there are some things we could do to
perhaps obtain this information in an easier way, in a quicker way than
what we\'ve done before. But Keith is right. The PK really just become
the starting point for then I think the whole continuum of
antiretroviral drug development in neonates, infants, and children.

Just a final comment on the point about phosphorylation of the
nucleosides. Right now zidovudine, AZT, really remains the drug about
which we know the most. What has really struck me from the studies
principally conducted at St. Jude in children ‑‑ granted phosphorylation
data are really quite limited, but when you look at the phosphorylation
of this drug to its active triphosphate form in children and you compare
those with adults, there are just no striking differences. There are
different dosing regimens that we use now because of differences in
pharmacokinetics, in absorption, distribution, and metabolism. But when
that is done, the intracellular triphosphate levels look very, very
comparable.

DR. CHESNEY: Dr. Nelson and Dr. Hudak.

DR. NELSON: As we were discussing questions 1 and 2, there were a number
of different criteria that we brought out for when we thought a trial
might be indicated in either HIV-infected or HIV-exposed infants. The
form of the question bothers me a little bit because the way that I
would want to ask it initially every antiretroviral under development
sort of implies that it\'s a drug-related request as opposed to a
population and study-related request.

One could look at this as just a question of whether you can extrapolate
scientifically, but I would want to bring into this all of the various
conditions that have previously been discussed as to whether a trial is
appropriate in the first place. And I personally would hope that one
would never request, as part of a written request, a study unless you
could imagine that it could be done ethically.

I\'m assuming that\'s true, but the question is just worded from a
scientific extrapolation point of view and I just want to make sure ‑‑
that\'s what\'s been bothering me ‑‑ that we\'re not going to ask for
studies just because we want the data as opposed to we think that this
study ought to be done and we need the data in order to do the second
study after we have that data.

DR. DIANNE MURPHY: I think I just have to respond to that.

(Laughter.)

DR. DIANNE MURPHY: This committee and certainly the members of it know
that we always consider the ethical issues or hope we do. And if we have
any concern, we frequently bring it to this committee and certainly
would not go forward with a study if we were concerned. Again, our
mandate is that it has to have a public health benefit, and certainly an
unethical study would not be a public health benefit.

DR. CHESNEY: Dr. Hudak.

DR. HUDAK: I\'d just like to probably state the obvious that maybe
everyone is thinking about. Some disproportionate percentage of these
babies are born preterm. And we\'re talking about pharmacokinetics and
so forth, and there have to be provisions made obviously to study some
adequate number of the very preterm babies to get good information
because we sort of fly by the seat of our pants many times with these
kids. And I don\'t know how this population pharmacokinetics works with
preterm babies who are clearly very different or can be very different
many times.

To anyone who has any doubts about how many babies might have to be
studied for these things, one can just think that every three years we
have different recommendations in vogue for the dosing of gentamicin and
vancomycin in preterm babies based on gestational age and postnatal age.
It really changes every three years, and clearly these are very
well-studied drugs.

DR. CHESNEY: Dr. Englund.

DR. ENGLUND: I think that\'s a very, very good point.

One thing I would like to say that might influence the FDA advisors is
whether the drug is an oral or intravenous formulation. In fact, we have
a paucity of intravenous formulations for these preterms because in fact
many of them have more oral formulations and that might be more
applicable to third world countries. But because there\'s such a
potential need for the intravenous formulation, that should be viewed by
the FDA as ‑‑ you know, a drug that would have different formulations
would be an advantage to those of us practicing clinical medicine and we
would encourage multiple routes of development depending on the
formulation of the drug.

DR. CHESNEY: With respect to the first part of this question, can
anybody give specifics as to when we would not request pharmacokinetic
and safety studies for a new antiretroviral drug, given that it was
safe, everything was being done ethically, and it had been looked at in
older children? Can you think of any me-too drug or new drug that you
don\'t think should be tested in children? Dr. Gorman.

DR. GORMAN: My answer to this question would be no. Every antiretroviral
drug should not be tested. The question that you just asked is the
answer. One is if there\'s an emerging resistance pattern that makes
that antiretroviral drug worthless, or two, if there\'s emerging
toxicity data that shows that other drugs in that class have a toxicity
which is unacceptable.

DR. CHESNEY: Dr. Wilfond.

DR. WILFOND: I can think of a second reason. Again, this gets back to
the distinction between use for treatment versus use for prevention. If
there was a drug where the intended goal was only to be used for
treatment of HIV-infected individuals, then it would make no sense to do
any studies in HIV-exposed and not infected individuals.

DR. CHESNEY: Are there existing examples of that kind of a drug, Dr.
Mofenson?

DR. MOFENSON: Linda?

DR. LEWIS: I don\'t know that we\'ve found one yet, but there could be
with some of our future drugs.

DR. CHESNEY: Dr. Fink.

DR. FINK: I was just, I guess, puzzling over that issue of if we were
looking at what kind of drugs ‑‑ it seems like usage for most drugs is
going to, first of all, occur in the pregnant female, and if it doesn\'t
have bad effects on the fetus, how much comfort or not can we take in
that. Particularly if it crosses the placenta, you\'re going to see a
large number of infants born with in utero exposure well before we
probably ever undertake clinical trials in that age group.

DR. LEWIS: Yes, certainly pregnant women are now being treated much more
aggressively than they were when I was coming through training. So they
are treated with multi-drug regimens. Some of the drugs we know are
mutagenic or carcinogenic at least in animal studies, and we accept that
risk in the pregnant woman both for her treatment and health and
well-being and hopefully for prevention of perinatal transmission.

I think there are still physicians who are a little hesitant to use very
new antiretrovirals for which there\'s not a great deal of data
available in pregnant women, but that\'s more a clinical management
issue.

We have very little data on these drugs actually in pregnant women, and
some of the studies that are being done now, as I said, enroll the women
during the second or third trimester and follow them very closely and
then follow the infants after delivery. So we have gathered some data
but not very much specifically in pregnant women.

DR. FINK: It raises a question since pregnant females are a large part
of this discussion if we\'re dealing with neonates. What is the FDA\'s
stance on asking companies to do pharmacokinetic studies on the pregnant
female? When your blood volume increases by 50 to 75 percent and there
are large circulatory changes in renal function, are we treating
pregnant females with the right doses?

DR. DIANNE MURPHY: Sandy Kweeder should be here. We have a group of
individuals at the FDA who basically have taken on the activity of
making sure that pregnant women do have those sort of questions
addressed and wherever possible, with all the usual caveats that
something you know would clearly be teratogenic, you would not. Talk
about the preemie having changes. We\'re still trying to find out how to
use some very old drugs in pregnant women and finding out that we are
achieving the right doses.

So the answer to that is that there\'s a group of people at FDA who are
very much focused on trying to make sure that these products are
appropriately studied in this population.

DR. CHESNEY: Can I ask a question of those of you who are caring for
these children all the time and very much a part of studies? Are there
toxicities that you would accept in a new drug that was very potent to
treat an infected child but would not accept to use in an exposure
prophylaxis setting? In other words, a child who had a very resistant
organism and this drug was going to do exactly what you wanted, but it
had some renal toxicity. Would you accept that in that child as opposed
to an exposure prophylaxis setting? Which I think goes back to what Dr.
Wilfond was saying that you might accept a drug in one setting and not
another. Maybe there\'s no precedent for that.

DR. MOFENSON: Just a comment. The use of drugs for prophylaxis is
different than chronic use for treatment. So when you\'re talking about
prophylaxis, you\'re talking somewhere between 1 dose and 6 weeks to the
baby. So you may have a drug that has a chronic toxicity, but that
chronic toxicity may not be seen with a shorter course. So your question
is I think more complicated than you thought it was.

DR. CHESNEY: That doesn\'t surprise me.

(Laughter.)

DR. CHESNEY: But I think it does pertain to the second part of this
question, which drugs might you study and which ones might you not.

DR. CHADWICK: Dr. Chesney, just as a treating physician, I think that
most of us would accept more toxicity in the treatment setting than we
would in the prophylaxis setting. Certainly Lynne\'s point, if it\'s
something that is reversible when you take away the medication, then
we\'d be more likely to accept the toxicity in prophylaxis as long as we
knew we\'re going to stop it.

DR. CHESNEY: Thank you.

Dr. Mofenson.

DR. MOFENSON: But take nevirapine. When we tested that in pregnant women
and newborns, we knew that it rarely caused Stevens-Johnson syndrome
which was occasionally fatal. It was a small percentage, but we took
that risk when we tested that drug. So yes, that\'s true, but yes, it
isn\'t true too.

DR. CHADWICK: But, again, you\'re talking about a very small percentage
of the time it\'s toxic as opposed to a more routinely toxic problem.

DR. CHESNEY: Dr. Nelson.

DR. NELSON: This morning when pharmacokinetics was discussed, the term
\"fade-out PK\" was used, and my question, for those who have the
scientific background, is how much mileage would you get from
identifying pregnant women who are on medications that cross the
placenta and then do fade-out pharmacokinetics to get the kind of
information you may want to know about the neonate. And how applicable
would that be to prospective dosing of that neonate, or at least of
other neonates like that neonate?

DR. FLETCHER: I think potentially you could get a lot of mileage out of
that. It was brought up earlier that if one were to do a PK study at 3
weeks of age, that may not be as informative as you would like if you
were going to use that drug for treatment in a newborn beginning at
24-48 hours of age because of some of these changes in metabolism. It
would seem to me, as you described, if the drug did cross and you were
able to then in the newborn, without giving a dose, follow that decay of
drug in the body, that that half-life would probably much more closely
mimic that half-life at birth than might a half-life determined at 3 or
4 weeks of age.

In a sense that\'s really the first study that was done with AZT. It was
following the decay in infants that had been exposed, and it was I think
quite informative in terms of how then to begin designing that initial
dosing regimen for the first 6 weeks of life.

DR. NELSON: As a follow-up, since the pregnant women who are infected
would be likely or ideally on highly active treatment with some of the
medications that we might be uncomfortable just starting off giving to
the neonate, if there is placental transfer, doing initially a fade-out
PK would give you data without making the choice to expose the neonate
to the drug after birth. So it may be a nice way to perhaps have your
cake and eat it too in some of these difficult classes of drugs to
study.

DR. FLETCHER: Again, I agree. Dr. Sever talked about some of the
analytical developments that have gone on. They\'re not in every lab
now, but certain tandem mass SPECTs that have higher degrees of
sensitivity so you can quantitate much, much lower concentrations than
you could before. They\'re reasonably available, which I think makes
these washout studies feasible for a larger number of drugs than might
have been five years ago.

DR. SPIELBERG: It is indeed a great way of looking at clearance. What it
doesn\'t tell you is the performance of a pharmaceutical product. And
the neonatal gut is a pretty finicky organ that sometimes simply rejects
molecules for reasons we never know. You can give oral phenytoin till
the cows come home and you don\'t achieve levels. So one way or another,
you\'re going to have to go back and actually look at the pharmaceutical
product, the specific formulation, and the way that formulation is
bioavailable in the patient population of concern.

So you still are going to have to do the studies. But as a starting
point for looking at clearance and getting an idea of half-life and of
metabolism, et cetera, sure, we should take advantage of those things.

DR. CHESNEY: Dr. Rodvold.

DR. RODVOLD: Yes. You\'d probably get half-life very accurately. You
probably won\'t even get clearance because you don\'t have the dose you
gave, and so you don\'t know how much was coming. You don\'t know the
starting spot. Mom sent something, but you don\'t what it was that she
sent. So you\'re missing dose, the amount that\'s coming, and that\'s
the critical parameter to calculate clearance and volume. And you would
never have volume. So you\'re missing the physiological parameters.

DR. SPIELBERG: You\'re not going to get Cmax.

DR. RODVOLD: But I mean, it gives you some information. I would still
encourage, just like what Courtney said, to do some studies in certain
selected drugs. The more toxic the drug was, you\'d up it. You\'d
probably do it that way. But like what Steve is saying, you still have
to come back to the issue to be able to sort out dose and dosing
interval with better science eventually. So in certain cases it would
work. Probably the higher the toxicity rate was on the compound or
concern to give the neonate the compound, that might be then the first
step you would do to be able to minimize that on the back side. So
there\'s some application.

DR. CHESNEY: What I think I have heard is that we would encourage every
new antiretroviral drug under development to be looked at in infants
except a drug that had unacceptable safety in older children and a drug
that, for whatever reason, didn\'t have potential use for HIV exposure
prophylaxis.

Were there other suggestions as to when we would not recommend that a
new antiretroviral drug be looked at?

(No response.)

DR. CHESNEY: Do you want an official vote on that? Is that enough
information?

Dr. Englund has thought of a reason.

DR. ENGLUND: This is an addition. I do think that we are not going to
encourage breastfeeding in our country, but it\'s something to consider
to evaluate if the drug is going to be used in other countries as to how
much of the drug is actually transmitted in the breast milk. But, of
course, we\'re not going to do it here. So you can say that\'s only for
non-U.S.-based things. But it\'s something to think about. We could get
toxicity of an agent potentially if we\'re dosing the baby and the
mother is transmitting it too.

DR. CHESNEY: If this is acceptable, I think Dr. Oleske had something
additional he wanted to add. It is our choice outside of the official
public hearing. So it is our choice to hear from you again.

(Laughter.)

DR. OLESKE: I\'m sorry, and I appreciate the privilege.

I\'ve been biting my tongue in the back, obviously. There are a lot of
things I had wanted to say. But I just wanted to make one point, and
that is the reason that many of us who have been taking care of patients
are anxious to see studies go on ‑‑ I just remind everyone, in \'83,
\'84, \'85, when we started thinking about AZT, it was 10 years or
almost 8-9 years before we showed it dropped transmission, and then the
transmission rate dropped very rapidly. So a delay of a few years can
mean a lot in pediatrics.

So if there\'s some anxiousness in some of the people maybe behind you,
as well as at the front of the table, it\'s that we want drugs
appropriately and ethically studied in infants and children as soon as
possible, and if you don\'t start with infants, they get delayed in
being studied in children and there\'s linkage between going from
pregnant women to infants to children that you have to sort of
understand.

DR. CHESNEY: Thank you.

Do you want any more input from the committee on your questions before
we move along?

DR. DIANNE MURPHY: No. I think what you\'ve heard from the division is
that they\'re clearly getting one side of the discussion from others.
They felt it very important to get input from a variety of other
perspectives.

I\'m whispering on the side here to make sure the division doesn\'t have
anything else that it would like to ask you today. It would be unfair,
but we would take advantage of it if we could. Linda?

DR. LEWIS: No. I think this discussion has been very helpful. As I said
earlier, the issuing of written requests for pediatric studies is a
collaboration between a pharmaceutical company and our division. We are
always happy, if the sponsor feels that a particular study design might
not be able to be done or if they feel there is some other study that
they can do better, to evaluate that in the context of now this
additional information we\'ve gotten. I think this has been a very
helpful discussion.

DR. CHESNEY: Given that we\'ve only been sitting here for an hour and 5
minutes, could we bypass the break and go on to at least hear Dr.
Murphy? Well, wait a minute. There\'s an objection.

DR. DIANNE MURPHY: I think they can release some of these individuals
who may wish to be released.

(Laughter.)

DR. CHESNEY: That was the objection. So I guess it is best if we take a
5-minute break and then reconvene just the members of the committee.
Sorry about that.

DR. DIANNE MURPHY: Thank you all very much. It really has been very
productive and helpful input.

(Recess.)

DR. CHESNEY: I think we\'re ready to get started for the second part of
the program, if people can take their seats.

So our next issue on the agenda is an overview of the Division of
Pediatric Drug Development, the Office of Pediatric Therapeutics by Dr.
Murphy, and I think we\'re all very eager to hear the picture from on
top. I don\'t think Dr. Murphy needs any introduction, although I can do
that if you would like, Dianne.

DR. DIANNE MURPHY: No. I\'ll keep my past sins quiet. Thank you, Joan.

Thank you all. This is the overview of alphabet soup. At the end of the
session, I hope you\'ll know the difference between OPT and OCTAP and a
variety of other acronyms.

This is what will happen through the rest of this afternoon. I\'m going
to provide a quick overview, as much as my Irish background can allow me
to anything succinctly, of the pediatric organization and the new Office
of Pediatric Therapeutics.

Then we\'re going to move into an arena, in which you will be involved
in the future, which is receiving updates on the safety reports that we
have on products that have been granted exclusivity. As you know, the
legislation mandates that we report this to this committee and you
advise us if we need to do anything further than what we\'re already
doing. You will hear about how we obtain reports and how we plan to
implement this new program and get the preliminary assessment of the
first product that we\'re able to provide this information on. This is a
product that was granted exclusivity and which has been out there almost
long enough for us to provide you data. So we\'re going to provide it to
you in a preliminary manner. Dr. Solomon Iyasu will do that for us.

Then finally, you\'re going to get to meet Dr. Shirley Murphy, who is
our new Division Director. And we don\'t just hire by name.

(Laughter.)

DR. DIANNE MURPHY: We try to stay out of jail. It just happened to be
the best qualified candidate. So what can I say?

We\'re just delighted to have her here, and she will be presenting to
you the tremendous range, the broad range of activities that are going
on in this division and the types of consults and types of activities
that we are involved with. She\'s described as the marriage made by
Congress, our collaboration with NIH and NICHD that is becoming quite
intense.

At the end here, Terrie Crescenzi will provide you with our latest
update on all the activities which have been ongoing, including the now
50 new labels that we have. It\'s sort of a new marker for us.

Also, before I move any further into this, I wanted to say Rosemary
Roberts says hello to everybody. She\'s sorry she cannot be here. This
would usually be something she would be doing, and I probably won\'t do
nearly as good a job. Rosemary, the deputy in OCTAP, which you\'re about
to hear about, is on detail down to the Department working on a
counter-terrorism issue for us for bioshields. So she is well utilized
at the moment but did wish to send her greetings to you.

At one time we were simply an activity within the FDA, a lot of
pediatricians advocating for children, and with the help of many other
people, were able to develop a number of groups and teams. You\'ve heard
pediatric team. You\'ve heard the pediatric committees. You\'ve heard of
PDIT, pediatric implementation team.

They finally made us an office about two years ago which was the Office
of Pediatric Drug Development Program Initiatives. And within those
program initiatives, as you\'ll remember, we had pregnancy labeling. We
had pediatric drug development. We had drug shortages. We had antibiotic
resistance and we had counter-terrorism, just because we didn\'t have
enough to do I guess. So those were all the initiatives that were in
this office.

As of 9/11, they decided they really needed to reorganize us once again
and very gratefully infuse more resources into this office. The OPDDPI,
which was unpronounceable even as an alphabet, morphed into OCTAP, which
is the Office of Counter-Terrorism and Pediatric Drug Development. We
now actually have, besides teams ‑‑ this is the big news ‑‑ real
divisions, which is an important step from a structural and
organizational point of view because you get more FTEs, you get
basically more recognition.

We now have two divisions. One division is dedicated to pediatric drug
development. That does not mean, as you will hear, that we are doing all
the pediatric drug development within FDA, but we are basically
coordinating the activities across the Center for Drugs. Also within
this office is the Division of Counter-Terrorism which handles drug
development for the Center for Drugs for antidotes for
counter-terrorism.

Now, that was before BPCA. What you see up here now is we have also
after BPCA the Office of Pediatric Therapeutics. Everyone knows Best
Pharmaceuticals for Children Act, BPCA. The Office of Pediatric
Therapeutics is placed in the Commissioner\'s Office and reports to Dr.
Mack Lumpkin who has been an advocate for children for many years within
the agency, and he heads up the Office of International Activities and
Strategic Initiatives so that the Office of Pediatric Therapeutics is
basically reporting to Mack up here, and all of this is within the
Office of the Commissioner, versus OCTAP which goes up through the
Center for Drugs, which is CDER. The Center Director is Janet Woodcock
who reports up to the Commissioner.

As I said, this office was established under section 6. Again, because
there might not be enough for us to do, this new office is supposed to
coordinate and facilitate all activities at FDA that may have any effect
on the pediatric population or the practice of pediatric medicine or may
in any way invoke pediatric issues. They got carried away at Congress
when they wrote this one up. So that\'s our job description.

Now, knowing that job description, they decided we needed an ethicist
and a safety person. So within the legislation, they only identified two
positions that we\'d actually really have to have, and then they left it
up to FDA to try to take care of all these tasks in the way it saw best.

We have the ad running for the ethicist in the New England Journal of
Medicine, and we have one or more experts in pediatrics, particularly
safety issues, with Dr. Solomon Iyasu. I am not going to read through
everybody\'s credentials but just say Solomon comes to us from CDC with
a tremendous background and experience working with NIH in epidemiology,
and we\'re very glad to have him on board.

Now, the impact for this committee, as far as the Office of Therapeutics
is concerned, is that we see subpart D and adverse event reporting as
two activities this committee will be progressively involved in, in
addition to the usual stuff that we\'ve been bringing to you.

I have to preface this by saying the organizational structure for how
we\'re going to handle the referrals to FDA under the subpart D section
in which an IRB sends a referral to FDA, because it\'s a regulated
product, is not completely defined. I should say this is my perspective
on it right now. We want these discussions of any referrals that come to
us from IRBs to be in the public domain. So we anticipate that if we
don\'t utilize this committee, we will utilize parts of this committee.
Plus, the ethicist people who have helped us on previous ethical issues
would be asked to participate in a panel that would be involved in
addressing any of these issues that come to us under ‑‑ I can never
remember all the numbers. What is it? 5054. Because you saw, it\'s more
the minimal risk and it\'s not direct benefit and they\'re having to
decide and they want additional input.

This does not usurp anything that would go to HHS that would be a
federally funded program. If it\'s federally funded and regulated, then
we have a joint committee. But what I\'m talking about the people in
this room may be involved with more in the future would be where it\'s a
regulated product only, not federally funded, and that there are issues
that an IRB is sending to us. So we would need to put together an expert
panel, and we anticipate that the future process would involve many
members of this committee plus others.

The adverse event reporting is pretty well described within the
legislation fairly succinctly. You\'re going to hear more about that, so
I\'m not going to talk much about that, how we\'re planning to do that
and the role we think you will play in that.

This summarizes basically the fact that we\'re supposed to report to you
on a yearly basis.

As I said, in developing the written requests for the off-patent
products, we have now developed a very delineated, focused relationship
with NIH, NICHD, in how we put together written requests that are going
to be going out for contract. Well, the same thing has happened
internally for us when developing this program of adverse event
reporting on products that have been granted exclusivity in working with
our own Office of Drug Safety. As I said, I\'m going to ask Dr. Iyasu to
explain more to you about how we see that this program will move
forward.

How to avoid overlap and duplication? You\'ve got this Office of
Pediatric Therapeutics at the Commissioner\'s Office. You\'ve got OCTAP,
which is an office that\'s overseeing pediatric drug development, and
you\'ve got a Division of Pediatrics. So this is how we do it. We all
hold up our sign when we answer the phone.

(Laughter.)

DR. DIANNE MURPHY: This is truly trying to avoid creating multiple
layers. So in a true government way, we all get multiple jobs instead.
It helps in the efficiency of the communication activities, needless to
say, in that most everybody is involved at all levels. And that\'s
Rosemary down there holding the OCTAP. She\'s the deputy in that office.

And the big news is ‑‑ we got this last week, folks ‑‑ we have an e-mail
address, opt@fda.gov, for the Office of Pediatric Therapeutics. We have
a phone, the one we were all answering, and we also have a fax number.
We would be glad to entertain questions that people have. Terrie
Crescenzi, whom you\'ll hear from, is the lady who is in charge of
making sure all of your questions are addressed and answered. That was
another job she got too in all of this.

That is really all I had to say about the alphabet soup, and I will let
others give you more meat and details as to how we\'re really going to
do this.

So, Min Chen. Was I supposed to do her background introduction? Do you
want to do it, Joan? Do you have it? I\'d appreciate it. Thank you.

DR. CHESNEY: So Min Chen is the Associate Director of the Division of
Drug Risk Evaluation in CDER\'s Office of Drug Safety. She\'s been with
the FDA\'s Postmarketing Safety Office for 13 years. Prior to that, she
was a project manager for a CDER New Drug Division and a practicing
clinical pharmacist for many years.

She graduated from the University of Missouri and National Taiwan
University with a masters in pharmacology, has special expertise in the
FDA\'s program for postmarketing safety evaluation and pharmacovigilance
practice and in the agency\'s postmarketing safety reporting regulations
and guidance.

She\'s going to be giving an overview of the FDA postmarketing safety
surveillance practice for drugs and biologics.

MS. CHEN: Good afternoon. This overview provides some introduction to
Dr. Iyasu\'s presentation later regarding how the Office of Drug Safety
supports the Office of Pediatric Therapeutics as far as drug monitoring
in the pediatric population. After Dr. Iyasu\'s presentation, if you
have any questions about our system, I\'ll be happy to answer them.

I\'ll go over some of the following: Office of Drug Safety organization,
postmarketing reporting regulations, the Adverse Event Reporting System,
often called AERS, and how we evaluate a case report and assess the
safety issues in CDER, some of the regulatory actions and the risk
management programs that can be proposed for some safety issues.

The Office of Drug Safety is in CDER under Dr. Janet Woodcock. We\'re
with the Office of Pharmacoepidemiology and Statistical Science headed
by Dr. Paul Seligman. The Office of Drug Safety is headed by Dr. Victor
Raczkowski. In the Office of Drug Safety, there are three divisions: the
Division of Drug Risk Evaluation, Division of Medication Errors and
Technical Support, and the Division of Surveillance, Research and
Communication Support.

Overall, the Office of Drug Safety has about 95 staff members, supports
15 Office of New Drugs reviewing divisions who have all the regulatory
authority. They review all the new drugs. We have safety evaluators,
epidemiologists, some social scientists and project managers as a
functional pool with different expertise.

I want to talk a little bit about postmarketing regulations, and I think
everybody is very familiar with this. Why do we need postmarketing
monitoring? Because there are limitations of premarketing clinical
trials such as the size of the patient population studied during
clinical trials. Usually it\'s limited about 3,000 or 4,000 people. And
a narrow population because the elderly, children, women may not be
included in a study. Narrow indications, certain disease states will not
be included in a study, and finally, there\'s a short duration, only
about a few months to a year maybe at most to study this. So it\'s not
reflective of the drug\'s potential chronic use problem.

Beyond approval, hopefully in the postmarketing arena, we can monitor
and detect low frequency reactions that have not been identified in
clinical trials. We can see some high risk populations that experience
some problem with the drugs, long-term effects or drug-drug and
drug-food interactions that have not been studied before and now we\'re
seeing them happening. Finally, a very important function we have here,
we hope to monitor the increased severity or increased frequency of some
recognized or known reactions identified during clinical trials.

The regulations started back in 1962, the Harris-Kefauver amendments to
the Food, Drug and Cosmetic Act. It mandates for the manufacturer not
just to prove there\'s efficacy from the drug, also they have to report
all the adverse events when they submit the information to the FDA.

Now, current regulations on safety reporting follow. There are quite a
few of them. It includes IND safety reporting and pre-1938. We call them
the grandfathered drugs reporting. Postmarketing prescription drugs
under the NDA, generic drugs, biologics, OTC drugs, and dietary
supplements. The most important one relevant to this initiative is
314.80. Most of the drugs have no reporting requirement unless the drug
was approved under the NDA. They follow the NDA requirement. Dietary
supplement and food is voluntary reporting now.

Source of the reports. We all know that it\'s voluntary from health care
professionals, consumers, patients, or others like lawyers. We\'ve often
heard about the spontaneous reporting, and that\'s the same thing,
voluntary reporting.

The manufacturers are required for postmarketing reporting, and actually
more than 90 percent of the reports come from manufacturers.

This is the MedWatch form as a vehicle of reporting. In your package,
you see a yellow sheet that\'s an example of a form.

The manufacturers should report the commercial marketing experience,
postmarketing studies, scientific literature that has any adverse event.
That means that all domestic spontaneous reports should be reported.
Foreign and literature reports, only serious unlabeled events should be
reported. For study reports, in addition to serious unlabeled criteria,
there should be a causality assessment in place, that if there is a
reasonable possibility that an event is related to the drug, then a
report should be submitted to the agency in an expedited manner. That
means within 15 days.

Well, it would probably be useful to list all the regulatory definitions
of \"serious\" in order to understand what kind of reports would be
qualified to be sent in to the agency in an expedited manner. Death.
Life-threatening. Hospitalization includes initial hospitalization or
prolonged hospitalization due to the adverse event experienced.
Persistent or significant disability, birth defects, congenital anomaly,
or any important medical events that may require medical or surgical
intervention to prevent one of the above outcomes. So this is an
outcome-based definition of serious.

There are many factors affecting reporting: nature of the adverse event.
As we know, more serious ones will get reported more. And type of drug
product and indication. More widely prescribed drugs will be reported
more than the orphan drug indications. And prescription OTC status.
Length of time on market or public or media attention such as this one
will probably stimulate more reporting. Sometimes the manufacturer\'s
surveillance system will give more reporting and probably a better
quality of information than we have received.

However, we all know there are plenty of limitations of this system,
this kind of reporting. It\'s a passive system, so we don\'t get all the
reports. We don\'t know the exact incidence out there. Reporting bias
may exist. Quality of the reports definitely are very variable and most
often they are incomplete. That\'s a major problem. Also, we cannot
reliably estimate the rates of the adverse event that we are interested
in because the numerator is uncertain and the denominator can only be
projected.

This is just a reporting trend in the last 10-12 years. As you can see,
it\'s been increasing due to many, many factors. We have more drugs and
public interest, so we get more reports. On average nowadays, we get
270,000 reports a year. The yellow part is the 15-day reports. Those are
the ones that are serious unlabeled events that got reported in a timely
manner within 15 days, and that has been increasing too.

This system is a database of spontaneous reports established in 1969 and
restructured in 1997 with greater capacity to accommodate
internationally accepted reporting standards such as E2B data element
for each safety case report and MedDRA coding terminology. That is a
medical dictionary for drug regulatory authority. So we use that to code
adverse events and the indications for retrieval of the case reports
from the system. It allows the electronic submission transmission
standard using the internationally established standard.

The process flow here for the paper MedWatch form you have sent. Some of
you have personally filled out a form and sent it to us. We appreciate
that. The form received by the FDA will be sent to the contractors to
scan every report into images for retrieval, and then each report will
be text data entered in E2B format. Adverse events and indications are
coded in MedDRA.

The safety evaluators ‑‑ and those are the reviewers in FDA in the
Office of Drug Safety ‑‑ will review this report in our electronic
in-box you will see on the next slide. For all the 15-day reports and
direct reports sent to the FDA, we screen and monitor any potential
signals from the reports.

The 15 reviewing division medical officers also have access to this data
through AERS Datamart. It\'s a database very similar to AERS.

The electronic submission allows some companies already in place to send
these case reports electronically directly into our database via a
gateway. That\'s very cool. We can get our reports right away.

As I said before, the safety evaluators will try to identify and assess
previously unrecognized new serious adverse events. We do hands-on
review of all these reports. Most intensive monitoring actually occurs
over the first several years of some new drugs, but it\'s continued over
the drug\'s lifetime.

This is a typical in-box of a safety evaluator. We\'ll have the line
listing of the case reports sent in to our office. Each person will
review each of the reports, and we can highlight each report in a line
listing, review a little more on this screen. This captures some of the
MedWatch information like patient information and reporter information,
manufacturer information, product information, reactions, and MedDRA
codes. The most important part is the event narrative, a description of
the adverse event. We review and read each of these and try to establish
the temporal relationship between a drug event based on the information
here. You probably know a lot of times the information is not complete.
We have to do a lot of follow-up with the reporter to get more detailed
clinical information to establish the relationship.

We\'re all looking for some good reports to help us out to evaluate
these safety issues to see whether there are really safety signals. What
are the elements of a good report? Hopefully it will contain complete
data about suspect drug therapy dates, concomitant drug therapy dates,
and patient medical history. Hopefully the patient\'s baseline status
has been documented, and there is confirmed diagnosis of the disease.
It\'s not he says/she says, but we have medical information to document
that. Trying to establish the temporal relationship between a drug event
by using dechallenge/rechallenge information.

How do we generate a signal? If there is no threshold, how do we define
the signal? One good case with a new drug a very serious event may
constitute a signal. Of course, many times we need more good case
reports from the system or from literature publication ‑‑ usually they
have better information ‑‑ or other sources like public interest can
trigger further evaluation of any potential safety signal.

From our database, if we find that there is a high number of reporting
for certain events coded as PT or other higher level grouping case
counts, that can trigger us to go into more investigation of potential
safety signals.

Evaluation of the reports. Hopefully we have one very good case or good
case series to review collectively to find out whether there is
something that we need to go further. We try to establish the temporal
relationship at the case level and we try to establish a case
definition, if possible, to give us a better criteria or better cases to
evaluate the safety issue. We look for trends and patterns of events
like age and gender, time to onset, dose severity, and outcome. We try
to identify risk factors among the case series and then we try to
evaluate strength of the evidence for a causal relationship between the
drug and event, and finally to assess the clinical significance of this
issue.

We have a big staff of epidemiologists. They will help us out to
calculate the reporting rate, if appropriate, using the drug utilization
database such as IMS, such as PCS, to find out a background incidence
rate of a certain adverse event by using the literature sources, the
knowledge to see how big the background rate is for that event, to help
us understand what is the reporting rate we have in our system.

If we don\'t have a good idea, we can always query large databases
outside the FDA via cooperative agreements such as the Medicaid or large
health plans\' databases. We can initiate a feasibility study to see
whether we can answer some questions from those searches,
investigations.

We\'re trying to develop some active surveillance methods to look for
drug-related adverse events in a more prospective fashion.

The drug safety assessment in the Office of Drug Safety does not just
provide signal generation. We also try to address many safety issues
outside of CDER, FDA, such as the Congress, the Government Auditing
Office, HHS, FBI, Consumer Product Safety Commission, and foreign
regulatory authorities. There are constant requests from all different
interested parties. We\'re trying to develop risk management programs,
and we\'re trying to be involved in advisory committee meetings such as
this one. In the past we have participated in PPA, COX-2 inhibitors, and
non-sedating antihistamines, just a few of the examples.

Communication within the FDA is very frequent. We maintain informal
communication with the reviewing divisions all the time. We have safety
evaluators collocated in the different buildings with a reviewing
division so they can talk to the medical officers all the time. We have
pre-approval safety conferences, that means those conferences right
before the drug is approved. We talk to the reviewing division about any
safety concerns trying to develop some strategy for postmarketing
monitoring. There are also regular safety conferences with the reviewing
division to go over the pending safety issues. We have written
communications to summarize the analysis and assessment of any specific
safety issues, or sometimes we do overall safety review of a drug. And
we have advisory committee meetings as a communicating vehicle too.

What are the possible regulatory actions or risk management programs
once the safety issues are identified? There are labeling changes in the
ADR sections, adverse drug reaction sections, precautions, warnings
sections. If needed where the risk is high, working with the reviewing
division, it\'s proposed to restrict the use of the drug, a registry, or
special monitoring being put in place. We try to evaluate the
effectiveness of any of the risk management programs and revisit this to
see whether it works, and if it does not work, what can we do. Of
course, if everything fails, there is the withdrawal from the market
option there.

Just to touch a little bit on risk communication, there is a physician
package insert everybody is familiar with. There\'s a patient labeling
the company put together to give to the patient, and there\'s a MedGuide
for high risk drugs that\'s dispensed every time the drug is dispensed
so a patient has information in hand to read. There are \"Dear Doctor\"
letters sent out by the company every time there is some specific
warnings needed to be communicated right away to the doctor. FDA will
issue talk papers, public health advisories, and then some peer-reviewed
journals, publications to inform the public about this safety
information. FDA has a MedWatch website posting all the FDA published
safety information that is public, actually worldwide. Interested people
can visit that to get the information.

That\'s it. Thank you.

(Applause.)

DR. DIANNE MURPHY: Joan, because we\'re going to move on, if people have
questions, maybe we could take them after each speaker.

DR. CHESNEY: Any questions? Yes, Dr. Glode.

DR. GLODE: I have a question. So if you have 270,000 a year, that\'s
about 1,000 a day that are being reviewed. Does the reviewer review the
same drug? Are all the reports on fosamax sent to the same person or on
any given day, might different people review those?

MS. CHEN: First, I\'d like to clarify that. We receive 270,000 reports.
There is no way anybody in the world can review all these reports. So in
practicality, we only review all those 15-day types, which is those
serious unlabeled event reports and direct reports sent to the FDA.
That\'s why we have about 20-23 people reviewing this by therapeutic
categories. So one person will monitor one drug, all the reports sent in
to the FDA.

DR. GLODE: Okay, that\'s what I was wondering because I just wondered
about sort of automatic red flags as opposed to supposing that the
person is going to use their own judgment in that regard. I mean,
life-threatening or death. I assume all of those are.

MS. CHEN: Yes. Based on the reviewer\'s clinical skills and knowledge of
the drug, every time they look at the reports, hands-on review of the
reports that are received in our in-box, they have to make a judgment
whether there is a safety issue there they should work on further, such
as retrieving other similar reports in our database to see is it 1 case
of aplastic anemia or 10. That can help us out to see whether we need to
follow up and get more information to work on that issue right away.

DR. CHESNEY: Dr. Nelson.

DR. NELSON: I guess let me ask a clarification of your answer to that
other question before I ask my question. When you say serious unlabeled,
do you mean that the adverse event you\'re reviewing is not listed on
the label?

MS. CHEN: Right. Each case report can have a lot of adverse events
happening. As long as there is one adverse event described there that\'s
not labeled and the outcome is a serious outcome there, that whole case
report constitutes a serious unlabeled event report to be submitted
within 15 days of the company\'s receipt. So not every adverse event is
unlabeled, but at least one of them.

DR. NELSON: My question. Whether you look at the full 270,000 or whether
you look at the ones that you review hands on, could you give a relative
percentage of those that would be an adverse event that occurs when
it\'s used within the label, meaning either for the population or the
indication, and those adverse events that occur because it\'s being used
off-label either in a different population or at a different dose or
indication?

MS. CHEN: When we look at a hands-on review of each report, whatever the
event that is very serious, we kind of prioritize all the different
kinds of events we have received. Of course, for those very serious
ones, death, life-threatening, liver transplant, or whatever procedure
needs to be in place, those are the ones that we will concentrate or
focus on first.

From that case series, if we find any risk factors such as off-label use
in pediatric population, we find out there\'s a high percentage use of
that, it certainly is a signal for us to look into that. If there\'s a
possibility of higher risk in a population, we need to address that if
it\'s not being addressed in the labeling.

So there are many, many issues in these reports that we can look into.
However, as you say, we have to look at something that is very serious
and something brand new and something that has more of a public health
impact.

DR. NELSON: If you had to describe the whole universe of adverse events,
can you say what percentage is related to on-label use where it\'s a
rare adverse event that occurs and it\'s just an extension postmarketing
of the same population or how many occur because it\'s being used
outside of the indications, in other words, off-label use?

MS. CHEN: We have not done any statistics like that in the past about
off-label use because the indication field is not usually very reliablly
captured by our database. Only since 1997 did we capture that field,
indication. Before that, it\'s not there. So it\'s hard to know the
exact proportion of off-label use.

But every time we look at any safety issue, we retrieve all the reports,
we do a hands-on review of each one of them, 20 or 100 or 200. We do a
hands-on review. Then we\'ll look at that data field to see what\'s the
possible off-label use. But for all the drugs, there\'s always some
off-label use. I just can\'t tell you what\'s the proportion of it.

DR. DIANNE MURPHY: Let me see if I can help with this. In their review,
they will try to obtain as much information as they can, calling the
physician, calling whomever they need to call. They will try to obtain
the information about was this used in a different way, in other words,
for a disease that wasn\'t listed as an indication, or even in a
different dosing way which would be off-label also. So they do try to
obtain that information.

I don\'t know, though, if anybody can give you a percentage of how many
times. We have certain drugs which have literally come off market
because, even though they were labeled for that, the dosing and the way
they were being used were incorrect. So it does occur, Skip. I don\'t
think anybody can give you an absolute percentage.

DR. CHESNEY: Dr. Gorman.

DR. GORMAN: Since all of this reporting is passive, whether voluntary by
individuals or mandatory by the companies, can you answer two questions?
One is the active surveillance that you mentioned. What strategies and
implementations are on the horizon, and are the obstacles to active
surveillance regulatory or resource?

MS. CHEN: I think that\'s a very good question. I don\'t have a lot of
answers. I think our office is trying to develop active surveillance
from different sources out there such as the child health agency and
then the AIDS population and I think Boston women\'s health, certain
populations that we can go in there and define what we want and
hopefully to find the information during a certain period of time of our
interest. I don\'t think we have gone very far yet. We\'re still using
spontaneous reports to identify some signals and then trying to go from
there, but I think that definitely that\'s a very important part of our
function in the Office of Drug Safety to develop that. If you have any
good ideas, also let us know.

DR. GORMAN: I guess do you have the regulatory authority to go to active
surveillance is the question I\'d like an answer to.

MS. CHEN: That I don\'t know. I don\'t think we have it in writing.

DR. DIANNE MURPHY: Well, I guess what we could say is that certainly
under PDUFA III we\'ve been given more authority. It\'s one of the
emphasis areas with more resources to become more aggressive
postmarketing. As part of the PDUFA III negotiations, the agency asked
for more resources and ability to do that. So it is an area which we are
actively looking at, as was described, as trying to develop a more
aggressive approach to what happens to a product after it gets on the
market.

I don\'t mean this in a negative way. I think the industry has realized
that it\'s really to their benefit for us to have better data and
information once a product goes out, or sometimes it may get blamed for
everything that happens to a person. So there has been a much more
structured process now going into place for trying to develop this
postmarketing surveillance in a very active way. Certainly if it\'s a
subpart H product or any of those under accelerated approval, they have
mandatory postmarketing activities.

But now I think what you\'re hearing ‑‑ as you heard earlier this
morning for some of the phase IV, the agency has been directed to become
more aggressive in how we follow up on our phase IV commitments. As I
said with PDUFA III, now we have more direction to become more active in
postmarketing follow-up when a product is marketed.

DR. CHESNEY: Thank you very much.

Dr. Solomon Iyasu is a lead medical officer in the Division of Pediatric
Drug Development and joined the FDA in November. Among his chief
responsibilities are monitoring postmarketing adverse events of
pediatric drugs, providing consults to other divisions within the FDA
and serving as the clinical contact point for the Office of Pediatric
Therapeutics and developing projection methodologies for inpatient
pediatric drug use.

Prior to coming to the FDA, he worked for 13 years as a perinatal
epidemiologist at CDC and most recently led the Infant Health Research
Program in the Division of Reproductive Health. He\'s a nationally
recognized expert in perinatal and pediatric epidemiology and has served
on the American Academy of Pediatrics\' Committee on Fetus and Newborn,
the Global Task Force on SIDS, and the National Children\'s Study,
Pregnancy and Infant Work Group.

He received his doctorate in medicine from the University of Delhi, his
masters of public health from Johns Hopkins, and is trained in both
pediatrics and epidemiology.

He\'s going to be speaking to us about adverse event reporting.

DR. IYASU: Good afternoon. I first would like to acknowledge Min and
Julie for their contribution to this presentation. They have been a very
supportive group for this presentation.

Min has provided you with an overview of FDA\'s postmarketing adverse
event surveillance system. I will be talking to you about one specific
surveillance activity, namely, adverse event tracking as mandated by the
Best Pharmaceuticals for Children Act. I will describe to you the
relevant section of the Best Pharmaceuticals for Children Act and also
will describe the FDA plan to carry out the mandate, including the
proposed adverse event report review template and finally give you an
example of a preliminary review of one of the drugs that has been given
exclusivity.

Section 17 of the Best Pharmaceuticals for Children Act, or BPCA,
enacted January 1, 2002, requires that FDA review adverse event reports
for a period of one year after a drug has been granted pediatric
exclusivity. It also mandates FDA to report to the Pediatric Advisory
Subcommittee for their review.

To comply with section 17 of the BPCA, we developed an adverse event
review plan and defined the roles and responsibilities of relevant FDA
competence. As Dr. Murphy mentioned before, the Office of Pediatric
Therapeutics will coordinate and facilitate all FDA activities that
affect the pediatric population or the practice of pediatrics. It\'s a
very broad definition, but its other main function is to receive
post-pediatric exclusivity adverse event reports and provide for the
review of the subcommittee.

The roles of this different FDA conference are described below. The
Office of Counter-Terrorism and Pediatric Drug Development, where I sit
now, will notify the Office of Drug Safety of drugs granted exclusivity
for the purpose of tracking adverse event reports. Although BPCA does
not specifically require us to track pediatric adverse events for the
drugs denied exclusivity, we will track them as they are also used in
children off-label. OCTAP will also serve as a clinical contact point
for the Office of Pediatric Therapeutics related to adverse event
reports.

And then the Office of Drug Safety will review all adverse event reports
for a one-year period after the date of granting exclusivity, and it
will complete their review within 90 days of the one-year
post-exclusivity date. However, when there are serious, unexpected
events, including deaths, the Office of Drug Safety will discuss them
with the Office of Pediatric Therapeutics immediately. An additional
role of the Office of Drug Safety is to share the adverse event reports
with the Office of New Drugs and, of course, with the Office of
Pediatric Therapeutics and OCTAP.

In collaboration with the Office of Drug Safety, an adverse event report
review template was developed. The proposed template identifies the
various components of the review. A copy of the proposed template is in
your handout which was handed out a few minutes ago. The template
contains an executive summary that must contain the important findings
and conclusions. It also contains the usage information for the drug to
help provide a national estimate of the extent to which a drug is used
in adult and pediatric patients. Use data is generated for two years
prior and one year after exclusivity is granted so as to provide some
trend data.

The next section pertains to the AERS search, or the Adverse Event
Reporting System search, and the search will be done for two time
periods. One will focus on the period from the drug approval date to the
present date, and the second search will focus on the one-year post
pediatric exclusivity. This search will generate counts of adverse
events for adults and pediatric age patients and also count the most
frequently adverse events and finally a count of unexpected or
previously not described events.

This is followed by a detailed review of post-exclusivity pediatric
event reports, which includes a description of the demographic
characteristics which mostly includes age and gender, and a description
of the serious outcomes, indications or conditions for which the drug
was used, and the dose ranges that may have been used, unexpected events
or events that are unique to pediatric patients or those occurring at
increased frequency more than expected are also described separately.
All pediatric deaths are reviewed, summarized, and evaluated to
determine if they are related to the drug in question. And finally, an
adverse event pattern or profile is developed based on the analysis of
all the available adverse event information, including the use data for
the drug so that we can at least have some preliminary estimate of some
reporting rates for each of those important adverse events.

To illustrate what the review looks like in real life, I will provide
you with an example of a review of sertraline, brand name Zoloft, the
first drug granted exclusivity after the law was enacted on January 4.
It\'s only 10 months\' worth of data and the review is based on
incomplete data and is very preliminary. So I just want to stress that.
No final conclusions can be drawn at this time. This was just done to
provide you with an example of how the system works so that you can give
us some feedback on the template. We plan to present to you a complete
analysis of the adverse events for this drug in the future and a few
additional drugs that will come due.

As shown on this slide, sertraline has several indications for use in
adult patients and recently was approved for use in children 6 years and
older for the treatment of obsessive-compulsive disorder. Sertraline is
a selective serotonin reuptake inhibitor and the first of March marks
the one-year post-exclusivity date for sertraline.

This table shows numbers of adverse event reports for sertraline from
international and domestic sources. The U.S. or domestic reports are
shown in parentheses on this table. When looking at this table, the
numbers are not going to add for two reasons. First, the total in the
first row includes reports with unknown age. Second, these counts may
include duplicate reports as well. Fortunately, duplicates are usually
easier to sort out by a very careful review.

Therefore, the AERS search for the 10 months since granting exclusivity
for sertraline generated about 892 adverse event reports domestic as
well as international, of which 577 were from the U.S. alone. Among
pediatric age patients, there were 41 adverse event reports, of which 30
we\'re serious and 4 were reports of death. One of the pediatric deaths
is a duplicate, so the number of unduplicated pediatric deaths will be
3.

Adverse event reports are categorized according to preferred terms and a
frequency distribution is generated. These are ranked in decreasing
order of frequency.

This slide presents the top 10 most frequently reported adult and
pediatric adverse events for sertraline. Note that adverse events not
previously described or not on the label are marked by an asterisk. This
includes maternal drug affecting the fetus, complications of maternal
exposure, and memory impairment. Sertraline, as you know, has a
pregnancy category C. There are no adequate and well-controlled studies
for pregnant women, so use of sertraline is only indicated if the
potential benefit justifies the risk to the fetus. And the other one,
memory impairment, may be synonymous with concentration impaired which
is an expected adverse event.

Now, I\'d like to turn my attention to the demographics of the 40
unduplicated reports for the 10-month period. Looking at the age
distribution, there were 7 reports among infants less than 1-month old.
All these that were less than 1 month, fall loosely under the category
of maternal exposure to the fetus. The rest of the age distribution is
really unremarkable. 23 of the 40 adverse event reports occurred among
females.

An examination of the serious pediatric outcomes revealed 3 pediatric
deaths. 15 were hospitalized, and 21 were life-threatening or required
some intervention or were medically important events. Please note that
these numbers are not mutually exclusive as each patient may have
experienced more than one of the outcomes.

Now, let\'s turn to the clinical condition for which sertraline was
used. The most common indication for which it was used was depression in
children in pediatric age groups. We also have several for which the
indication for use was unknown or accidental. Just as an aside, the
accidental use was in 3 cases where a 15-month baby and a 13-month baby
had accidentally ingested sertraline, and another one was a dispensing
error.

Now, let me turn to the 3 patients for which death was reported. Patient
number 1 was a 7-year-old male prescribed sertraline for depression,
also using amitriptyline and clonidine. Dose and duration was unknown,
so this shows some of the quality issues that Min mentioned before in
terms of MedWatch reports being sometimes incomplete. Also the drug
levels were two to three times higher in the liver than the prescribed
amount. Again, the MedWatch report doesn\'t say what kind of assay they
did in this case, so it\'s not clear. The possible conclusion, though,
is death probably is due to chronic multiple drug toxicity as there were
multiple drugs being used in this case.

Patient number 2 was a premature male child born to an HIV-positive
mother. The mother was using sertraline for depression, also using
multiple other medications during the last 3 months of pregnancy,
including L-dopa and antiretroviral drugs also. The baby died 15 days
after birth secondary to pneumothorax and septic shock. The possible
conclusion is death probably is unrelated to sertraline in this case.

The last case, patient number 3, was a 13-year-old male who committed
suicide following 1-week of trial of 50 milligrams a day of sertraline
therapy for depression. The patient remained significantly depressed
during therapy, according to the mother. The parents did not notice any
agitation or mood changes. Again, this is based on parents reporting.
The exact event, however, is not know, but the initial report was really
in 1997. So this technically doesn\'t fall within the one-year
post-exclusivity, but there were multiple updates to the report. Suicide
ideation is labeled but is a rare event. So the possible conclusion is
we\'re not really certain whether there is a relationship between the
sertraline use and this event. This case was being treated for
depression and suicide ideation is a risk there.

Now, in summary, therefore we developed a plan and process for tracking
adverse events as mandated by BPCA. We\'ve defined the roles and
responsibilities of the Office of Drug Safety, Office of
Counter-Terrorism and Pediatric Drug Development, and also the Office of
Pediatric Therapeutics. We discussed the proposed adverse event review
template and finally I presented an example of a preliminary review.

What would we like you to do? Today we would like for you to provide
feedback on the review template and plan that we have just presented.
And starting with the next advisory committee meeting, we will be
presenting to you reviews of adverse event reports for each drug that
has completed 12 months post granting of exclusivity and the 3 months it
takes to complete the review.

At these future meetings, we are hoping that you will help us review the
adverse event reports that we\'ll present to you and also give us
insights, which are very important, and your feedback, which will be
critical in helping us reach valid conclusions.

And last but not least, if warranted, your recommendations regarding
further investigations or actions would be also equally important.

Thank you very much. If there are any questions, I\'ll be happy to
answer them.

(Applause.)

DR. CHESNEY: Thank you.

Dr. Spielberg.

DR. SPIELBERG: Thank you, Solomon. Obviously one of the real concerns we
all have is how we\'re going to go about both postmarket follow-up and
long-term follow-up on kids, and I think everybody is delighted that
things are beginning to happen within the pediatric office towards those
ends.

A question, though, and it really relates to time frame. If part of what
our interest is is evaluating the impact of new data generating under
the Best Pharmaceuticals for Children Act on potential outcomes, a
1-year follow-up after exclusivity ain\'t the right time to do it. We
won\'t even have labeling done. If we do have labeling done, it
certainly won\'t be reflected by that time in the current labeling.

So if one of the questions that we\'re asking ourselves and that
Congress may ask us and the public may well ask us is what is really the
impact of all of these studies and of the labeling process on pediatric
outcomes, we are going to have to look rather longer after. So clearly
we\'re going to need to collect data before and collect data afterwards,
but we\'re going to have to go well beyond that year after exclusivity
at a time that most of the labeling negotiations aren\'t even done.

DR. IYASU: I think that\'s a very critical point and I completely agree
with you. Today\'s presentation was just really restricted to what the
law says and what we\'re doing towards complying with the law.

But clearly there\'s a need for long-term follow-up for all pediatric
drugs really and some of them more important than others. Right now
besides maybe having some phase IV commitments for certain drugs, we
don\'t really have a program that is implemented that looks at
long-term. So that is a discussion that is ongoing. I think there are a
lot of people who are interested, including Bill, who when he recruited
me and Shirley and Dianne, said this will be one of the areas that we
need to work on. So I think it\'s an important area and I do agree with
you completely.

DR. SPIELBERG: We also do have to be a little bit careful, though,
because if in a couple years Congress comes back and asks us ‑‑ people
get hung up on what happens during that one year afterwards. We\'re
going to have to be very careful how we explain those numbers so that
they\'re not misinterpreted in context. Something that isn\'t
disseminated can\'t possibly have an impact until those data are out
there.

DR. CHESNEY: Dr. Nelson.

DR. NELSON: It\'s difficult to interpret the importance of some of these
events without knowing the denominator. How hard would it be to work
with, hopefully, cooperative dispensers, national pharmacies or either
large HMOs to actually have an ability to say, well, how much is this
drug actually being used in the population at what ages so that when you
see an adverse event, you have some idea of what the incidence might be.

DR. IYASU: I think you\'re absolutely right. Interpreting this data is
dependent on what the reporting rate is, and I think Min touched upon
this issue before in terms of what kind of data systems are available to
FDA to try to estimate the use data among the pediatric population, the
IMS data.

We\'ll also try to work on inpatient use data to try to project from
data systems that are out there from vendors so that we can have a
pretty good estimate of what the projected use is in the inpatient
pediatric population.

So I really agree with what you\'re saying. It\'s just that there
aren\'t really that many good data sets except the IMS system which
we\'ve been working with. But we\'re trying to work with groups to try
to find good data systems outside FDA.

DR. NELSON: But if you do find them, I assume then that will show up in
the template?

DR. IYASU: Oh, absolutely. In fact, it\'s one of the things that would
be included in the future reports that we\'ll provide to you. We\'ll try
to give you an estimate of what the background rate is, at least from
the literature, compared to a reporting rate based on estimates of the
numerator and the denominator.

DR. NELSON: I guess not just background rate of the event itself, but
the prescribing patterns.

DR. IYASU: Absolutely.

DR. DIANNE MURPHY: Yes. We\'re going to provide that to you for what we
have.

DR. NELSON: I didn\'t see that in the current template.

DR. DIANNE MURPHY: Yes. And the thing is, as you know and I think this
committee knows, we usually use IMS for outpatient and we now have these
children\'s hospital inpatient data that Solomon was referring to, which
unfortunately right now is the best we have. It\'s 24 hospitals, and
they\'re spread throughout the country, but it doesn\'t have a
projection methodology. That\'s what we\'re working on, is trying to get
a national projection methodology validated so that you could use that
inpatient data for national use. Because as you know, you can\'t get the
use data from every pharmacy, so you have to have some sort of
projection methodology for it. So that we will be providing to you.

Then the next question I think would be if we bring something to you and
there are still questions, we can go out and, assuming we have the
funds, we can purchase additional information if we have to from other
databases looking at adverse events, I mean, different databases that do
different things. So that might be something the committee might want if
there\'s a question that needed further development.

DR. CHESNEY: Dr. Gorman.

DR. GORMAN: This is somewhat tangential but in some of the labeling that
is approved under exclusivity, there are concerns raised about use in
pediatrics, but the drug is approved and labeled in children. One of the
other selective serotonin reuptake inhibitors seems to have some impact
on growth in adolescence. Is that going to be captured under your
system, or is there another pathway in which those potential adverse
events will be pursued?

DR. IYASU: This system, the Adverse Events Reports System, doesn\'t
really do a good job on that. It doesn\'t capture it very well. So the
best alternative there is for a phase IV commitment from manufacturers,
the drug sponsors, for some of those drugs. In fact, there is one out
for Prozac which is one of the SRIs. So unless we can increase the
number of willing participants who would do this phase IV commitment,
we\'ll just have to be creative and come up with other ways to track
growth and development.

DR. CHESNEY: Dr. Spielberg and then Dr. Santana.

DR. SPIELBERG: Just one potential recommendation for some denominator
data. There\'s a group, the Pediatric Pharmacy Advocacy Group, PPAG,
which is a group of national pediatric pharmacists. We\'ve used them in
the past when we\'ve been interested in changes in utilization trends of
various medicines and they have fairly good data and certainly could be
encouraged to continue to collect data. They have both inpatient and
outpatient data from their pharmacies. It doesn\'t necessarily reflect
what\'s going on in the community pharmacy base, but for a lot of
medicines, I think they could be of some help and would probably be
delighted to help in that regard.

DR. IYASU: Thank you very much for that suggestion.

DR. SANTANA: So I\'m going to try to address this differently. I\'m
going to ask the question if you come to me with some data to look at
and the two issues central to this whole discussion is the safety of
children and getting more information about how these drugs can be
applied in children and what is their safety profile, the two issues to
me are, is the frequency of the adverse events different from what we
already know in different populations like adults. And for that, the
adult data set should be as vigorous as the pediatric data set. If not,
it will be misleading potentially. And then the other endpoint is, are
there unique adverse events in the pediatric population, unique to that
population, and how do we capture those? How do we identify the greater
percentage of those so we can identify those in a quick manner and do
correct labeling, so on and so forth?

So knowing that those are the goals, establishing the frequency in
comparison to something that we already know that we trust, which is the
adult data, and on the other hand, identifying the uniqueness of the
pediatric population and the uniqueness of those events, I would go back
to the points that have been discussed around the table that I think we
really need a very vigorous data set and we need to tap into the
sponsors to provide as much data on patients in which the exclusivity
medications are being used so we can develop that. Because if not, what
I fear is that we will be presented or you will be presented with data
sets that potentially will lead to the wrong conclusions. So I think the
numerators, denominators, the usage patterns, are they being used for
the indication like Skip suggested, that is, what the label says, I
think would be very important information.

And I have a fear, just like I have a fear with the MedWatch, that
that\'s a voluntary system and you\'re only capturing a set of the data
and it\'s not a universe of data that potentially is going to lead us to
the wrong conclusions if you come to us to seek advice. So it\'s just a
general comment of precautionary notes, as you come to us and present
this data and seek our advice, of the limitations that I will have if
the data is not clearly coming from sources that are very trustworthy or
represent the universe at large. And the universe at large is not very
big. We\'re talking about pediatrics. We\'re not talking about a big
universe. So we should make a major effort to try to get as much as
possible.

DR. DIANNE MURPHY: Well, let me see if I understand what you\'re saying
then. What you\'re saying is that you think that for these products that
we\'re going to be tracking the adverse event reporting and bringing
this back to you, that we need to have a formal follow-up mechanism in
place. Is that what you\'re suggesting? Because that would become a very
different situation. Or are you suggesting that we have additional
databases that you think we would automatically survey besides the IMS
and the CHC data?

DR. SANTANA: Let me try it again. So the whole issue here is that we
need to improve on the safety information so that the label says the
correct things in regard to pediatric use. That\'s the goal.

DR. DIANNE MURPHY: Right.

DR. SANTANA: There are two ways of getting at that. One is comparing the
frequency of adverse events in children as they relate to what is known
in adults. Just to be very simplistic, I know a lot about oncology.
Nausea and vomiting occurs in the same frequency in this population as
it occurs in this other population. So it\'s not an issue. It\'s the
same adverse event profile in adults as it is in kids, and the label
reflects that. How do we capture that information? How do we have the
comparator numbers to say that the side effect profile is equivalent or
is the same? That\'s one issue. Right?

DR. DIANNE MURPHY: Okay. So we would have the use data, which will give
you the denominator of how many people are using it so you\'d have a
comparison of those numbers. You could do it percentage-wise. But then
you\'re asking for is the reporting for adults and kids on adverse
events somehow going to be different. That\'s your question.

DR. SANTANA: Right.

DR. DIANNE MURPHY: And how can we ascertain that, how it would be
different.

DR. SANTANA: Yes, because if not, the label is not going to adequately
reflect what\'s happening in the pediatric population or the uniqueness
of the pediatric population, which is what the intent is. Right? The
uniqueness of this population as it relates to adverse events. If it\'s
all the same, it doesn\'t matter.

DR. DIANNE MURPHY: Right.

DR. SANTANA: But if it\'s unique, how do you get that information
correctly?

DR. IYASU: Let me comment. One of the things that we will be doing is
looking at the adverse event profile for adults and for children, and
one of the comparisons that we\'ll do, at least from the raw data, is
trying to identify pediatric adverse events that are unique and not seen
in adults. So bear in mind this is a limitation of the AERS system, but
it gives us some idea of some of the adverse events that are just unique
to pediatrics and not seen in adults. There\'s a longer history for the
adult use. So that will I think give us some idea. It\'s not probably
the best, but at least it will give us some flags.

And the other thing is, also looking at having the denominator data for
both adults and also the pediatric population, and then comparing maybe
the reporting rate for events that we expect, whether they\'re occurring
more commonly in pediatric patients than in adults, although they are
both expected. So if they have an increased frequency more than the
expected, that may also raise some flags.

So there are ways of tweaking the data, but it\'s still not the best
approach probably. We may have to do more, and that is a question that
we all have to discuss.

DR. SANTANA: Does the agency know if there\'s a natural tendency for
more reporting of pediatric events than there are of adult counterpart
events? Are people more sensitive to reporting pediatric events than
they are adults?

DR. IYASU: I don\'t know. Julie, can you answer that question? I think
there\'s more sense in terms of reporting at the earlier time a drug is
approved than later, but I don\'t know whether there is more pediatric
than adult.

MS. CHEN: In a special population, either pediatric or elderly, as far
as I know, they have similar proportions. They\'re all being reported,
especially for the high-risk situations. We have seen them. Yes, I would
say people tend to report more if they experience more rare and serious
events for those in the extreme population.

Recently we also look at the antipsychotic drugs in pediatrics and found
out there is also some use there. They\'re all off-label, but we found
out that\'s a typical class of drugs that\'s being used in the pediatric
population and we got similar reports in our system too. So that\'s
consistent as far as reporting and the use.

DR. BEITZ: This is Julie Beitz. I just wanted to say that there are
many, many reporting biases to the AERS database, some of which we know
about and many of which we don\'t know about. There could be a new
publication that comes out about children that could cause a spike in
reporting for children relative to adults. So that may be very obvious,
but there may be media attention and so forth. So it\'s going to be
crude. The best we can do is to give you numbers of reports in the
system for adults versus children. Bear in mind that it\'s noisy data.

DR. DIANNE MURPHY: So I think what she\'s trying to say is that there
are biases and there are many and this is just one of them, and we
probably have about as good a handle on this bias as we do any other.
You will have the baseline comparisons for use. You will have the
percentages to look at, and that\'s going to be the best. So actually I
have seen them give reports where they will show a recent article, like
she said, came out and we had a spike or we had a change in a label or
there was an advisory committee meeting and we\'ll have a spike. So they
do actually go back and try to look at some of that that clearly might
impact the reporting.

But other than that, we\'d have to come up with a hypothesis and test
the system that there\'s a differential between adults and pediatrics,
and we have not anticipated that at this point.

DR. CHESNEY: Dr. Gorman.

DR. GORMAN: I think we all have the same opinion that we have a database
that has more than a few flaws, and for 10 years as the medical director
of a poison center, which has a report system ‑‑ it\'s another voluntary
reporting system ‑‑ the data is poorly reported, not complete. The flaws
are obvious I think even on short-sighted review.

It probably brings us back as a committee to ask for a renewed look at
the active surveillance system where I think a lot of the questions that
we\'re concerned about in terms of reporting kind of disappear if
you\'re seeking out the answers rather than waiting for them to bubble
up to you even though those systems are going to be very different. And
you\'ll have no trend data in those systems because they\'ll be new.

DR. DIANNE MURPHY: One of the things that could possibly happen is that
we bring to you ‑‑ again, I don\'t think the unique things, the things
that we\'ve seen learning difficulties in school ‑‑ we\'ll be able to
pick up those. It\'s going to be is this really a higher incidence than
what you\'re seeing in adults or is it just a reporting artifact.

We\'ll bring something to you all, and I think that because the
legislation was clearly vague in that it didn\'t tell us how we\'re
supposed to do this, we\'re going to be developing this process as we go
along. We are trying to put together a report that we think is the best
we can do at this point. And it may be that we find, as I said, the
questions are basically more and that we have to go out and develop
different databases or different approaches or for a certain type of
product, we may need to bring the divisions in and have a combined
advisory committee with a subspecialty group to talk about a better way
to approach labeling. That gets back to some of the activities with
labeling.

But I don\'t know right now that we can really promise you anything
better than the data systems that we\'ve tried to put together knowing
that they are flawed at this point and ask certain questions. Are there
known reasons something would be different?

DR. CHESNEY: Thank you very, very much.

Our next speaker for the afternoon is Dr. Shirley Murphy. Dr. Murphy,
many of you may know, is a pulmonologist who was on the faculty at New
Mexico in the School of Medicine and College of Pharmacy and also chair
of the department there for a period of time. She was Vice President of
the Neuro-health Specialty Division at Glaxo Smith-Kline Pharmaceutical
Company before coming here to the FDA a few months ago?

DR. SHIRLEY MURPHY: Five months ago, but who\'s counting?

(Laughter.)

DR. CHESNEY: Many other qualifications, including serving as chair of
the NHLBI\'s Asthma Expert Panel which produced the national guidelines
for the diagnosis and management of asthma and chair of the FDA\'s
Pulmonary and Allergy Committee.

Now Dr. Murphy is the Division Director for the new Division of
Pediatric Drug Development.

DR. SHIRLEY MURPHY: Thank you very much. It\'s a pleasure to be here.
I\'m the other Murphy.

First of all, I\'d like to really thank the committee for giving up
Sunday and Monday and coming here and to warn you that we have a lot of
work ahead for you. We really value your input. If I could call you
together every day, I would at 5 o\'clock for a little conference call,
but I can\'t. Please mark your calendars because we have a lot of issues
to bring to you.

What I would like to do today is to provide an overview of the Division
of Pediatric Drug Development and to update you on some of the
activities that we\'ve been doing this past year, particularly in the
months since I\'ve come.

First of all, we were a glimmer in Dianne Murphy\'s eye just a year ago,
but being the recruiter she is, she started up the division even before
I got here, and we have gone from 0 to 16 in the last few months. We
have nine medical officers with two more on their way. This is really a
fantastic group, a very intellectual group, a very diverse group,
ranging from pediatricians who are experienced in practice to
pediatricians who have FDA experience to subspecialists to people with
pediatric boards and also M.P.H.s. So we have a very diverse group.

We also have three project managers, a couple of whom were stolen from
Capitol Hill, and they are extremely capable and keep us on track.

And then we have three support staff for the glue that keeps us all
together and makes it all work.

Just to show you the dedication of this division, this is the day after
the big snowstorm, and this is over half the division, through rain and
sleet and 26 inches of snow, who made it in.

DR. DIANNE MURPHY: Post 2 feet of snow, for those who weren\'t here.

(Laughter.)

DR. SHIRLEY MURPHY: But these are the people who got in to come to work
at the FDA.

What\'s the role of our division? What do we do? Well, we\'re the
champions of pediatrics throughout the FDA. Just like you have to have
champions of pediatrics in hospitals and in organizations, you have to
have it in the FDA. Dianne Murphy certainly was the champion of getting
this division up and going, and now we are able to champion pediatrics
throughout the FDA.

One of our most important roles is our partnership with the National
Institute of Child Health and Human Development that I\'ll be talking
about in a little bit.

We also provide a consultative service to all the centers within the
FDA. So that\'s Biologics, that\'s Devices, that\'s Foods, as well as
Drugs.

We conduct detailed reviews of proposed pediatric trials for the
on-patent drugs. We\'re often the referees. We put on our striped shirts
and we contribute to the resolution of scientific and ethical issues,
and we disseminate new pediatric labeling information both through the
website and also through giving external talks.

Now, I\'d first like to turn to one of our most important roles, and
this is our partnership, which is mandated by BPCA. This is not my
quote. This is George Giacoia\'s quote from NICHD that we\'re a marriage
made in Congress, and I think it really does sum it up. We\'ve been
married about a year. We\'re back from the honeymoon.

(Laughter.)

DR. SHIRLEY MURPHY: We know each other\'s relatives. We\'re getting to
know each other\'s cultures. We are just doing some terrific things
together, and that\'s what I\'d like to talk about, is some of the
things that we\'re doing together. It is a work in progress, just like a
new marriage, and we\'re really happy for all your input on the things
that we\'re doing.

Our first task was to develop a list of drugs for which pediatric
studies are needed. This is mandated by BPCA and it is mandated for NIH
to do this and publish it in the Federal Register. This is a very long,
involved, iterative process which you all participated in the last
advisory committee and this has been led very capably by Bill Rodriguez
from the FDA and George Giacoia from NICHD. Input was obtained from a
whole lot of sources to produce this list.

Now, there are three criteria that were laid out in the law that the
list should consider and that\'s the availability of information,
whether additional information on children is needed, and whether new
pediatric studies will produce a health benefit for pediatric patients.

I want to show you this process a little up close and personal in some
detail. This is a work in progress, and we\'re already talking about how
we might do this differently.

Every year FDA published a list under FDAMA of 426 drugs where further
pediatric studies were needed. There was a list published in 2001, but
it wasn\'t as detailed with information as the one in 2000. So the 2000
was picked. You gave input at the advisory committee, and some drugs
were presented to you. NIH was given this list of 426 drugs and they
gave it to the United States Pharmacopeia which removed some of the
on-patent drugs and also produced some references of what was existing
in the literature.

The NIH then sent this list back to the FDA with now 284 drugs on it.
Terrie Crescenzi spent a lot of time on this researching all these drugs
and basically cleaning this up, and then it was grouped by drugs and
their indications and the divisions at the FDA.

We then sent this dwindling list back, now 180 drugs, to NIH. NIH ‑‑ and
this is NICHD when I speak of NIH here ‑‑ ranked the 180 drugs with
input from their institutes, the AAP, and outside subspecialty experts.

This list was then further whittled down to 34 high priority drugs. That
was sent back to the FDA, and with Bill and Terrie leading the charge,
the review divisions then ranked the drugs on what they thought the
public health benefit was, whether there were other approved drugs in
the class or other therapeutic options available. And then the use data
that we were talking about, outpatient from IMS and inpatient from the
children\'s hospitals database, was added to this list.

We sent this 34-drug list back with the information to NIH, and then
they sent this out to one to two experts in each field that reviewed
each one of these drugs. And then these reviews were actually typed
reviews, just like a grant review, and were sent back to NIH.

NIH convened an expert panel. Some of the members on this committee were
on that that looked at each drug and really scored each drug of the 34
from 100 being a good priority to 500 being a low priority. These scores
were totaled, and then FDA and NIH met, and we took the top 16 and then
selected 12 drugs from that, and the list was published in the Federal
Register on the 21st of January.

This is the list of drugs for 2003, and this process will be updated
every year and may be updated in the middle of the year. We are looking
for input into how to improve this process, so maybe during the
discussion period ‑‑ several of the people from NICHD are here ‑‑ we
could talk a little bit about that.

Now, what happens to these drugs when they\'re on the list? Well,
there\'s a mechanism ready to receive these drugs, and that\'s the BPCA
process to study off-patent drugs in which the FDA again collaborates
with NIH. In this process, the Division of Pediatric Drug Development
performs a label review and a very, very extensive literature review of
everything that\'s out there in the literature, and we hope to be
publishing these reviews in the future.

And then, working with NIH and the reviewing divisions at the FDA, the
Division of Pediatric Drug Development writes a detailed plan for the
studies, and that\'s called a written request. This is sent out to the
sponsors and if there\'s no company that wants to do this, then this is
referred to NICHD to be let as a contract.

This is a diagram of the process in which industry has 30 days to
respond if they don\'t want to conduct the studies, and it would be very
unexpectedly that they would want to do it on an off-patent drug. Then
it is referred to NIH.

Now, where do we stand in this process right now? The RFC has been
published in the Federal Business Opportunities. There are three more
RFCs that will be published soon, and that\'s nitroprusside and then
lorazepam for two different indications. There are five other off-patent
drugs in process that currently the Division of Pediatric Drug
Development is working on. So that\'s the off-patent drug process.

Another very important role that the NIH and the FDA have had for a long
time has been collaborating on scientific issues and on ethical issues.
This newborn drug development initiative is really the brain child of
George Giacoia from NICHD and Debbie Birenbaum from the FDA. Debbie was
on the phone to me as soon as I took this job, pushing this initiative.
It is really such an important initiative. Really BPCA looks at neonates
as a special subpopulation. And as Debbie would say, if she were
speaking up here, the orphans of the orphans, and we need to develop
passion around these babies and study medications in them. And that\'s a
gaol, to really foster the development of safe and effective drug
therapies for this population.

We are marching down the road towards a workshop that will be held in
early 2004 that will look at the state of the art and will define the
research priorities for pain control, cardiac disease, neurologic
disease, and pulmonary disease, the four topics that were picked for
this. We had a planning meeting in which 50 experts came from around the
country, and working groups are established, and we are moving forward.

Now, Dianne spoke a few moments ago about another role we play and that
is being the consultative service to all the centers within FDA, and
this is really one of the most interesting things that we do. Just like
when you get a consult in the hospital of subspecialists, these are
usually the patients that everybody else has given their best guess at,
and then they call you in for the tough cases. And these are usually the
tough cases.

Most of the information about what we do is proprietary, and Dianne
Murphy will personally shoot me ‑‑ or at least fire me ‑‑ if I talk too
much in depth about this. So I want to give you a little bit of feel for
some of the diverse things that we are doing.

We\'ve been involved with the Division of Devices in several areas.
First of all, you probably read about the potential association of
cochlear implants with meningitis, and Hari Sachs has been working on
that. Hari is a pediatrician and came to us from her practice and really
has lent a lot of practical information to that. She\'s also involved in
silicone breast implants and what the effect on the infant might be if
it is breastfed from a silicone breast transplant.

Lisa Mathis, a pediatrician who came to us from the Dermatology
Division, has gotten steeped in GI devices and there\'s a lot new
exciting devices coming out.

The other area is the Center for Food Safety and Nutrition, or CFSAN.
Formula companies want to add everything into formulas, and Lisa Mathis
has been taking a look to make sure that these are appropriate.

We\'re very fortunate to have Susan Cummins join us with all her
environmental expertise, and she\'s been looking at safety issues
regarding exposure from phthalates that soften plastics in medical
devices and what the effect can be on children.

We also have a formal consulting process with Counter-Terrorism to make
sure that children are in all those labels that are countermeasures to
all the horrible things that we read about in the newspapers. Lisa
Mathis has been spearheading this.

I\'ll show you one label. This is Prussian blue. This is a chelator in
the gut for the treatment of contamination of both radioactive and
non-radioactive cesium or thallium. We would have had to just
extrapolate from adult data, but there was a very unfortunate exposure
in Brazil, which is a subject of a recent Nova program, in which adults
and children were going into the dump piles in Brazil and looking for
waste to recycle, metals, and they got into medical waste that had
cesium in it. These patients, the adults and the children, received
Prussian blue after this exposure and a lot of data was gained from
that. I have to say that all the children lived except for one who went
home and ate a peanut butter sandwich with their hands and got another
exposure instead of going to the hospital. Just like in adults, the
half-life was reduced by the Prussian blue by about 46 percent in
adolescents and 43 percent in children. So this is an example of the
labeling that we\'re doing in Counter-Terrorism.

I\'m happy to report to you that we have 15 new labeled products for
children since you last met, and I don\'t want to go through each one of
them, but I would like to highlight a few of these products for you.

First of all is montelukast which, as a person who takes care of asthma,
is near and dear to my heart. This is for the prophylaxis and chronic
treatment of asthma. It\'s a leukotriene receptor antagonist. It was
only approved to 6 years of age. Now it\'s approved in ages 12 to 23
months using a new formulation which was developed, an oral granule
packet, and it\'s also approved for 2 to 5 years using the granules or
the chewable tablets.

Next is Elocon, which is a very popular, mid-potency steroid that\'s
used in corticosteroid responsive dermatoses. New safety information was
obtained on this looking at HPA axis suppression using the cosyntropin
test. In the cream, there was 16 percent of the patients ages 6 to 23
months that had suppression. In the ointment, there were 27 percent of
the patients. So we did discover that there was HPA axis suppression in
these patients. It was reversible in all, I think, but one of the
patients that were followed up. Skin atrophy was found, but only in 1
patient and it was very, very mild.

All of the corticosteroids that are mid-potency are now labeled that
they shouldn\'t be used for the treatment of diaper dermatitis because
that\'s an occlusive dressing and it just causes more absorption.

Tamoxifen is a drug that is used for the treatment of breast cancer in
women, not a drug that\'s usually thought of as a pediatric drug, but
here\'s a very unique indication. This was 27 female patients, I think
all the patients in the United States with McCune-Albright syndrome
which has an associated precocious puberty with it. They were treated
with tamoxifen for up to 12 months, and they found a 50 percent
reduction in the frequency of vaginal bleeding, reduction in the mean
increase of bone age, and the linear growth rate was reduced in these
patients. There was a safety concern in that the mean uterine volume
increased after 6 months and doubled at the end of 1 year. This is all
now laid out very, very nicely in the label.

Three statins were approved for use in children for familial
hypercholesterolemia in sort of late childhood and adolescence.

Vinorelbine, or Navelbine, is very interesting. In the spirit of trying
to identify active cancer compounds earlier, Navelbine was tested in a
phase II trial in children who had refractory or relapsed solid tumors.
There was a lack of activity noted, and this will be going into the
label. I use this as an opportunity to advertise tomorrow\'s advisory
committee, which is the Oncology Pediatric Subcommittee, and they\'re
going to be talking about labeling of oncology drugs.

Atomoxetine, or Strattera, is a very exciting new compound. It\'s the
first non-stimulant, non-scheduled drug for ADHD. It\'s labeled down to
6 years of age. It\'s a selective norepinephrine reuptake inhibitor. The
caveat is we really don\'t know what the effect is on final height, and
in the label it actually says that consideration should be given to
interrupting the therapy if a growth problem is seen.

We talked a little bit about fluoxetine, or Prozac, which is approved
now for major depressive disorder and obsessive-compulsive disorder. I
think the worrisome thing that is now in the label that has been
reported in several case reports is the decrease in height. In a 19-week
study, the patients treated with fluoxetine gained an average of 1.1
centimeter less in height, and I think the Washington Post translated
that into a half an inch. So the label says that height and weight
should be monitored periodically and there is a phase IV commitment for
a long-term growth study.

Also the other side effect that was seen is what is seen with other
SSRIs, and when used for depression in bipolar patients, it will often
unmask the bipolar state and flip the patients into mania. And that
occurred in the children in this study and it has been reported before
in adults.

I close with my former boss\' quote to me when I called her up and asked
her ‑‑ when I saw Dianne\'s ad in the New England Journal, I called her
up and I said, you know, Jane, what do you think? Is this a good job? Is
this a good fit for me? And she said the FDA is the most fun and
interesting place you could ever work, and I have to say that that\'s
very, very true. And I would like for you to send me the CVs of all your
friends, yourselves, and any burned-out colleagues that you have because
this is really a place to reenergize yourself. And there\'s no night
call and no weekend call.

(Laughter.)

DR. SHIRLEY MURPHY: Thank you very much.

(Applause.)

DR. SHIRLEY MURPHY: I\'d like to turn it over now to Terrie Crescenzi.

DR. CHESNEY: Terrie Crescenzi is the Associate Director for Regulatory
Affairs in the Office of Counter-Terrorism and Pediatric Drug
Development and assists the Office of Pediatric Therapeutics on issues
related to subpart D. She has been involved in pediatrics at the FDA
since June of 1999, and before that, she was a project manager in the
Division of Antiviral Drugs. Before coming to the FDA in 1997, she
served as the Director of Pharmacy Services in the United States Air
Force at various hospitals throughout the country, and she\'s going to
give us an update on pediatric statistics.

MS. CRESCENZI: Good afternoon, and thank you very much for sticking
around. I will try to keep this somewhat brief since it is late and I
know people have planes to catch and whatnot.

The first thing I would like to talk about and direct your attention to
is our pediatric drug development page. This page was recently updated.
I think we finally got it live around the January time frame. We tried
to revise it, make it a little bit more user friendly. We do have new
information on the page, and we recommend that you definitely take a
look at it.

With regard to some numbers, as far as the proposed pediatric studies
request, so far, since section 111 of FDAMA was passed, we\'ve had 324
proposals come into the agency, and to date we\'ve actually issued 264
written requests. The number of determinations is now up to 82
determinations, and we\'ve granted exclusivity to 73 drugs. As far as
new labeling goes, we\'re actually up to 50 new labels and that is since
the beginning of exclusivity.

As far as studies breakdown goes, there\'s not really anything new and
earth-shattering here. We still remain at about a third of the studies
asked for are efficacy and safety and a third are PK and safety. We\'re
actually up to asking for 616 studies so far, and that could potentially
involve over 36,000 patients. Remember too, all the studies that we ask
for ‑‑ we don\'t always have the exact number of patients listed in
those studies, so we think it will be quite large.

This is another web page that we\'ve developed. It is brand new. We
actually just got it up on the Web on Friday. This is part of the
mandate in BPCA under section 9 where we have to have dissemination of
information. With regard to this, any pediatric studies that are
submitted in response to a written request have to be reviewed in 180
days if it\'s submitted as a supplement. In addition to that, we also
must post on the Web medical and clinical pharmacology summary reviews.
This is actually the first summary that we\'ve posted, and as I said, we
just did this on Friday. We hope to have the next one either today or
tomorrow, so this page will be growing.

One other point to make with this as well is BPCA did give us a mandate
where we can disseminate a lot more information that we could not in the
past. With regard to this page, we can actually now put up summaries for
actions that are taken. That includes approval actions, non-approvals,
and approvables, where in the past, you never heard about those. The
only thing you ever saw were approval actions. You never actually
received the information for the non-approvable or the NAs. So those
summaries will get posted.

With regard to the pediatric rule, we still are posting numbers on the
rule even though the rule was struck down last year. There is a lot of
activity on the Hill with regard to codifying the rule. FDA is certainly
working with the folks on the Hill to hopefully get the rule codified.
We believe that the rule and pediatric exclusivity work hand in hand and
we\'d like to see both of them.

So with regard to our numbers, these numbers actually date back to April
1st of \'99 when the pediatric rule became a regulation. At that time,
up until December of last year, we had 517 applications that triggered
the pediatric rule.

The biggest numbers that I really want to point out at this point are
the applications with completed studies. Out of the 517, there are 130
that have pediatric information. Now, what we\'ve done is we\'ve
actually subtracted out any of those that were studies submitted in
response to a written request and received exclusivity. So, needless to
say, we have a bottom line number of 54 applications that now have new
pediatric information in the labels that we can attribute to the rule.

Another new page that we have up ‑‑ and this in regards to the rule ‑‑
we\'re trying to get the labeling up similar to what we do for
exclusivity. We have gone through a number of the labels. Right now the
first posting ‑‑ we only got 12 labels up, but the labels are there. You
can\'t see them all obviously from here, but if you take a look at the
site, you will see them. We are in the process of looking at an
additional 30 and eventually hope to have all 54 of them up there so
that you can see some of the pediatric studies that were done and the
new indications that were attributed to the pediatric rule.

Some of the reasons for concern with regards to the rule. What we\'ve
seen in our office previously, when the rule was still in effect, the
number of cases where we deferred pediatric studies under the rule,
sponsors are now coming in and asking for waivers. We think that is a
concern because it may indicate that they actually are not going to
bother doing the pediatric studies. Technically they really don\'t have
to ask for a waiver at this point since the rule is not in effect and we
really can\'t waive or defer something that we have no authority to do.
But we are getting those questions.

And last but not least is discussion of pediatrics early in drug
development. The pediatric rule clearly outlined some of the areas, and
this was with regard to some of the key meetings where pediatric drug
development was to be discussed. We\'d like to see the rule codified to
help bring these back.

With regard to contacting us, I do want to point out we have a lot of
new information. We have a lot of new phone numbers, and we\'re actually
going to have an additional pediatric website. It will be the Office of
Pediatric Therapeutics website which will be accessible from the FDA
home page. The page we hope to have up within a couple weeks and that
page will contain some of the information and issues that the Office of
Pediatric Therapeutics is addressing.

As Dianne said earlier, we do have an e-mail account for the Office of
Pediatric Therapeutics, and thanks to her, I will be taking those
e-mails.

(Laughter.)

MS. CRESCENZI: She wanted to share the dual hats.

That\'s really all I have at this time. Thank you.

DR. CHESNEY: Thank you very much.

(Applause.)

DR. DIANNE MURPHY: Before everybody starts asking questions, Terrie
pointed out to you the fact that we are now posting up on the Web the
reports that are coming in. If a company conducts the trials that we ask
and they submit them to us, we will have them up on the Web within the
6-month deadline. That is such a wonderful, new piece of information.
You know, tell all your friends not only to send their CVs, but also
tell them to go to our website because that information, if it was
approvable but we want more information or not approvable, that wasn\'t
public before, and this is one of the good things that the legislation
has done so that pediatricians now, even for products that didn\'t make
it, can access that information. I think that that\'s really critical
that that is out there.

We would like feedback from you about how to make it more useful. There
are some things that we can control and some we can\'t. We can\'t really
put up our own format. It has to be in the format in which these reports
are written. But if there\'s anything else that we could do to make the
information more useful, we would really like to know or link it with
something else. Please let us know because I think this is going to be
very important information for pediatricians.

Thank you.

DR. CHESNEY: Very impressive. Comments for Dr. Murphy and Terrie? Dr.
Santana.

DR. SANTANA: Dianne, one thing that I found, for example, in oncology
that\'s been very useful is that ASCO, the American Society of Clinical
Oncology, communicates to all their members periodically all FDA actions
regarding oncology products. I think that\'s a good example of how your
office, instead of waiting for people to hit your web page, proactively
can communicate that kind of information through the current pediatric
organizations, AAEP and some others, if they give you access to that. I
find those summaries, at least from the oncology side, very useful. They
are very succinct and they go to the point and it keeps everybody in the
oncology community updated with what ODAC has been doing. So I think
that may be another vehicle proactively to provide the information
rather than having people download.

DR. CHESNEY: Well, I don\'t see any other comments or questions, but I
really, on behalf of everybody sitting here, would like to thank the FDA
for just always very professional presentations and a very, very
impressive amount of work and how much you\'ve accomplished since we
last met.

Does anybody have any other last-minute comments?

(No response.)

DR. CHESNEY: Well, thank you very, very much.

We\'re meeting again in June for three days.

DR. DIANNE MURPHY: Yes. Please do try to make it. We\'ve got some very
interesting topics and some that I think will be quite controversial,
and we\'re going to need your input. We always appreciate it. Do block
it off. Thank you again, everybody.

(Whereupon, at 4:34 p.m., the subcommittee was adjourned.)