1
DEPARTMENT OF HEALTH AND HUMAN
SERVICES
FOOD AND DRUG
ADMINISTRATION
CENTER FOR DRUG EVALUATION AND
RESEARCH
PEDIATRIC ADVISORY
SUBCOMMITTEE
OF THE ANTI-INFECTIVE DRUGS
ADVISORY COMMITTEE
ACS Conference Room
Room 1066
2
PARTICIPANTS
Joan P. Chesney, M.D., Chair
Thomas H. Perez, M.P.H., Executive
Secretary
CONSULTANTS (VOTING):
Mark Hudak, M.D.
David Danford, M.D.
Richard Gorman, M.D.
Robert Nelson, M.D., Ph.D.
Susan Fuchs, M.D.
Victor
Santana, M.D.
Naomi Luban, M.D.
Judith
O'Fallon, Ph.D.
Katherine L. Wisner, M.D.
MEMBER OF THE ANTI-INFECTIVE DRUGS
ADVISORY
COMMITTEE (VOTING):
Steve Ebert, Pharm.D., Consumer
Representative
FEDERAL GOVERNMENT EMPLOYEE (VOTING):
Janet Cragan, M.D.
INDUSTRY REPRESENTATIVE TO
ANTI-INFECTIVE DRUGS
ADVISORY COMMITTEE (NON-VOTING):
Sam Maldonado, M.D., industry
representative
FDA STAFF:
Solomon Iyasu, M.D.
Susan Cummins, M.D.
Shirley Murphy, M.D.
Dianne
Murphy, M.D.
3
C O N T E N T S
Call to Order and
Introductions,
Joan P. Chesney, M.D. 5
Meeting Statement, Thomas H. Perez,
M.P.H. 7
Welcome, Dianne Murphy, M.D. 10
Adverse Event Reports per Section 17 of
Best
Pharmaceutical for Children Act,
Solomon Iyasu, M.D. 15
Fexofenodine, Jane Filie, M.D. 22
Topotecan and Temozolomide, Susan
McCune, M.D. 34
Moxifloxacin and Ciprofloxacin,
Harry Gunkel, M.D. 59
Fosinopril, Larry Grylack, M.D. 66
Fentanyl, ShaAvhree Buckman, M.D. 78
David J. Lee, Ph.D. 89
D.
Elizabeth McNeil, M.D. 91
Discussion of Question 1 92
Adverse Event Reports per Section 17 of
BPCA
(cont.), Venlafaxine, Hari
Sachs, M.D. 115
Pediatric Update, Dianne
Murphy, M.D. 148
Meeting Statement, Thomas H. Perez,
M.P.H. 170
Update on Neonatal Withdrawal Syndrome:
Kathleen Phelan, R.Ph. 174
Robert Levin, M.D. 189
Katherine Wisner, M.D.,
Women's Behavioral Health CARE 216
Discussion of Questions 2 and 3 254
Update on Congenital Eye Malformations in
Infants,
Solomon
Iyasu, M.D.
303
4
C O N T E N T S
(Continued)
Open Public Hearing:
Philip Sanford Zeskind, Ph.D.,
University
of
Pediatric Research Equity Act,
Shirley Murphy, M.D. 326
Overview of
Conduct of Clinical Research Involving
Children," Robert Nelson,
M.D. 340
5
1 P R O C E E D I N G S
2 Call to Order, Introductions
3
DR. CHESNEY: Good morning. I think we
4 are
ready to get started. I would like to
welcome
5
everybody to this meeting which, for those in the
6
room who don't know, and Dr. Murphy will elaborate
7 on
this, this is the last meeting for this group of
8 the
Pediatric Subcommittee as currently
9
constituted. I would like to also
mention that Dr.
10
Mimi Glode will not be with us because her father
11
became ill on Sunday and she had to cancel at the
12
last minute.
13
Tom has just told me that traffic is going
14 to
become very bad this afternoon because of
15
President Reagan's funeral so we want to keep that
16 in
mind as we move on throughout the day.
So, I
17
think we will start with introductions and, Dr.
18
Maldonado, would you like to start?
19
DR. MALDONADO: Sam Maldonado,
from
20
Johnson & Johnson, the industry representative on
21
this committee.
22
DR. FUCHS: Susan Fuchs, pediatric
6
1
emergency medicine physician from Children's
2
Memorial Hospital in Chicago.
3
DR. O'FALLON: Judith O'Fallon,
4
statistics, retired from the Mayo Clinic.
5
DR. SANTANA: Victor Santana,
pediatric
6
hematologist/oncologist from St. Jude's Children's
7
Research Hospital in Memphis, Tennessee.
8
DR. GORMAN: Rich Gorman,
pediatric
9
private practice in Ellicott City, Maryland.
10
DR. EBERT: Steve Ebert,
pharmacist,
11
infectious diseases, Meriter Hospital and
12
University of Wisconsin, Madison.
13
DR. PEREZ: Tom Perez, executive
secretary
14 to
this committee meeting.
15
DR. CHESNEY: Joan Chesney,
pediatric
16
infectious disease at the University of Tennessee
17 in
Memphis, and also St. Jude's Children's Research
18
Hospital.
19
DR. HUDAK: Mark Hudak,
neonatologist,
20
University of Florida, Jacksonville.
21
DR. DANFORD: Dave Danford,
pediatric
22
cardiology, University of Nebraska Medical Center,
7
1
Omaha.
2
DR. NELSON: Robert Nelson,
pediatric
3
critical care medicine, Children's Hospital,
4
Philadelphia and University of Pennsylvania.
5
DR. IYASU: Solomon Iyasu, lead
medical
6
officer in pediatrics, FDA.
7
DR. CUMMINS: Susan Cummins, lead
medical
8
officer, pediatrics, FDA.
9
DR. S. MURPHY: Shirley Murphy,
Division
10
Director, Division of Pediatric Drug Development,
11
FDA.
12
DR. D. MURPHY: Dianne Murphy,
Office
13
Director, Office of Counter-terrorism and Pediatric
14
Drug Development, in the Office of Pediatric
15
Therapeutics.
16
DR. CHESNEY: Thank you. Now Tom Perez
17
will read the meeting statement.
18 Meeting Statement
19
DR. PEREZ: Thank you and good
morning.
20 The
following announcement addresses the issue of
21
conflict of interest with regard to the adverse
22
event reporting session and is made part of the
8
1
record to preclude even the appearance of such at
2
this meeting.
3
Based on the submitted agenda for the
4
meeting and all financial interests reported by the
5
committee participants, it has been determined that
6 all
interests in firms regulated by the Center for
7
Drug Evaluation and Research present no potential
8 for
an appearance of a conflict of interest at this
9
meeting, with the following exceptions:
10
In accordance with 18 USC 208(b)(3), full
11
waivers have been granted to the following
12
participants, Dr. Richard Gorman for ownership of
13
stock in a company with a product at issue, valued
14
between $50,001 to $100,000; Dr. Judith O'Fallon
15 for
her and her sponsor's ownership of stock in a
16
company with a product at issue, between $5,001 and
17
$25,000; Dr. Katherine Wisner, for her speaker's
18
bureau activities for a company with a product at
19
issue for which she receives less than $10,001 per
20
year; Dr. Patricia Chesney for her spouse's
21
ownership of stock in a company with a product at
22
issue, valued from $5,001 to $25,000 and unrelated
9
1
consultant earnings less than $10,001 per year. In
2
addition, Dr. Chesney's spouse owns stock in a
3
company with a product at issue, worth less than
4
$5,001. Because this stock
interest falls below
5 the
minimis exception allowed under 5 CFR
6
2640.202(b)(2), a waiver under 18 USC 208 is not
7
required. Further, Dr. Chesney is
recused from
8
participating from the subcommittee's discussion
9
regarding Duragesic due to a conflict of interest.
10
A copy of the waiver statements may be
11
obtained by submitting a written request to the
12
agency's Freedom of Information Office, Room 12A-30
13 of
the Parklawn Building. In the event that
the
14
discussions involve any other products or firms not
15
already on the agenda for which an FDA participant
16 has
a financial interest, the participants are
17
aware of the need to exclude themselves from such
18
involvement and their exclusion will be noted for
19 the
record.
20
We would also like to note that Dr. Samuel
21
Maldonado has been invited to participate as an
22 industry representative, acting on behalf of
10
1
regulated industry. Dr. Maldonado
is employed by
2
Johnson & Johnson. With
respect to all other
3
participants, we ask in the interest of fairness
4
that they address any current or previous financial
5
involvement with any firm whose product they may
6
wish to comment upon. Thank you.
7
DR. CHESNEY: Thank you. Our first
8
speaker for the morning will be Dr. Dianne Murphy,
9
Director of the Counter-terrorism and Pediatric
10
Drug Development Office.
11 Welcome
12
DR. D. MURPHY: And just as you
all
13
understand how those two got to be combined, we
14
have come to the end of an era.
That was really
15 the
substance of my opening comments this morning
16 and
I am going to talk more about this later in the
17
day, that this is a milestone.
18
But I wanted to take this morning to focus
19 on
the importance of the activity of this committee
20 in
the review of the safety or adverse events that
21
occur after a product has been granted exclusivity.
22 It
has been clearly legislatively mandated that
11
1
this is going to occur and that task has come to
2
this committee.
3
I wanted to make sure that you all
4
realized how much you have contributed to this
5
process. We have received
feedback from you during
6 the
time about what was useful and have tried to
7
maintain a course, as we have to, that obeys the
8
legislative intent and, yet, makes it more
9
scientifically interesting within the constraints
10
that we have. I think probably
years from now we
11
could come and ask you all what are the problems
12
with the AERS data reporting system.
So, you have
13
been mandated to participate in a process in which
14 you
were told every meeting that you come here that
15 the
limitations are numerous with passive
16
reporting; that when we do get reporting it is
17
either poor or limited in nature; that there is
18
little ability to go back and reconstruct in detail
19 any
of that information; and it basically doesn't
20
have the same quality as a prospective surveillance
21 or
active process. Yet, during this time I
think
22 we
have evolved a process, again with your feedback
12
1 and
assistance, that has allowed us to make it more
2
valuable.
3
I would like to say that I think that what
4 we
have been able to identify over the past year or
5 so
has been the benefits of this system, and that
6 is
that it ensures that attention is focused on
7
what is happening postmarketing to these products
8
that the government initiates and rewards for
9
studies being conducted. As most
of you are aware,
10 one
of the largest safety databases that occurs
11
with any product is the postmarketing activities.
12
That is where you find your rare serious events.
13
And, this process has been critical for this
14 committee and this has been a very important
15
activity that I do think has focused and ensured
16
that products that are marketed for children are
17
looked at in a studied way, a reliable way, a
18
predictable way, and I think that that is
19
important.
20
Now, why is it important? Because
I don't
21
know how many times you have sat through these
22
meetings where we said, "well, here are the
13
1
problems and we didn't see anything.
Okay?" But
2
that is good news. We would hope
that the majority
3 by
far, if not 100 percent of these products that
4 are
studied and marketed don't have serious hidden
5
adverse events. So, in a say, it
is like
6
prophylaxis. We hope we don't
find major issues.
7
But I think the other thing that this
8
process has done that I wanted you all to know
9
about that was important is that it has the effect
10 on the agency of re-prioritizing pediatric
safety
11
assessments. As everyone knows,
there are many
12
deadlines the agency has to meet and it is hard
13
often to see the plate for all the things that are
14 on
it. But clearly the legislation, your
15 participation and our c