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
Tuesday, February 3,
2004
9:00 a.m.
Advisors and Consultants Staff
Conference Room
5630 Fishers Lane
Rockville, Maryland
2
PARTICIPANTS
P. Joan Chesney, M.D., Chair
Thomas H. Perez, MPH, Executive Secretary
SGE CONSULTANTS (VOTING):
Mark Hudak, M.D.
David Danford, M.D.
Richard Gorman, M.D., FAAP
Robert Nelson, M.D., Ph.D.
Susan Fuchs, M.D.
Robert Fink, M.D.
Victor Santana, M.D.
Norman Fost, M.D., MPH
Judith O'Fallon, Ph.D.
Ralph D'Agostino, Ph.D.
Mark Fogel, M.D.
Tal Geva, M.D.
Craig Sable, M.D.
Vasken Dilsizian, M.D.
Marilyn Siegel, M.D.
Phillip Moore, M.D.
MEMBERS (VOTING):
Mary Glode, M.D.
Steven Ebert, Pharm.D. (Consumer
Representative)
FEDERAL EMPLOYEE (VOTING):
Mario Stylianou, Ph.D.
INDUSTRY REPRESENTATIVE:
Samuel Maldonado, M.D.
FDA:
Shirley Murphy, M.D.
Solomon Iyasu, M.D.
Hari Sachs, M.D.
Julie Beitz, M.D.
Sally Loewke, M.D.
Shavhree Buckley, 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.,
Executive Secretary 8
Welcome, Rosemary Roberts, M.D., Office
of
Counterterrorism and Pediatric Drug
Development 11
Adverse Event Reports Per Section 17 of
BPCA,
Solomon Iyasu, M.D., Division of
Pediatric
Drug Development 12
Use of Imaging Drugs in Conjunction
with Cardiac
Imaging Procedures in the Pediatric
Population:
Pediatric Regulatory Update, Susan
Cummins, M.D.,
Division of Pediatric Drug
Development 58
FDA Perspective, Sally Loewke, M.D.,
Division of
Medical Imaging and
Radiopharmaceutical Drug
Products 73
American Academy of Pediatrics
Perspective,
John Ring, M.D., University of
Tennessee
Health Science Center 91
Cardiologist Perspective, Tel Geva, M.D.,
Children's Hospital Boston 106
Q&A for Speakers 126
Contrast Enhanced Magnetic Resonance
Imaging,
Mark Fogel, M.D., The Children's
Hospital
Philadelphia 143
Contrast Enhanced Cardiac Computed
Tomography,
Marilyn Siegel, M.D., Washington
University
School of Medicine 172
Contrast Enhanced Invasive Cardiac
Imaging,
Phillip Moore, M.D., UCSF Children's
Hospital 174
Contrast Enhanced Cardiac Ultrasound,
Craig Sable,
M.D., Children's National Medical
Center 213
Radiopharmaceuticals in Nuclear Cardiac
Imaging,
Vasken Dilsizian, M.D., University of
Maryland
School of Medicine 234
Q&A for Speakers 253
4
C O N T E N T S (Continued)
Open Public Hearing:
Michael J. Gelfand, M.D., Children's
Hospital,
Cincinnati 296
Manuel D. Cerqueira, M.D.,
American Society of Nuclear
Cardiology 311
Peter Gardiner, MB ChB, MRCP,
Bristol-Myers Squibb 316
Jack Rychik, M.D., American Society of
Echocardiography 320
5
1 P R O C E E D I N G S
2 Call to Order and
Introductions
3
DR. CHESNEY: Good morning and
welcome to
4
what should be a very fascinating day and a half.
5 I
would like to start by saying that there is the
6
potential for us to finish our work today if we
7
stay very focused and very attentive to the
8
specific issues that the FDA is asking us to
9
address. But first we need to
have the
10
introductions and I think maybe we could start with
11 Dr.
Maldonado and go around this way, please.
12
DR. MALDONADO: Samuel Maldonado,
from
13
Johnson & Johnson.
14
DR. MOORE: Phillip Moore, from
the
15 University of California San Francisco,
pediatric
16
cardiology.
17
DR. SIEGEL: Marilyn Siegel, from
18
Washington University in St. Louis, pediatric
19
radiologist.
20
DR. DILSIZIAN: Vasken Dilsizian,
21
University of Maryland, Director of Nuclear
22
Cardiology, both adult and cardiology and nuclear
23
medicine.
24
DR. SABLE: Craig Sable,
Children's
25
National Medical Center in Washington, Director of
6
1
Echocardiography.
2
DR. GEVA: Tel Geva, Department of
3
Cardiology at Children's Hospital in Boston.
4
DR. D'AGOSTINO: Ralph D'Agostino,
Boston
5
University, statistician.
6
DR. FOGEL: Mark Fogel, pediatric
7
cardiology, Children's Hospital, Philadelphia.
8
DR. SANTANA: Victor Santana,
pediatric
9
hematologist, oncologist at St. Jude's Children's
10
Research Hospital in Memphis, Tennessee.
11
DR. GORMAN: Rich Gorman,
pediatrician,
12
private practice, Ellicott City, Maryland.
13
DR. EBERT: Steve Ebert,
infectious
14
disease pharmacist, Meriter Hospital, Professor of
15
Pharmacy, University of Wisconsin, Madison.
16
MR. PEREZ: Tom Perez, executive
secretary
17 to
this meeting.
18
DR. CHESNEY: Joan Chesney,
Professor of
19
Pediatrics at the University of Tennessee in
20
Memphis and also at St. Jude's Children's Research
21
Hospital.
22
DR. FOST: Norm Fost, Professor of
23
Pediatrics and Director of the Beioethics Program
24 at
the University of Wisconsin, Madison.
25
DR. NELSON: Robert Nelson,
Critical Care
7
1
Medicine, Children's Hospital, Philadelphia.
2
DR. FINK: Bob Fink, pediatric
3
pulmanology, Professor of Pediatrics, Children's
4
Medical Center, Dayton, Ohio.
5
DR. O'FALLON: Judith O'Fallon,
6
biostatistician, recently retired from the Mayo
7
Clinic.
8
DR. FUCHS: Susan Fuchs, pediatric
9
emergency medicine, Children's Memorial Hospital,
10
Chicago.
11
DR. DANFORD: Dave Danford,
Professor of
12
Pediatrics, Section of Cardiology, University of
13
Nebraska Medical Center and Crayton University in
14
Omaha.
15
DR. GLODE: Mimi Glode, pediatric
16
infectious disease at Children's Hospital,
17
University of Colorado in Denver.
18
DR. HUDAK: Mark Hudak, Professor
of
19
Pediatrics and Neonatology, University of Florida,
20
Jacksonville.
21
DR. SACHS: Hari Sachs, Professor
of
22
Pediatrics and medical officer at FDA.
23
DR. IYASU: Solomon Iyasu. I am team
24
leader at the FDA.
25
DR. S. MURPHY: Shirley Murphy,
the "other
8
1
Murphy." I am the Director
of the Division of
2
Pediatric Drug Development and I am going to be
3
sitting here today because the "other Murphy" may
4
have to deal with counterterrorism.
5
DR. CHESNEY: Thank you and we
6
particularly welcome our cardiology and imaging
7
consultants so that we have some expertise on the
8
committee. We are going to be
very dependent on
9 you
to talk to us about degrading nuclear particles
10 and
so on in the major session for this morning.
11 But
next we would like Tom to give us the meeting
12
statement, please.
13 Meeting Statement
14
MR. PEREZ: Thank you. The following
15
announcement addresses the issue of conflict of
16
interest with respect to Section 17, Best
17
Pharmaceuticals for Children Act Adverse Event
18
Reporting, and is made a part of the record to
19
preclude even the appearance of such at this
20
meeting.
21
This morning you will hear from Dr.
22
Solomon Iyasu, lead medical officer with the
23
Division of Pediatric Development.
As mandated in
24 the
Best Pharmaceuticals for Children Act, Dr.
25
Iyasu will report on adverse events for the
9
1
following drugs that were granted market
2
exclusivity under 505(a) under the Federal Food,
3
Drug and Cosmetic Act, Paxil, paroxetine; Celexa,
4
citalopram; Pravachol, pravastatin and Navebjne,
5
vinorelbine.
6
Because the agency is not seeking advice
7 or
recommendations from the subcommittee with
8
respect to these products there is no potential for
9 an
actual or apparent conflict of interest.
10
The following announcement addresses the
11
issue of conflict of interest with respect to the
12 use
of imaging drugs in conjunction with cardiac
13
imaging procedures in the pediatric population and
14 is
made a part of the record to preclude even the
15
appearance of such at this meeting.
Based on the
16
agenda, it has been determined that the topics of
17
today's meeting are issues of broad applicability.
18
Unlike issues before a committee in which a
19
particular firm's product is discussed, issues of
20
broader applicability involve many sponsors and
21
their products. All subcommittee
participants have
22
been screened for their financial interests as they
23 may
apply to products and companies that could be
24
affected by the subcommittee's discussions of
25
imaging drugs used in conjunction with cardiac
10
1
imaging procedures in pediatric populations.
2
To determine if any conflicts of interest
3
existed, the agency has reviewed the agenda and all
4
relevant financial interests reported by the
5
meeting participants. Based on
this review, it has
6
been determined that there is no potential for an
7
actual or apparent conflict of interest at this
8
meeting.
9
With respect to FDA's invited industry
10
representative, we would like to disclose that Dr.
11
Samuel Maldonado is participating in this meeting
12 as
an industry representative acting on behalf of
13
regulated industry. Dr. Maldonado
is employed by
14
Johnson & Johnson.
15
In the event that the discussions involve
16 any
other products or firms not already on the
17
agenda for which FDA participants have a financial
18
interest, the participant's involvement and
19
exclusion will be noted for the record.
20
With respect to all other participants, we
21 ask
in the interest of fairness that they address
22 any
current or previous financial involvement with
23 any
firm whose product they may wish to comment
24
upon.
25
Ted Treves is Chief of the Division of
11
1
Nuclear Medicine at Children's Hospital, Harvard,
2 who
was an invited speaker for today, will not be
3
able to attend.
4
DR. CHESNEY: Thank you. Our first
5
speaker this morning will be Dr. Rosemary Roberts,
6 who
is going to offer a welcome on behalf of the
7
Office of Counteterrorism and Pediatric Drug
8
Development.
9 Welcome
10
DR. ROBERTS: Good morning. I would like
11 to
take this opportunity to thank you all for
12
coming today. I would also like
to thank the
13
"Murphys" for allowing me to come up and speak. I
14
rarely get to do it; you know, I am sort of the guy
15 in
the middle. I know some of you had to
16
experience much worse weather than we have here
17
today in order to get here so we certainly
18
appreciate all of your dedication in coming.
19
Our office, as you know, has two high
20
priority areas, counterterrorism which we might be
21
dealing with today unfortunately, and also
22
pediatric drug development, and we are certainly
23
happy that we have this program today.
24
We are excited about learning more about
25
cardiac imaging and having this opportunity to
12
1
discuss it and have such a distinguished group of
2
people here to help us see how to move forward in
3
this area. So, thank you very
much for coming. I
4
hope that you have a good day and we appreciate all
5 the
advice that you can give us.
6
One other thing, as you know because Diane
7
Murphy mentioned it yesterday, with the recent
8
legislation, the Pediatric Research Equity Act, we
9 now
have a full pediatric advisory committee.
We
10 are
working on that charter and hope to have
11
something going on with that in the next couple of
12
months and then we will be setting up that advisory
13
committee. Thank you.
14
DR. CHESNEY: Thank you, Dr.
Roberts. Our
15
next speaker is Dr. Solomon Iyasu who is going to
16
bring us up to date on the adverse event reports as
17
required by the BPCA.
18
Adverse Event Reports per Section
17 of BPCA
19
DR. IYASU: Good morning. Yesterday I
20
presented adverse event reports for paroxetine and
21
citalopram pertaining to psychiatric adverse
22
events. Today I will be
presenting on adverse
23
events reported for paroxetine and citalopram and
24
then, subsequently, I will report on adverse events
25 for
vinorelbine and pravastatin.
13
1
[Slide]
2
First I would like to acknowledge the
3
contributions of these individuals.
4
[Slide]
5
First I will speak about paroxetine and
6
citalopram and then vinorelbine and pravastatin.
7
[Slide]
8
The data source for the adverse events is
9
from the FDA's Adverse Event Reporting System which
10 is
a spontaneous and voluntary system. This
system
11 has
several limitations which I wanted to bring to
12
your attention. The
under-reporting is a very
13
significant problem. There are
reporting biases
14
that may be associated with either media publicity
15 or
depending on how long the drug has been on the
16
market. The quality of the
reports is variable,
17
often very scanty. And, this
database only
18
includes the numerator data, therefore, it is very
19
difficult to estimate the true incidence rate of
20
events or exposure risk.
21
[Slide]
22
Since I will be talking about the use of
23
these medications in the pediatric population, I
24
would like to also tell you a little bit about this
25
database that FDA has. The first
is IMS Health,
14
1
National Prescription Audit Plus which measures
2
prescriptions dispensed from retail pharmacies, but
3 the
disadvantage is that it does not provide
4
demographic information or prescription use. So,
5 it only
gives you total prescriptions dispensed.
6
The other database is the National Disease
7 and
Therapeutic Index, which is a survey based on a
8
sample size of about 2,000 to 3,000 office-based
9
physicians. The small sample size
can make these
10
data projections unstable, particularly when use is
11 not
very prevalent as in the case of the pediatric
12
population.
13
[Slide]
14
Another database available to FDA is based
15 on
a large prescription claims database but, again,
16
these data cannot be projected nationally. There
17 is
no methodology developed for that.
18
Premier is another database which contains
19
inpatient drug use from about 400 acute,
20
short-stay, non-federal hospitals.
There is
21
national projection methodology available for this
22
data, but accurate national estimates are
23
selectively available. Drug use
cannot be linked
24 to
diagnosis or procedures, and the treatments
25
administered at hospital outpatient clinics are not
15
1
included in this database.
2
[Slide]
3
There is one more inpatient database,
4
which is the Child Health Corporation of American
5
Pediatric Health Information System which captures
6
information from about 26 free-standing children's
7
hospitals with charge level drug utilization data.
8
Again, although this is very pediatric specific,
9 the
data are from a limited number of hospitals
10
and, therefore, cannot be projected nationally.
11
[Slide]
12
Now coming to the drugs that I will be
13
talking about today, there is some background about
14
Paxil which I mentioned in yesterday's
15
presentation. It is an
antidepressant which is
16
marketed by GlaxoSmithKline, first approved in
17
December, 1992. Its adult
indications are several
18
psychiatric conditions--major depressive disorder,
19
obsessive-compulsive disorder, panic disorder,
20
social anxiety disorder and generalized anxiety
21
disorder, post-traumatic stress disorder. There
22 are
no approved pediatric indications. Exclusivity
23 for
this drug was granted on June 27, 2002.
24
[Slide]
25
The relevant safety information on the
16
1
label as it currently exists refers to pregnancy
2
category C, which means that the drug has not been
3
studied in pregnant women and, therefore, when
4
using it in pregnant women the risks and the
5
benefits have to be weighed.
6
I talked about precautions specifically
7
pertaining to psychiatric events yesterday. Today
8 I
have listed them here but what is specifically
9
important here are the seizures and the adverse
10
reactions with abrupt discontinuation of this
11
medication, and in patients with a history of
12
seizures caution should be exercised with the use
13 of
this medication.
14
[Slide]
15
Additionally, there is information in the
16
adverse event section of the label pertaining to
17
pre-marketing reports and that includes
18
hypertension, diabetes, dysphagia and nausea and
19
vomiting.
20
In post-marketing reports there are
21
reports of serotonin syndrome, hepatic dysfunction
22 and
anaphylaxis, and also in the overdose section
23 of
the label about dangerous hepatic dysfunction.
24
[Slide]
25
Coming to the use data for this
17
1
medication, it is the second most commonly used
2
SSRI in children. For some of you
who were here
3
yesterday at the other meeting this is a repetition
4
but, for the benefit of the others who were not at
5
that meeting I am repeating this information. Both
6
pediatric and adult prescriptions have increased
7
steadily in recent years.
Pediatric diagnoses most
8
often linked with use of this medication include
9
depression, anxiety and obsessive-compulsive
10
disorders. And, pediatric
patients account for
11
approximately 3.5 percent of total U.S.
12
prescriptions of Paxil between July, 2002 and June,
13
2003.
14
[Slide]
15
When we looked at the one-year
16
post-exclusivity determination period, there was a
17
total of 127 pediatric adverse event reports.
18
After my review and excluding all the duplicates,
19
these are the unique reports for pediatrics in one
20
year. We categorized them into
different
21
categories and psychiatric adverse events accounted
22 for
about 68. The rest of them are
discontinuation
23
syndrome, about 7 patients.
Maternal exposure was
24
about 33; neurologic about 8; accidental ingestion
25 in
2 and then others were 9. So, today we
will be
18
1
talking mostly about the non-psychiatric which
2
includes the 5 categories that I have here which
3 are
on this slide.
4
[Slide]
5 First I will talk about the adverse
events
6
pertaining to pediatric deaths.
There were about
7 10
deaths involving direct pediatric exposures; 9
8
completed suicides, which I discussed yesterday;
9 and
1 case of Stevens-Johnson syndrome. That
10
patient was also receiving valproic acid, with a
11
known association with Stevens-Johnson syndrome.
12
[Slide]
13
There were 3 deaths among patients with
14
pediatric exposure. The pediatric
exposures
15
included congenital heart disease and 36 premature
16
infants who died after 75 days postnatally. The
17
second case was a 53-day old infant who was also
18
getting OxyContin and immediate-release oxycodone
19 and
Paxil exposure prenatally--not the kid.
20
Autopsy was done and it was determined to be a SIDS
21
death by the medical examiner.
The third case was
22 a
multiple congenital anomaly, possibly a genetic
23
syndrome. This was an aborted
fetus and it was a
24
fetal death.
25
[Slide]
19
1
Going into detail about the 33 in utero
2
exposures or breast feeding exposures, there was a
3
possible withdrawal syndrome reported in 11
4
patients, one of the fatalities previously
5
described; and congenital anomalies in 5 patients
6 and
seizures in about 4 patients; developmental
7
delay or abnormality in 4 and murmur or congenital
8 heart disease in about 3; and insufficient
weight
9
gain in 2 patients; and there were others that
10
included various events that could not be
11
classified.
12
[Slide]
13
Focusing on the direct exposures, there
14
were 8 patients with neurologic events.
Among
15
these, 3 patients had extrapyramidal or movement
16
disorders. Two of these involved
other medications
17 as
well that are listed here, which are known drugs
18
associated with this kind of syndrome.
Seizures
19
were reported in 3 patients. Two
of these patients
20 had
existing seizure disorders and were also
21
receiving Paxil.
22
There was one patient where there was a
23
loss of consciousness and hallucinations. The
24
patient was also on amphetamine-dextro-amphetamine
25 at
the same time. Then, there was one
patient
20
1
where serotonin syndrome was reported as an adverse
2
event.
3
[Slide]
4
Continuing with the pediatric adverse
5
events, there were also reports of accidental
6
ingestion. One was a 2-year old
who ingested 6
7
tablets of paroxetine and recovered without
8
sequelae. A 2-year old was a
comatose patient with
9
ingestion of multiple medications including
10
paroxetine who recovered after an ICU course.
11
There were a number of medications that were
12
involved as concomitant medications, including
13
other psychotropic agents, theophylline,
14
amytriptyline--there were several of them so this
15 was
a very complicated polypharmacy case.
Other
16
events--there were 9 single occurrences and the
17
majority were labeled.
18
[Slide]
19
In closing, most of the events were
20
labeled or related to labeled events.
Unlabeled
21
events involved maternal exposures.
And, the
22
safety of paroxetine will continue to be monitored
23 in
the future. We could not determine
causality of
24 any
of these medications because of the multiple
25
medications and also the scant histories in some of
21
1 the
case reports. Nevertheless, we will
continue
2 to
monitor adverse events for paroxetine in the
3
Adverse Events Reporting System.
4
[Slide]
5
Now I will talk a little bit about Celexa,
6
citalopram which is also an antidepressant,
7
marketed by Forest Pharmaceuticals.
Its only adult
8
indication is for major depressive disorder and the
9
typical adult dose is about 20-40 mg/day. Again,
10
there are no approved pediatric indications. This
11 was
first marketed in July, 1998 and pediatric
12
exclusivity was granted in July, 2002.
13
[Slide]
14
Again just mentioning some of the relevant
15
safety labeling associated with this drug, it is
16
again a pregnancy category C drug.
It is also
17
excreted in breast milk so caution should be
18
exercised when used in nursing mothers.
19
In the precautions section there are
20
precautions regarding impairment of intellectual or
21
psychomotor functions with the use of citalopram.
22
Also, there is danger of seizures, especially in
23
ones who have history of seizure, and citalopram
24
should be used with care. In the
post-marketing
25
reports and overdose section of the label, there
22
1 are
adverse events pertaining to QTc prolongation.
2
[Slide]
3
Summarizing some of the use data for
4
citalopram, it is the fourth most commonly used
5
SSRI in children. Both pediatric
and adult
6
prescriptions have, again, increased steadily in
7
recent years. Pediatric patients
account for
8
approximately 3.3 percent of the total U.S.
9
prescriptions of Celexa.
Pediatric diagnosis is
10
often linked with its use in depressive disorders,
11
obsessive-compulsive disorder and attention deficit
12
disorder.
13
[Slide]
14
For the one-year period of review, which
15 includes
the post-exclusivity period, there were 42
16
unduplicated pediatric reports after this review
17 was
undertaken, and 16 out of the 42 were in utero
18
exposures and mostly resulted in unlabeled events
19 and
one death that I will discuss later; 26
20
children involved direct exposure and 8 resulted in
21
unlabeled events and no deaths.
As I mentioned
22
yesterday, there were 16 serious adverse events, 10
23
hospitalizations and about 4 life-threatening and 2
24 with
disability.
25
[Slide]
23
1
Going to the gender and age distribution
2 of
these adverse events, they were both in females
3 in
both direct and in utero exposure. As
expected,
4 the
in utero exposures were reported in 4 patients
5 who
were less than 2 years. The majority of
them
6
were actually less than 1. In the
direct exposure
7
they were mostly in the older patients, 9 from 6-11
8
years and 15 patients in 12-16.
9
[Slide]
10
Looking at the reasons for exposure to
11
citalopram in these reports, as I mentioned, 16 of
12
them were in utero and included 13 patients who
13
were receiving citalopram for the treatment of
14
depression. Two involved
ingestion of another
15
person's prescription and then other events which
16 are
post-traumatic syndrome and GAD and RDD and
17
also anxiety, aggression and one was ADHD, just one
18
single occurrence of those conditions.
Then, in 6
19
patients it was unknown why they were receiving
20
citalopram.
21
[Slide]
22
Focusing on the known adverse events, of
23 the
16, as I mentioned, there was one death.
There
24 was
an autopsy done and there was no cause of death
25
identified by the medical officer.
It was signed
24
1 out
as a SIDS death in a 4-month old. There
were
2
congenital anomalies in 7 patients.
Three were
3
unrelated kidney malformations; 1 eye malformation;
4 1
cardiac defect; 1 cleft lip and 1 congenital
5
megacolon. Then, there were 5
patients where
6
potentially there was a neonatal withdrawal
7
syndrome, and then there were 3 other patients with
8
myoclonus and otitis in 1 patient and delayed head
9
control at 1-month in 1 patient.
In the last
10
patient there was a report of fetal asphyxia.
11 [Slide]
12
Among the direct exposure group there were
13 21
patients, excluding the 5 psychiatric events
14
that I reported on yesterday.
There were 4
15
patients in which cardiovascular events were
16
reported. One was a
supraventricular tachycardia
17 in
an 8-year old with a prior history of similar
18
episodes. It resolved after
Celexa was
19
discontinued. There were 2
patients with prolonged
20
QTc. One involved syncope and
seizure in a 13-year
21 old
who was also taking other medications
22
concomitantly, albuterol, cetirizine and
23
montelukast. There was also a
patient where an
24
overdose of citalopram was involved in a 14-year
25
old. Whether this was an
intentional overdose or
25
1
accidental was not reported so we cannot give you
2
additional details on that. There
was 1 patient
3
where arrhythmia was reported in an 8-year old with
4
overdose of citalopram.
5
[Slide]
6
In the group where there were reports of
7
neurological or special senses adverse events,
8
there were 8 patients. One
involved demyelinating
9
spinal lesion in a 13-year old who was also on
10
methylphenidate and multivitamins.
There was a
11
patient with a visual field cut in a 15-year old
12 who
was also on Depo Provera and who improved after
13
discontinuation of Depo. There
was one patient
14 with
a cataract, a 10-year old, also on
15
risperidone, and 5 patients with seizures.
16
[Slide]
17
Among other events that were reported
18
there were 2 patients where serotonin syndrome was
19
predominantly given but also, as part of the
20
syndrome, seizures occurred in both of these cases.
21
Then, there was 1 where only syncope was reported
22
with the use of Celexa.
23
There was one curious report of a
24
false-positive drug screen for cocaine on crushed
25
tablet. We tried to get
additional information on
26
1
this and from the chemistry point of view there is
2 no
relationship between these two structurally or
3
chemically. It may have been a
problem of
4
adulteration of the patient's medicine.
We do not
5
have any details but this involved a police test
6
that tested a crushed tablet found on a person
7
found to be positive for cocaine.
There were
8
others. Five patients involved
concomitant
9
medications and/or complicated underlying disease
10
which could not be categorized into a specific
11
category.
12
[Slide]
13
In summary, unlabeled events included in
14 the
non-psychiatric adverse events are the ones
15
that I mentioned involving in utero exposure and
16 the
case where demyelinating spinal cord lesion was
17
reported for one patient; visual field cut in one
18
patient and the supraventricular tachycardia in
19
another patient. These are single
occurrences.
20
Supraventricular tachycardia is not specifically
21
labeled but tachycardia and sinus tachycardia are
22 in
the label.
23
[Slide]
24
In conclusion, we will continue to monitor
25
these adverse events but I wanted to bring to your
27
1
attention that there will be updates that will be
2
provided in the future meetings regarding three
3
issues that are under review, neonatal withdrawal,
4
ophthalmologic malformation and then the QTc
5
prolongations. We will be
reporting on this in
6
future meetings.
7
So, I am done with
paroxetine and
8
citalopram and if there are questions about this
9
section I will entertain any questions.
There are
10
more details that are needed but Dr. Hari Sachs
11
will work very closely with me on these issues and
12 we
will have some details about the cases if there
13 are
any questions. Yes?
14
DR. CHESNEY: Yes, Dr. Nelson?
15
DR. NELSON: Remind me, given our
16
discussion yesterday, can you tell from the data
17 or,
if you can't is it worth finding out what the
18
timing of the suicide events on paroxetine is in
19
respect to when the drug was started?
In other
20
words, within a week, the first two weeks of
21
exposure to the drug?
22 DR. IYASU: It varied.
It varied from
23
patient to patient. There was no
clear pattern.
24
Most of them were on therapy at the time that the
25
suicide events occurred. It
varied from about 14
28
1
days to about a year in terms of how long they had
2
been on therapy. The events that
were reported
3
varied also. But there was not
much detail so that
4 we
can make a clear, distinct pattern as to when.
5
Some of them were early; some of them were later.
6 It
was very difficult, as I mentioned yesterday, to
7 try
to pin it down because of the scanty
8
descriptions that were provided in the case reports
9 but
most of them were on therapy. There were
a few
10
that were post-therapy and during the withdrawal
11
period.
12
DR. CHESNEY: Dr. Ebert?
13
DR. EBERT: Of the 33 maternal
exposures
14 you
noted with paroxetine, do you know what
15
proportion of those were in utero versus breast
16
feeding?
17
DR. IYASU: Out of the 33, about 6
of them
18
involved also breast feeding exposure.
19
DR. EBERT: I noticed there was no
caution
20
regarding breast feeding, or you didn't mention one
21
specifically with that product in the labeling.
22
DR. IYASU: Yes, I think I may not
have
23
mentioned it but there is also in the label
24
information about nursing mothers.
25
DR. CHESNEY: Dr. Glode?
29
1
DR. GLODE: I just want to
clarify, as
2
part of the pediatric exclusivity there is no
3
requirement for the sponsor to do any sort of
4
random sample or active surveillance for safety
5
issues or adverse events? They
just also use this
6
passive reporting system? Is that
right?
7
DR. IYASU: Well, as part of the
BPCA, it
8 is
my understanding that the manufacturers are
9
required, just by FDA regulations, to report all
10
adverse events that come to them to the FDA. But
11
this is for the passive surveillance system.
12
Unless there are specific sorts of adverse events
13 that
are agreed upon in the pediatric studies for
14
follow-up, they do not have to report on follow-up.
15
Diane can add to this.
16
DR. D. MURPHY: The only thing I
wanted to
17 add
is that we have asked for specific
18
post-studies, you know, completion of study
19
surveillance for certain products.
But it has to
20 be
asked for in the written request.
Outside of
21
exclusivity there are Phase IV commitments that
22
could be asked for. But, in
general, what you
23
heard is what usually happens--studies are
24
completed and unless there is a specific
25
requirement they revert to the passive reporting
30
1
system unless a company notices a signal that they
2
then bring to the attention of FDA.
3
DR. S. MURPHY: Joan, I just
wanted to add
4 for
our guests that are here from imaging that this
5 is
mandatory one-year reporting required under the
6 Best
Pharmaceuticals for Children's Act in which a
7
drug gets pediatric exclusivity, which you will
8
learn about in a little while from Susan's talk.
9
Then we are required by law to report to this
10
committee publicly the adverse events that occur
11
forward for one year. So, that is
why you are
12
seeing reporting on these drugs.
They have
13
triggered a time point for the committee to hear
14
about the reports.
15
DR. CHESNEY: Could I ask a
question,
16
please? Could you clarify
this--Dr. O'Fallon
17
mentioned in the van this morning reading about
18
this neonatal withdrawal syndrome and it didn't
19
come up yesterday. I notice with
paroxetine you
20
commented that these are unlabeled events involving
21
maternal exposure. What exactly
is the withdrawal
22
syndrome, and is this something that should be in
23 the
label? Could you elaborate a little?
24
DR. IYASU: These are issues that
are
25
under review right now, but to give you sort of
31
1
additional information on what the concern is I
2
have some notes here. It is
usually associated
3
with reports that involve nervous or neuromuscular
4
effects after birth when the mother is exposed to
5
some of these SSRIs, including citalopram or Paxil.
6
This may include symptoms like irritable or
7
agitated crying, hyperreflexia, hypertonia,
8
seizures or seizure-like movements, and also
9
include some breathing difficulties as well as
10
feeding difficulties. So, this is
sort of a
11
syndrome that is increasingly being recognized with
12
babies who have been exposed prenatally to some of
13
these drugs. It is still under
continued review
14
right now to see whether this is information that
15
needs either to be communicated to the public or be
16 put
in the label. I can't give you more
details
17
except that we are looking at it very closely.
18
DR. CHESNEY: Presumably, these
were
19
serious enough to cause somebody to make a report
20
which is impressive to me. This
is quite an
21
impressive number for just voluntary reporting. Do
22 you
have any more information about whether they
23
needed to be managed? I assume if
they had
24
seizures they had to have some specific management
25
issues.
32
1 DR. IYASU: I don't have additional
2
information right now about what specific measures
3
will be taken regarding this, except to say I think
4
this is something that we are concerned about and
5
specific recommendations as to what would happen as
6
follow-up are still open.
7
DR. CHESNEY: Maybe I can ask some
of the
8 FDA
folk, is there anything that we can do to help
9
move this along? This seems like
it might be a
10
significant issue.
11 DR. S. MURPHY: I think just what you have
12
done is expressing your concern and we will take
13
that back to the Division. I
think that it is
14
under review right now and I think that is why
15
Solomon can't say more.
16 DR. IYASU: Yes.
17
DR. CHESNEY: Dr. Gorman?
18
DR. GORMAN: Are you aware of the
Canadian
19
literature surrounding this withdrawal syndrome
20
from the unit in Toronto that looks at
21
maternal-fetal exposure rate and has noted an
22
increased transfer to NICUs for babies born with
23
these agents?
24
DR. IYASU: Yes, I am and it is
good that
25 you
are pointing that out, and the Division is also
33
1
aware of the data.
2
DR. CHESNEY: I have one other
question
3
relative, I guess, to yesterday's discussion, the
4
paroxetine 68 psychiatric adverse events in
5
children, were those along the lines of what we
6
were talking about yesterday, which is activation
7 of
stimulant syndrome, or do you have any further
8
breakdown of those?
9
DR. IYASU: Actually, we were
talking
10
about this with Hari. Hari, do
you want to comment
11 on
that?
12
DR. SACHS: You know, as Solomon
pointed
13 out
yesterday, there are the 9 completed suicides
14 and
17 suicide attempts. I went back and
just
15
checked the case reports to see how many of them
16
were associated with agitation. I
picked up 8, 2
17 of
which have resulted in completed suicide, 2 with
18
suicidal ideation, 2 with suicide attempts and 2
19
with self-mutilation.
Interestingly enough, for 4
20 of
them the kids' reasons for treatment were not
21
major depression; they were OCD and anxiety; 4 of
22
them were for depression and it was pretty split,
23
half female, half male, and half of them were on
24
concomitant medications, including other
25
psychotropics or having a history of substance
34
1
abuse. So, it is definitely a
very mixed bag.
2
DR. CHESNEY: If we subtract out
the
3
suicidal issues, that still leaves a significant
4
number of other children. What
were their adverse
5
events?
6
DR. S. MURPHY: The other
psychiatric
7
adverse events, as I said, the totals were the 9
8
completed suicides, 17 suicide attempts, several
9
cases of suicidal ideation and 10 of self-injury.
10
Then, the rest of them were kind of emergence of
11
other psychiatric symptoms such as mania. So, it
12
depends I guess on what you look at but what I was
13 thinking
was that the agitation was picked up, or
14 at
least the other suicidality issue was picked up
15 as
well as the agitation. It wasn't that
agitation
16
looked, you know, linked to anything else at least
17 in
these 68 reports.
18
DR. IYASU: Yes, I think just
looking at
19
these case reports there was tremendous variability
20
also. But you can find some
agitation in some of
21 the
case reports and no mention of it in others.
22 So,
it was hard to sort of see which one is
23
predominant there; there is a mixture.
24
DR. CHESNEY: Dr. Nelson?
25
DR. NELSON: I realize this
suggestion may
35
1 be
naive from a resource point of view but, given
2 the
discussion, does it make sense to do a more
3
in-depth case ascertainment both for the cases you
4
have got and to see if there are other cases, and
5 to
see if someone could do a case study design
6
approach to see if they could ascertain that
7
this--you know, similar to what happened with the
8
rotaviral vaccine--might be a hint relative to the
9
timing and to this issue of agitation?
I mean,
10
that might be one way to try to sort this out?
11
DR. IYASU: I think that is a good
12
suggestion. These kind of studies
always require
13
additional resources that the Office of Drug Safety
14 may
not have available, but theoretically I think
15 you
can go back and try to ascertain some of these
16
cases. But one thing that we have
to be careful
17
about is that the cases that come to our attention
18 are
a selected few and we don't know what they
19
actually represent because, you know, it is really
20 a
small percentage of an unknown group of adverse
21
events. So, it requires I think
careful assessment
22 of
what the cases actually represent. Do
they
23
represent other cases that are occurring in the
24 population?
But it is a good suggestion.
25
DR. CHESNEY: Dr. Glode?
36
1
DR. GLODE: I would just like to
2
emphasize, and I think this came up for many people
3
yesterday, that with a database of between 3,000
4 and
4,000 children with regard to safety issues, it
5 is
a very inadequate number for safety. So,
there
6
needs to be some mechanism I think, other than this
7
passive surveillance reporting, for doing
8
additional safety studies whether that is by Phase
9 IV
studies from the sponsor, or whatever, but there
10
needs to be more safety data beyond 3,000 to 4,000
11 I
think for children for these drugs.
12
DR. IYASU: I think your point is
well
13
taken.
14
DR. CHESNEY: Thank you.
15
DR. IYASU: All right, thank you.
16
[Slide]
17
Now I will report on two other medications
18 that
have received exclusivity. The first
drug is
19
vinorelbine which is an anti-tumor drug marketed by
20
GlaxoSmithKline. The indications
which are
21
approved are in adults as a single agent or in
22
combination with cisplatin for the first-line
23
treatment of ambulatory patients with unresectable,
24
advanced non-small cell lung cancer.
Again, there
25 are
no approved pediatric indications for this
37
1 medication.
Exclusivity was granted on August 15,
2
2002.
3
[Slide]
4
Summarizing the use data, there wasn't
5
much in terms of our databases that revealed a lot
6 of
use for this medication in the pediatric
7
population.
8
In CHCA, which is a children's hospital
9
corporation database which is 26 children's
10
hospitals that I mentioned before, which is a
11
discharge-based database, there were 5 discharges
12 in
2001 and about 21 discharges in 2002 that
13
indicated that this medication may have been used.
14 The
diagnoses that were closely linked with its use
15
were put under the category of chemotherapy and
16
most of them were Hodgkin's disease.
17 [Slide]
18
Looking at the adverse event reports for
19
vinorelbine, the total raw number of adult and
20
pediatric reports that were received were about
21
495, and 181 of them were domestic and 314 were
22
international reports. These are
not adjusted for
23
duplicates so this includes duplicates also.
24
Looking at the pediatric reports for the
25 one
year, there were 3 unduplicated pediatric
38
1
reports and 1 was U.S. and 2 were foreign. All
2
were reported as having serious outcomes but there
3
were no deaths with the use of this medication in
4 the
one-year period that was evaluated. Five
of
5 the
16 adverse events that were reported were
6
considered unlabeled. The
diagnosis or the reason
7 its
use was for the treatment of rhabdomyosarcoma
8 in
2 of the patients and 1 of the patients had
9
neuroblastoma and the drug was being given for that
10
treatment.
11
[Slide]
12
I am just summarizing the 3 patients who
13
were reported to us with adverse events.
The first
14 one
is a 14-year old with rhabdomyosarcoma who
15
developed neutropenia, a labeled event, and was
16
successfully treated with Nupogen.
17
The second patient was a 2-year old with
18
rhabdomyosarcoma who developed life-threatening
19
adverse events including unlabeled events that
20
included epidermolysis, muscle inflammation,
21
somnolence and tachypnea. This
patient was also on
22
cytoxan. The patient was
hospitalized for about 16
23
days and eventually recovered and was discharged.
24
A 6-year old was diagnosed neuroblastoma
25 and
developed adverse events including one of the
39
1
unlabeled events, the muscle spasm, but the adverse
2
events that reported for this patient resolved
3 after
lowering the dose of vinorelbine.
4
[Slide]
5
So, it was a small number of reports that
6 we
got for the labeled and unlabeled adverse events
7
were reported, as I mentioned before.
The
8
unlabeled events have also been reported in adults
9 and
are not unique to pediatrics. The FDA
will
10
continue its routine monitoring of additional data
11 on
adverse events in all populations, including
12
pediatrics, to follow-up on the significance of any
13 of
these events.
14
[Slide]
15
The last drug I will be presenting on is
16
pravastatin, which is one of the statins. It is
17
marketed by Bristol-Myers Squibb.
In adults it is
18
indicated for the prevention of coronary and
19
cardiovascular events and hyperlipidemia. In
20
children it is approved for 8 years and older for
21 the
treatment of heterozygous familial
22
hypercholesterolemia. Pediatric
exclusivity was
23
granted on July 10, 2002.
24
[Slide]
25
Drug use databases indicate that the total
40
1
dispensed prescriptions have increased by about
2
17.5 percent between September, 1999 and August,
3
2003. That is, from 13.4 to 15.8
million per year
4 for
pravastatin and that is adults and pediatrics.
5
This is total dispensed prescriptions.
6
Pediatricians wrote about 47,000 or about 0.4
7
percent of the total of the 15.8 million
8
pravastatin prescriptions during that period.
9
[Slide]
10
Looking at the proportion of pediatric
11
prescriptions, an estimated 7,900 prescriptions
12
were dispensed nationwide to pediatric patients
13
aged 1-16 years. This is based on
a calculation of
14 the
proportions that were obtained from advanced
15
PCS, which is a database that I mentioned before
16
which has demographic information, and applying it
17 to
the total dispensed prescriptions. It is
a
18
small number but this has to be interpreted with
19
caution because really this is an estimate.
20
[Slide]
21
There was a total number of adult reports,
22
about 993 reports during the exclusivity period and
23 691
were U.S. and 302 were international reports.
24
There were no pediatric adverse event reports that
25
were mentioned in the one-year exclusivity period.
41
1
[Slide]
2
Therefore, I don't have any additional
3
comments on pravastatin in the pediatric
4
population, except to say that we will continue to
5
monitor the database and see if there are any
6
adverse events that emerge. Thank
you very much.
7
DR. CHESNEY: Thank you. Are there any
8
questions? Yes, Dr. D'Agostino?
9
DR. D'AGOSTINO: Could you tell me
or us
10
what the physicians do with the statins in terms of
11
muscle, liver and so forth in the pediatric
12
population? Do they do anything
routinely in terms
13 of
the side effects? I mean, what do you do
with a
14
child with muscle problems? The
children are
15 growing
and so forth so how do you recognize that
16
that is happening?
17
DR. IYASU: Well, from the adverse
event
18
reports there is no way to tell, or there is no
19
information as to what actually is being done to
20
treat that, except in the cases that were presented
21
today where they were admitted but what actual
22
treatment was given was not clearly specified.
23
DR. D'AGOSTINO: Do we know if
there is
24
withdrawal of the drug in the children where things
25
like that might be happening?
That is not an
42
1
adverse event necessarily but if the children are
2
complaining about muscle pains and so forth.
3
DR. IYASU: I can't tell you because the
4
narratives that were provided to us were very
5
scanty. So, what treatment was
given to these
6
individual patients is not clearly stated in those
7
narrative reports, except that there was an ICU
8
course for one of them where it was considered to
9 be
serious enough that the patient was admitted.
10 In
terms of the complaints, they were elicited and
11
reported by a health professional.
Whether these
12
were based on clinical records or medical records
13 or
whether they were just clinical encounters, I
14
couldn't tell from the narrative.
15
DR. CHESNEY: Dr. Santana?
16
DR. SANTANA: Can you clarify for
me a
17
process issue? My understanding
is that when an
18
agent is granted exclusivity there is a commitment
19 to
do a number of studies and those studies may
20
occur in different time lines.
When does that data
21
from those studies surface in adverse event
22
reporting to this committee?
Because it seems to
23 me
that what we are seeing are reports that are
24
coming from different sources, more public kind of
25
usage sources, but the data from the actual studies
43
1
that are being done or have been done under the
2
exclusivity--when does that surface for us to see
3 in
these reports?
4
What made me think about that question is
5
that for a lot of the oncology drugs that may be
6
granted exclusivity, and I think this one is a good
7
example, those studies will occur in a semi-closed
8
system either through the cooperative group
9
mechanism or through large oncology institutions,
10 and
those data may not necessarily show up in these
11
other databases. For the oncology
drugs, why don't
12 you
go to the NCI and request their adverse event
13
reporting for the pediatric patients that are
14
participating in those studies under drugs that
15
have been granted exclusivity?
That would be a
16
more enriched data set than using this other
17
system. Can you comment, please?
18
DR. IYASU: My comment is that the
adverse
19 events
are reported to FDA, again, through this
20
passive system. The exclusivity
is granted on a
21
specific data and then, if there is a change in
22
labeling for example, it may not happen for several
23
months after exclusivity is granted.
So, in
24
theory, what you would expect is that there would
25
have been a change in the label and then there
44
1
would be increased usage of the medication and then
2 we
have to monitor or would pick up if there are
3 any
adverse events that emerge as use expands.
But
4
with many of these drugs maybe the indication is
5 not
approved and, secondly, there is a time lag
6
between the use and the period that we are looking
7 at
because this is immediately the one-year after.
8
Now, we depend on adverse event reporting
9
with the system that we have. We
don't have any
10
other system. But an active
surveillance mechanism
11 is
where we actually go to do case finding and
12
querying other databases is something that is a
13
good idea. But, again, as I said
before, that
14
system is not in place to go after that.
15
DR. SANTANA: So, the data that is
being
16
collected by the sponsors for the studies that may
17 be
related to exclusivity, when does that data
18
surface for us to see?
19
DR. IYASU: Oh, that is a question
that--
20
DR. S. MURPHY: Yes, the medical
officers'
21
reviews have to be posted on the web 180 days after
22
exclusivity is granted. I think
you bring up an
23
excellent point. I think what we
are trying to do
24 is
interpret the law and figure out the best way to
25 report to you, and that is one of the things I
was
45
1
going to ask you, if this is the best information.
2
What we are doing now is going to the AERS passive
3
system and picking up all the reports for a year
4
after exclusivity. We are not
going into the
5
trials and pulling those out.
6
DR. SANTANA: Yes, what
highlighted my
7
comment was the oncology example.
8
DR. S. MURPHY: That is a very
good
9
example.
10
DR. SANTANA: You would not pick
up a lot
11 of
the oncology adverse event reports through these
12
databases. You would have to go
to a very enriched
13
data set that already exists.
14
DR. IYASU: I agree.
15
DR. SANTANA: There is a lot of
16
under-reporting here.
17
DR. S. MURPHY: Yes, there is a
lot of
18
under-reporting.
19
DR. SANTANA: This drug is an
example but
20 I
suspect if we continue that practice with
21
oncology drugs we will see a lot of under-reporting
22
that will not come out until years later when the
23
drugs are being used in a different way.
24
DR. S. MURPHY: Well, I agree with
you. I
25
think that the reporting of a lot of this, you
46
1
know, can be enhanced and we have sort of taken a
2
year now to report this way. I
think we also
3 realize
that the label is going to get out there
4 for
six months at least. So, is there
really,
5
after exclusivity, a big peak in pediatric use, or
6
does the use come later, or was it used off-label
7
before?
8
DR. D. MURPHY: I think the
question is
9
really good but it gets to a different process and
10 I
think it is an important process for this
11
committee to think about because it has huge
12
ramifications. What the law
mandates we do is, as
13 has
been noted, to report on the adverse event
14
reporting after exclusivity. At
some period in
15
that exclusivity the product will be approved and
16
labeled.
17
The issue is that the BPCA has said that
18
this information will be posted.
The studies will
19 be
posted on the web and theoretically in the
20
medical review information on the oncology
21
product--I mean, the information that came out
22
during the studies should be up on the web at that
23
point.
24
Now, I think the other issue though that
25
people are pointing out, and that I think this
47
1
committee is now very familiar with is that if you
2 have a new label and that label is supposed
to
3
reflect the adverse events that were defined in
4
those studies, then that is the way of
5
communicating to the public what those adverse
6
events were that were found in that better process,
7
which is controlled studies, versus this passive
8
adverse event reporting. That
label sometimes is
9 not
available except up on the web site somewhere
10 for
different periods of time depending on how many
11
labels are out there already, etc.
So, it will
12
vary.
13
So, I think you are bringing forth a very
14
important question which is access to this
15
information, which we talked about yesterday quite
16 a
bit. Second is the issue--and I really
think the
17
committee needs to think about this for a long
18
time--are you asking us to review every study that
19 is
approved under exclusivity? There have
been
20
over a hundred determinations and over 60, 70
21
labels. That would be 60 meetings
literally to go
22
over each of the studies. So, I
think that is a
23
different question. I just want
to make sure that
24 we
define when the information will be available.
25
DR. CHESNEY: Dr. O'Fallon had her
hand up
48
1
next.
2
DR. O'FALLON: I have another
process
3
issue. I was curious because in
looking at
4
pravastatin, or whatever it is, there are two
5
different estimates of the size of the prescription
6 to
the pediatric population. On one slide
it says
7
pediatricians wrote 47,000 of the total
8
prescriptions during that year and the other one
9
says an estimated 7,900 prescriptions were
10
dispensed. Now, I realize you are
working off two
11
different sets but the difference between 8,000 and
12
47,000 is big in my mind and I am wondering is that
13
sort of a very high upper bound and a very low
14
lower bound, or what. You are
trying to get at
15
what is the piece of the pie that goes for
16
prescriptions to this age group.
17
DR. IYASU: Yes, I think that is
an
18
important point. There is
obviously a big
19
discrepancy between the two estimates.
One is
20
referring to dispensed prescriptions written by
21
different specialties. The other
one is getting
22
proportions out of a database that is not
23
nationally representative and applying the
24
demographic percentage to the national database.
25 So,
we are trying to get sort of two estimates but
49
1
they are giving us different estimates and we don't
2
know how to sort of marry the two.
But we thought
3
that we would give these databases and explain what
4 the
limitations of both of these databases are,
5
which I mentioned before. So,
that is a good
6
point. It is something that we
have to work on to
7 try
to get better databases that could give us
8
better estimates and not miss significant portions
9 of
dispensed prescriptions. That is a good
point.
10
Thanks.
11
DR. CHESNEY: Dr. Gorman and then
Dr.
12
D'Agostino.
13
DR. GORMAN: I can explain four of
those
14
pravastatin prescriptions, I wrote them for my
15
mother.
16
[Laughter]
17
So, a pediatrician wrote them but it
18
didn't go to a pediatric patient. So, that is four
19 and
you only have 47,000 more to go. So.
20
The other issue that I think is a little
21 bit
more global is that I think I hear a different
22
theme emerging from our discussion which is that we
23
have listened to the AERS data reporting system and
24 its
weaknesses and we have listened to the concerns
25
that there are safety signals we will not meet
50
1
during the controlled clinical trials for efficacy.
2 I
think the AERS system grew up in a totally
3
different generation of information collection and
4
distribution and perhaps there needs to be a more
5
active system looking for safety signals than we
6 presently have. I think I heard Dr. Glode say that
7 and
I have heard other people say that with active
8
case finding there is a more active searching, and
9 I
am not sure that is inside the charge of the FDA
10 but
I am sure that that is something that would
11
enhance the safety of these agents.
Rather than
12
demanding of sponsors that the clinical trials get
13
larger and larger and larger, look for clinical
14
safety signals and perhaps there can be another
15
mechanism that allows us to look for safety signals
16 for
the rare events after post-marketing.
17
DR. CHESNEY: Dr. D'Agostino?
18
DR. D'AGOSTINO: My comment is
similar to
19
that. I mean, in some fields like
cardiology with
20 the
statins we have an idea, we have a very good
21
idea of what some of the problems are and there are
22
lots of different companies and lots of different
23
trials, but it is quite quick in some cases to put
24
together how many problems are developing. Instead
25 of
each study being reported separately, I know
51
1
with the OTCs and things that we do in some of the
2
cardiology we can quickly find out how many muscle
3
problems are developing, how many liver problems
4 are
developing without having a list of each study
5
being laid out but these companies are constantly
6
surveying. They know what some of
the problems are
7 and
they have active ways of getting at them.
Are
8 we
doing the same here? I mean, I presume
we are
9 and
the question is how do we get that information
10 to
the committee here and how you are actually
11
pulling that data together because, as we said, the
12
AERS is not really going to do it.
13
DR. D. MURPHY: The companies are
required
14 to
report this to us so it is coming into AERS.
If
15 the
company knows about it, it is coming in to us.
16
DR. D'AGOSTINO: What I was saying
is some
17 of
these are doing active registries, surveillances
18 and
so forth so they are actively looking.
They
19 are
not just waiting for a passive.
20
DR. D. MURPHY: I think what Dr.
Gorman
21 and
you all are trying to say is that you have
22
heard the limitations, and we have sort of pounded
23 you
with it multiple times, and that there needs to
24 be
a better way but that we can't power safety
25
studies for rare events. That
just won't go
52
1
forward; it is not feasible.
2
I was just trying to see if somebody from
3 our
ODS Office was here because it would be good
4 for
them to hear your concerns and we will relay
5
those back to them, how can we improve the process?
6 Can
we target--I think one of the questions is can
7 we
target areas, which it sounds like others have,
8
where we think there needs to be an active
9
surveillance system? Certainly,
as I mentioned
10
earlier, we have done that in a few cases where we
11
know what the safety signal is.
If you know what
12 the
safety signal is, then it is a lot easier to
13
design that kind of surveillance system.
So, you
14
know, it gets back to that kind of focused system
15
versus finding in kids unexpected results which I
16
don't know that we are able to do yet.
17
DR. CHESNEY: Dr. Danford?
18
DR. DANFORD: To briefly address
Dr.
19
D'Agostino's earlier question about what would the
20
response of a pediatric cardiologist be to muscle
21
pains, myalgias or muscle problems we might
22
encounter in starting these medicines in children,
23 I
think that we would be pretty quick to withdraw
24 the
medicines under those circumstances. I
don't
25
think, watching the people who handle our childhood
53
1
lipid problems in our town--I don't think that the
2
discovery of that or any of the other relatively
3
well-known complications discovered by our adult
4
colleagues would necessarily trigger a report that
5
would show up in AERS. You know,
we know about
6
these things; we stop the medicines and we don't
7
think about it. It highlights
once again the
8
inadequacies of this approach and our need to look
9 for
other ways.
10
DR. IYASU: I think these are all
very
11
good comments and, in terms of the limitations of
12 the
AERS database, I think everybody recognizes
13
that it has very limited utility in terms of
14
picking up adverse events. It is
useful to sort of
15
maybe generate some potential signals, especially
16
rare events that have not been picked up in
17
clinical trials, but to confirm the existence of an
18
event in association with a particular drug it is
19
terribly inadequate and I understand and I hear
20
what you are saying in terms of are there any
21
better ways of looking at adverse events and
22
monitoring them that would be a step forward. But
23
there are also limitations in terms of whether you
24 do
it for specific adverse events for a specific
25
drug or whether you do it for all the medications
54
1
that are regulated by FDA. As
Diane said, it has
2
been done for certain specific events of concern
3 but
when you try to do it to capture all potential
4
adverse events, that is a big undertaking and we
5
look forward to having some specific
6
recommendations from the committee.
Thank you very
7
much.
8
DR. CHESNEY: Thank you. Just thinking
9 out
loud, Dr. Danford raises a very interesting
10
point which is that if there were a difference in
11 the
incidence of a labeled adverse event in
12
children we would never pick that up because we
13
would just say, well, yes, we know that happens but
14 if
it were more common in children than adults we
15
wouldn't pick that up. Does that
make sense?
16
DR. IYASU: Well, we look at sort
of the
17
pediatrics and compare whether it is more common in
18
pediatrics for a specific event than in adults.
19 But
it is always very difficult also to sort of
20
have a relative rate of the event in the two
21
populations because of the different use patterns
22 and
different frequencies of use in the different
23
populations. So, a sort of
head-to-head comparison
24
sometimes doesn't work but it gives us some idea in
25
terms of whether there is a potential signal that
55
1 we
need to look further into.
2
DR. CHESNEY: Right, but a lot of
these
3
wouldn't be reported to AERS because, "well, this
4 is
something that we know happens" and unless it
5 may
be happening much more often in pediatrics it
6
wouldn't be reported because it is a labeled
7
adverse event.
8
DR. IYASU: Absolutely. Under-reporting
9 is
one of the big issues in AERS. Thank
you.
10 DR. CHESNEY: Thank you very much. I
11
think we have one new person at the table, Dr.
12
Stylianou, would you mind introducing yourself,
13
please?
14
DR. STYLIANOU: Mario Stylianou,
15
statistician from NIH. I do some
work with
16
pediatric clinical trials at the National Heart,
17
Lung and Blood Institute.
18
DR. CHESNEY: Thank you. There is nobody
19
scheduled to speak at the open public hearing but
20 let
me ask if there is anybody not scheduled who
21
would like to come to the microphone.
Apparently
22
not. We are scheduled for a
15-minute break.
23
Given the small room and small number of people and
24
potential to move ahead today, maybe we could take
25 10 minutes and, according to this clock, be
back
56
1
between 10:20 and 10:25 to begin our discussion of
2 the
cardiac imaging drugs. Thank you.
3
[Brief recess]
4
DR. CHESNEY: Let's get started if
5
everybody could find their seats, please. We do
6
have some new people at the table so I thought we
7
might take this opportunity to let them introduce
8
themselves and start over here.
9
DR. BEITZ: I am Julie Beitz. I am the
10
Deputy Director of the Office of Drug Evaluation
11
III.
12
DR. LOEWKE: I am Sally
Loewke. I am the
13
Acting Division Director of the Division of Medical
14 Imaging
and Radiopharmaceutical Drug Products.
15
DR. BUCKLEY: Hi, I am Shavhree
Buckley.
16 I
am a medical officer in the Division of Pediatric
17
Drug Development, and a pediatrician.
18
DR. CHESNEY: Thank you. Just one
19
technical or business detail, it was brought to my
20
attention that some people would be willing to
21
either forego lunch or make it a brief 15-minute
22
lunch in order to keep on going.
So, please keep
23
that in mind and we will raise it again at the end
24 of
this morning's session as to whether you want to
25 do
that.
57
1
The rest of our session very briefly, as I
2
understand it--and this will be repeated to us a
3
number of times but for the committee's benefit and
4 for
me thinking out loud, our challenge is to help
5 the
FDA determine what cardiac imaging drugs, not
6
devices or procedures but what cardiac imaging
7
drugs do we need pediatric labeling for.
Very few
8 of
these imaging agents or drugs currently have
9
pediatric labeling, and how many need it and for
10 how
many could the use simply be extrapolated from
11
adult labeling? Specifically,
they are interested
12 in
what imaging drug classes need further study.
13
Secondly, what patient populations would be
14
available to receive these drugs.
Along that line,
15
utilization information is particularly important.
16 In
other words, how many children would undergo a
17
procedure involving the agent such that there would
18 be
enough to do a study with the agent?
19
So with that, I am pleased to introduce
20 Dr.
Susan Cummins who is the lead medical officer
21 in
the Division of Pediatric Development. I
22
understand that in addition to introducing this
23
session, she may have some comments for us about
24 the
previous issue of adverse drug reporting.
25
Use of Imaging Drugs in
Conjunction with
58
1
Cardiac Imaging Procedures in the Pediatric
2
Population Pediatric Regulatory Update
3
DR. CUMMINS: Good morning. First, just
4 to
comment on the adverse drug reporting feedback
5
that you gave us, I wanted to let you know that we
6
kibitzed over the break and what we will do for our
7
next meeting and into the future is provide you
8
with the medical officers' summaries for the drugs
9
that are granted exclusivity. We
will also provide
10 you
with the labeling changes, as well as the AERS
11
summary that you get now in the summary that is
12
provided to you in your packets.
13
Diane Murphy has already shared your
14
concerns with the Office of Drug Safety who,
15
themselves, are always interested in strengthening
16
drug safety reporting to the FDA and we will be
17
talking with them about your concerns and see how
18 to
go forward with them.
19
[Slide]
20
I want to welcome you all here.
There are
21 a
lot of new faces at the table. I am
Susan
22
Cummins. I am a medical team
leader in the
23
Division of Pediatric Drug Development and Shirley
24
Murphy asked me to tell you a little bit about
25
myself so here is a 30-second story.
59
1
I came to the Division from the National
2
Academy of Sciences a little over a year ago where
3 I
was the Director of the Board on Children, Youth
4 and
Families. This board was a joint board
with
5
both the Institute of Medicine and the National
6
Research Council.
7
I also brought along a long experience
8
with environmental health, especially in childhood
9
lead poisoning. For many years I
managed the
10
childhood lead poisoning prevention program for the
11
State of California. In that role
we used meetings
12
such as this one, advisory committees, extensively.
13 We
were actually mandated by state law to use
14
advisory committees to help us with complex issues
15 of
science, medicine, public health and policy.
16 So,
I have a lot of experience with meeting
17
processes both at the National Academy of Sciences
18 and
in California, and I love meetings like this.
19 I
think your input is just so valuable and really
20 helps
us be able to move forward.
21
I want to thank you in advance for all
22
your time and wisdom, and at the end of the day for
23 the
advice that you are going to give us.
Many of
24
you, in addition to coming today, participated in a
25
series of scoping interviews that we conducted to
60
1
plan this meeting and to help us define the issues
2
that we needed to address. That
was just
3
unbelievably helpful. I don't
know that we could
4
have moved forward in planning this meeting without
5 the
input that you have given us already. We
also
6
look forward to a very stimulating and productive
7 day
so I want to thank you already for all that you
8
have done.
9
[Slide]
10
What I am going to do today is give you a
11
brief overview of the last decade of pediatric drug
12
development efforts at the FDA. I
am also pleased
13 to
report that the agency is fully engaged in
14
efforts to strengthen labeling of products for use
15 in
the pediatric populations.
16
Today I am going to talk about the issues
17
listed here. First I am going to
review pediatric
18 issues,
especially pediatric safety issues which
19
have long influenced the evolution of FDA law,
20
regulation and policy. That said,
today I am going
21 to
focus on recent milestones, those of the last
22
decade.
23
I will also briefly review the written
24
request process, discuss current pediatric labeling
25 and
exclusivity statistics, the big goals of these
61
1
efforts and pediatric resources that are available
2 at
the FDA Internet web site. For the
standing
3
committee members this will be yet another review
4 and
I apologize for that, though I appreciate Joan
5
Chesney's gracious comments yesterday that no
6
review could be too many.
However, many of you are
7
new, as I just mentioned and have just come for
8
this meeting and this topic is intended to provide
9 you
with a quick primer on how these issues have
10
unfolded at the FDA.
11
[Slide]
12
As in every field, we at the FDA conduct
13 our
work with many acronym shortcuts. You
have
14
your MRI, your PET, your SPECT, your XR, and we
15
have our FDAMA, BPCA, PREA and WR.
The acronyms I
16
will use for my talk are listed here.
The first
17
three refer to recent laws. FDAMA
is the Food,
18
Drug and Cosmetic Modernization Act.
BPCA is the
19
Best Pharmaceuticals for Children Act.
PREA is the
20
Pediatric Research Equity Act. WR
refers to a
21
written request and PPSR refers to a proposed
22
pediatric study request. I will
describe all of
23
these throughout the course of my talk.
24
[Slide]
25
In 1994 FDA issued pediatric regulations
62
1
that required data review for pediatric labeling.
2
This rule required sponsors to review both their
3
existing data as well as available published
4
literature to see if enough data was available to
5
support pediatric labeling. No
clinical studies
6
were required by this rule.
Importantly, this rule
7
introduced the concept of extrapolation of efficacy
8
data from adults to children when that
9 extrapolation
seemed scientifically appropriate.
10
[Slide]
11
In 1997 FDAMA was passed by Congress.
12
FDAMA actually brought the FDA law up to date. It
13 was
a big law that modernized the Food, Drug and
14
Cosmetic Act. Included in this
law were several
15
pediatric provisions, most importantly the
16
exclusivity incentive, which is a big carrot based
17 on
compliance with terms of a written request
18
issued by the FDA to drug sponsors.
Before the
19
passage of FDAMA the pediatric market, with the
20
exception of perhaps antibiotics and a few other
21
product classes, was too small to support a drug
22
development program so pediatric studies were not
23
done. Pediatric exclusivity
changed all of that,
24 as
you will see in a minute. The pediatric
25
exclusivity provisions of FDAMA sunsetted on
63
1
January 1, 2002.
2
[Slide]
3 Now, what is pediatric exclusivity?
4
Pediatric exclusivity is an additional 6-month
5
period during which a sponsor retains exclusive
6
marketing control of all forms of a drug product
7
line. It requires either an
existing patent or
8
exclusivity and is not a patent extension. FDA
9
doesn't have the authority to grant a patent
10
extension; only the Patent Office can do that.
11
Pediatric exclusivity attaches to an existing
12
patent or to other exclusivities which have been
13
granted by the FDA.
14
This is a very powerful economic incentive
15 for
pediatric drug development because it confers
16 to
the entire drug moiety and every product that
17
contains that active drug product.
It delays for 6
18
months the introduction of generic products. As
19
soon as the generic product is introduced the sale
20 of
the branded product declines dramatically.
21
For example, consider the steroid
22
fluticasone. When exclusivity was
granted to
23
fluticaszone it attached to Flovent, the inhaled
24
product; to Flonase, the nasal spray; to Cutivate,
25 the
topical product; and to Advair, the combined
64
1
fluticasone and salmeterol product.
Imagine, for
2
example, a product with 2 billion dollars annually
3 in
sales. Exclusivity translates to an
additional
4 1
billion dollars in sales. So, this is a
very,
5
very powerful economic incentive for pediatric
6
studies, and this was the carrot that made
7
pediatric studies economically feasible.
8
[Slide]
9
I want to touch on one part of FDAMA about
10
which there has been some confusion on the part of
11
industry, the FDAMA priority list.
The priority
12
list consisted of several hundred drugs that were
13
prioritized for pediatric studies by the FDA. If a
14
drug was on the priority list it did not require
15 FDA
to issue a written request. Issuance of
a
16
written request if a drug was on the priority list
17 was
optional. But important for now, this
list has
18
sunsetted. Its sunset was on
January 1, 2002. So,
19 it
sunsetted when the pediatric provisions of FDAMA
20
sunsetted so now this list is a piece of history;
21 it
really no longer exists.
22
[Slide]
23
The next advance I want to mention is the
24
Best Pharmaceuticals for Children Act, the BPCA,
25
which became law on January 4, 2002.
The BPCA
65
1
re-authorized the exclusivity provisions of FDAMA
2 for
on-patent drugs. In addition, it also
includes
3 an
additional mechanism for obtaining information
4 on
the safe and efficacious use of off-patent drugs
5 in
the pediatric populations.
6
There is a slide missing so I am going to
7
tell you what it says. The Best Pharmaceuticals
8 for
Children Act--as I just mentioned, BPCA
9
establishes mechanisms for study of both on-patent
10 and
off-patent products. It requires in
addition
11 the
FDA to collaborate with NIH on these studies.
12 For
off-patent products that is the major focus of
13 the
work of our Office and for on-patent products
14
that industry does not want to study.
So, if
15
industry does not want to study an on-patent
16
product we have a mechanism through BPCA to get
17
studies done aon that product for pediatric
18
labeling, as well as mechanisms for doing studies
19 of
off-patent products. For both on-patent
and
20
off-patent products industry has the right of first
21
refusal to conduct studies that are requested
22
through the written request process.
23
[Slide]
24
There are two paths to a written request.
25
First, FDA can itself issue a written request and
66
1
this happens when the agency determines that there
2 is
a public health need for the studies that are
3
being requested. The definition
of a public health
4
need can vary on many factors, such as whether
5 there
is substantial off-label use; if the proposed
6 use
is a significant pediatric issue; and whether
7
there are other treatment options available.
8
Having a disease be prevalent is not the only
9
factor that we fold into a decision about the
10
public health need. Pediatric
studies for drugs to
11
treat rare diseases may also have a high priority,
12
especially when no other treatment options are
13
available.
14
The other path is when industry submits a
15
PPSR to the FDA. In that
circumstance the FDA may
16
accept the proposal as it is and issue a written
17
request. It may modify the
proposal and issue a
18
modified written request, or it may not accept the
19
proposal at all and the factors that we just
20
described fold into the decision-making process.
21 In
that case, if the FDA decides not to issue a
22
written request then it will issue an inadequate
23
letter.
24
[Slide]
25
Now, what is a written request? A
written
67
1
request is a legal document that provides a
2
detailed outline of the studies needed by the FDA
3 to
adequately label the product for us in the
4
pediatric population. It is an
outline, a detailed
5
outline that does not have the kind of detail you
6
usually see in a protocol. Once a
study is moving
7
forward based on a written request, then a protocol
8 is
developed. The written request specifies
all
9 the
study needs to label the product, including
10
indication, population, types of studies, PK,
11
safety and efficacy studies for example, safety
12
parameters that need to be monitored, whether there
13 is
a need for long-term follow-up and what that
14
might be and the time frame for response. In the
15
next few slides I am going to review the written
16
request process.
17
[Slide]
18
These slides focus on the on-patent
19
process. The off-patent process
is fairly similar.
20 In
this example the industry sponsor submits the
21
proposed pediatric study request to the agency and
22 the
FDA reviews the PPSR to determine whether there
23 is
a public health benefit to the proposed studies.
24
Again, the public health benefit issue here is
25
important. The agency only issues
a written
68
1
request if it determines that there is a public
2
health benefit to the studies. If
so, it issues a
3
written request and, again, if not, it issues an
4
inadequate letter.
5
[Slide]
6
Once the FDA has issued its written
7 request, the industry has 180 days to respond
to
8
that request. If it declines the
request, then the
9 WR
may be referred to the National Institutes of
10
Health Foundation for funding of the requested
11
studies. I would add though that
currently there
12 are
very limited funds available within the NIH
13
Foundation to conduct studies of on-patent
14
products.
15
[Slide]
16
I am not going to talk about this slide.
17 I
want to move on and talk a little bit more about
18 the
on-patent drug exclusivity process because that
19 has
been somewhat of a mystery, what happens at the
20 FDA
in this on-patent written request review
21
issuance, and then review studies once they come in
22 to
the FDA.
23
[Slide]
24
This slide addresses all of that and I
25
want you to focus on the right side of the diagram,
69
1
this column right here. Prior to
issuing a written
2
request the agency does background research on the
3
drug product and the issues at hand and conducts a
4
literature review. That
literature review is used
5 to
inform the drafting of a written request.
The
6
draft request is then reviewed by PdIT, the
7
pediatric implementation team which is a
8
cross-functional team that meets regularly within
9 the
agency to discuss draft written requests.
10
Once the draft is reviewed, has been
11
discussed, has been revised and finally approved,
12 it
is issued to industry by the review division.
13 The
studies are completed by the sponsor, if the
14
sponsor agrees to perform them, and the results are
15
submitted to the agency. So, we
are right here.
16
Once the FDA receives the submitted study
17
reports a time clock starts. It
has 60-90 days to
18
review the reports and make an exclusivity
19
determination. The submission is
reviewed
20
eventually by the exclusivity board which is a
21
cross-CDER team. It is a very
formal meeting and
22 the
team is chaired by Dr. John Jenkins. The
23
review focuses not on whether efficacy has been
24
demonstrated but, rather, on whether the sponsor
25 has
fairly met the terms of the written request.
70
1
That is the legal standard that we must meet. This
2 is
determined by making a very careful comparison
3 of
the submission that we have received from the
4
sponsor compared to the written request that was
5
issued.
6
If, for example, the written request asks
7
that 10 children between the ages of 6 and 10 be
8
included in the study population, then the review
9
carefully checks to see if, in fact, 6 [sic]
10
children were included in the study population in
11 the
submission. If exclusivity is granted,
then
12
that notice is posted on the pediatric page and on
13 the
web. Other actions to the label follow
within
14 a
few months.
15
[Slide]
16
This incentive has really been a
17
tremendous success. Please note
here, this slide
18
reports on industry response to the written request
19
process as of January, 2004. Your
handout may say
20
2003. It is one of those last
minute errors you
21 see
after looking at a slide a dozen times.
To
22
date we have received over 300 proposals from
23
industry. We have issued nearly
300 written
24
requests. We have made
exclusivity determinations
25 for
101 cases and granted exclusivity in 91 of
71
1
those cases. This effort has led
to 63 new labels.
2
The significance of these new labels
3
really cannot be underestimated.
It isn't just
4
data; the labeling changes determine how we use
5
these drugs and provide new information on how to
6 use
these drugs safely in the pediatric population
7 on
issues such as dose, unanticipated adverse
8
events and the like.
9
[Slide]
10
I want to move forward to the present.
On
11
December 3, 2003 the President signed the Pediatric
12
Research Equity Act, PREA, into law.
PREA mimics
13 the
Pediatric Rule which was overturned by the
14
courts in 2002, and this form provides the stick
15
that balances the carrot that I talked about
16 earlier. PREA is retroactive for applications back
17 to
April 1, 1999.
18
[Slide]
19
PREA requires pediatric studies of certain
20
drugs and biologics for the issues listed here: if
21
there is a new indication; if there is a new dosage
22
form; a new route; a new dosing regimen; or a new
23
active ingredient. Biologics are
included because
24
biologics have not been eligible for exclusivity in
25 the
past because they don't have patents.
72
1
The Act also establishes, as was mentioned
2
earlier, a formal pediatric advisory committee and
3
this committee will be seated at the Commissioner's
4
level so it will advise the agency on pediatric
5
issues for most of the FDA centers--for drugs,
6
biologics, foods and devices, probably not
7
veterinary medicine. Its range of
issues will be
8
even broader than that of the current subcommittee
9 which has tackled a number of issues. The range of
10
issues we have tackled since I have been here is
11
just extraordinary.
Implementation of the Act is
12
still under discussion within the agency. The FDA
13 is
currently in the process of developing a
14
guidance to advise on how we plan on implementing
15 the
Act.
16
[Slide]
17
This is our goal for all of these efforts,
18 to
add new pediatric information to the labels of
19
drug products that are commonly used in children.
20
Before pediatrics came to the FDA drugs were
21
commonly used off-label, as I know you all know,
22 and
in that circumstance each child was an N of 1.
23
Little was learned from any of these individual
24
treatment experiments and we already have gathered
25 a
lot of very valuable information since this
73
1
effort has started.
2
[Slide]
3
I want to close by mentioning just a
4
couple of resources that are available on the FDA
5
Internet. If you go to the FDA
home page, which is
6
shown here, at www.fda.gov and you look at the
7
lower right corner--this little arrow right here,
8
there is a little link to the pediatrics web home
9
page.
10
[Slide]
11
Then if you go to the pediatric home page
12
there is a lot of valuable information--statistics,
13
guidances, information about pediatric advisory
14
subcommittee meetings and much, much more.
15
That concludes my comments. I
want to
16
thank you for your attention and I will turn the
17
podium over to Sally Loewke.
18
DR. CHESNEY: Just in advance of
Dr.
19
Loewke, I wonder if all of the speakers who follow
20
her, and including her, could tell us just very
21
briefly, 30 seconds, about your background, please.
22 FDA Perspective
23
DR. LOEWKE: Good morning and
welcome all.
24
[Slide]
25
My name is Sally Loewke. I am the
Acting
74
1
Division Director for the Division of Medical
2
Imaging and Radiopharmaceutical Drug Products. I
3 am
a nuclear medicine physician and I am going to
4
note some bias here. I am a
mother of twins with a
5 son
who has had some cardiac problems, who has
6
actually had to have cardiac catheterization and
7
some cardiac procedures. So, I am
going to throw
8
that out just so you know.
9
[Slide]
10
Dr. Chesney and panel members, I really
11
want to thank you very much for coming here today
12 and
taking time out of your busy schedules to talk
13
about this very important topic, the use of imaging
14
drugs in conjunction with cardiac imaging
15
procedures in the pediatric population.
As you
16
know, cardiac imaging plays an important role in
17 the
management of patients with cardiac disease and
18 to
date we have very few drugs that are approved
19 for
cardiac indications in the pediatric
20
population.
21
We are here today to get needed input from
22 you about the use of these products in the
23
pediatric population. The
information that you
24
will bring forward will be invaluable to the agency
25 as
we proceed in our efforts to provide safe and
75
1
effective drugs for the pediatric population.
2
[Slide]
3
These are several areas that I will be
4
addressing over the course of this presentation
5
this morning.
6
[Slide]
7
The FDA is a regulatory agency.
It is
8
made up of 6 centers. The center
that is
9
responsible for review of drugs for human use is
10 the
Center for Drug Evaluation Research. We
are
11
also known as CDER. An important
piece of
12
information to also take away from this slide is
13
that the devices are regulated by a different
14
center within the FDA, CDRH, Center for Devices and
15
Radiologic Health.
16
[Slide]
17
CDER's mission is to assure that safe and
18
effective drugs are made available to the American
19
people.
20
[Slide]
21
The Division of Medical Imaging and
22
Radiopharmaceutical Drug Products is one of 18
23
divisions that makes up the Office of New Drugs
24
within CDER. The Division is
responsible for the
25
review of drugs that are utilized for diagnostic
76
1
imaging including some radiotherapeutic products as
2
well. The medical imaging drugs
have been broken
3
down into two categories, the contrast agents and
4 the
radiopharmaceuticals. The definitions
you are
5
about to see come from the FDA draft guidance which
6 is
in your packet.
7
[Slide]
8
A contrast agent is a medical imaging
9
agent used to improve the visualization of tissues,
10
organs and physiologic processes by increasing the
11
relative difference of imaging signal intensities
12 in
adjacent regions of the body. Some
common
13
examples of these types of agents include iodinated
14
contrast, gadolinium and microspheres.
15
[Slide]
16
A diagnostic radiopharmaceutical is an
17
article that is intended for use in the diagnosis
18 or
monitoring of a disease or a manifestation of a
19
disease in humans that exhibits spontaneous
20
disintegration of unstable nuclei with the emission
21 of
nuclear particles or photons, or any radioactive
22
reagent kit or nuclide generator that is intended
23 to
be used in the preparation of such an article.
24 One
of the common radioactive tags that is used in
25
nuclear medicine imaging, including nuclear cardiac
77
1
imaging, would be technetium 99-M.
2
[Slide]
3
As an aid to your understanding of the
4
Division and its thinking about the development of
5
medical imaging drugs, you were provided with the
6
draft guidance for developing clinical imaging drug
7 and
biologic products in your preparatory package.
8
This document provides information on important
9
areas that need to be discussed during the course
10 of
drug development. I refer you to the
guidance
11 for
specifics, however, I will briefly touch upon
12 the
types of indications that could be sought for
13
both the pediatric and adult indications.
14
Structure delineation--an imaging agent is
15
able to locate and outline normal anatomic
16
structures and, in doing so, can clarify the
17
spatial relationship of that structure with respect
18 to
other body parts or regions.
19
Disease or pathology detection--an agent
20 is
able to detect and locate specific disease or
21
pathological states.
22
Functional, physiological or biochemical
23
assessment--an agent is able to evaluate function,
24
physiology of biochemistry of a tissue, organ
25
system or body region. This type
of indication
78
1
could apply to an agent that is used to detect
2
either a decrease or an increase of a normal
3
function or physiological or biochemical process.
4
Diagnostic or therapeutic patient
5
management--a medical imaging agent would improve
6
patient management decisions or improved patient
7
outcomes, including predicting survival or patient
8
response to specific therapies.
9
[Slide]
10
To provide you with a framework of the
11
types of information we routinely see when new drug
12
applications come into the agency, I have this one
13
slide. It is not all-inclusive
for the clinical
14
assessment and it is not all-inclusive for the
15
information that we seek in a new drug application
16 but
it highlights a couple of points I wanted to
17
discuss further. For efficacy,
obviously, we
18
review the data and review the studies to make sure
19 an
appropriate dose has been selected that is going
20 to
give you a useful image. We look at the
21
pharmacokinetics and make sure they are well
22
defined.
23
The pivotal Phase III trials are the
24
trials where we get most of our efficacy
25
information and what we like to see is a trial
79
1
design that includes clinically relevant endpoints,
2
relevant patient populations and an appropriate
3
standard of truth.
4
The question is what does all that mean?
5 I
am going to give you an example to help
6
illustrate my point here. It is
not a cardiac
7
example but I still think it makes the point
8
effectively. If you are
developing a medical
9
imaging agent that you felt could distinguish
10
between benign versus malignant lesions, having an
11
agent that could identify a malignant lesion
12
obviously has clinical utility.
Physicians will
13
know what to do with that information and it is
14
very useful. So, you would then
pursue study of
15
that agent in a patient population who would
16
present with a tumor or a lesion that needed
17
further evaluation. Ultimately,
how do you
18
validate the performance of the new drug? You
19
would do so in this case by getting biopsy and
20
confirming the pathology of those lesions.
21
From a safety perspective, we identify any
22
major toxicities that might have come about during
23 the
course of drug development and we put together
24 an
adverse event profile that, if the drug is
25
approved, generally is put into drug labeling.
80
1
So, overall our review and action on a
2
drug, whether it be approval or non-approval, is
3 based
on a risk/benefit assessment. In this
case
4
risk can mean a safety hazard or risk. It could
5
also mean hazard could be occurring from a
6
misdiagnosis as a result of the imaging drug.
7
[Slide]
8
The Division has several drugs in which
9
cardiac indications are approved.
This slide lists
10
drug classes and some of the general indications
11
that are approved in both the adult and pediatric
12
populations. The iodinated
contrast drug class is
13 the
only drug class that has a cardiac indication
14
approval in both the adult and pediatric
15
populations, that being for conventional
16
angiography. The pediatric
approval goes down to
17 the
age of 1.
18
The gadolinium drug products are not
19
approved in either the adult or pediatric
20
populations for a cardiac indication, however they
21 do
have other indications that are approved in both
22
populations.
23
The radiopharmaceuticals--we have approval
24 for
myocardial perfusion identifying cardiac
25
ischemia and other myocardial functional
81
1
assessments such as ejection fraction, wall motion
2 and viability. Again, those are studied and
3
approved in the adult population.
4
Microspheres are one of our most recent
5
drugs that have been on the market.
They have been
6
approved for left ventricular opacification and
7
endocardial border delineation but have only been
8
approved in the adult population.
9
[Slide]
10
Historically, children were felt to be
11
considered like little adults and we could dose on
12 a
milligram/kilogram basis and, therefore, research
13 in
children really wasn't necessary.
However, in
14 the
1970s there was a change in that thinking where
15
people actually felt it was unethical not to study
16
drugs in the pediatric population as many new drugs
17
were flooding the market and were being used in
18
this population.
19
Today, as Susan has mentioned, we have the
20
Best Pharmaceuticals for Children Act and the
21
Pediatric Research Equity Act which are
22
congressionally mandated, and Congress has clearly
23
stated that children deserve the same level of
24
evidence as that provided for the adult approvals.
25
[Slide]
82
1
The agency has tried to foster pediatric
2
drug development and, in doing so, has made
3
comments about the potential use of extrapolation
4
from efficacy data from adults to the pediatric
5
population. Therefore, if the
course of disease
6 and
the effects of the drug are similar in adults
7 and
pediatric patients, then the FDA may conclude
8
that pediatric efficacy can be extrapolated from
9
adequate and well-controlled studies in adults,
10
usually supplemented with other information
11
obtained in the pediatric population such as
12
pharmacokinetic and safety studies.
13
[Slide]
14
When may it not be appropriate to
15
extrapolate? When the disease is
different in
16
etiology, pathophysiology or in its manifestations;
17
when the response to therapy is different; when the
18
pathophysiology may be comparable but the response
19
unpredictable; or when pharmacokinetic parameters
20 are
not well-defined in the adult population.
21
[Slide]
22
We know that there are differences in
23
pathophysiology of cardiac disease between the
24
pediatric and adult populations.
Pediatric
25
population presents with congenital heart disease
83
1 and
the adults with atherosclerotic heart disease,
2 and
most of our drug approvals for cardiac
3
indications in adults have revolved around patient
4
populations that have signs and symptoms of
5
atherosclerotic disease. So, the
question to
6
ponder later today is do differences in the
7
etiology and pathophysiology affect imaging drug
8
performance?
9
[Slide]
10
We have had great difficulty in getting
11
accurate use data of these products.
In an effort
12 to
try to give you some perspective, we looked at
13 the
Child Health Corporation of America's Pediatric
14
Health Information System database.
Currently,
15
this is inpatient data from 31 free-standing
16
children's hospitals with charge level drug
17
utilization information. It is
our first access to
18
pediatric inpatient drug use and, since many
19
children's hospitals are the sites of research
20
trials, we feel that we probably get great
21
information on potential off-label use of these
22
products.
23
This database, however, has a lot of
24
limitations to it. You cannot
nationally project.
25 The
FDA only has access to data dating back to
84
1
1999. There is no direct link
between drug and
2
diagnosis procedure. It does not
capture
3
outpatient use and free-standing image center use.
4
And, the contrast media radiopharmaceuticals are
5
usually bundled together with the imaging procedure
6 and
cannot be specifically separated out.
7
[Slide]
8
So, this is the result of our database
9
search and this is specifically from 26
10
free-standing children's hospitals at the time this
11 was
done. These are drug mentions in the
pediatric
12
population for the years 2001 and 2002 out of the
13
total discharges that you see at the bottom of the
14
slide. The iodinated contrast
agents have the most
15
drug mentions for both 2001 and 2002, followed by
16 the
gadolinium contrasts, radiopharmaceuticals and
17 the
microspheres.
18
[Slide]
19
Since most of our products are not
20
approved in pediatrics we have little knowledge
21
about their safety. I just want
to step back for
22 one
second to make one more comment about that
23
database information on use. We
are fully aware
24
that it is not an accurate representation of the
25 use
of these products because we know many imaging
85
1 procedures are performed on an outpatient
basis and
2 are
performed at free-standing imaging centers.
3 So,
we hope that the discussions later today and
4 the
presentations from our experts will help
5
enhance our knowledge of the frequency of use of
6
these products.
7
[Slide]
8
Unfortunately, we have a limited knowledge
9
base for pediatric safety data as well since we
10
have few approvals. So, in an
attempt again to
11
give you some kind of flavor of what we do know, we
12 did
a data search of the Adverse Event Reporting
13
System, also known as the AERS database.
It is a
14
spontaneous and voluntary reporting system and it
15 too
has many limitations which you heard about
16
earlier today. There is
under-reporting; reporting
17
bias; the quality of the reports is very limited;
18 and
you cannot estimate the true incidence rate of
19
events or exposure risk.
20
[Slide]
21
I just want to go over the
methodology
22
briefly of our search. We did not
want this whole
23
meeting to revolve around any one specific drug
24
but, rather, the drug classes so in an attempt to
25
keep that theme with the search of this database we
86
1
selected two drugs per drug class which we thought
2
were relative market leaders and did a search of
3 the
database in both the adult and pediatric
4 population.
5
Once we got those results, we then
6
combined them and, as you will see, the slides that
7
will be forthcoming are combined data for the drug
8
class per se. We report out the
most common
9
adverse events reported in 10 percent of the total
10 or
greater. We report out the deaths and
the
11
search time frames were variable depending on the
12
specific drug product that we used and their
13
original approval dates. Again,
be warned that
14
this database has its limitations and cannot be
15
construed as an accurate representation of the
16
adverse event profiles for these drug classes.
17
[Slide]
18
This is the data we generated for the
19
iodinated contrast agents. As you
can see here,
20
there were 2,997 reports in the adult population
21
versus 68 in the pediatric population.
The common
22
event types were pruritus, dermatitis and urticaria
23 in
the adults and urticaria, dyspnea and facial
24
edema in pediatrics. There was a
total of 274
25
deaths in the adults and 2 reported in the
87
1
pediatric population.
2
Those 2 deaths in the pediatric population
3
included a 9-year old male having an abdominal CT
4 who
had an anaphylactic reaction and died.
This
5
patient was noted to have a history of asthma. The
6
other patient was a 7-month old with multiple
7
cardiac anomalies who died approximately 6 hours
8
after a cardiac cath procedure.
As you can note,
9
these common events are really a hypersensitivity
10
type reaction and these are very common for
11
iodinated contrast agents.
12
[Slide]
13
This slide represents the gadolinium drug
14
class. There is a total of 5,163
reports in the
15
adult population versus 233 in the pediatric
16
population. Common events in
adults include
17
urticaria, vomiting, nausea, dyspnea and pruritus,
18 and
in children vomiting, nausea and urticaria.
19
There was a total of 108 deaths in the adult
20
population and 3 in the pediatric population.
21
Those 3 deaths were as follows, a 7-month
22 old
with gastroenteritis had an MRI to exclude
23
meningitis. The patient had spina
bifida and the
24
patient died 2 hours after the procedure from
25
septic shock.
88
1 A 12-year old female died from
2
complications of brain stem glioma and a 5-year old
3
male with meningeal toxemia died approximately 8
4
hours after an MRI from complications of
5
hemorrhagic stroke. Again, as I
stated earlier,
6 the
gadolinium drug class does not have a cardiac
7
indication approval in either population.
8
[Slide]
9
The radiopharmaceutical drug class--a
10
total of 334 reports in the adult population versus
11 no reports in the pediatric population. Common
12
events in adults include dermatitis, pruritus,
13
urticaria, nausea, cough, headache and dyspnea and
14 a
total of 16 deaths were reported.
15
[Slide]
16
The microsphere drug class--a total of 107
17
reports in the adult population, no reports in the
18
pediatric population. Common
events in adults are
19
back pain and headache and no deaths reported.
20
[Slide]
21
Overall, to date we have few approvals of
22
cardiac imaging drugs in the pediatric population.
23 We
have limited use data and limited safety data,
24 and
we have the question to ponder whether the
25
differences between cardiac disease processes in
89
1
adults and kids can actually allow us to
2
extrapolate the efficacy data.
3
[Slide]
4
These are basically the questions for the
5
panel that will be coming up either later today or
6
tomorrow. I just flash them on
the screen for the
7
benefit of the audience so you can understand as
8 you
listen to the speakers talk later.
9
The first question basically revolves
10
around extrapolation. Is it
possible? If so,
11
when? The second question is a
series of questions
12
that we would like addressed per drug class
13
category, asking whether there is needed study for
14 the
drug class and, if so, what patient
15
populations, what disease states, etc.
16
[Slide]
17
The third and last question is the
18
relevance of new drug developments in the field of
19
adult cardiac imaging and whether they are
20
applicable to the pediatric population.
21
[Slide]
22
So, we would really like today's focus to
23 be
on the imaging drugs. I know it is hard
to
24
separate the imaging procedure and the device but I
25 ask
that people try. We also know that there
are
90
1
many ethical issues in pediatric research. Again,
2 we
would like today's discussion to focus on the
3
science and trial design issues.
Do we need
4
additional drug labeling, and for what classes, and
5
what do we need to know? How are
these products
6
being used and for what purpose and what
7
population? And, how do they
alter your management
8
decisions, the information that you gather? The
9
bottom line, do you feel that extrapolation is
10
potentially possible?
11
[Slide]
12
I want to thank you very much for
13
attending today. As Susan had
alluded to, we
14 counted
on many people on this panel and others who
15 are
not present to help organize this meeting and
16
your help has been very invaluable and I thank you
17
very much.
18
DR. CHESNEY: Thank you, Dr.
Loewke. We
19
will have time for questions and answers of the
20
speakers after the next two presentations. The
21
next presentation is by Dr. John Ring, representing
22 the
American Academy of Pediatrics, to give their
23
perspective on the issues Dr. Loewke just outlined.
24
American Academy of Pediatrics Perspective
25
DR. RING: One of the advantages
of
91
1
becoming middle aged is that you get a bit
2 farsighted
over time so I am thinking that this
3
will probably work.
4
[Slide]
5
Apropos Joan's request to identify
6
oneself, I have found, now that I am clearly
7
unequivocally middle aged, that it is important for
8 me
to start each day by orienting myself to a
9
person, place and time--
10
[Laughter]
11
--so, this is who I am. This is
where we
12 are
and this is who you are, in case any of you
13
require this type of orientation as well.
14
The five physicians sitting to my right
15
along this part of the table will offer detailed
16
information this afternoon regarding the
17
application of intravascular contrast agents and
18
radiopharmaceuticals to various pediatric cardiac
19
diagnostic modalities. My
assignment is more
20
general. It is to present the
position of the
21
American Academy of Pediatrics as to whether these
22
agents should be studied at all.
I believe I have
23
been selected for this role because I have
24
practiced pediatric cardiology for over 20 years
25
with extensive experience in the cardiac
92
1
catheterization lab and because I am also a member
2 of
the national AAP Committee on Drugs. My
two
3
sons, Jack and Patrick who are sitting in the
4
audience feel that I was selected for this
5
presentation today so that they could miss three
6 days of school.
7
[Laughter]
8
[Slide]
9
The four points which I am about to
10
summarize represent what we know for sure about the
11 use
of intravenous contrast agents and
12
radiopharmaceuticals in pediatric cardiology.
13
These points are that congenital and acquired heart
14
disease is common in children and of considerable
15
clinical importance; that accurate diagnosis is
16
central in order to effect a good clinical outcome;
17
that the diagnostic use of intravascular contrast
18
agents and probably radiopharmaceuticals is likely
19 to
increase in the target patient population; and,
20
finally, that our current use of these agents is
21
guided really by good intentions rather than by
22
data.
23
Taken together, these points identify a
24
clinical problem that is of major clinical
25
significance in children. They
indicate that there
93
1 is
a trend toward increased utilization of these
2
diagnostic units and they highlight what the
3
Academy feels is a glaring deficiency in our
4
knowledge base regarding their use.
5
[Slide]
6 As a good academician I did a
literature
7
search. I did a literature search
in large part
8
because the American Academy of Pediatrics has not
9
given these agents focused consideration and, thus,
10
there are no official AAP policies, technical
11
reports or practice guidelines that speak to their
12
use. Regardless, the AAP
recognizes that in
13
general children's health care needs are unique,
14
that these needs commonly vary with the patient's
15
age, and that optimal pediatric therapy, regardless
16 of
type, is predicated on the performance of
17
appropriate scientific studies performed in
18
children.
19
[Slide]
20
Put very simply, knowledge is good and
21 children
are not little adults. I spoke a minute
22 ago
in regards to a literature search in order to
23 see
what guidance we had there. With the
help of
24
three research librarians at two institutions, the
25
University of Tennessee and St. Jude Children's
94
1
Research Hospital, we searched key words such as
2
intravascular contrast agents and
3
radiopharmaceuticals. We focused
the search on
4
children rather than adults. We
specified that we
5
were most interested in cardiac disease and we had
6 a
particular interest in identifying complications.
7
[Slide]
8
The databases searched are those that are
9
listed and the time frame for the search is a
10
particularly long one.
Unfortunately, but not to
11
much to my surprise, what we found is that there is
12
virtually no information extant in the literature
13
which speaks to the contemporaneous usage of
14
contrast agents in pediatric cardiology or, by
15
extension, radiopharmaceuticals.
16
Something has happened to my script.
17
Well, let's go back to the four things that we
18
actually know for sure.
19
[Slide]
20
What in particular is the scope of the
21
problem? The reported frequency
of congenital
22
heart disease in the population is 2.03 to 8.56 per
23
1,000 live births, with a median figure of 5.93.
24 The
figure that is generally quoted for the quiz is
25 the
higher of these. Even when one requires
more
95
1
firm diagnostic criteria, for example cardiac
2
catheterization, intraoperative inspection or
3
postmortem examination, the figure is still
4
substantial, up to 4.3 per 1,000 live births.
5
We have a population of children with
6
congenital heart disease which is aging.
An
7
article from The American Journal of Cardiology, in
8
1982, so a relatively dated reference, indicated
9
that there were at that time approximately 8,500
10
children with operated congenital heart disease
11
reaching adulthood each year.
Thanks to advances
12 in
diagnosis and therapy that number is actually
13
increasing. In addition, those
patients constitute
14 an
aging population, the natural history for which
15 is
entirely unclear. So, we are obviously
on a
16
voyage of discovery.
17
As far as inflammatory cardiac disease is
18
concerned, the first two points indicate that the
19
incidence and prevalence of Kawasaki syndrome and
20
acute rheumatic fever are substantial in the
21
pediatric population. As far as
myocarditis is
22
concerned, more frequent myocardial biopsy in
23
children coupled with better diagnostic modalities,
24 for
example PCR analysis, are beginning to extend
25 the
scope and define the specificity of this
96
1
diagnosis which to date has been largely
2
descriptive.
3
[Slide]
4
One of the ways in which pediatrics
5
differs from adult medicine is with its focus on
6 the
future. The mission statement of the
American
7
Academy of Pediatrics is very clear on this point:
8 The
AAP is committed to the attainment of optimal
9
physical, mental and social health and well being
10 for
all infants, children, adolescents and young
11
adults. Balance this against the
fact that
12
congenital anomalies are the fifth ranked cause of
13
premature mortality in the United States. That is
14
taken from a reference in Morbidity and Mortality
15
weekly reports in 1998. Of
interest for this
16
group's deliberations, structural congenital heart
17
diseases account for 6 of the 15 most lethal
18
congenital malformations in this group.
19
[Slide]
20
Optimal interventions in pediatric
21
cardiology really do depend, in large part, on good
22
imaging. A good picture is worth
a thousand words.
23
Pediatric cardiologists and cardiovascular surgeons
24 are
visually oriented practitioners. We
cannot
25
treat effectively what we cannot see well. This
97
1
applies both to surgical and catheterization
2
laboratory interventions.
3
Our patient population today is undergoing
4
higher risk interventions both in the cath lab and
5 in
the operating room. These interventions
reduce
6
what we consider to be the acceptable margin of
7
diagnostic error. Our patients
are usually
8 younger,
sometimes much older--for example, adults
9
with grown up congenital heart disease--and usually
10
sicker. They have a limited
tolerance for long,
11
stressful procedures. Accurate
imaging then
12
provides the road map to reach our therapeutic
13
destination in a timely fashion.
Just as the
14
children's oncologist can now choose the safest,
15
most effective treatment for his or her patients
16
with leukemia through use of genetic subtyping, so
17 the
pediatric cardiologist can choose, at least to
18 a
degree, the safest, most effective dilation
19
balloon or closure device provided that he or she
20 has
a detailed and accurate image with which to
21
work.
22
Finally, different imaging modalities are
23
complementary rather than competitive.
The
24
echocardiogram, for example, will certainly
25
satisfactorily define the basic anatomy of
98
1
tetralogy of flow. Angiography,
however, is
2
necessary to dilate and stent the focal pulmonary
3
artery stenoses that often complicate this lesion
4 and
affect its clinical outcome.
5
[Slide]
6
The use of these agents is likely to
7
increase. The volume, for
example, of
8
interventional cardiac procedures performed in
9
children is increasing rapidly and in most centers
10
interventional procedures take place in a third to
11
two-thirds of cardiac catheterizations.
These
12
interventional procedures oftentimes require more
13
angiograms, though of a different type or programs,
14 and
smaller but more frequent injections.
15
The number of adult patients with
16
congenital heart disease is increasing as well.
17
Thus, the assessment of myocardial function and
18
blood flow becomes clinically of greater
19
significance. This may be
particularly true in
20
those structural cardiac lesions which involve
21
abnormalities of coronary arteries, for example
22
transposition of the great arteries or anomalous
23
origin of the left coronary artery from the
24
pulmonary artery. This may apply
particularly to
25
children who survive acute Kawasaki disease but may
99
1 go
on to be at cardiac risk for myocardial
2
ischemia.
3
Our colleagues in interventional radiology
4
apply procedures to non-cardiac areas in pediatric
5
practice as well. For example
embolization of
6
venous malformations in the central nervous system
7 and
catheter-directed thrombolysis have
8
implications for the use of these agents as well.
9
[Slide]
10
Young people search extensive databases on
11 the
web. Older people, like myself, pick up
the
12
telephone and call respected colleagues at big
13
programs. So, what I did to
prepare for this
14
meeting was to query the cardiac cath lab directors
15 at
five programs throughout the United States.
16
Four of these five programs are university
17
affiliated. One is a respected
adult in a
18
pediatric multi-specialty clinic that does a large
19
volume of pediatric cardiac disease.
These five
20
centers do a total of approximately 3,000 pediatric
21
cardiac catheterizations in a year's time. The
22
number of children they catheterize who are under
23 one
year of age is 30-50 percent and in some
24
programs somewhat greater. The
number of
25
interventional procedures performed during these
100
1
cardiac catheterizations at present are upwards of
2 50
percent of these cases. Each of the
programs
3 did
a handful, in one case approaching 5 percent of
4
their cath lab volume, of immediate postoperative
5
catheterizations. All of the
centers had an
6
increasing population of adults with congenital
7
heart disease, 10-15 percent and in some cases
8
larger.
9
What do these inquiring pediatric
10
cardiologists want to know? the
first thing they
11
want to know is are nonionic contrast agents really
12 that
safe or have they just been lucky or good in
13
their practice? The type of
complications that we
14 are
talking about do not really reference nausea
15 and
vomiting; they reflect the sort of
16
complications which are meaningful to this
17
gun-slinging subgroup of pediatricians.
That would
18 be
death, shock, anaphylaxis, life-threatening
19
respiratory distress, gross hematuria, acute renal
20
failure and so on.
21
Their experience is that with the
22 development
of nonionic contrast agents those
23
complications, all of which were seen previously in
24
frighteningly high numbers, have now disappeared
25
almost completely. But there
still is a question
101
1 in
the mind of the practitioners as to what is
2
safe. That is important
particularly when we
3
consider whether there is a maximum volume of
4
contrast that I can inject safely.
Most pediatric
5 centers will limit contrast injection to a
total of
6
somewhere between 5-7 cc/kg of body weight during
7 the
course of a single cardiac catheterization.
8
Some centers have hinted that as they approach that
9
contrast wall they will forego indicated diagnostic
10
procedures till another day for safety-related
11
reasons. Is that a good
practice? Nobody really
12
knows.
13
So, cardiologists would like to know how
14
safe these contrast agents are and does that safety
15
factor vary with age, vary with lesion, vary with
16
co-morbidities, or vary with the program of
17
injection? Are a couple of great,
big angiograms
18
like we used to do better or worse for the patient
19
than a whole bunch of small angiograms that might
20
guide an intervention during a dilation and
21
stenting? The data is simply not
there.
22
Finally, is there an agent that will give
23
adequate opacification at lower volumes of contrast
24
administered in large patients?
This is
25
particularly apropos to that increasing patient
102
1
population, the adult with congenital heart
2
disease.
3
The final question is one that many
4
pediatric cardiologists ask themselves at the end
5 of
the day, especially if their day is ending in
6 the
middle of the night, how can I earn as much as
7 my
colleagues in internal medicine do? I know
that
8 is
beyond the scope of this committee to answer.
9
[Slide]
10
Why wouldn't you study these agents?
That
11 is
the question that I came to ask myself as I
12
tried to prepare these comments.
There may be
13
philosophical considerations at work here. Some
14
feel that data-driven decision-making is of no
15
particular value. Others may feel
that children
16 are
unable for some reason to receive the benefits
17
that accrue to the adult patient through scientific
18
study. Evidence-based medicine
has refuted, I
19
think quite effectively, both of these contentions
20 and
Congress has mandated that the benefits of
21
study should be available to children as well as to
22
adults. There may be some who
believe that
23
clinical resources do not exist to study this
24
problem effectively in children.
25
Each of the institutions I have surveyed
103
1
indicated that they would be pleased to participate
2 in
studies to answer some of the questions that
3
were raised. That doesn't
represent written in
4
stone commitment but it certainly does indicate
5
interest and, coupled both with the incidence and
6
prevalence factors that I spoke of initially,
7
indicates that I think there is a patient
8
population there readily available for study.
9
Finally, there may be some hard-core
10 skeptics
who are either unfamiliar with or frankly
11
doubtful that important practice improvements have
12
been made as the result of the fruits of FDAMA.
13
[Slide]
14
Dr. Cummins pointed you toward the FDA web
15 site
which, much to my surprise, I was actually
16
able to access in a user-friendly fashion. That is
17 a
comment on me; that is not a comment on you.
18
What I found is that the FDA has so far issued
19
approximately 300 written requests and that, as a
20
result of the studies requested, there have been
21
over 90 changes in labeling. I
can say as a
22
pediatrician that fully 15 of those 90 changes are
23
changes that impact my practice, five of which very
24
directly and I am a niche practitioner--studies on
25
midazolam, studies on fentanyl, studies on all of
104
1 the
statins, studies on all of the prils have been
2
important to me as a practicing pediatric
3
cardiologist. As the Carpenters
would say, we have
4
only just begun to gather this information.
5
[Slide]
6
If you look at the exclusivity statistics
7 you
will see that some divisions have been very
8
active in requesting studies in pediatric patients,
9 and
one particular division has not, the Division
10
of--what do you call yourselves?--Medical Imaging
11 and
Radiopharmaceutical Drug Products. We
single
12
this out because it is the subject of today's
13
discussion. We feel clearly, as
pediatricians,
14
that this area deserves study as well.
15
[Slide]
16
So, what are the recommendations of the
17
American Academy of Pediatrics?
We feel that the
18 FDA
should exercise its authority to require that
19
appropriate studies be performed regarding the use
20 of
intravascular contrast agents and
21
radiopharmaceuticals in children cardiac disease.
22
We feel that those contrast
studies should
23
focus on dosing considerations, balancing safety
24
concerns with imaging effectiveness.
As an aside,
25
there is a question in the mind at least of all the
105
1
practitioners as to whether the new nonionic
2
contrasts achieve a comparable level of
3
opacification and, therefore, diagnostic
4
information. Inadequate data or
erroneous data can
5 be
as damaging as no data at all. So,
clearly,
6
that has to be balanced against the safety
7
consideration.
8
Finally, we wonder, and this is just a
9
question, whether a different regulatory posture
10 may
be needed on the part of the FDA in order to
11
study these agents as effectively as others have
12
been studied. It is our
understanding that
13
currently intravascular contrast agents and
14
radiopharmaceuticals are regulated or studied under
15 the
auspices of a device rather than a drug, and we
16 are
not certain, if that is the case, whether this
17 is
the most effective way to pursue that.
18
Regardless of whether it is a drug or whether it is
19 a
device, whether it is done through this division
20 or
that division, we feel there is a substantial
21
problem to address a large pediatric population
22
which can potentially benefit from an informed
23
consideration of these agents.
Thank you.
24
DR. CHESNEY: Thank you, Dr. Ring.
25
Because of how these meetings are run, since Dr.
106
1
Ring is not at the table this is our only
2
opportunity to ask him questions that the committee
3 may
have. Once our next speaker begins we
can no
4
longer ask him questions. Are
there any questions
5 for
Dr. Ring?
6
[No response]
7
Thank you very much.
8
DR. LOEWKE: Excuse me, I just
wanted to
9
clarify that the contrast agents and
10
radiopharmaceuticals are approved at the Center for
11
Drugs.
12
DR. CHESNEY: Our next speaker is
Dr.
13
Geva, from the Children's Hospital Boston. Please,
14 do
give us a few seconds of your background.
15 Cardiologist Perspective
16
[Slide]
17
DR. GEVA: My name is Tel Geva and
I am
18
from the Children's Hospital in Boston.
Just give
19 me
a second here to set this up. I spend
the
20
majority of my time--I divide my time between
21
taking care of children with congenital heart
22
disease and imaging. With regard
to imaging, I
23
divide my time between the cardiovascular MRI
24
program in Children's Hospital in Boston, which I
25
direct, and the echocardiography laboratory.
107
1
[Slide]
2
My task this morning is to give you an
3
overview of progress in the field of pediatric
4
cardiology. This is, of course, a
mammoth task but
5
what I will focus on are the following areas, first
6 the
scope of congenital heart disease; trends in
7
congenital heart disease outcomes; trends in
8
management; trends in imaging of pediatric and
9
adult congenital heart disease; and, finally, I
10
will try to identify some of the gaps in knowledge
11 as
they pertain to imaging.
12
[Slide]
13
As the previous speaker has alluded to,
14 the
incidence of congenital heart disease as widely
15
quoted is approximately 8 per 1,000 live births.
16
This comes from the American Heart Association.
17
With approximately 40,000 patients born every year
18
with some form of congenital heart disease there
19 are
presently approximately a million Americans
20
currently living with congenital heart disease.
21
An extensive review by Hoffman and Kaplan,
22
published in The Journal of the American College of
23
Cardiology in 2002, analyzed 62 studies on the
24
incidence of congenital heart disease published
25
since 1955. They found an
incidence ranging from
108
1
4-50 per 1,000 live births. It
turned out that the
2
variations between those studies had mostly to do
3
with the inclusion of small ventricular septal
4
defects and it has to do with what kind of imaging
5 or
diagnostic modality was used to identify those
6
ventricular septal defects.
7
However, moderate and severe congenital
8
heart disease--the incidence of those is
9
approximately 6 per 1,000. Those
are patients that
10
require some active management of their heart
11
disease, and the incidence of 6 per 1,000 relates
12 to
the population of patients without excluding
13
bicuspid aortic valve. If you
include bicuspid
14
aortic valve, then the incidence increases to
15
approximately 19 per 1,000 live births.
16
[Slide]
17
Here is a rundown of the types of
18
congenital heart disease, and that is taken from
19
that paper published in JACC and the numbers here
20 are
the median incidence per one million live
21
births excluding non-stenotic bicuspid aortic
22
valves and silent PDAs. Also
excluded are tiny
23
ventricular septal defects.
Still, VSD or
24
ventricular septal defect is the most common form
25 of congenital heart disease, followed by
several
109
1
acyanotic congenital heart diseases.
Tetralogy of
2
flow is the most common form of cyanotic congenital
3
heart disease, followed by transposition of the
4
great arteries. If you look down
here, at the
5
bottom, all cyanotic congenital heart diseases
6
account for approximately 1,270 per million of live
7
births; all congenital heart disease, approximately
8
7,600, which is close to the 8 per 1,000; and then
9
bicuspid aortic valve being the commonest form of
10
congenital heart disease. However
it manifests
11
clinically oftentimes later in life.
12
[Slide]
13
Moving on to outcomes of
congenital heart
14
disease first looking at mortality, mortality has
15
consistently decreased over the years.
This is a
16
paper that originated here from the CDC, published
17 in
Circulation in 2001, showing the deaths per
18
100,000, age adjusted, and showing a trend of
19
declining overall mortality from congenital heart
20
disease from 1979 through 1993.
21
[Slide]
22
When you look at age at death, then it
23 turns
out that 51 percent of the deaths occur in
24
infants; additional 7 percent between 1-4 years of
25
age. So, the majority of deaths
occur early in
110
1
life and then it plateaus for several decades until
2 it
starts to pick up again in the elderly.
There
3 are
some racial differences with approximately 19
4
percent higher mortality in Blacks compared with
5
Whites, as found in that paper, and slight gender
6
variations, as you can see from this graph.
7
[Slide]
8
This is data from Children's Hospital in
9
Boston looking at the cardiac intensive care unit
10
admissions--the blue bars here, from 1992 through
11
2003. Here, in red, is the
overall mortality from
12 all
causes in cardiac patients. This does
not
13
capture all deaths from congenital heart disease,
14
nevertheless, the majority do occur in the cardiac
15
intensive care unit and that is a relatively
16
accurate representation of mortality in a large
17
tertiary care acute care referral facility. If you
18
look at the numbers, about 14 years ago overall
19
mortality was approximately 6 percent and that has
20 decreased
quite consistently in the last several
21
years to somewhere between 2.5 and 2.8 percent for
22
overall mortality.
23
[Slide]
24
Still, despite the overall decrease in
25
mortality there are some pockets of resistance and
111
1
there are certain types of lesions that are still
2 at
a high level of mortality. I am just
bringing
3 as
an example pulmonary vein stenosis which is
4
nearly universally a fatal condition.
There are
5
fortunately not too many similar conditions,
6
nevertheless, there are some challenges in the
7
field of pediatric cardiology even when it comes to
8
mortality.
9
[Slide]
10
However, the majority of patients with
11
congenital heart disease survive and the majority
12 of
the therapeutic interventions--surgeries,
13
interventional catheterization, medical therapy--do
14 not
lead to cure. Residual anatomical and
15
functional abnormalities are very common in our
16
patients. Neurodevelopmental
issues are of
17
substantial interest, as well as social and
18
insurability issues.
19
[Slide]
20
As survival of patients with congenital
21
heart disease improved attention shifted from
22
getting these patients alive out of the hospital to
23
improving their functional, psychological and
24
social outcomes. These are just a
few slides
25 showing some of the work that has been done
in that
112
1
field. This is from the
circulatory arrest versus
2 low
flow cardiopulmonary bypass trial where
3
patients with transposition of the great arteries
4
were randomized into circulatory arrest versus low
5
flow cardiopulmonary bypass, and this is the 8-year
6
full-scale IQ results showing that in patients
7
transposition in ventricular septum--their
8
full-scale IQ is nearly normal as a group, whereas
9
patients with transposition in ventricular septal
10
defect who were randomized to the circulatory
11
arrest arm actually as a group,had lower overall
12 IQ.
13
[Slide]
14
There is similar data on patients after
15 the
Fontan operation, again showing full-scale IQ
16
verbal and performance tests, and showing that
17
overall these patients are doing nearly as well as
18 the
normal population.
19
[Slide]
20
Here is a group that doesn't do as well,
21
albeit a small group of patients with interrupted
22
aortic arch. Their performance is
sub-normal in
23 all
levels of tests.
24
[Slide]
25
It is interesting to compare patients with
113
1
congenital heart disease to other pediatric
2 patients with different problems.