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
Advisors and Consultants Staff Conference Room
5630 Fishers Lane
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.
Mary Glode, M.D.
Steven Ebert, Pharm.D. (Consumer Representative)
FEDERAL EMPLOYEE (VOTING):
Mario Stylianou, Ph.D.
Samuel Maldonado, M.D.
Shirley Murphy, M.D.
Solomon Iyasu, M.D.
Hari Sachs, M.D.
Julie Beitz, M.D.
Sally Loewke, M.D.
Shavhree Buckley, M.D.
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
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
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
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
C O N T E N T S (Continued)
Open Public Hearing:
Michael J. Gelfand, M.D., Children's Hospital,
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
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
17 DR. SIEGEL: Marilyn Siegel, from
18 Washington University in St. Louis, pediatric
20 DR. DILSIZIAN: Vasken Dilsizian,
21 University of Maryland, Director of Nuclear
22 Cardiology, both adult and cardiology and nuclear
24 DR. SABLE: Craig Sable, Children's
National Medical Center in Washington, Director of
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
22 DR. FOST: Norm Fost, Professor of
23 Pediatrics and Director of the Beioethics Program
24 at the University of Wisconsin, Madison.
DR. NELSON: Robert Nelson,
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
8 DR. FUCHS: Susan Fuchs, pediatric
9 emergency medicine, Children's Memorial Hospital,
11 DR. DANFORD: Dave Danford, Professor of
12 Pediatrics, Section of Cardiology, University of
13 Nebraska Medical Center and Crayton University in
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,
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.
DR. S. MURPHY: Shirley Murphy,
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
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.
Iyasu will report on adverse events for the
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,
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
imaging drugs used in conjunction with cardiac
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
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
Ted Treves is Chief of the Division of
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
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
cardiac imaging and having this opportunity to
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
vinorelbine and pravastatin.
2 First I would like to acknowledge the
3 contributions of these individuals.
5 First I will speak about paroxetine and
6 citalopram and then vinorelbine and pravastatin.
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.
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
database that FDA has. The first
is IMS Health,
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
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
administered at hospital outpatient clinics are not
1 included in this database.
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.
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.
The relevant safety information on the
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.
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
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.
Coming to the use data for this
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,
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
2 and then others were 9. So, today we
1 talking mostly about the non-psychiatric which
2 includes the 5 categories that I have here which
3 are on this 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.
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.
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
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
the same time. Then, there was one
1 where serotonin syndrome was reported as an adverse
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.
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
medications and also the scant histories in some of
1 the case reports. Nevertheless, we will continue
2 to monitor adverse events for paroxetine in the
3 Adverse Events Reporting System.
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.
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
reports and overdose section of the label, there
1 are adverse events pertaining to QTc prolongation.
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
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.
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.
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
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
identified by the medical officer.
It was signed
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.
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
old. Whether this was an
intentional overdose or
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.
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.
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
tablet. We tried to get
additional information on
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
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.
24 In conclusion, we will continue to monitor
these adverse events but I wanted to bring to your
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
suicide events occurred. It
varied from about 14
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
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
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.
DR. CHESNEY: Dr. Glode?
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
requirement they revert to the passive reporting
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
under review right now, but to give you sort of
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
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
are pointing that out, and the Division is also
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
psychotropics or having a history of substance
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
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?
DR. NELSON: I realize this
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.
DR. CHESNEY: Dr. Glode?
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
14 DR. CHESNEY: Thank you.
15 DR. IYASU: All right, thank you.
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
no approved pediatric indications for this
1 medication. Exclusivity was granted on August 15,
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
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.
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
year, there were 3 unduplicated pediatric
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
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
developed adverse events including one of the
1 unlabeled events, the muscle spasm, but the adverse
2 events that reported for this patient resolved
3 after lowering the dose of vinorelbine.
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.
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.
Drug use databases indicate that the total
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.
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.
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
were mentioned in the one-year exclusivity period.
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
like that might be happening?
That is not an
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
usage sources, but the data from the actual studies
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
have been a change in the label and then there
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
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
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
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
think that the reporting of a lot of this, you
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
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
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
24 Now, I think the other issue though that
people are pointing out, and that I think this
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
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.
DR. CHESNEY: Dr. O'Fallon had her
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.
we are trying to get sort of two estimates but
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.
11 DR. CHESNEY: Dr. Gorman and then Dr.
13 DR. GORMAN: I can explain four of those
14 pravastatin prescriptions, I wrote them for my
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
that there are safety signals we will not meet
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
each study being reported separately, I know
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
studies for rare events. That
just won't go
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
think, watching the people who handle our childhood
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
drug or whether you do it for all the medications
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
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
terms of whether there is a potential signal that
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,
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
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
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
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.
Use of Imaging Drugs in
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.
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
myself so here is a 30-second story.
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
series of scoping interviews that we conducted to
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.
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
23 I will also briefly review the written
24 request process, discuss current pediatric labeling
exclusivity statistics, the big goals of these
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.
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.
In 1994 FDA issued pediatric regulations
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.
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
exclusivity provisions of FDAMA sunsetted on
1 January 1, 2002.
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,
topical product; and to Advair, the combined
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.
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.
23 The next advance I want to mention is the
24 Best Pharmaceuticals for Children Act, the BPCA,
which became law on January 4, 2002.
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.
24 There are two paths to a written request.
First, FDA can itself issue a written request and
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
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
Now, what is a written request? A
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.
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
important. The agency only issues
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.
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
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.
24 This slide addresses all of that and I
want you to focus on the right side of the diagram,
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
fairly met the terms of the written request.
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
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.
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
101 cases and granted exclusivity in 91 of
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.
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.
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
past because they don't have patents.
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.
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
lot of very valuable information since this
1 effort has started.
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
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.
My name is Sally Loewke. I am the
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.
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
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
we proceed in our efforts to provide safe and
1 effective drugs for the pediatric population.
3 These are several areas that I will be
4 addressing over the course of this presentation
5 this morning.
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.
17 CDER's mission is to assure that safe and
18 effective drugs are made available to the American
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
review of drugs that are utilized for diagnostic
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.
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.
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
nuclear medicine imaging, including nuclear cardiac
1 imaging, would be technetium 99-M.
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
system or body region. This type
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.
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
23 The pivotal Phase III trials are the
24 trials where we get most of our efficacy
information and what we like to see is a trial
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
approved, generally is put into drug labeling.
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.
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
23 The radiopharmaceuticals--we have approval
24 for myocardial perfusion identifying cardiac
ischemia and other myocardial functional
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.
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.
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.
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.
22 We know that there are differences in
23 pathophysiology of cardiac disease between the
24 pediatric and adult populations. Pediatric
population presents with congenital heart disease
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
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
23 This database, however, has a lot of
24 limitations to it. You cannot nationally project.
FDA only has access to data dating back to
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.
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.
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
of these products because we know many imaging
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.
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.
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
keep that theme with the search of this database we
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
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.
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
deaths in the adults and 2 reported in the
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.
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
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.
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.
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.
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
differences between cardiac disease processes in
1 adults and kids can actually allow us to
2 extrapolate the efficacy data.
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.
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.
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
that people try. We also know that there
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?
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
DR. RING: One of the advantages
1 becoming middle aged is that you get a bit
2 farsighted over time so I am thinking that this
3 will probably work.
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--
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
with extensive experience in the cardiac
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.
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
23 Taken together, these points identify a
24 clinical problem that is of major clinical
significance in children. They
indicate that there
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.
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
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
University of Tennessee and St. Jude Children's
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.
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.
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
higher of these. Even when one requires
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
scope and define the specificity of this
1 diagnosis which to date has been largely
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.
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
treat effectively what we cannot see well. This
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
22 Finally, different imaging modalities are
23 complementary rather than competitive. The
24 echocardiogram, for example, will certainly
satisfactorily define the basic anatomy of
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.
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
children who survive acute Kawasaki disease but may
1 go on to be at cardiac risk for myocardial
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.
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
interventional procedures performed during these
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
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
almost completely. But there
still is a question
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
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
particularly apropos to that increasing patient
1 population, the adult with congenital heart
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.
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.
Each of the institutions I have surveyed
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.
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
midazolam, studies on fentanyl, studies on all of
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.
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.
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,
there is a question in the mind at least of all the
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
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.
Because of how these meetings are run, since Dr.
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
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
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
direct, and the echocardiography laboratory.
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.
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
since 1955. They found an
incidence ranging from
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.
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
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.
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.
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
age. So, the majority of deaths
occur early in
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.
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.
24 Still, despite the overall decrease in
mortality there are some pockets of resistance and
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
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.
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
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
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.
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.
It is interesting to compare patients with
1 congenital heart disease to other pediatric
2 patients with different problems.