1

DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

PEDIATRIC ADVISORY SUBCOMMITTEE OF THE

ANTI-INFECTIVE DRUGS ADVISORY COMMITTEE

Tuesday, February 3, 2004

9:00 a.m.

Advisors and Consultants Staff Conference Room

5630 Fishers Lane

Rockville, Maryland

PARTICIPANTS

P. Joan Chesney, M.D., Chair

Thomas H. Perez, MPH, Executive Secretary

SGE CONSULTANTS (VOTING):

Mark Hudak, M.D.

David Danford, M.D.

Richard Gorman, M.D., FAAP

Robert Nelson, M.D., Ph.D.

Susan Fuchs, M.D.

Robert Fink, M.D.

Victor Santana, M.D.

Norman Fost, M.D., MPH

Judith O'Fallon, Ph.D.

Ralph D'Agostino, Ph.D.

Mark Fogel, M.D.

Tal Geva, M.D.

Craig Sable, M.D.

Vasken Dilsizian, M.D.

Marilyn Siegel, M.D.

Phillip Moore, M.D.

MEMBERS (VOTING):

Mary Glode, M.D.

Steven Ebert, Pharm.D. (Consumer Representative)

FEDERAL EMPLOYEE (VOTING):

Mario Stylianou, Ph.D.

INDUSTRY REPRESENTATIVE:

Samuel Maldonado, M.D.

FDA:

Shirley Murphy, M.D.

Solomon Iyasu, M.D.

Hari Sachs, M.D.

Julie Beitz, M.D.

Sally Loewke, M.D.

Shavhree Buckley, M.D.

C O N T E N T S

Call to Order and Introductions,

Joan P. Chesney, M.D., 5

Meeting Statement, Thomas H. Perez, M.P.H.,

Executive Secretary 8

Welcome, Rosemary Roberts, M.D., Office of

Counterterrorism and Pediatric Drug

Development 11

Adverse Event Reports Per Section 17 of BPCA,

Solomon Iyasu, M.D., Division of Pediatric

Drug Development 12

Use of Imaging Drugs in Conjunction with Cardiac

Imaging Procedures in the Pediatric Population:

Pediatric Regulatory Update, Susan Cummins, M.D.,

Division of Pediatric Drug Development 58

FDA Perspective, Sally Loewke, M.D., Division of

Medical Imaging and Radiopharmaceutical Drug

Products 73

American Academy of Pediatrics Perspective,

John Ring, M.D., University of Tennessee

Health Science Center 91

Cardiologist Perspective, Tel Geva, M.D.,

Children's Hospital Boston 106

Q&A for Speakers 126

Contrast Enhanced Magnetic Resonance Imaging,

Mark Fogel, M.D., The Children's Hospital

Philadelphia 143

Contrast Enhanced Cardiac Computed Tomography,

Marilyn Siegel, M.D., Washington University

School of Medicine 172

Contrast Enhanced Invasive Cardiac Imaging,

Phillip Moore, M.D., UCSF Children's Hospital 174

Contrast Enhanced Cardiac Ultrasound, Craig Sable,

M.D., Children's National Medical Center 213

Radiopharmaceuticals in Nuclear Cardiac Imaging,

Vasken Dilsizian, M.D., University of Maryland

School of Medicine 234

Q&A for Speakers 253

C O N T E N T S (Continued)

Open Public Hearing:

Michael J. Gelfand, M.D., Children's Hospital,

Cincinnati 296

Manuel D. Cerqueira, M.D.,

American Society of Nuclear Cardiology 311

Peter Gardiner, MB ChB, MRCP, Bristol-Myers Squibb 316

Jack Rychik, M.D., American Society of

Echocardiography 320

1 P R O C E E D I N G S

2 Call to Order and Introductions

3 DR. CHESNEY: Good morning and welcome to

4 what should be a very fascinating day and a half.

5 I would like to start by saying that there is the

6 potential for us to finish our work today if we

7 stay very focused and very attentive to the

8 specific issues that the FDA is asking us to

9 address. But first we need to have the

10 introductions and I think maybe we could start with

11 Dr. Maldonado and go around this way, please.

12 DR. MALDONADO: Samuel Maldonado, from

13 Johnson & Johnson.

14 DR. MOORE: Phillip Moore, from the

15 University of California San Francisco, pediatric

16 cardiology.

17 DR. SIEGEL: Marilyn Siegel, from

18 Washington University in St. Louis, pediatric

19 radiologist.

20 DR. DILSIZIAN: Vasken Dilsizian,

21 University of Maryland, Director of Nuclear

22 Cardiology, both adult and cardiology and nuclear

23 medicine.

24 DR. SABLE: Craig Sable, Children's

25 National Medical Center in Washington, Director of

1 Echocardiography.

2 DR. GEVA: Tel Geva, Department of

3 Cardiology at Children's Hospital in Boston.

4 DR. D'AGOSTINO: Ralph D'Agostino, Boston

5 University, statistician.

6 DR. FOGEL: Mark Fogel, pediatric

7 cardiology, Children's Hospital, Philadelphia.

8 DR. SANTANA: Victor Santana, pediatric

9 hematologist, oncologist at St. Jude's Children's

10 Research Hospital in Memphis, Tennessee.

11 DR. GORMAN: Rich Gorman, pediatrician,

12 private practice, Ellicott City, Maryland.

13 DR. EBERT: Steve Ebert, infectious

14 disease pharmacist, Meriter Hospital, Professor of

15 Pharmacy, University of Wisconsin, Madison.

16 MR. PEREZ: Tom Perez, executive secretary

17 to this meeting.

18 DR. CHESNEY: Joan Chesney, Professor of

19 Pediatrics at the University of Tennessee in

20 Memphis and also at St. Jude's Children's Research

21 Hospital.

22 DR. FOST: Norm Fost, Professor of

23 Pediatrics and Director of the Beioethics Program

24 at the University of Wisconsin, Madison.

25 DR. NELSON: Robert Nelson, Critical Care

1 Medicine, Children's Hospital, Philadelphia.

2 DR. FINK: Bob Fink, pediatric

3 pulmanology, Professor of Pediatrics, Children's

4 Medical Center, Dayton, Ohio.

5 DR. O'FALLON: Judith O'Fallon,

6 biostatistician, recently retired from the Mayo

7 Clinic.

8 DR. FUCHS: Susan Fuchs, pediatric

9 emergency medicine, Children's Memorial Hospital,

10 Chicago.

11 DR. DANFORD: Dave Danford, Professor of

12 Pediatrics, Section of Cardiology, University of

13 Nebraska Medical Center and Crayton University in

14 Omaha.

15 DR. GLODE: Mimi Glode, pediatric

16 infectious disease at Children's Hospital,

17 University of Colorado in Denver.

18 DR. HUDAK: Mark Hudak, Professor of

19 Pediatrics and Neonatology, University of Florida,

20 Jacksonville.

21 DR. SACHS: Hari Sachs, Professor of

22 Pediatrics and medical officer at FDA.

23 DR. IYASU: Solomon Iyasu. I am team

24 leader at the FDA.

25 DR. S. MURPHY: Shirley Murphy, the "other

1 Murphy." I am the Director of the Division of

2 Pediatric Drug Development and I am going to be

3 sitting here today because the "other Murphy" may

4 have to deal with counterterrorism.

5 DR. CHESNEY: Thank you and we

6 particularly welcome our cardiology and imaging

7 consultants so that we have some expertise on the

8 committee. We are going to be very dependent on

9 you to talk to us about degrading nuclear particles

10 and so on in the major session for this morning.

11 But next we would like Tom to give us the meeting

12 statement, please.

13 Meeting Statement

14 MR. PEREZ: Thank you. The following

15 announcement addresses the issue of conflict of

16 interest with respect to Section 17, Best

17 Pharmaceuticals for Children Act Adverse Event

18 Reporting, and is made a part of the record to

19 preclude even the appearance of such at this

20 meeting.

21 This morning you will hear from Dr.

22 Solomon Iyasu, lead medical officer with the

23 Division of Pediatric Development. As mandated in

24 the Best Pharmaceuticals for Children Act, Dr.

25 Iyasu will report on adverse events for the

1 following drugs that were granted market

2 exclusivity under 505(a) under the Federal Food,

3 Drug and Cosmetic Act, Paxil, paroxetine; Celexa,

4 citalopram; Pravachol, pravastatin and Navebjne,

5 vinorelbine.

6 Because the agency is not seeking advice

7 or recommendations from the subcommittee with

8 respect to these products there is no potential for

9 an actual or apparent conflict of interest.

10 The following announcement addresses the

11 issue of conflict of interest with respect to the

12 use of imaging drugs in conjunction with cardiac

13 imaging procedures in the pediatric population and

14 is made a part of the record to preclude even the

15 appearance of such at this meeting. Based on the

16 agenda, it has been determined that the topics of

17 today's meeting are issues of broad applicability.

18 Unlike issues before a committee in which a

19 particular firm's product is discussed, issues of

20 broader applicability involve many sponsors and

21 their products. All subcommittee participants have

22 been screened for their financial interests as they

23 may apply to products and companies that could be

24 affected by the subcommittee's discussions of

25 imaging drugs used in conjunction with cardiac

1 imaging procedures in pediatric populations.

2 To determine if any conflicts of interest

3 existed, the agency has reviewed the agenda and all

4 relevant financial interests reported by the

5 meeting participants. Based on this review, it has

6 been determined that there is no potential for an

7 actual or apparent conflict of interest at this

8 meeting.

9 With respect to FDA's invited industry

10 representative, we would like to disclose that Dr.

11 Samuel Maldonado is participating in this meeting

12 as an industry representative acting on behalf of

13 regulated industry. Dr. Maldonado is employed by

14 Johnson & Johnson.

15 In the event that the discussions involve

16 any other products or firms not already on the

17 agenda for which FDA participants have a financial

18 interest, the participant's involvement and

19 exclusion will be noted for the record.

20 With respect to all other participants, we

21 ask in the interest of fairness that they address

22 any current or previous financial involvement with

23 any firm whose product they may wish to comment

24 upon.

25 Ted Treves is Chief of the Division of

1 Nuclear Medicine at Children's Hospital, Harvard,

2 who was an invited speaker for today, will not be

3 able to attend.

4 DR. CHESNEY: Thank you. Our first

5 speaker this morning will be Dr. Rosemary Roberts,

6 who is going to offer a welcome on behalf of the

7 Office of Counteterrorism and Pediatric Drug

8 Development.

9 Welcome

10 DR. ROBERTS: Good morning. I would like

11 to take this opportunity to thank you all for

12 coming today. I would also like to thank the

13 "Murphys" for allowing me to come up and speak. I

14 rarely get to do it; you know, I am sort of the guy

15 in the middle. I know some of you had to

16 experience much worse weather than we have here

17 today in order to get here so we certainly

18 appreciate all of your dedication in coming.

19 Our office, as you know, has two high

20 priority areas, counterterrorism which we might be

21 dealing with today unfortunately, and also

22 pediatric drug development, and we are certainly

23 happy that we have this program today.

24 We are excited about learning more about

25 cardiac imaging and having this opportunity to

1 discuss it and have such a distinguished group of

2 people here to help us see how to move forward in

3 this area. So, thank you very much for coming. I

4 hope that you have a good day and we appreciate all

5 the advice that you can give us.

6 One other thing, as you know because Diane

7 Murphy mentioned it yesterday, with the recent

8 legislation, the Pediatric Research Equity Act, we

9 now have a full pediatric advisory committee. We

10 are working on that charter and hope to have

11 something going on with that in the next couple of

12 months and then we will be setting up that advisory

13 committee. Thank you.

14 DR. CHESNEY: Thank you, Dr. Roberts. Our

15 next speaker is Dr. Solomon Iyasu who is going to

16 bring us up to date on the adverse event reports as

17 required by the BPCA.

18 Adverse Event Reports per Section 17 of BPCA

19 DR. IYASU: Good morning. Yesterday I

20 presented adverse event reports for paroxetine and

21 citalopram pertaining to psychiatric adverse

22 events. Today I will be presenting on adverse

23 events reported for paroxetine and citalopram and

24 then, subsequently, I will report on adverse events

25 for vinorelbine and pravastatin.

1 [Slide]

2 First I would like to acknowledge the

3 contributions of these individuals.

4 [Slide]

5 First I will speak about paroxetine and

6 citalopram and then vinorelbine and pravastatin.

7 [Slide]

8 The data source for the adverse events is

9 from the FDA's Adverse Event Reporting System which

10 is a spontaneous and voluntary system. This system

11 has several limitations which I wanted to bring to

12 your attention. The under-reporting is a very

13 significant problem. There are reporting biases

14 that may be associated with either media publicity

15 or depending on how long the drug has been on the

16 market. The quality of the reports is variable,

17 often very scanty. And, this database only

18 includes the numerator data, therefore, it is very

19 difficult to estimate the true incidence rate of

20 events or exposure risk.

21 [Slide]

22 Since I will be talking about the use of

23 these medications in the pediatric population, I

24 would like to also tell you a little bit about this

25 database that FDA has. The first is IMS Health,

1 National Prescription Audit Plus which measures

2 prescriptions dispensed from retail pharmacies, but

3 the disadvantage is that it does not provide

4 demographic information or prescription use. So,

5 it only gives you total prescriptions dispensed.

6 The other database is the National Disease

7 and Therapeutic Index, which is a survey based on a

8 sample size of about 2,000 to 3,000 office-based

9 physicians. The small sample size can make these

10 data projections unstable, particularly when use is

11 not very prevalent as in the case of the pediatric

12 population.

13 [Slide]

14 Another database available to FDA is based

15 on a large prescription claims database but, again,

16 these data cannot be projected nationally. There

17 is no methodology developed for that.

18 Premier is another database which contains

19 inpatient drug use from about 400 acute,

20 short-stay, non-federal hospitals. There is

21 national projection methodology available for this

22 data, but accurate national estimates are

23 selectively available. Drug use cannot be linked

24 to diagnosis or procedures, and the treatments

25 administered at hospital outpatient clinics are not

1 included in this database.

2 [Slide]

3 There is one more inpatient database,

4 which is the Child Health Corporation of American

5 Pediatric Health Information System which captures

6 information from about 26 free-standing children's

7 hospitals with charge level drug utilization data.

8 Again, although this is very pediatric specific,

9 the data are from a limited number of hospitals

10 and, therefore, cannot be projected nationally.

11 [Slide]

12 Now coming to the drugs that I will be

13 talking about today, there is some background about

14 Paxil which I mentioned in yesterday's

15 presentation. It is an antidepressant which is

16 marketed by GlaxoSmithKline, first approved in

17 December, 1992. Its adult indications are several

18 psychiatric conditions--major depressive disorder,

19 obsessive-compulsive disorder, panic disorder,

20 social anxiety disorder and generalized anxiety

21 disorder, post-traumatic stress disorder. There

22 are no approved pediatric indications. Exclusivity

23 for this drug was granted on June 27, 2002.

24 [Slide]

25 The relevant safety information on the

1 label as it currently exists refers to pregnancy

2 category C, which means that the drug has not been

3 studied in pregnant women and, therefore, when

4 using it in pregnant women the risks and the

5 benefits have to be weighed.

6 I talked about precautions specifically

7 pertaining to psychiatric events yesterday. Today

8 I have listed them here but what is specifically

9 important here are the seizures and the adverse

10 reactions with abrupt discontinuation of this

11 medication, and in patients with a history of

12 seizures caution should be exercised with the use

13 of this medication.

14 [Slide]

15 Additionally, there is information in the

16 adverse event section of the label pertaining to

17 pre-marketing reports and that includes

18 hypertension, diabetes, dysphagia and nausea and

19 vomiting.

20 In post-marketing reports there are

21 reports of serotonin syndrome, hepatic dysfunction

22 and anaphylaxis, and also in the overdose section

23 of the label about dangerous hepatic dysfunction.

24 [Slide]

25 Coming to the use data for this

1 medication, it is the second most commonly used

2 SSRI in children. For some of you who were here

3 yesterday at the other meeting this is a repetition

4 but, for the benefit of the others who were not at

5 that meeting I am repeating this information. Both

6 pediatric and adult prescriptions have increased

7 steadily in recent years. Pediatric diagnoses most

8 often linked with use of this medication include

9 depression, anxiety and obsessive-compulsive

10 disorders. And, pediatric patients account for

11 approximately 3.5 percent of total U.S.

12 prescriptions of Paxil between July, 2002 and June,

13 2003.

14 [Slide]

15 When we looked at the one-year

16 post-exclusivity determination period, there was a

17 total of 127 pediatric adverse event reports.

18 After my review and excluding all the duplicates,

19 these are the unique reports for pediatrics in one

20 year. We categorized them into different

21 categories and psychiatric adverse events accounted

22 for about 68. The rest of them are discontinuation

23 syndrome, about 7 patients. Maternal exposure was

24 about 33; neurologic about 8; accidental ingestion

25 in 2 and then others were 9. So, today we will be

1 talking mostly about the non-psychiatric which

2 includes the 5 categories that I have here which

3 are on this slide.

4 [Slide]

5 First I will talk about the adverse events

6 pertaining to pediatric deaths. There were about

7 10 deaths involving direct pediatric exposures; 9

8 completed suicides, which I discussed yesterday;

9 and 1 case of Stevens-Johnson syndrome. That

10 patient was also receiving valproic acid, with a

11 known association with Stevens-Johnson syndrome.

12 [Slide]

13 There were 3 deaths among patients with

14 pediatric exposure. The pediatric exposures

15 included congenital heart disease and 36 premature

16 infants who died after 75 days postnatally. The

17 second case was a 53-day old infant who was also

18 getting OxyContin and immediate-release oxycodone

19 and Paxil exposure prenatally--not the kid.

20 Autopsy was done and it was determined to be a SIDS

21 death by the medical examiner. The third case was

22 a multiple congenital anomaly, possibly a genetic

23 syndrome. This was an aborted fetus and it was a

24 fetal death.

25 [Slide]

1 Going into detail about the 33 in utero

2 exposures or breast feeding exposures, there was a

3 possible withdrawal syndrome reported in 11

4 patients, one of the fatalities previously

5 described; and congenital anomalies in 5 patients

6 and seizures in about 4 patients; developmental

7 delay or abnormality in 4 and murmur or congenital

8 heart disease in about 3; and insufficient weight

9 gain in 2 patients; and there were others that

10 included various events that could not be

11 classified.

12 [Slide]

13 Focusing on the direct exposures, there

14 were 8 patients with neurologic events. Among

15 these, 3 patients had extrapyramidal or movement

16 disorders. Two of these involved other medications

17 as well that are listed here, which are known drugs

18 associated with this kind of syndrome. Seizures

19 were reported in 3 patients. Two of these patients

20 had existing seizure disorders and were also

21 receiving Paxil.

22 There was one patient where there was a

23 loss of consciousness and hallucinations. The

24 patient was also on amphetamine-dextro-amphetamine

25 at the same time. Then, there was one patient

1 where serotonin syndrome was reported as an adverse

2 event.

3 [Slide]

4 Continuing with the pediatric adverse

5 events, there were also reports of accidental

6 ingestion. One was a 2-year old who ingested 6

7 tablets of paroxetine and recovered without

8 sequelae. A 2-year old was a comatose patient with

9 ingestion of multiple medications including

10 paroxetine who recovered after an ICU course.

11 There were a number of medications that were

12 involved as concomitant medications, including

13 other psychotropic agents, theophylline,

14 amytriptyline--there were several of them so this

15 was a very complicated polypharmacy case. Other

16 events--there were 9 single occurrences and the

17 majority were labeled.

18 [Slide]

19 In closing, most of the events were

20 labeled or related to labeled events. Unlabeled

21 events involved maternal exposures. And, the

22 safety of paroxetine will continue to be monitored

23 in the future. We could not determine causality of

24 any of these medications because of the multiple

25 medications and also the scant histories in some of

1 the case reports. Nevertheless, we will continue

2 to monitor adverse events for paroxetine in the

3 Adverse Events Reporting System.

4 [Slide]

5 Now I will talk a little bit about Celexa,

6 citalopram which is also an antidepressant,

7 marketed by Forest Pharmaceuticals. Its only adult

8 indication is for major depressive disorder and the

9 typical adult dose is about 20-40 mg/day. Again,

10 there are no approved pediatric indications. This

11 was first marketed in July, 1998 and pediatric

12 exclusivity was granted in July, 2002.

13 [Slide]

14 Again just mentioning some of the relevant

15 safety labeling associated with this drug, it is

16 again a pregnancy category C drug. It is also

17 excreted in breast milk so caution should be

18 exercised when used in nursing mothers.

19 In the precautions section there are

20 precautions regarding impairment of intellectual or

21 psychomotor functions with the use of citalopram.

22 Also, there is danger of seizures, especially in

23 ones who have history of seizure, and citalopram

24 should be used with care. In the post-marketing

25 reports and overdose section of the label, there

1 are adverse events pertaining to QTc prolongation.

2 [Slide]

3 Summarizing some of the use data for

4 citalopram, it is the fourth most commonly used

5 SSRI in children. Both pediatric and adult

6 prescriptions have, again, increased steadily in

7 recent years. Pediatric patients account for

8 approximately 3.3 percent of the total U.S.

9 prescriptions of Celexa. Pediatric diagnosis is

10 often linked with its use in depressive disorders,

11 obsessive-compulsive disorder and attention deficit

12 disorder.

13 [Slide]

14 For the one-year period of review, which

15 includes the post-exclusivity period, there were 42

16 unduplicated pediatric reports after this review

17 was undertaken, and 16 out of the 42 were in utero

18 exposures and mostly resulted in unlabeled events

19 and one death that I will discuss later; 26

20 children involved direct exposure and 8 resulted in

21 unlabeled events and no deaths. As I mentioned

22 yesterday, there were 16 serious adverse events, 10

23 hospitalizations and about 4 life-threatening and 2

24 with disability.

25 [Slide]

1 Going to the gender and age distribution

2 of these adverse events, they were both in females

3 in both direct and in utero exposure. As expected,

4 the in utero exposures were reported in 4 patients

5 who were less than 2 years. The majority of them

6 were actually less than 1. In the direct exposure

7 they were mostly in the older patients, 9 from 6-11

8 years and 15 patients in 12-16.

9 [Slide]

10 Looking at the reasons for exposure to

11 citalopram in these reports, as I mentioned, 16 of

12 them were in utero and included 13 patients who

13 were receiving citalopram for the treatment of

14 depression. Two involved ingestion of another

15 person's prescription and then other events which

16 are post-traumatic syndrome and GAD and RDD and

17 also anxiety, aggression and one was ADHD, just one

18 single occurrence of those conditions. Then, in 6

19 patients it was unknown why they were receiving

20 citalopram.

21 [Slide]

22 Focusing on the known adverse events, of

23 the 16, as I mentioned, there was one death. There

24 was an autopsy done and there was no cause of death

25 identified by the medical officer. It was signed

1 out as a SIDS death in a 4-month old. There were

2 congenital anomalies in 7 patients. Three were

3 unrelated kidney malformations; 1 eye malformation;

4 1 cardiac defect; 1 cleft lip and 1 congenital

5 megacolon. Then, there were 5 patients where

6 potentially there was a neonatal withdrawal

7 syndrome, and then there were 3 other patients with

8 myoclonus and otitis in 1 patient and delayed head

9 control at 1-month in 1 patient. In the last

10 patient there was a report of fetal asphyxia.

11 [Slide]

12 Among the direct exposure group there were

13 21 patients, excluding the 5 psychiatric events

14 that I reported on yesterday. There were 4

15 patients in which cardiovascular events were

16 reported. One was a supraventricular tachycardia

17 in an 8-year old with a prior history of similar

18 episodes. It resolved after Celexa was

19 discontinued. There were 2 patients with prolonged

20 QTc. One involved syncope and seizure in a 13-year

21 old who was also taking other medications

22 concomitantly, albuterol, cetirizine and

23 montelukast. There was also a patient where an

24 overdose of citalopram was involved in a 14-year

25 old. Whether this was an intentional overdose or

1 accidental was not reported so we cannot give you

2 additional details on that. There was 1 patient

3 where arrhythmia was reported in an 8-year old with

4 overdose of citalopram.

5 [Slide]

6 In the group where there were reports of

7 neurological or special senses adverse events,

8 there were 8 patients. One involved demyelinating

9 spinal lesion in a 13-year old who was also on

10 methylphenidate and multivitamins. There was a

11 patient with a visual field cut in a 15-year old

12 who was also on Depo Provera and who improved after

13 discontinuation of Depo. There was one patient

14 with a cataract, a 10-year old, also on

15 risperidone, and 5 patients with seizures.

16 [Slide]

17 Among other events that were reported

18 there were 2 patients where serotonin syndrome was

19 predominantly given but also, as part of the

20 syndrome, seizures occurred in both of these cases.

21 Then, there was 1 where only syncope was reported

22 with the use of Celexa.

23 There was one curious report of a

24 false-positive drug screen for cocaine on crushed

25 tablet. We tried to get additional information on

1 this and from the chemistry point of view there is

2 no relationship between these two structurally or

3 chemically. It may have been a problem of

4 adulteration of the patient's medicine. We do not

5 have any details but this involved a police test

6 that tested a crushed tablet found on a person

7 found to be positive for cocaine. There were

8 others. Five patients involved concomitant

9 medications and/or complicated underlying disease

10 which could not be categorized into a specific

11 category.

12 [Slide]

13 In summary, unlabeled events included in

14 the non-psychiatric adverse events are the ones

15 that I mentioned involving in utero exposure and

16 the case where demyelinating spinal cord lesion was

17 reported for one patient; visual field cut in one

18 patient and the supraventricular tachycardia in

19 another patient. These are single occurrences.

20 Supraventricular tachycardia is not specifically

21 labeled but tachycardia and sinus tachycardia are

22 in the label.

23 [Slide]

24 In conclusion, we will continue to monitor

25 these adverse events but I wanted to bring to your

1 attention that there will be updates that will be

2 provided in the future meetings regarding three

3 issues that are under review, neonatal withdrawal,

4 ophthalmologic malformation and then the QTc

5 prolongations. We will be reporting on this in

6 future meetings.

7 So, I am done with paroxetine and

8 citalopram and if there are questions about this

9 section I will entertain any questions. There are

10 more details that are needed but Dr. Hari Sachs

11 will work very closely with me on these issues and

12 we will have some details about the cases if there

13 are any questions. Yes?

14 DR. CHESNEY: Yes, Dr. Nelson?

15 DR. NELSON: Remind me, given our

16 discussion yesterday, can you tell from the data

17 or, if you can't is it worth finding out what the

18 timing of the suicide events on paroxetine is in

19 respect to when the drug was started? In other

20 words, within a week, the first two weeks of

21 exposure to the drug?

22 DR. IYASU: It varied. It varied from

23 patient to patient. There was no clear pattern.

24 Most of them were on therapy at the time that the

25 suicide events occurred. It varied from about 14

1 days to about a year in terms of how long they had

2 been on therapy. The events that were reported

3 varied also. But there was not much detail so that

4 we can make a clear, distinct pattern as to when.

5 Some of them were early; some of them were later.

6 It was very difficult, as I mentioned yesterday, to

7 try to pin it down because of the scanty

8 descriptions that were provided in the case reports

9 but most of them were on therapy. There were a few

10 that were post-therapy and during the withdrawal

11 period.

12 DR. CHESNEY: Dr. Ebert?

13 DR. EBERT: Of the 33 maternal exposures

14 you noted with paroxetine, do you know what

15 proportion of those were in utero versus breast

16 feeding?

17 DR. IYASU: Out of the 33, about 6 of them

18 involved also breast feeding exposure.

19 DR. EBERT: I noticed there was no caution

20 regarding breast feeding, or you didn't mention one

21 specifically with that product in the labeling.

22 DR. IYASU: Yes, I think I may not have

23 mentioned it but there is also in the label

24 information about nursing mothers.

25 DR. CHESNEY: Dr. Glode?

1 DR. GLODE: I just want to clarify, as

2 part of the pediatric exclusivity there is no

3 requirement for the sponsor to do any sort of

4 random sample or active surveillance for safety

5 issues or adverse events? They just also use this

6 passive reporting system? Is that right?

7 DR. IYASU: Well, as part of the BPCA, it

8 is my understanding that the manufacturers are

9 required, just by FDA regulations, to report all

10 adverse events that come to them to the FDA. But

11 this is for the passive surveillance system.

12 Unless there are specific sorts of adverse events

13 that are agreed upon in the pediatric studies for

14 follow-up, they do not have to report on follow-up.

15 Diane can add to this.

16 DR. D. MURPHY: The only thing I wanted to

17 add is that we have asked for specific

18 post-studies, you know, completion of study

19 surveillance for certain products. But it has to

20 be asked for in the written request. Outside of

21 exclusivity there are Phase IV commitments that

22 could be asked for. But, in general, what you

23 heard is what usually happens--studies are

24 completed and unless there is a specific

25 requirement they revert to the passive reporting

1 system unless a company notices a signal that they

2 then bring to the attention of FDA.

3 DR. S. MURPHY: Joan, I just wanted to add

4 for our guests that are here from imaging that this

5 is mandatory one-year reporting required under the

6 Best Pharmaceuticals for Children's Act in which a

7 drug gets pediatric exclusivity, which you will

8 learn about in a little while from Susan's talk.

9 Then we are required by law to report to this

10 committee publicly the adverse events that occur

11 forward for one year. So, that is why you are

12 seeing reporting on these drugs. They have

13 triggered a time point for the committee to hear

14 about the reports.

15 DR. CHESNEY: Could I ask a question,

16 please? Could you clarify this--Dr. O'Fallon

17 mentioned in the van this morning reading about

18 this neonatal withdrawal syndrome and it didn't

19 come up yesterday. I notice with paroxetine you

20 commented that these are unlabeled events involving

21 maternal exposure. What exactly is the withdrawal

22 syndrome, and is this something that should be in

23 the label? Could you elaborate a little?

24 DR. IYASU: These are issues that are

25 under review right now, but to give you sort of

1 additional information on what the concern is I

2 have some notes here. It is usually associated

3 with reports that involve nervous or neuromuscular

4 effects after birth when the mother is exposed to

5 some of these SSRIs, including citalopram or Paxil.

6 This may include symptoms like irritable or

7 agitated crying, hyperreflexia, hypertonia,

8 seizures or seizure-like movements, and also

9 include some breathing difficulties as well as

10 feeding difficulties. So, this is sort of a

11 syndrome that is increasingly being recognized with

12 babies who have been exposed prenatally to some of

13 these drugs. It is still under continued review

14 right now to see whether this is information that

15 needs either to be communicated to the public or be

16 put in the label. I can't give you more details

17 except that we are looking at it very closely.

18 DR. CHESNEY: Presumably, these were

19 serious enough to cause somebody to make a report

20 which is impressive to me. This is quite an

21 impressive number for just voluntary reporting. Do

22 you have any more information about whether they

23 needed to be managed? I assume if they had

24 seizures they had to have some specific management

25 issues.

1 DR. IYASU: I don't have additional

2 information right now about what specific measures

3 will be taken regarding this, except to say I think

4 this is something that we are concerned about and

5 specific recommendations as to what would happen as

6 follow-up are still open.

7 DR. CHESNEY: Maybe I can ask some of the

8 FDA folk, is there anything that we can do to help

9 move this along? This seems like it might be a

10 significant issue.

11 DR. S. MURPHY: I think just what you have

12 done is expressing your concern and we will take

13 that back to the Division. I think that it is

14 under review right now and I think that is why

15 Solomon can't say more.

16 DR. IYASU: Yes.

17 DR. CHESNEY: Dr. Gorman?

18 DR. GORMAN: Are you aware of the Canadian

19 literature surrounding this withdrawal syndrome

20 from the unit in Toronto that looks at

21 maternal-fetal exposure rate and has noted an

22 increased transfer to NICUs for babies born with

23 these agents?

24 DR. IYASU: Yes, I am and it is good that

25 you are pointing that out, and the Division is also

1 aware of the data.

2 DR. CHESNEY: I have one other question

3 relative, I guess, to yesterday's discussion, the

4 paroxetine 68 psychiatric adverse events in

5 children, were those along the lines of what we

6 were talking about yesterday, which is activation

7 of stimulant syndrome, or do you have any further

8 breakdown of those?

9 DR. IYASU: Actually, we were talking

10 about this with Hari. Hari, do you want to comment

11 on that?

12 DR. SACHS: You know, as Solomon pointed

13 out yesterday, there are the 9 completed suicides

14 and 17 suicide attempts. I went back and just

15 checked the case reports to see how many of them

16 were associated with agitation. I picked up 8, 2

17 of which have resulted in completed suicide, 2 with

18 suicidal ideation, 2 with suicide attempts and 2

19 with self-mutilation. Interestingly enough, for 4

20 of them the kids' reasons for treatment were not

21 major depression; they were OCD and anxiety; 4 of

22 them were for depression and it was pretty split,

23 half female, half male, and half of them were on

24 concomitant medications, including other

25 psychotropics or having a history of substance

1 abuse. So, it is definitely a very mixed bag.

2 DR. CHESNEY: If we subtract out the

3 suicidal issues, that still leaves a significant

4 number of other children. What were their adverse

5 events?

6 DR. S. MURPHY: The other psychiatric

7 adverse events, as I said, the totals were the 9

8 completed suicides, 17 suicide attempts, several

9 cases of suicidal ideation and 10 of self-injury.

10 Then, the rest of them were kind of emergence of

11 other psychiatric symptoms such as mania. So, it

12 depends I guess on what you look at but what I was

13 thinking was that the agitation was picked up, or

14 at least the other suicidality issue was picked up

15 as well as the agitation. It wasn't that agitation

16 looked, you know, linked to anything else at least

17 in these 68 reports.

18 DR. IYASU: Yes, I think just looking at

19 these case reports there was tremendous variability

20 also. But you can find some agitation in some of

21 the case reports and no mention of it in others.

22 So, it was hard to sort of see which one is

23 predominant there; there is a mixture.

24 DR. CHESNEY: Dr. Nelson?

25 DR. NELSON: I realize this suggestion may

1 be naive from a resource point of view but, given

2 the discussion, does it make sense to do a more

3 in-depth case ascertainment both for the cases you

4 have got and to see if there are other cases, and

5 to see if someone could do a case study design

6 approach to see if they could ascertain that

7 this--you know, similar to what happened with the

8 rotaviral vaccine--might be a hint relative to the

9 timing and to this issue of agitation? I mean,

10 that might be one way to try to sort this out?

11 DR. IYASU: I think that is a good

12 suggestion. These kind of studies always require

13 additional resources that the Office of Drug Safety

14 may not have available, but theoretically I think

15 you can go back and try to ascertain some of these

16 cases. But one thing that we have to be careful

17 about is that the cases that come to our attention

18 are a selected few and we don't know what they

19 actually represent because, you know, it is really

20 a small percentage of an unknown group of adverse

21 events. So, it requires I think careful assessment

22 of what the cases actually represent. Do they

23 represent other cases that are occurring in the

24 population? But it is a good suggestion.

25 DR. CHESNEY: Dr. Glode?

1 DR. GLODE: I would just like to

2 emphasize, and I think this came up for many people

3 yesterday, that with a database of between 3,000

4 and 4,000 children with regard to safety issues, it

5 is a very inadequate number for safety. So, there

6 needs to be some mechanism I think, other than this

7 passive surveillance reporting, for doing

8 additional safety studies whether that is by Phase

9 IV studies from the sponsor, or whatever, but there

10 needs to be more safety data beyond 3,000 to 4,000

11 I think for children for these drugs.

12 DR. IYASU: I think your point is well

13 taken.

14 DR. CHESNEY: Thank you.

15 DR. IYASU: All right, thank you.

16 [Slide]

17 Now I will report on two other medications

18 that have received exclusivity. The first drug is

19 vinorelbine which is an anti-tumor drug marketed by

20 GlaxoSmithKline. The indications which are

21 approved are in adults as a single agent or in

22 combination with cisplatin for the first-line

23 treatment of ambulatory patients with unresectable,

24 advanced non-small cell lung cancer. Again, there

25 are no approved pediatric indications for this

1 medication. Exclusivity was granted on August 15,

2 2002.

3 [Slide]

4 Summarizing the use data, there wasn't

5 much in terms of our databases that revealed a lot

6 of use for this medication in the pediatric

7 population.

8 In CHCA, which is a children's hospital

9 corporation database which is 26 children's

10 hospitals that I mentioned before, which is a

11 discharge-based database, there were 5 discharges

12 in 2001 and about 21 discharges in 2002 that

13 indicated that this medication may have been used.

14 The diagnoses that were closely linked with its use

15 were put under the category of chemotherapy and

16 most of them were Hodgkin's disease.

17 [Slide]

18 Looking at the adverse event reports for

19 vinorelbine, the total raw number of adult and

20 pediatric reports that were received were about

21 495, and 181 of them were domestic and 314 were

22 international reports. These are not adjusted for

23 duplicates so this includes duplicates also.

24 Looking at the pediatric reports for the

25 one year, there were 3 unduplicated pediatric

1 reports and 1 was U.S. and 2 were foreign. All

2 were reported as having serious outcomes but there

3 were no deaths with the use of this medication in

4 the one-year period that was evaluated. Five of

5 the 16 adverse events that were reported were

6 considered unlabeled. The diagnosis or the reason

7 its use was for the treatment of rhabdomyosarcoma

8 in 2 of the patients and 1 of the patients had

9 neuroblastoma and the drug was being given for that

10 treatment.

11 [Slide]

12 I am just summarizing the 3 patients who

13 were reported to us with adverse events. The first

14 one is a 14-year old with rhabdomyosarcoma who

15 developed neutropenia, a labeled event, and was

16 successfully treated with Nupogen.

17 The second patient was a 2-year old with

18 rhabdomyosarcoma who developed life-threatening

19 adverse events including unlabeled events that

20 included epidermolysis, muscle inflammation,

21 somnolence and tachypnea. This patient was also on

22 cytoxan. The patient was hospitalized for about 16

23 days and eventually recovered and was discharged.

24 A 6-year old was diagnosed neuroblastoma

25 and developed adverse events including one of the

1 unlabeled events, the muscle spasm, but the adverse

2 events that reported for this patient resolved

3 after lowering the dose of vinorelbine.

4 [Slide]

5 So, it was a small number of reports that

6 we got for the labeled and unlabeled adverse events

7 were reported, as I mentioned before. The

8 unlabeled events have also been reported in adults

9 and are not unique to pediatrics. The FDA will

10 continue its routine monitoring of additional data

11 on adverse events in all populations, including

12 pediatrics, to follow-up on the significance of any

13 of these events.

14 [Slide]

15 The last drug I will be presenting on is

16 pravastatin, which is one of the statins. It is

17 marketed by Bristol-Myers Squibb. In adults it is

18 indicated for the prevention of coronary and

19 cardiovascular events and hyperlipidemia. In

20 children it is approved for 8 years and older for

21 the treatment of heterozygous familial

22 hypercholesterolemia. Pediatric exclusivity was

23 granted on July 10, 2002.

24 [Slide]

25 Drug use databases indicate that the total

1 dispensed prescriptions have increased by about

2 17.5 percent between September, 1999 and August,

3 2003. That is, from 13.4 to 15.8 million per year

4 for pravastatin and that is adults and pediatrics.

5 This is total dispensed prescriptions.

6 Pediatricians wrote about 47,000 or about 0.4

7 percent of the total of the 15.8 million

8 pravastatin prescriptions during that period.

9 [Slide]

10 Looking at the proportion of pediatric

11 prescriptions, an estimated 7,900 prescriptions

12 were dispensed nationwide to pediatric patients

13 aged 1-16 years. This is based on a calculation of

14 the proportions that were obtained from advanced

15 PCS, which is a database that I mentioned before

16 which has demographic information, and applying it

17 to the total dispensed prescriptions. It is a

18 small number but this has to be interpreted with

19 caution because really this is an estimate.

20 [Slide]

21 There was a total number of adult reports,

22 about 993 reports during the exclusivity period and

23 691 were U.S. and 302 were international reports.

24 There were no pediatric adverse event reports that

25 were mentioned in the one-year exclusivity period.

1 [Slide]

2 Therefore, I don't have any additional

3 comments on pravastatin in the pediatric

4 population, except to say that we will continue to

5 monitor the database and see if there are any

6 adverse events that emerge. Thank you very much.

7 DR. CHESNEY: Thank you. Are there any

8 questions? Yes, Dr. D'Agostino?

9 DR. D'AGOSTINO: Could you tell me or us

10 what the physicians do with the statins in terms of

11 muscle, liver and so forth in the pediatric

12 population? Do they do anything routinely in terms

13 of the side effects? I mean, what do you do with a

14 child with muscle problems? The children are

15 growing and so forth so how do you recognize that

16 that is happening?

17 DR. IYASU: Well, from the adverse event

18 reports there is no way to tell, or there is no

19 information as to what actually is being done to

20 treat that, except in the cases that were presented

21 today where they were admitted but what actual

22 treatment was given was not clearly specified.

23 DR. D'AGOSTINO: Do we know if there is

24 withdrawal of the drug in the children where things

25 like that might be happening? That is not an

1 adverse event necessarily but if the children are

2 complaining about muscle pains and so forth.

3 DR. IYASU: I can't tell you because the

4 narratives that were provided to us were very

5 scanty. So, what treatment was given to these

6 individual patients is not clearly stated in those

7 narrative reports, except that there was an ICU

8 course for one of them where it was considered to

9 be serious enough that the patient was admitted.

10 In terms of the complaints, they were elicited and

11 reported by a health professional. Whether these

12 were based on clinical records or medical records

13 or whether they were just clinical encounters, I

14 couldn't tell from the narrative.

15 DR. CHESNEY: Dr. Santana?

16 DR. SANTANA: Can you clarify for me a

17 process issue? My understanding is that when an

18 agent is granted exclusivity there is a commitment

19 to do a number of studies and those studies may

20 occur in different time lines. When does that data

21 from those studies surface in adverse event

22 reporting to this committee? Because it seems to

23 me that what we are seeing are reports that are

24 coming from different sources, more public kind of

25 usage sources, but the data from the actual studies

1 that are being done or have been done under the

2 exclusivity--when does that surface for us to see

3 in these reports?

4 What made me think about that question is

5 that for a lot of the oncology drugs that may be

6 granted exclusivity, and I think this one is a good

7 example, those studies will occur in a semi-closed

8 system either through the cooperative group

9 mechanism or through large oncology institutions,

10 and those data may not necessarily show up in these

11 other databases. For the oncology drugs, why don't

12 you go to the NCI and request their adverse event

13 reporting for the pediatric patients that are

14 participating in those studies under drugs that

15 have been granted exclusivity? That would be a

16 more enriched data set than using this other

17 system. Can you comment, please?

18 DR. IYASU: My comment is that the adverse

19 events are reported to FDA, again, through this

20 passive system. The exclusivity is granted on a

21 specific data and then, if there is a change in

22 labeling for example, it may not happen for several

23 months after exclusivity is granted. So, in

24 theory, what you would expect is that there would

25 have been a change in the label and then there

1 would be increased usage of the medication and then

2 we have to monitor or would pick up if there are

3 any adverse events that emerge as use expands. But

4 with many of these drugs maybe the indication is

5 not approved and, secondly, there is a time lag

6 between the use and the period that we are looking

7 at because this is immediately the one-year after.

8 Now, we depend on adverse event reporting

9 with the system that we have. We don't have any

10 other system. But an active surveillance mechanism

11 is where we actually go to do case finding and

12 querying other databases is something that is a

13 good idea. But, again, as I said before, that

14 system is not in place to go after that.

15 DR. SANTANA: So, the data that is being

16 collected by the sponsors for the studies that may

17 be related to exclusivity, when does that data

18 surface for us to see?

19 DR. IYASU: Oh, that is a question that--

20 DR. S. MURPHY: Yes, the medical officers'

21 reviews have to be posted on the web 180 days after

22 exclusivity is granted. I think you bring up an

23 excellent point. I think what we are trying to do

24 is interpret the law and figure out the best way to

25 report to you, and that is one of the things I was

1 going to ask you, if this is the best information.

2 What we are doing now is going to the AERS passive

3 system and picking up all the reports for a year

4 after exclusivity. We are not going into the

5 trials and pulling those out.

6 DR. SANTANA: Yes, what highlighted my

7 comment was the oncology example.

8 DR. S. MURPHY: That is a very good

9 example.

10 DR. SANTANA: You would not pick up a lot

11 of the oncology adverse event reports through these

12 databases. You would have to go to a very enriched

13 data set that already exists.

14 DR. IYASU: I agree.

15 DR. SANTANA: There is a lot of

16 under-reporting here.

17 DR. S. MURPHY: Yes, there is a lot of

18 under-reporting.

19 DR. SANTANA: This drug is an example but

20 I suspect if we continue that practice with

21 oncology drugs we will see a lot of under-reporting

22 that will not come out until years later when the

23 drugs are being used in a different way.

24 DR. S. MURPHY: Well, I agree with you. I

25 think that the reporting of a lot of this, you

1 know, can be enhanced and we have sort of taken a

2 year now to report this way. I think we also

3 realize that the label is going to get out there

4 for six months at least. So, is there really,

5 after exclusivity, a big peak in pediatric use, or

6 does the use come later, or was it used off-label

7 before?

8 DR. D. MURPHY: I think the question is

9 really good but it gets to a different process and

10 I think it is an important process for this

11 committee to think about because it has huge

12 ramifications. What the law mandates we do is, as

13 has been noted, to report on the adverse event

14 reporting after exclusivity. At some period in

15 that exclusivity the product will be approved and

16 labeled.

17 The issue is that the BPCA has said that

18 this information will be posted. The studies will

19 be posted on the web and theoretically in the

20 medical review information on the oncology

21 product--I mean, the information that came out

22 during the studies should be up on the web at that

23 point.

24 Now, I think the other issue though that

25 people are pointing out, and that I think this

1 committee is now very familiar with is that if you

2 have a new label and that label is supposed to

3 reflect the adverse events that were defined in

4 those studies, then that is the way of

5 communicating to the public what those adverse

6 events were that were found in that better process,

7 which is controlled studies, versus this passive

8 adverse event reporting. That label sometimes is

9 not available except up on the web site somewhere

10 for different periods of time depending on how many

11 labels are out there already, etc. So, it will

12 vary.

13 So, I think you are bringing forth a very

14 important question which is access to this

15 information, which we talked about yesterday quite

16 a bit. Second is the issue--and I really think the

17 committee needs to think about this for a long

18 time--are you asking us to review every study that

19 is approved under exclusivity? There have been

20 over a hundred determinations and over 60, 70

21 labels. That would be 60 meetings literally to go

22 over each of the studies. So, I think that is a

23 different question. I just want to make sure that

24 we define when the information will be available.

25 DR. CHESNEY: Dr. O'Fallon had her hand up

1 next.

2 DR. O'FALLON: I have another process

3 issue. I was curious because in looking at

4 pravastatin, or whatever it is, there are two

5 different estimates of the size of the prescription

6 to the pediatric population. On one slide it says

7 pediatricians wrote 47,000 of the total

8 prescriptions during that year and the other one

9 says an estimated 7,900 prescriptions were

10 dispensed. Now, I realize you are working off two

11 different sets but the difference between 8,000 and

12 47,000 is big in my mind and I am wondering is that

13 sort of a very high upper bound and a very low

14 lower bound, or what. You are trying to get at

15 what is the piece of the pie that goes for

16 prescriptions to this age group.

17 DR. IYASU: Yes, I think that is an

18 important point. There is obviously a big

19 discrepancy between the two estimates. One is

20 referring to dispensed prescriptions written by

21 different specialties. The other one is getting

22 proportions out of a database that is not

23 nationally representative and applying the

24 demographic percentage to the national database.

25 So, we are trying to get sort of two estimates but

1 they are giving us different estimates and we don't

2 know how to sort of marry the two. But we thought

3 that we would give these databases and explain what

4 the limitations of both of these databases are,

5 which I mentioned before. So, that is a good

6 point. It is something that we have to work on to

7 try to get better databases that could give us

8 better estimates and not miss significant portions

9 of dispensed prescriptions. That is a good point.

10 Thanks.

11 DR. CHESNEY: Dr. Gorman and then Dr.

12 D'Agostino.

13 DR. GORMAN: I can explain four of those

14 pravastatin prescriptions, I wrote them for my

15 mother.

16 [Laughter]

17 So, a pediatrician wrote them but it

18 didn't go to a pediatric patient. So, that is four

19 and you only have 47,000 more to go. So.

20 The other issue that I think is a little

21 bit more global is that I think I hear a different

22 theme emerging from our discussion which is that we

23 have listened to the AERS data reporting system and

24 its weaknesses and we have listened to the concerns

25 that there are safety signals we will not meet

1 during the controlled clinical trials for efficacy.

2 I think the AERS system grew up in a totally

3 different generation of information collection and

4 distribution and perhaps there needs to be a more

5 active system looking for safety signals than we

6 presently have. I think I heard Dr. Glode say that

7 and I have heard other people say that with active

8 case finding there is a more active searching, and

9 I am not sure that is inside the charge of the FDA

10 but I am sure that that is something that would

11 enhance the safety of these agents. Rather than

12 demanding of sponsors that the clinical trials get

13 larger and larger and larger, look for clinical

14 safety signals and perhaps there can be another

15 mechanism that allows us to look for safety signals

16 for the rare events after post-marketing.

17 DR. CHESNEY: Dr. D'Agostino?

18 DR. D'AGOSTINO: My comment is similar to

19 that. I mean, in some fields like cardiology with

20 the statins we have an idea, we have a very good

21 idea of what some of the problems are and there are

22 lots of different companies and lots of different

23 trials, but it is quite quick in some cases to put

24 together how many problems are developing. Instead

25 of each study being reported separately, I know

1 with the OTCs and things that we do in some of the

2 cardiology we can quickly find out how many muscle

3 problems are developing, how many liver problems

4 are developing without having a list of each study

5 being laid out but these companies are constantly

6 surveying. They know what some of the problems are

7 and they have active ways of getting at them. Are

8 we doing the same here? I mean, I presume we are

9 and the question is how do we get that information

10 to the committee here and how you are actually

11 pulling that data together because, as we said, the

12 AERS is not really going to do it.

13 DR. D. MURPHY: The companies are required

14 to report this to us so it is coming into AERS. If

15 the company knows about it, it is coming in to us.

16 DR. D'AGOSTINO: What I was saying is some

17 of these are doing active registries, surveillances

18 and so forth so they are actively looking. They

19 are not just waiting for a passive.

20 DR. D. MURPHY: I think what Dr. Gorman

21 and you all are trying to say is that you have

22 heard the limitations, and we have sort of pounded

23 you with it multiple times, and that there needs to

24 be a better way but that we can't power safety

25 studies for rare events. That just won't go

1 forward; it is not feasible.

2 I was just trying to see if somebody from

3 our ODS Office was here because it would be good

4 for them to hear your concerns and we will relay

5 those back to them, how can we improve the process?

6 Can we target--I think one of the questions is can

7 we target areas, which it sounds like others have,

8 where we think there needs to be an active

9 surveillance system? Certainly, as I mentioned

10 earlier, we have done that in a few cases where we

11 know what the safety signal is. If you know what

12 the safety signal is, then it is a lot easier to

13 design that kind of surveillance system. So, you

14 know, it gets back to that kind of focused system

15 versus finding in kids unexpected results which I

16 don't know that we are able to do yet.

17 DR. CHESNEY: Dr. Danford?

18 DR. DANFORD: To briefly address Dr.

19 D'Agostino's earlier question about what would the

20 response of a pediatric cardiologist be to muscle

21 pains, myalgias or muscle problems we might

22 encounter in starting these medicines in children,

23 I think that we would be pretty quick to withdraw

24 the medicines under those circumstances. I don't

25 think, watching the people who handle our childhood

1 lipid problems in our town--I don't think that the

2 discovery of that or any of the other relatively

3 well-known complications discovered by our adult

4 colleagues would necessarily trigger a report that

5 would show up in AERS. You know, we know about

6 these things; we stop the medicines and we don't

7 think about it. It highlights once again the

8 inadequacies of this approach and our need to look

9 for other ways.

10 DR. IYASU: I think these are all very

11 good comments and, in terms of the limitations of

12 the AERS database, I think everybody recognizes

13 that it has very limited utility in terms of

14 picking up adverse events. It is useful to sort of

15 maybe generate some potential signals, especially

16 rare events that have not been picked up in

17 clinical trials, but to confirm the existence of an

18 event in association with a particular drug it is

19 terribly inadequate and I understand and I hear

20 what you are saying in terms of are there any

21 better ways of looking at adverse events and

22 monitoring them that would be a step forward. But

23 there are also limitations in terms of whether you

24 do it for specific adverse events for a specific

25 drug or whether you do it for all the medications

1 that are regulated by FDA. As Diane said, it has

2 been done for certain specific events of concern

3 but when you try to do it to capture all potential

4 adverse events, that is a big undertaking and we

5 look forward to having some specific

6 recommendations from the committee. Thank you very

7 much.

8 DR. CHESNEY: Thank you. Just thinking

9 out loud, Dr. Danford raises a very interesting

10 point which is that if there were a difference in

11 the incidence of a labeled adverse event in

12 children we would never pick that up because we

13 would just say, well, yes, we know that happens but

14 if it were more common in children than adults we

15 wouldn't pick that up. Does that make sense?

16 DR. IYASU: Well, we look at sort of the

17 pediatrics and compare whether it is more common in

18 pediatrics for a specific event than in adults.

19 But it is always very difficult also to sort of

20 have a relative rate of the event in the two

21 populations because of the different use patterns

22 and different frequencies of use in the different

23 populations. So, a sort of head-to-head comparison

24 sometimes doesn't work but it gives us some idea in

25 terms of whether there is a potential signal that

1 we need to look further into.

2 DR. CHESNEY: Right, but a lot of these

3 wouldn't be reported to AERS because, "well, this

4 is something that we know happens" and unless it

5 may be happening much more often in pediatrics it

6 wouldn't be reported because it is a labeled

7 adverse event.

8 DR. IYASU: Absolutely. Under-reporting

9 is one of the big issues in AERS. Thank you.

10 DR. CHESNEY: Thank you very much. I

11 think we have one new person at the table, Dr.

12 Stylianou, would you mind introducing yourself,

13 please?

14 DR. STYLIANOU: Mario Stylianou,

15 statistician from NIH. I do some work with

16 pediatric clinical trials at the National Heart,

17 Lung and Blood Institute.