FOOD AND DRUG ADMINISTRATION














                       Tuesday, February 3, 2004


                               9:00 a.m.




             Advisors and Consultants Staff Conference Room

                           5630 Fishers Lane

                          Rockville, Maryland






      P. Joan Chesney, M.D., Chair

      Thomas H. Perez, MPH, Executive Secretary




         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)




         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

         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.


 18             DR. CHESNEY:  Thank you.  There is nobody


 19   scheduled to speak at the open public hearing but


 20   let me ask if there is anybody not scheduled who


 21   would like to come to the microphone.  Apparently


 22   not.  We are scheduled for a 15-minute break.


 23   Given the small room and small number of people and


 24   potential to move ahead today, maybe we could take


 25   10 minutes and, according to this clock, be back




  1   between 10:20 and 10:25 to begin our discussion of


  2   the cardiac imaging drugs.  Thank you.


  3             [Brief recess]


  4             DR. CHESNEY:  Let's get started if


  5   everybody could find their seats, please.  We do


  6   have some new people at the table so I thought we


  7   might take this opportunity to let them introduce


  8   themselves and start over here.


  9             DR. BEITZ:  I am Julie Beitz.  I am the


 10   Deputy Director of the Office of Drug Evaluation


 11   III.


 12             DR. LOEWKE:  I am Sally Loewke.  I am the


 13   Acting Division Director of the Division of Medical


 14   Imaging and Radiopharmaceutical Drug Products.


 15             DR. BUCKLEY:  Hi, I am Shavhree Buckley.


 16   I am a medical officer in the Division of Pediatric


 17   Drug Development, and a pediatrician.


 18             DR. CHESNEY:  Thank you.  Just one


 19   technical or business detail, it was brought to my


 20   attention that some people would be willing to


 21   either forego lunch or make it a brief 15-minute


 22   lunch in order to keep on going.  So, please keep


 23   that in mind and we will raise it again at the end


 24   of this morning's session as to whether you want to


 25   do that.




  1             The rest of our session very briefly, as I


  2   understand it--and this will be repeated to us a


  3   number of times but for the committee's benefit and


  4   for me thinking out loud, our challenge is to help


  5   the FDA determine what cardiac imaging drugs, not


  6   devices or procedures but what cardiac imaging


  7   drugs do we need pediatric labeling for.  Very few


  8   of these imaging agents or drugs currently have


  9   pediatric labeling, and how many need it and for


 10   how many could the use simply be extrapolated from


 11   adult labeling?  Specifically, they are interested


 12   in what imaging drug classes need further study.


 13   Secondly, what patient populations would be


 14   available to receive these drugs.  Along that line,


 15   utilization information is particularly important.


 16   In other words, how many children would undergo a


 17   procedure involving the agent such that there would


 18   be enough to do a study with the agent?


 19             So with that, I am pleased to introduce


 20   Dr. Susan Cummins who is the lead medical officer


 21   in the Division of Pediatric Development.  I


 22   understand that in addition to introducing this


 23   session, she may have some comments for us about


 24   the previous issue of adverse drug reporting.


 25             Use of Imaging Drugs in Conjunction with




  1           Cardiac Imaging Procedures in the Pediatric


  2              Population Pediatric Regulatory Update


  3             DR. CUMMINS:  Good morning.  First, just


  4   to comment on the adverse drug reporting feedback


  5   that you gave us, I wanted to let you know that we


  6   kibitzed over the break and what we will do for our


  7   next meeting and into the future is provide you


  8   with the medical officers' summaries for the drugs


  9   that are granted exclusivity.  We will also provide


 10   you with the labeling changes, as well as the AERS


 11   summary that you get now in the summary that is


 12   provided to you in your packets.


 13             Diane Murphy has already shared your


 14   concerns with the Office of Drug Safety who,


 15   themselves, are always interested in strengthening


 16   drug safety reporting to the FDA and we will be


 17   talking with them about your concerns and see how


 18   to go forward with them.


 19             [Slide]


 20             I want to welcome you all here.  There are


 21   a lot of new faces at the table.  I am Susan


 22   Cummins.  I am a medical team leader in the


 23   Division of Pediatric Drug Development and Shirley


 24   Murphy asked me to tell you a little bit about


 25   myself so here is a 30-second story.




  1             I came to the Division from the National


  2   Academy of Sciences a little over a year ago where


  3   I was the Director of the Board on Children, Youth


  4   and Families.  This board was a joint board with


  5   both the Institute of Medicine and the National


  6   Research Council.


  7             I also brought along a long experience


  8   with environmental health, especially in childhood


  9   lead poisoning.  For many years I managed the


 10   childhood lead poisoning prevention program for the


 11   State of California.  In that role we used meetings


 12   such as this one, advisory committees, extensively.


 13   We were actually mandated by state law to use


 14   advisory committees to help us with complex issues


 15   of science, medicine, public health and policy.


 16   So, I have a lot of experience with meeting


 17   processes both at the National Academy of Sciences


 18   and in California, and I love meetings like this.


 19   I think your input is just so valuable and really


 20   helps us be able to move forward.


 21             I want to thank you in advance for all


 22   your time and wisdom, and at the end of the day for


 23   the advice that you are going to give us.  Many of


 24   you, in addition to coming today, participated in a


 25   series of scoping interviews that we conducted to




  1   plan this meeting and to help us define the issues


  2   that we needed to address.  That was just


  3   unbelievably helpful.  I don't know that we could


  4   have moved forward in planning this meeting without


  5   the input that you have given us already.  We also


  6   look forward to a very stimulating and productive


  7   day so I want to thank you already for all that you


  8   have done.


  9             [Slide]


 10             What I am going to do today is give you a


 11   brief overview of the last decade of pediatric drug


 12   development efforts at the FDA.  I am also pleased


 13   to report that the agency is fully engaged in


 14   efforts to strengthen labeling of products for use


 15   in the pediatric populations.


 16             Today I am going to talk about the issues


 17   listed here.  First I am going to review pediatric


 18   issues, especially pediatric safety issues which


 19   have long influenced the evolution of FDA law,


 20   regulation and policy.  That said, today I am going


 21   to focus on recent milestones, those of the last


 22   decade.


 23             I will also briefly review the written


 24   request process, discuss current pediatric labeling


 25   and exclusivity statistics, the big goals of these




  1   efforts and pediatric resources that are available


  2   at the FDA Internet web site.  For the standing


  3   committee members this will be yet another review


  4   and I apologize for that, though I appreciate Joan


  5   Chesney's gracious comments yesterday that no


  6   review could be too many.  However, many of you are


  7   new, as I just mentioned and have just come for


  8   this meeting and this topic is intended to provide


  9   you with a quick primer on how these issues have


 10   unfolded at the FDA.


 11             [Slide]


 12             As in every field, we at the FDA conduct


 13   our work with many acronym shortcuts.  You have


 14   your MRI, your PET, your SPECT, your XR, and we


 15   have our FDAMA, BPCA, PREA and WR.  The acronyms I


 16   will use for my talk are listed here.  The first


 17   three refer to recent laws.  FDAMA is the Food,


 18   Drug and Cosmetic Modernization Act.  BPCA is the


 19   Best Pharmaceuticals for Children Act.  PREA is the


 20   Pediatric Research Equity Act.  WR refers to a


 21   written request and PPSR refers to a proposed


 22   pediatric study request.  I will describe all of


 23   these throughout the course of my talk.


 24             [Slide]


 25             In 1994 FDA issued pediatric regulations




  1   that required data review for pediatric labeling.


  2   This rule required sponsors to review both their


  3   existing data as well as available published


  4   literature to see if enough data was available to


  5   support pediatric labeling.  No clinical studies


  6   were required by this rule.  Importantly, this rule


  7   introduced the concept of extrapolation of efficacy


  8   data from adults to children when that


  9   extrapolation seemed scientifically appropriate.


 10             [Slide]


 11             In 1997 FDAMA was passed by Congress.


 12   FDAMA actually brought the FDA law up to date.  It


 13   was a big law that modernized the Food, Drug and


 14   Cosmetic Act.  Included in this law were several


 15   pediatric provisions, most importantly the


 16   exclusivity incentive, which is a big carrot based


 17   on compliance with terms of a written request


 18   issued by the FDA to drug sponsors.  Before the


 19   passage of FDAMA the pediatric market, with the


 20   exception of perhaps antibiotics and a few other


 21   product classes, was too small to support a drug


 22   development program so pediatric studies were not


 23   done.  Pediatric exclusivity changed all of that,


 24   as you will see in a minute.  The pediatric


 25   exclusivity provisions of FDAMA sunsetted on




  1   January 1, 2002.


  2             [Slide]


  3             Now, what is pediatric exclusivity?


  4   Pediatric exclusivity is an additional 6-month


  5   period during which a sponsor retains exclusive


  6   marketing control of all forms of a drug product


  7   line.  It requires either an existing patent or


  8   exclusivity and is not a patent extension.  FDA


  9   doesn't have the authority to grant a patent


 10   extension; only the Patent Office can do that.


 11   Pediatric exclusivity attaches to an existing


 12   patent or to other exclusivities which have been


 13   granted by the FDA.


 14             This is a very powerful economic incentive


 15   for pediatric drug development because it confers


 16   to the entire drug moiety and every product that


 17   contains that active drug product.  It delays for 6


 18   months the introduction of generic products.  As


 19   soon as the generic product is introduced the sale


 20   of the branded product declines dramatically.


 21             For example, consider the steroid


 22   fluticasone.  When exclusivity was granted to


 23   fluticaszone it attached to Flovent, the inhaled


 24   product; to Flonase, the nasal spray; to Cutivate,


 25   the topical product; and to Advair, the combined




  1   fluticasone and salmeterol product.  Imagine, for


  2   example, a product with 2 billion dollars annually


  3   in sales.  Exclusivity translates to an additional


  4   1 billion dollars in sales.  So, this is a very,


  5   very powerful economic incentive for pediatric


  6   studies, and this was the carrot that made


  7   pediatric studies economically feasible.


  8             [Slide]


  9             I want to touch on one part of FDAMA about


 10   which there has been some confusion on the part of


 11   industry, the FDAMA priority list.  The priority


 12   list consisted of several hundred drugs that were


 13   prioritized for pediatric studies by the FDA.  If a


 14   drug was on the priority list it did not require


 15   FDA to issue a written request.  Issuance of a


 16   written request if a drug was on the priority list


 17   was optional.  But important for now, this list has


 18   sunsetted.  Its sunset was on January 1, 2002.  So,


 19   it sunsetted when the pediatric provisions of FDAMA


 20   sunsetted so now this list is a piece of history;


 21   it really no longer exists.


 22             [Slide]


 23             The next advance I want to mention is the


 24   Best Pharmaceuticals for Children Act, the BPCA,


 25   which became law on January 4, 2002.  The BPCA




  1   re-authorized the exclusivity provisions of FDAMA


  2   for on-patent drugs.  In addition, it also includes


  3   an additional mechanism for obtaining information


  4   on the safe and efficacious use of off-patent drugs


  5   in the pediatric populations.


  6             There is a slide missing so I am going to


  7   tell you what it says.  The Best Pharmaceuticals


  8   for Children Act--as I just mentioned, BPCA


  9   establishes mechanisms for study of both on-patent


 10   and off-patent products.  It requires in addition


 11   the FDA to collaborate with NIH on these studies.


 12   For off-patent products that is the major focus of


 13   the work of our Office and for on-patent products


 14   that industry does not want to study.  So, if


 15   industry does not want to study an on-patent


 16   product we have a mechanism through BPCA to get


 17   studies done aon that product for pediatric


 18   labeling, as well as mechanisms for doing studies


 19   of off-patent products.  For both on-patent and


 20   off-patent products industry has the right of first


 21   refusal to conduct studies that are requested


 22   through the written request process.


 23             [Slide]


 24             There are two paths to a written request.


 25   First, FDA can itself issue a written request and




  1   this happens when the agency determines that there


  2   is a public health need for the studies that are


  3   being requested.  The definition of a public health


  4   need can vary on many factors, such as whether


  5   there is substantial off-label use; if the proposed


  6   use is a significant pediatric issue; and whether


  7   there are other treatment options available.


  8   Having a disease be prevalent is not the only


  9   factor that we fold into a decision about the


 10   public health need.  Pediatric studies for drugs to


 11   treat rare diseases may also have a high priority,


 12   especially when no other treatment options are


 13   available.


 14             The other path is when industry submits a


 15   PPSR to the FDA.  In that circumstance the FDA may


 16   accept the proposal as it is and issue a written


 17   request.  It may modify the proposal and issue a


 18   modified written request, or it may not accept the


 19   proposal at all and the factors that we just


 20   described fold into the decision-making process.


 21   In that case, if the FDA decides not to issue a


 22   written request then it will issue an inadequate


 23   letter.


 24             [Slide]


 25             Now, what is a written request?  A written




  1   request is a legal document that provides a


  2   detailed outline of the studies needed by the FDA


  3   to adequately label the product for us in the


  4   pediatric population.  It is an outline, a detailed


  5   outline that does not have the kind of detail you


  6   usually see in a protocol.  Once a study is moving


  7   forward based on a written request, then a protocol


  8   is developed.  The written request specifies all


  9   the study needs to label the product, including


 10   indication, population, types of studies, PK,


 11   safety and efficacy studies for example, safety


 12   parameters that need to be monitored, whether there


 13   is a need for long-term follow-up and what that


 14   might be and the time frame for response.  In the


 15   next few slides I am going to review the written


 16   request process.


 17             [Slide]


 18             These slides focus on the on-patent


 19   process.  The off-patent process is fairly similar.


 20   In this example the industry sponsor submits the


 21   proposed pediatric study request to the agency and


 22   the FDA reviews the PPSR to determine whether there


 23   is a public health benefit to the proposed studies.


 24   Again, the public health benefit issue here is


 25   important.  The agency only issues a written




  1   request if it determines that there is a public


  2   health benefit to the studies.  If so, it issues a


  3   written request and, again, if not, it issues an


  4   inadequate letter.


  5             [Slide]


  6             Once the FDA has issued its written


  7   request, the industry has 180 days to respond to


  8   that request.  If it declines the request, then the


  9   WR may be referred to the National Institutes of


 10   Health Foundation for funding of the requested


 11   studies.  I would add though that currently there


 12   are very limited funds available within the NIH


 13   Foundation to conduct studies of on-patent


 14   products.


 15             [Slide]


 16             I am not going to talk about this slide.


 17   I want to move on and talk a little bit more about


 18   the on-patent drug exclusivity process because that


 19   has been somewhat of a mystery, what happens at the


 20   FDA in this on-patent written request review


 21   issuance, and then review studies once they come in


 22   to the FDA.


 23             [Slide]


 24             This slide addresses all of that and I


 25   want you to focus on the right side of the diagram,




  1   this column right here.  Prior to issuing a written


  2   request the agency does background research on the


  3   drug product and the issues at hand and conducts a


  4   literature review.  That literature review is used


  5   to inform the drafting of a written request.  The


  6   draft request is then reviewed by PdIT, the


  7   pediatric implementation team which is a


  8   cross-functional team that meets regularly within


  9   the agency to discuss draft written requests.


 10             Once the draft is reviewed, has been


 11   discussed, has been revised and finally approved,


 12   it is issued to industry by the review division.


 13   The studies are completed by the sponsor, if the


 14   sponsor agrees to perform them, and the results are


 15   submitted to the agency.  So, we are right here.


 16             Once the FDA receives the submitted study


 17   reports a time clock starts.  It has 60-90 days to


 18   review the reports and make an exclusivity


 19   determination.  The submission is reviewed


 20   eventually by the exclusivity board which is a


 21   cross-CDER team.  It is a very formal meeting and


 22   the team is chaired by Dr. John Jenkins.  The


 23   review focuses not on whether efficacy has been


 24   demonstrated but, rather, on whether the sponsor


 25   has fairly met the terms of the written request. 




  1   That is the legal standard that we must meet.  This


  2   is determined by making a very careful comparison


  3   of the submission that we have received from the


  4   sponsor compared to the written request that was


  5   issued.


  6             If, for example, the written request asks


  7   that 10 children between the ages of 6 and 10 be


  8   included in the study population, then the review


  9   carefully checks to see if, in fact, 6 [sic]


 10   children were included in the study population in


 11   the submission.  If exclusivity is granted, then


 12   that notice is posted on the pediatric page and on


 13   the web.  Other actions to the label follow within


 14   a few months.


 15             [Slide]


 16             This incentive has really been a


 17   tremendous success.  Please note here, this slide


 18   reports on industry response to the written request


 19   process as of January, 2004.  Your handout may say


 20   2003.  It is one of those last minute errors you


 21   see after looking at a slide a dozen times.  To


 22   date we have received over 300 proposals from


 23   industry.  We have issued nearly 300 written


 24   requests.  We have made exclusivity determinations


 25   for 101 cases and granted exclusivity in 91 of




  1   those cases.  This effort has led to 63 new labels.


  2             The significance of these new labels


  3   really cannot be underestimated.  It isn't just


  4   data; the labeling changes determine how we use


  5   these drugs and provide new information on how to


  6   use these drugs safely in the pediatric population


  7   on issues such as dose, unanticipated adverse


  8   events and the like.


  9             [Slide]


 10             I want to move forward to the present.  On


 11   December 3, 2003 the President signed the Pediatric


 12   Research Equity Act, PREA, into law.  PREA mimics


 13   the Pediatric Rule which was overturned by the


 14   courts in 2002, and this form provides the stick


 15   that balances the carrot that I talked about


 16   earlier.  PREA is retroactive for applications back


 17   to April 1, 1999.


 18             [Slide]


 19             PREA requires pediatric studies of certain


 20   drugs and biologics for the issues listed here: if


 21   there is a new indication; if there is a new dosage


 22   form; a new route; a new dosing regimen; or a new


 23   active ingredient.  Biologics are included because


 24   biologics have not been eligible for exclusivity in


 25   the past because they don't have patents.




  1             The Act also establishes, as was mentioned


  2   earlier, a formal pediatric advisory committee and


  3   this committee will be seated at the Commissioner's


  4   level so it will advise the agency on pediatric


  5   issues for most of the FDA centers--for drugs,


  6   biologics, foods and devices, probably not


  7   veterinary medicine.  Its range of issues will be


  8   even broader than that of the current subcommittee


  9   which has tackled a number of issues.  The range of


 10   issues we have tackled since I have been here is


 11   just extraordinary.  Implementation of the Act is


 12   still under discussion within the agency.  The FDA


 13   is currently in the process of developing a


 14   guidance to advise on how we plan on implementing


 15   the Act.


 16             [Slide]


 17             This is our goal for all of these efforts,


 18   to add new pediatric information to the labels of


 19   drug products that are commonly used in children.


 20   Before pediatrics came to the FDA drugs were


 21   commonly used off-label, as I know you all know,


 22   and in that circumstance each child was an N of 1.


 23   Little was learned from any of these individual


 24   treatment experiments and we already have gathered


 25   a lot of very valuable information since this




  1   effort has started.


  2             [Slide]


  3             I want to close by mentioning just a


  4   couple of resources that are available on the FDA


  5   Internet.  If you go to the FDA home page, which is


  6   shown here, at www.fda.gov and you look at the


  7   lower right corner--this little arrow right here,


  8   there is a little link to the pediatrics web home


  9   page.


 10             [Slide]


 11             Then if you go to the pediatric home page


 12   there is a lot of valuable information--statistics,


 13   guidances, information about pediatric advisory


 14   subcommittee meetings and much, much more.


 15             That concludes my comments.  I want to


 16   thank you for your attention and I will turn the


 17   podium over to Sally Loewke.


 18             DR. CHESNEY:  Just in advance of Dr.


 19   Loewke, I wonder if all of the speakers who follow


 20   her, and including her, could tell us just very


 21   briefly, 30 seconds, about your background, please.


 22                         FDA Perspective


 23             DR. LOEWKE:  Good morning and welcome all.


 24             [Slide]


 25             My name is Sally Loewke.  I am the Acting




  1   Division Director for the Division of Medical


  2   Imaging and Radiopharmaceutical Drug Products.  I


  3   am a nuclear medicine physician and I am going to


  4   note some bias here.  I am a mother of twins with a


  5   son who has had some cardiac problems, who has


  6   actually had to have cardiac catheterization and


  7   some cardiac procedures.  So, I am going to throw


  8   that out just so you know.


  9             [Slide]


 10             Dr. Chesney and panel members, I really


 11   want to thank you very much for coming here today


 12   and taking time out of your busy schedules to talk


 13   about this very important topic, the use of imaging


 14   drugs in conjunction with cardiac imaging


 15   procedures in the pediatric population.  As you


 16   know, cardiac imaging plays an important role in


 17   the management of patients with cardiac disease and


 18   to date we have very few drugs that are approved


 19   for cardiac indications in the pediatric


 20   population.


 21             We are here today to get needed input from


 22   you about the use of these products in the


 23   pediatric population.  The information that you


 24   will bring forward will be invaluable to the agency


 25   as we proceed in our efforts to provide safe and




  1   effective drugs for the pediatric population.


  2             [Slide]


  3             These are several areas that I will be


  4   addressing over the course of this presentation


  5   this morning.


  6             [Slide]


  7             The FDA is a regulatory agency.  It is


  8   made up of 6 centers.  The center that is


  9   responsible for review of drugs for human use is


 10   the Center for Drug Evaluation Research.  We are


 11   also known as CDER.  An important piece of


 12   information to also take away from this slide is


 13   that the devices are regulated by a different


 14   center within the FDA, CDRH, Center for Devices and


 15   Radiologic Health.


 16             [Slide]


 17             CDER's mission is to assure that safe and


 18   effective drugs are made available to the American


 19   people.


 20             [Slide]


 21             The Division of Medical Imaging and


 22   Radiopharmaceutical Drug Products is one of 18


 23   divisions that makes up the Office of New Drugs


 24   within CDER.  The Division is responsible for the


 25   review of drugs that are utilized for diagnostic




  1   imaging including some radiotherapeutic products as


  2   well.  The medical imaging drugs have been broken


  3   down into two categories, the contrast agents and


  4   the radiopharmaceuticals.  The definitions you are


  5   about to see come from the FDA draft guidance which


  6   is in your packet.


  7             [Slide]


  8             A contrast agent is a medical imaging


  9   agent used to improve the visualization of tissues,


 10   organs and physiologic processes by increasing the


 11   relative difference of imaging signal intensities


 12   in adjacent regions of the body.  Some common


 13   examples of these types of agents include iodinated


 14   contrast, gadolinium and microspheres.


 15             [Slide]


 16             A diagnostic radiopharmaceutical is an


 17   article that is intended for use in the diagnosis


 18   or monitoring of a disease or a manifestation of a


 19   disease in humans that exhibits spontaneous


 20   disintegration of unstable nuclei with the emission


 21   of nuclear particles or photons, or any radioactive


 22   reagent kit or nuclide generator that is intended


 23   to be used in the preparation of such an article.


 24   One of the common radioactive tags that is used in


 25   nuclear medicine imaging, including nuclear cardiac




  1   imaging, would be technetium 99-M.


  2             [Slide]


  3             As an aid to your understanding of the


  4   Division and its thinking about the development of


  5   medical imaging drugs, you were provided with the


  6   draft guidance for developing clinical imaging drug


  7   and biologic products in your preparatory package.


  8   This document provides information on important


  9   areas that need to be discussed during the course


 10   of drug development.  I refer you to the guidance


 11   for specifics, however, I will briefly touch upon


 12   the types of indications that could be sought for


 13   both the pediatric and adult indications.


 14             Structure delineation--an imaging agent is


 15   able to locate and outline normal anatomic


 16   structures and, in doing so, can clarify the


 17   spatial relationship of that structure with respect


 18   to other body parts or regions.


 19             Disease or pathology detection--an agent


 20   is able to detect and locate specific disease or


 21   pathological states.


 22             Functional, physiological or biochemical


 23   assessment--an agent is able to evaluate function,


 24   physiology of biochemistry of a tissue, organ


 25   system or body region.  This type of indication




  1   could apply to an agent that is used to detect


  2   either a decrease or an increase of a normal


  3   function or physiological or biochemical process.


  4             Diagnostic or therapeutic patient


  5   management--a medical imaging agent would improve


  6   patient management decisions or improved patient


  7   outcomes, including predicting survival or patient


  8   response to specific therapies.


  9             [Slide]


 10             To provide you with a framework of the


 11   types of information we routinely see when new drug


 12   applications come into the agency, I have this one


 13   slide.  It is not all-inclusive for the clinical


 14   assessment and it is not all-inclusive for the


 15   information that we seek in a new drug application


 16   but it highlights a couple of points I wanted to


 17   discuss further.  For efficacy, obviously, we


 18   review the data and review the studies to make sure


 19   an appropriate dose has been selected that is going


 20   to give you a useful image.  We look at the


 21   pharmacokinetics and make sure they are well


 22   defined.


 23             The pivotal Phase III trials are the


 24   trials where we get most of our efficacy


 25   information and what we like to see is a trial




  1   design that includes clinically relevant endpoints,


  2   relevant patient populations and an appropriate


  3   standard of truth.


  4             The question is what does all that mean?


  5   I am going to give you an example to help


  6   illustrate my point here.  It is not a cardiac


  7   example but I still think it makes the point


  8   effectively.  If you are developing a medical


  9   imaging agent that you felt could distinguish


 10   between benign versus malignant lesions, having an


 11   agent that could identify a malignant lesion


 12   obviously has clinical utility.  Physicians will


 13   know what to do with that information and it is


 14   very useful.  So, you would then pursue study of


 15   that agent in a patient population who would


 16   present with a tumor or a lesion that needed


 17   further evaluation.  Ultimately, how do you


 18   validate the performance of the new drug?  You


 19   would do so in this case by getting biopsy and


 20   confirming the pathology of those lesions.


 21             From a safety perspective, we identify any


 22   major toxicities that might have come about during


 23   the course of drug development and we put together


 24   an adverse event profile that, if the drug is


 25   approved, generally is put into drug labeling.




  1             So, overall our review and action on a


  2   drug, whether it be approval or non-approval, is


  3   based on a risk/benefit assessment.  In this case


  4   risk can mean a safety hazard or risk. It could


  5   also mean hazard could be occurring from a


  6   misdiagnosis as a result of the imaging drug.


  7             [Slide]


  8             The Division has several drugs in which


  9   cardiac indications are approved.  This slide lists


 10   drug classes and some of the general indications


 11   that are approved in both the adult and pediatric


 12   populations.  The iodinated contrast drug class is


 13   the only drug class that has a cardiac indication


 14   approval in both the adult and pediatric


 15   populations, that being for conventional


 16   angiography.  The pediatric approval goes down to


 17   the age of 1.


 18             The gadolinium drug products are not


 19   approved in either the adult or pediatric


 20   populations for a cardiac indication, however they


 21   do have other indications that are approved in both


 22   populations.


 23             The radiopharmaceuticals--we have approval


 24   for myocardial perfusion identifying cardiac


 25   ischemia and other myocardial functional




  1   assessments such as ejection fraction, wall motion


  2   and viability.  Again, those are studied and


  3   approved in the adult population.


  4             Microspheres are one of our most recent


  5   drugs that have been on the market.  They have been


  6   approved for left ventricular opacification and


  7   endocardial border delineation but have only been


  8   approved in the adult population.


  9             [Slide]


 10             Historically, children were felt to be


 11   considered like little adults and we could dose on


 12   a milligram/kilogram basis and, therefore, research


 13   in children really wasn't necessary.  However, in


 14   the 1970s there was a change in that thinking where


 15   people actually felt it was unethical not to study


 16   drugs in the pediatric population as many new drugs


 17   were flooding the market and were being used in


 18   this population.


 19             Today, as Susan has mentioned, we have the


 20   Best Pharmaceuticals for Children Act and the


 21   Pediatric Research Equity Act which are


 22   congressionally mandated, and Congress has clearly


 23   stated that children deserve the same level of


 24   evidence as that provided for the adult approvals.


 25             [Slide]




  1             The agency has tried to foster pediatric


  2   drug development and, in doing so, has made


  3   comments about the potential use of extrapolation


  4   from efficacy data from adults to the pediatric


  5   population.  Therefore, if the course of disease


  6   and the effects of the drug are similar in adults


  7   and pediatric patients, then the FDA may conclude


  8   that pediatric efficacy can be extrapolated from


  9   adequate and well-controlled studies in adults,


 10   usually supplemented with other information


 11   obtained in the pediatric population such as


 12   pharmacokinetic and safety studies.


 13             [Slide]


 14             When may it not be appropriate to


 15   extrapolate?  When the disease is different in


 16   etiology, pathophysiology or in its manifestations;


 17   when the response to therapy is different; when the


 18   pathophysiology may be comparable but the response


 19   unpredictable; or when pharmacokinetic parameters


 20   are not well-defined in the adult population.


 21             [Slide]


 22             We know that there are differences in


 23   pathophysiology of cardiac disease between the


 24   pediatric and adult populations.  Pediatric


 25   population presents with congenital heart disease




  1   and the adults with atherosclerotic heart disease,


  2   and most of our drug approvals for cardiac


  3   indications in adults have revolved around patient


  4   populations that have signs and symptoms of


  5   atherosclerotic disease.  So, the question to


  6   ponder later today is do differences in the


  7   etiology and pathophysiology affect imaging drug


  8   performance?


  9             [Slide]


 10             We have had great difficulty in getting


 11   accurate use data of these products.  In an effort


 12   to try to give you some perspective, we looked at


 13   the Child Health Corporation of America's Pediatric


 14   Health Information System database.  Currently,


 15   this is inpatient data from 31 free-standing


 16   children's hospitals with charge level drug


 17   utilization information.  It is our first access to


 18   pediatric inpatient drug use and, since many


 19   children's hospitals are the sites of research


 20   trials, we feel that we probably get great


 21   information on potential off-label use of these


 22   products.


 23             This database, however, has a lot of


 24   limitations to it.  You cannot nationally project.


 25   The FDA only has access to data dating back to




  1   1999.  There is no direct link between drug and


  2   diagnosis procedure.  It does not capture


  3   outpatient use and free-standing image center use.


  4   And, the contrast media radiopharmaceuticals are


  5   usually bundled together with the imaging procedure


  6   and cannot be specifically separated out.


  7             [Slide]


  8             So, this is the result of our database


  9   search and this is specifically from 26


 10   free-standing children's hospitals at the time this


 11   was done.  These are drug mentions in the pediatric


 12   population for the years 2001 and 2002 out of the


 13   total discharges that you see at the bottom of the


 14   slide.  The iodinated contrast agents have the most


 15   drug mentions for both 2001 and 2002, followed by


 16   the gadolinium contrasts, radiopharmaceuticals and


 17   the microspheres.


 18             [Slide]


 19             Since most of our products are not


 20   approved in pediatrics we have little knowledge


 21   about their safety.  I just want to step back for


 22   one second to make one more comment about that


 23   database information on use.  We are fully aware


 24   that it is not an accurate representation of the


 25   use of these products because we know many imaging




  1   procedures are performed on an outpatient basis and


  2   are performed at free-standing imaging centers.


  3   So, we hope that the discussions later today and


  4   the presentations from our experts will help


  5   enhance our knowledge of the frequency of use of


  6   these products.


  7             [Slide]


  8             Unfortunately, we have a limited knowledge


  9   base for pediatric safety data as well since we


 10   have few approvals.  So, in an attempt again to


 11   give you some kind of flavor of what we do know, we


 12   did a data search of the Adverse Event Reporting


 13   System, also known as the AERS database.  It is a


 14   spontaneous and voluntary reporting system and it


 15   too has many limitations which you heard about


 16   earlier today.  There is under-reporting; reporting


 17   bias; the quality of the reports is very limited;


 18   and you cannot estimate the true incidence rate of


 19   events or exposure risk.


 20             [Slide]


 21             I just want to go over the methodology


 22   briefly of our search.  We did not want this whole


 23   meeting to revolve around any one specific drug


 24   but, rather, the drug classes so in an attempt to


 25   keep that theme with the search of this database we




  1   selected two drugs per drug class which we thought


  2   were relative market leaders and did a search of


  3   the database in both the adult and pediatric


  4   population.


  5             Once we got those results, we then


  6   combined them and, as you will see, the slides that


  7   will be forthcoming are combined data for the drug


  8   class per se.  We report out the most common


  9   adverse events reported in 10 percent of the total


 10   or greater.  We report out the deaths and the


 11   search time frames were variable depending on the


 12   specific drug product that we used and their


 13   original approval dates.  Again, be warned that


 14   this database has its limitations and cannot be


 15   construed as an accurate representation of the


 16   adverse event profiles for these drug classes.


 17             [Slide]


 18             This is the data we generated for the


 19   iodinated contrast agents.  As you can see here,


 20   there were 2,997 reports in the adult population


 21   versus 68 in the pediatric population.  The common


 22   event types were pruritus, dermatitis and urticaria


 23   in the adults and urticaria, dyspnea and facial


 24   edema in pediatrics.  There was a total of 274


 25   deaths in the adults and 2 reported in the




  1   pediatric population.


  2             Those 2 deaths in the pediatric population


  3   included a 9-year old male having an abdominal CT


  4   who had an anaphylactic reaction and died.  This


  5   patient was noted to have a history of asthma.  The


  6   other patient was a 7-month old with multiple


  7   cardiac anomalies who died approximately 6 hours


  8   after a cardiac cath procedure.  As you can note,


  9   these common events are really a hypersensitivity


 10   type reaction and these are very common for


 11   iodinated contrast agents.


 12             [Slide]


 13             This slide represents the gadolinium drug


 14   class.  There is a total of 5,163 reports in the


 15   adult population versus 233 in the pediatric


 16   population.  Common events in adults include


 17   urticaria, vomiting, nausea, dyspnea and pruritus,


 18   and in children vomiting, nausea and urticaria.


 19   There was a total of 108 deaths in the adult


 20   population and 3 in the pediatric population.


 21             Those 3 deaths were as follows, a 7-month


 22   old with gastroenteritis had an MRI to exclude


 23   meningitis.  The patient had spina bifida and the


 24   patient died 2 hours after the procedure from


 25   septic shock.




  1             A 12-year old female died from


  2   complications of brain stem glioma and a 5-year old


  3   male with meningeal toxemia died approximately 8


  4   hours after an MRI from complications of


  5   hemorrhagic stroke.  Again, as I stated earlier,


  6   the gadolinium drug class does not have a cardiac


  7   indication approval in either population.


  8             [Slide]


  9             The radiopharmaceutical drug class--a


 10   total of 334 reports in the adult population versus


 11   no reports in the pediatric population.  Common


 12   events in adults include dermatitis, pruritus,


 13   urticaria, nausea, cough, headache and dyspnea and


 14   a total of 16 deaths were reported.


 15             [Slide]


 16             The microsphere drug class--a total of 107


 17   reports in the adult population, no reports in the


 18   pediatric population.  Common events in adults are


 19   back pain and headache and no deaths reported.


 20             [Slide]


 21             Overall, to date we have few approvals of


 22   cardiac imaging drugs in the pediatric population.


 23   We have limited use data and limited safety data,


 24   and we have the question to ponder whether the


 25   differences between cardiac disease processes in




  1   adults and kids can actually allow us to


  2   extrapolate the efficacy data.


  3             [Slide]


  4             These are basically the questions for the


  5   panel that will be coming up either later today or


  6   tomorrow.  I just flash them on the screen for the


  7   benefit of the audience so you can understand as


  8   you listen to the speakers talk later.


  9             The first question basically revolves


 10   around extrapolation.  Is it possible?  If so,


 11   when?  The second question is a series of questions


 12   that we would like addressed per drug class


 13   category, asking whether there is needed study for


 14   the drug class and, if so, what patient


 15   populations, what disease states, etc.


 16             [Slide]


 17             The third and last question is the


 18   relevance of new drug developments in the field of


 19   adult cardiac imaging and whether they are


 20   applicable to the pediatric population.


 21             [Slide]


 22             So, we would really like today's focus to


 23   be on the imaging drugs.  I know it is hard to


 24   separate the imaging procedure and the device but I


 25   ask that people try.  We also know that there are




  1   many ethical issues in pediatric research.  Again,


  2   we would like today's discussion to focus on the


  3   science and trial design issues.  Do we need


  4   additional drug labeling, and for what classes, and


  5   what do we need to know?  How are these products


  6   being used and for what purpose and what


  7   population?  And, how do they alter your management


  8   decisions, the information that you gather?  The


  9   bottom line, do you feel that extrapolation is


 10   potentially possible?


 11             [Slide]


 12             I want to thank you very much for


 13   attending today.  As Susan had alluded to, we


 14   counted on many people on this panel and others who


 15   are not present to help organize this meeting and


 16   your help has been very invaluable and I thank you


 17   very much.


 18             DR. CHESNEY:  Thank you, Dr. Loewke.  We


 19   will have time for questions and answers of the


 20   speakers after the next two presentations.  The


 21   next presentation is by Dr. John Ring, representing


 22   the American Academy of Pediatrics, to give their


 23   perspective on the issues Dr. Loewke just outlined.


 24            American Academy of Pediatrics Perspective


 25             DR. RING:  One of the advantages of




  1   becoming middle aged is that you get a bit


  2   farsighted over time so I am thinking that this


  3   will probably work.


  4             [Slide]


  5             Apropos Joan's request to identify


  6   oneself, I have found, now that I am clearly


  7   unequivocally middle aged, that it is important for


  8   me to start each day by orienting myself to a


  9   person, place and time--


 10             [Laughter]


 11             --so, this is who I am.  This is where we


 12   are and this is who you are, in case any of you


 13   require this type of orientation as well.


 14             The five physicians sitting to my right


 15   along this part of the table will offer detailed


 16   information this afternoon regarding the


 17   application of intravascular contrast agents and


 18   radiopharmaceuticals to various pediatric cardiac


 19   diagnostic modalities.  My assignment is more


 20   general.  It is to present the position of the


 21   American Academy of Pediatrics as to whether these


 22   agents should be studied at all.  I believe I have


 23   been selected for this role because I have


 24   practiced pediatric cardiology for over 20 years


 25   with extensive experience in the cardiac




  1   catheterization lab and because I am also a member


  2   of the national AAP Committee on Drugs.  My two


  3   sons, Jack and Patrick who are sitting in the


  4   audience feel that I was selected for this


  5   presentation today so that they could miss three


  6   days of school.


  7             [Laughter]


  8             [Slide]


  9             The four points which I am about to


 10   summarize represent what we know for sure about the


 11   use of intravenous contrast agents and


 12   radiopharmaceuticals in pediatric cardiology.


 13   These points are that congenital and acquired heart


 14   disease is common in children and of considerable


 15   clinical importance; that accurate diagnosis is


 16   central in order to effect a good clinical outcome;


 17   that the diagnostic use of intravascular contrast


 18   agents and probably radiopharmaceuticals is likely


 19   to increase in the target patient population; and,


 20   finally, that our current use of these agents is


 21   guided really by good intentions rather than by


 22   data.


 23             Taken together, these points identify a


 24   clinical problem that is of major clinical


 25   significance in children.  They indicate that there




  1   is a trend toward increased utilization of these


  2   diagnostic units and they highlight what the


  3   Academy feels is a glaring deficiency in our


  4   knowledge base regarding their use.


  5             [Slide]


  6             As a good academician I did a literature


  7   search.  I did a literature search in large part


  8   because the American Academy of Pediatrics has not


  9   given these agents focused consideration and, thus,


 10   there are no official AAP policies, technical


 11   reports or practice guidelines that speak to their


 12   use.  Regardless, the AAP recognizes that in


 13   general children's health care needs are unique,


 14   that these needs commonly vary with the patient's


 15   age, and that optimal pediatric therapy, regardless


 16   of type, is predicated on the performance of


 17   appropriate scientific studies performed in


 18   children.


 19             [Slide]


 20             Put very simply, knowledge is good and


 21   children are not little adults.  I spoke a minute


 22   ago in regards to a literature search in order to


 23   see what guidance we had there.  With the help of


 24   three research librarians at two institutions, the


 25   University of Tennessee and St. Jude Children's




  1   Research Hospital, we searched key words such as


  2   intravascular contrast agents and


  3   radiopharmaceuticals.  We focused the search on


  4   children rather than adults.  We specified that we


  5   were most interested in cardiac disease and we had


  6   a particular interest in identifying complications.


  7             [Slide]


  8             The databases searched are those that are


  9   listed and the time frame for the search is a


 10   particularly long one.  Unfortunately, but not to


 11   much to my surprise, what we found is that there is


 12   virtually no information extant in the literature


 13   which speaks to the contemporaneous usage of


 14   contrast agents in pediatric cardiology or, by


 15   extension, radiopharmaceuticals.


 16             Something has happened to my script.


 17   Well, let's go back to the four things that we


 18   actually know for sure.


 19             [Slide]


 20             What in particular is the scope of the


 21   problem?  The reported frequency of congenital


 22   heart disease in the population is 2.03 to 8.56 per


 23   1,000 live births, with a median figure of 5.93.


 24   The figure that is generally quoted for the quiz is


 25   the higher of these.  Even when one requires more




  1   firm diagnostic criteria, for example cardiac


  2   catheterization, intraoperative inspection or


  3   postmortem examination, the figure is still


  4   substantial, up to 4.3 per 1,000 live births.


  5             We have a population of children with


  6   congenital heart disease which is aging.  An


  7   article from The American Journal of Cardiology, in


  8   1982, so a relatively dated reference, indicated


  9   that there were at that time approximately 8,500


 10   children with operated congenital heart disease


 11   reaching adulthood each year.  Thanks to advances


 12   in diagnosis and therapy that number is actually


 13   increasing.  In addition, those patients constitute


 14   an aging population, the natural history for which


 15   is entirely unclear.  So, we are obviously on a


 16   voyage of discovery.


 17             As far as inflammatory cardiac disease is


 18   concerned, the first two points indicate that the


 19   incidence and prevalence of Kawasaki syndrome and


 20   acute rheumatic fever are substantial in the


 21   pediatric population.  As far as myocarditis is


 22   concerned, more frequent myocardial biopsy in


 23   children coupled with better diagnostic modalities,


 24   for example PCR analysis, are beginning to extend


 25   the scope and define the specificity of this




  1   diagnosis which to date has been largely


  2   descriptive.


  3             [Slide]


  4             One of the ways in which pediatrics


  5   differs from adult medicine is with its focus on


  6   the future.  The mission statement of the American


  7   Academy of Pediatrics is very clear on this point:


  8   The AAP is committed to the attainment of optimal


  9   physical, mental and social health and well being


 10   for all infants, children, adolescents and young


 11   adults.  Balance this against the fact that


 12   congenital anomalies are the fifth ranked cause of


 13   premature mortality in the United States.  That is


 14   taken from a reference in Morbidity and Mortality


 15   weekly reports in 1998.  Of interest for this


 16   group's deliberations, structural congenital heart


 17   diseases account for 6 of the 15 most lethal


 18   congenital malformations in this group.


 19             [Slide]


 20             Optimal interventions in pediatric


 21   cardiology really do depend, in large part, on good


 22   imaging.  A good picture is worth a thousand words.


 23   Pediatric cardiologists and cardiovascular surgeons


 24   are visually oriented practitioners.  We cannot


 25   treat effectively what we cannot see well.  This




  1   applies both to surgical and catheterization


  2   laboratory interventions.


  3             Our patient population today is undergoing


  4   higher risk interventions both in the cath lab and


  5   in the operating room.  These interventions reduce


  6   what we consider to be the acceptable margin of


  7   diagnostic error.  Our patients are usually


  8   younger, sometimes much older--for example, adults


  9   with grown up congenital heart disease--and usually


 10   sicker.  They have a limited tolerance for long,


 11   stressful procedures.  Accurate imaging then


 12   provides the road map to reach our therapeutic


 13   destination in a timely fashion.  Just as the


 14   children's oncologist can now choose the safest,


 15   most effective treatment for his or her patients


 16   with leukemia through use of genetic subtyping, so


 17   the pediatric cardiologist can choose, at least to


 18   a degree, the safest, most effective dilation


 19   balloon or closure device provided that he or she


 20   has a detailed and accurate image with which to


 21   work.


 22             Finally, different imaging modalities are


 23   complementary rather than competitive.  The


 24   echocardiogram, for example, will certainly


 25   satisfactorily define the basic anatomy of




  1   tetralogy of flow.  Angiography, however, is


  2   necessary to dilate and stent the focal pulmonary


  3   artery stenoses that often complicate this lesion


  4   and affect its clinical outcome.


  5             [Slide]


  6             The use of these agents is likely to


  7   increase.  The volume, for example, of


  8   interventional cardiac procedures performed in


  9   children is increasing rapidly and in most centers


 10   interventional procedures take place in a third to


 11   two-thirds of cardiac catheterizations.  These


 12   interventional procedures oftentimes require more


 13   angiograms, though of a different type or programs,


 14   and smaller but more frequent injections.


 15             The number of adult patients with


 16   congenital heart disease is increasing as well.


 17   Thus, the assessment of myocardial function and


 18   blood flow becomes clinically of greater


 19   significance.  This may be particularly true in


 20   those structural cardiac lesions which involve


 21   abnormalities of coronary arteries, for example


 22   transposition of the great arteries or anomalous


 23   origin of the left coronary artery from the


 24   pulmonary artery.  This may apply particularly to


 25   children who survive acute Kawasaki disease but may




  1   go on to be at cardiac risk for myocardial


  2   ischemia.


  3             Our colleagues in interventional radiology


  4   apply procedures to non-cardiac areas in pediatric


  5   practice as well.  For example embolization of


  6   venous malformations in the central nervous system


  7   and catheter-directed thrombolysis have


  8   implications for the use of these agents as well.


  9             [Slide]


 10             Young people search extensive databases on


 11   the web.  Older people, like myself, pick up the


 12   telephone and call respected colleagues at big


 13   programs.  So, what I did to prepare for this


 14   meeting was to query the cardiac cath lab directors


 15   at five programs throughout the United States.


 16   Four of these five programs are university


 17   affiliated.  One is a respected adult in a


 18   pediatric multi-specialty clinic that does a large


 19   volume of pediatric cardiac disease.  These five


 20   centers do a total of approximately 3,000 pediatric


 21   cardiac catheterizations in a year's time.  The


 22   number of children they catheterize who are under


 23   one year of age is 30-50 percent and in some


 24   programs somewhat greater.  The number of


 25   interventional procedures performed during these




  1   cardiac catheterizations at present are upwards of


  2   50 percent of these cases.  Each of the programs


  3   did a handful, in one case approaching 5 percent of


  4   their cath lab volume, of immediate postoperative


  5   catheterizations.  All of the centers had an


  6   increasing population of adults with congenital


  7   heart disease, 10-15 percent and in some cases


  8   larger.


  9             What do these inquiring pediatric


 10   cardiologists want to know?  the first thing they


 11   want to know is are nonionic contrast agents really


 12   that safe or have they just been lucky or good in


 13   their practice?  The type of complications that we


 14   are talking about do not really reference nausea


 15   and vomiting; they reflect the sort of


 16   complications which are meaningful to this


 17   gun-slinging subgroup of pediatricians.  That would


 18   be death, shock, anaphylaxis, life-threatening


 19   respiratory distress, gross hematuria, acute renal


 20   failure and so on.


 21             Their experience is that with the


 22   development of nonionic contrast agents those


 23   complications, all of which were seen previously in


 24   frighteningly high numbers, have now disappeared


 25   almost completely.  But there still is a question




  1   in the mind of the practitioners as to what is


  2   safe.  That is important particularly when we


  3   consider whether there is a maximum volume of


  4   contrast that I can inject safely.  Most pediatric


  5   centers will limit contrast injection to a total of


  6   somewhere between 5-7 cc/kg of body weight during


  7   the course of a single cardiac catheterization.


  8   Some centers have hinted that as they approach that


  9   contrast wall they will forego indicated diagnostic


 10   procedures till another day for safety-related


 11   reasons.  Is that a good practice?  Nobody really


 12   knows.


 13             So, cardiologists would like to know how


 14   safe these contrast agents are and does that safety


 15   factor vary with age, vary with lesion, vary with


 16   co-morbidities, or vary with the program of


 17   injection?  Are a couple of great, big angiograms


 18   like we used to do better or worse for the patient


 19   than a whole bunch of small angiograms that might


 20   guide an intervention during a dilation and


 21   stenting?  The data is simply not there.


 22             Finally, is there an agent that will give


 23   adequate opacification at lower volumes of contrast


 24   administered in large patients?  This is


 25   particularly apropos to that increasing patient




  1   population, the adult with congenital heart


  2   disease.


  3             The final question is one that many


  4   pediatric cardiologists ask themselves at the end


  5   of the day, especially if their day is ending in


  6   the middle of the night, how can I earn as much as


  7   my colleagues in internal medicine do?  I know that


  8   is beyond the scope of this committee to answer.


  9             [Slide]


 10             Why wouldn't you study these agents?  That


 11   is the question that I came to ask myself as I


 12   tried to prepare these comments.  There may be


 13   philosophical considerations at work here.  Some


 14   feel that data-driven decision-making is of no


 15   particular value.  Others may feel that children


 16   are unable for some reason to receive the benefits


 17   that accrue to the adult patient through scientific


 18   study.  Evidence-based medicine has refuted, I


 19   think quite effectively, both of these contentions


 20   and Congress has mandated that the benefits of


 21   study should be available to children as well as to


 22   adults.  There may be some who believe that


 23   clinical resources do not exist to study this


 24   problem effectively in children.


 25             Each of the institutions I have surveyed




  1   indicated that they would be pleased to participate


  2   in studies to answer some of the questions that


  3   were raised.  That doesn't represent written in


  4   stone commitment but it certainly does indicate


  5   interest and, coupled both with the incidence and


  6   prevalence factors that I spoke of initially,


  7   indicates that I think there is a patient


  8   population there readily available for study.


  9             Finally, there may be some hard-core


 10   skeptics who are either unfamiliar with or frankly


 11   doubtful that important practice improvements have


 12   been made as the result of the fruits of FDAMA.


 13             [Slide]


 14             Dr. Cummins pointed you toward the FDA web


 15   site which, much to my surprise, I was actually


 16   able to access in a user-friendly fashion.  That is


 17   a comment on me; that is not a comment on you.


 18   What I found is that the FDA has so far issued


 19   approximately 300 written requests and that, as a


 20   result of the studies requested, there have been


 21   over 90 changes in labeling.  I can say as a


 22   pediatrician that fully 15 of those 90 changes are


 23   changes that impact my practice, five of which very


 24   directly and I am a niche practitioner--studies on


 25   midazolam, studies on fentanyl, studies on all of




  1   the statins, studies on all of the prils have been


  2   important to me as a practicing pediatric


  3   cardiologist.  As the Carpenters would say, we have


  4   only just begun to gather this information.


  5             [Slide]


  6             If you look at the exclusivity statistics


  7   you will see that some divisions have been very


  8   active in requesting studies in pediatric patients,


  9   and one particular division has not, the Division


 10   of--what do you call yourselves?--Medical Imaging


 11   and Radiopharmaceutical Drug Products.  We single


 12   this out because it is the subject of today's


 13   discussion.  We feel clearly, as pediatricians,


 14   that this area deserves study as well.


 15             [Slide]


 16             So, what are the recommendations of the


 17   American Academy of Pediatrics?  We feel that the


 18   FDA should exercise its authority to require that


 19   appropriate studies be performed regarding the use


 20   of intravascular contrast agents and


 21   radiopharmaceuticals in children cardiac disease.


 22             We feel that those contrast studies should


 23   focus on dosing considerations, balancing safety


 24   concerns with imaging effectiveness.  As an aside,


 25   there is a question in the mind at least of all the




  1   practitioners as to whether the new nonionic


  2   contrasts achieve a comparable level of


  3   opacification and, therefore, diagnostic


  4   information.  Inadequate data or erroneous data can


  5   be as damaging as no data at all.  So, clearly,


  6   that has to be balanced against the safety


  7   consideration.


  8             Finally, we wonder, and this is just a


  9   question, whether a different regulatory posture


 10   may be needed on the part of the FDA in order to


 11   study these agents as effectively as others have


 12   been studied.  It is our understanding that


 13   currently intravascular contrast agents and


 14   radiopharmaceuticals are regulated or studied under


 15   the auspices of a device rather than a drug, and we


 16   are not certain, if that is the case, whether this


 17   is the most effective way to pursue that.


 18   Regardless of whether it is a drug or whether it is


 19   a device, whether it is done through this division


 20   or that division, we feel there is a substantial


 21   problem to address a large pediatric population


 22   which can potentially benefit from an informed


 23   consideration of these agents.  Thank you.


 24             DR. CHESNEY:  Thank you, Dr. Ring.


 25   Because of how these meetings are run, since Dr.




  1   Ring is not at the table this is our only


  2   opportunity to ask him questions that the committee


  3   may have.  Once our next speaker begins we can no


  4   longer ask him questions.  Are there any questions


  5   for Dr. Ring?


  6             [No response]


  7             Thank you very much.


  8             DR. LOEWKE:  Excuse me, I just wanted to


  9   clarify that the contrast agents and


 10   radiopharmaceuticals are approved at the Center for


 11   Drugs.


 12             DR. CHESNEY:  Our next speaker is Dr.


 13   Geva, from the Children's Hospital Boston.  Please,


 14   do give us a few seconds of your background.


 15                     Cardiologist Perspective


 16             [Slide]


 17             DR. GEVA:  My name is Tel Geva and I am


 18   from the Children's Hospital in Boston.  Just give


 19   me a second here to set this up.  I spend the


 20   majority of my time--I divide my time between


 21   taking care of children with congenital heart


 22   disease and imaging.  With regard to imaging, I


 23   divide my time between the cardiovascular MRI


 24   program in Children's Hospital in Boston, which I


 25   direct, and the echocardiography laboratory.




  1             [Slide]


  2             My task this morning is to give you an


  3   overview of progress in the field of pediatric


  4   cardiology.  This is, of course, a mammoth task but


  5   what I will focus on are the following areas, first


  6   the scope of congenital heart disease; trends in


  7   congenital heart disease outcomes; trends in


  8   management; trends in imaging of pediatric and


  9   adult congenital heart disease; and, finally, I


 10   will try to identify some of the gaps in knowledge


 11   as they pertain to imaging.


 12             [Slide]


 13             As the previous speaker has alluded to,


 14   the incidence of congenital heart disease as widely


 15   quoted is approximately 8 per 1,000 live births.


 16   This comes from the American Heart Association.


 17   With approximately 40,000 patients born every year


 18   with some form of congenital heart disease there


 19   are presently approximately a million Americans


 20   currently living with congenital heart disease.


 21             An extensive review by Hoffman and Kaplan,


 22   published in The Journal of the American College of


 23   Cardiology in 2002, analyzed 62 studies on the


 24   incidence of congenital heart disease published


 25   since 1955.  They found an incidence ranging from




  1   4-50 per 1,000 live births.  It turned out that the


  2   variations between those studies had mostly to do


  3   with the inclusion of small ventricular septal


  4   defects and it has to do with what kind of imaging


  5   or diagnostic modality was used to identify those


  6   ventricular septal defects.


  7             However, moderate and severe congenital


  8   heart disease--the incidence of those is


  9   approximately 6 per 1,000.  Those are patients that


 10   require some active management of their heart


 11   disease, and the incidence of 6 per 1,000 relates


 12   to the population of patients without excluding


 13   bicuspid aortic valve.  If you include bicuspid


 14   aortic valve, then the incidence increases to


 15   approximately 19 per 1,000 live births.


 16             [Slide]


 17             Here is a rundown of the types of


 18   congenital heart disease, and that is taken from


 19   that paper published in JACC and the numbers here


 20   are the median incidence per one million live


 21   births excluding non-stenotic bicuspid aortic


 22   valves and silent PDAs.  Also excluded are tiny


 23   ventricular septal defects.  Still, VSD or


 24   ventricular septal defect is the most common form


 25   of congenital heart disease, followed by several




  1   acyanotic congenital heart diseases.  Tetralogy of


  2   flow is the most common form of cyanotic congenital


  3   heart disease, followed by transposition of the


  4   great arteries.  If you look down here, at the


  5   bottom, all cyanotic congenital heart diseases


  6   account for approximately 1,270 per million of live


  7   births; all congenital heart disease, approximately


  8   7,600, which is close to the 8 per 1,000; and then


  9   bicuspid aortic valve being the commonest form of


 10   congenital heart disease.  However it manifests


 11   clinically oftentimes later in life.


 12             [Slide]


 13             Moving on to outcomes of congenital heart


 14   disease first looking at mortality, mortality has


 15   consistently decreased over the years.  This is a


 16   paper that originated here from the CDC, published


 17   in Circulation in 2001, showing the deaths per


 18   100,000, age adjusted, and showing a trend of


 19   declining overall mortality from congenital heart


 20   disease from 1979 through 1993.


 21             [Slide]


 22             When you look at age at death, then it


 23   turns out that 51 percent of the deaths occur in


 24   infants; additional 7 percent between 1-4 years of


 25   age.  So, the majority of deaths occur early in




  1   life and then it plateaus for several decades until


  2   it starts to pick up again in the elderly.  There


  3   are some racial differences with approximately 19


  4   percent higher mortality in Blacks compared with


  5   Whites, as found in that paper, and slight gender


  6   variations, as you can see from this graph.


  7             [Slide]


  8             This is data from Children's Hospital in


  9   Boston looking at the cardiac intensive care unit


 10   admissions--the blue bars here, from 1992 through


 11   2003.  Here, in red, is the overall mortality from


 12   all causes in cardiac patients.  This does not


 13   capture all deaths from congenital heart disease,


 14   nevertheless, the majority do occur in the cardiac


 15   intensive care unit and that is a relatively


 16   accurate representation of mortality in a large


 17   tertiary care acute care referral facility.  If you


 18   look at the numbers, about 14 years ago overall


 19   mortality was approximately 6 percent and that has


 20   decreased quite consistently in the last several


 21   years to somewhere between 2.5 and 2.8 percent for


 22   overall mortality.


 23             [Slide]


 24             Still, despite the overall decrease in


 25   mortality there are some pockets of resistance and




  1   there are certain types of lesions that are still


  2   at a high level of mortality.  I am just bringing


  3   as an example pulmonary vein stenosis which is


  4   nearly universally a fatal condition.  There are


  5   fortunately not too many similar conditions,


  6   nevertheless, there are some challenges in the


  7   field of pediatric cardiology even when it comes to


  8   mortality.


  9             [Slide]


 10             However, the majority of patients with


 11   congenital heart disease survive and the majority


 12   of the therapeutic interventions--surgeries,


 13   interventional catheterization, medical therapy--do


 14   not lead to cure.  Residual anatomical and


 15   functional abnormalities are very common in our


 16   patients.  Neurodevelopmental issues are of


 17   substantial interest, as well as social and


 18   insurability issues.


 19             [Slide]


 20             As survival of patients with congenital


 21   heart disease improved attention shifted from


 22   getting these patients alive out of the hospital to


 23   improving their functional, psychological and


 24   social outcomes.  These are just a few slides


 25   showing some of the work that has been done in that




  1   field.  This is from the circulatory arrest versus


  2   low flow cardiopulmonary bypass trial where


  3   patients with transposition of the great arteries


  4   were randomized into circulatory arrest versus low


  5   flow cardiopulmonary bypass, and this is the 8-year


  6   full-scale IQ results showing that in patients


  7   transposition in ventricular septum--their


  8   full-scale IQ is nearly normal as a group, whereas


  9   patients with transposition in ventricular septal


 10   defect who were randomized to the circulatory


 11   arrest arm actually as a group,had lower overall


 12   IQ.


 13             [Slide]


 14             There is similar data on patients after


 15   the Fontan operation, again showing full-scale IQ


 16   verbal and performance tests, and showing that


 17   overall these patients are doing nearly as well as


 18   the normal population.


 19             [Slide]


 20             Here is a group that doesn't do as well,


 21   albeit a small group of patients with interrupted


 22   aortic arch.  Their performance is sub-normal in


 23   all levels of tests.


 24             [Slide]


 25             It is interesting to compare patients with




  1   congenital heart disease to other pediatric


  2   patients with different problems.