FOOD AND DRUG ADMINISTRATION

 

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PEDIATRIC ADVISORY COMMITTEE

 

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WEDNESDAY,

MARCH 22, 2006

 

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            The conference convened in Salons A, B, C, D of the Hilton Washington D.C. North, 620 Perry Parkway, Gaithersburg, Maryland, 20877, at 7:30 a.m., pursuant to notice, Robert M. Nelson, M.D., Ph.D., Chair, presiding.

 

COMMITTEE MEMBERS PRESENT:

 

ROBERT M. NELSON, M.D., Ph.D., Chair

JAN. N. JOHANNESSEN, Ph.D, Executive Secretary

DENNIS M. BIER, M.D., Member

ROBERT S. DAUM, M.D., Member

ANGELA DIAZ, M.D., M.P.H., Member

DEBORAH L. DOKKEN, MPA, Member

ELIZABETH GAROFALO, M.D., Industry Representative

RICHARD L. GORMAN, M.D., Member

MELISSA M. HUDSON, M.D., Member

JOHN W. M. MOORE, M.D., M.P.H., Member

THOMAS B. NEWMAN, M.D., M.P.H., Member

JUDITH R. O'FALLON, Ph.D., Member

MARSHA D. RAPPLEY, M.D., Member

 

VOTING CONSULTANTS:

 

JORGE ARMENTEROS, M.D.

PAULA KNUDSON

LAUREL K. LESLIE, M.D., M.P.H.

CYNTHIA PFEFFER, M.D.

DANIEL S. PINE, M.D.

BENEDETTO VITIELLO, M.D.

ROBERT WARD, M.D.

FDA STAFF PRESENT:

 

PAUL ANDREASON, M.D.

GERALD DAL PAN, M.D., M.H.S.

SOLOMON IYASU, M.D., M.P.H.

ROSEMARY JOHANN-LIANG, M.D.

TOM LAUGHREN, M.D.

DIANE MURPHY, M.D.

ROSEMARY ROBERTS, M.D.

ROBERT TEMPLE, M.D.

 

PRESENTERS:

 

A.J. ALLEN, M.D., PH.D.

ERIC COLEMAN, M.D.

SUSAN MCCUNE, M.D.

DAVID GRAHAM, M.D., M.P.H.

KATHERINE GELPERIN, M.D., M.P.H.

LARRY GRYLACK, M.D.

ANDREW MOSHOLDER, M.D., M.P.H.

HARI SACHS, M.D.

 

ALSO PRESENT:

 

FREDER BAUGHMAN, JR., M.D.

JACQUELINE BESSNER

SEN. CURTIS BRAMBLE

PETER BREGGIN, M.D.

LAWRENCE DILLER, M.D.

MOIRA DOLAN, M.D.

GLEN ELLIOT, PH.D., M.D.

DAVID FASSLER, M.D.

SAM GOLDSTEIN, PH.D

LAWRENCE GREENHILL, M.D.

TODD GRUBER, M.D., M.P.H.

BARBARA HAWKINS

GRACE JACKSON, M.D.

WINNI JOHNSON

SHARON KEINTZ

THOMAS KOBYLSKI

CLINTON LIBBY

CHRISTINE LIMBERS

ELLEN LIVERSIDGE

KENDRICK MOXON

 

ALSO PRESENT: (CONT.)

 

TAMAR OSTERMAN

JIM PAICOPOLOS

JUDITH RAPPOPORT, M.D.

DUBOSE RAVENEL, M.D.

DARREL REGIER, M.D., M.P.H.

ALDELAIDE ROBB, M.D.

GAYLE RUZICKA

VERA SHARAV

LEE SPILLER

DAVID STEIN, PH.D

L. READ SULIK, M.D., FAAP

THOMAS SULLIVAN, M.D.

JAMES SWANSON

W. DOUGLAS TYNAN, PH.D.

CYNTHIA WAINSCOTT

KATY WARREN

CAROL WATKINS, M.D.

BRUCE WISEMAN

JULIE ZITO, PH.D

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

                    A G E N D A

 

CALL TO ORDER, INTRODUCTIONS ................... 7

 

      Robert Nelson, M.D., Ph.D. (Chair)

 

CONFLICT OF INTEREST STATEMENTS ............... 10

 

      Jan Johannessen, Ph.D.

 

COMMITTEE ROLE IN BPCA SAFETY REVIEWS ......... 12

 

      Solomon Iyasu, M.D., M.P.H.

 

CLOFARABINE (Clolar), IRBESARTAN (Avapro), SIBUTRAMINE

(Meridia) ..................................... 21

 

      Larry Grylack, M.D.

      Alan Shapiro, M.D.

      Eric Colman, M.D.

      Hari Sachs, M.D.

 

OPPORTUNITY FOR SPONSOR COMMENTS AND RESPONSE TO

COMMITTEE QUESTIONS ........................... 43

 

      Sponsors

 

 

OVERVIEW OF ADHD PORTION OF THE MEETING

INTRODUCTION OF QUESTIONS FOR THE COMMITTEE ... 52

 

      Dianne Murphy, M.D.

 

NEW PHYSICIAN LABELING: Where is the Safety Information? 59

 

      Rosemary Roberts, M.D.

 

SUMMARY OF JUNE 2005 PAC

INTERIM ACTIONS AND LANDMARK EVENTS ........... 71

 

      Paul Andreason, M.D.

 

                    A G E N D A

 

GENERAL OVERVIEW OF RECENT DsaRM MEETING ...... 83

 

      Marsha Rappley, M.D.

 

BREAK.......................................... 86

 

EFFICACY OF PHARMACOLOGICAL TREATMENT OF ADHD 86

 

      Benedetto Vitiello, M.D.

 

ADDERALL XR - BPCA REVIEW .................... 101

 

      Susan McCune, M.D.

 

USE OF DRUGS FOR ADHD IN THE U.S. ............ 121

 

      Andrew Mosholder, M.D., M.P.H.

 

CARDIOVASCULAR RISK WITH DRUG TREATMENTS OF ADHD:

OVERVIEW OF AVAILABLE SAFETY DATA IN CHILDREN 130

 

      Kate Gelperin, M.D., M.P.H.

 

ADHD DRUGS AND CARDIOVASCULAR OUTCOMES:

PRELIMINARY FEASIBILITY RESULTS AND POTENTIAL

OBSERVATIONAL STUDIES ........................ 144

 

      David Graham, M.D., M.P.H.

 

PSYCHIATRIC ADVERSE EVENTS IN ADHD

CLINICAL TRIALS .............................. 157

 

      Andrew Mosholder, M.D., M.P.H.

 

PSYCHIATRIC ADVERSE EVENTS WITH DRUG TREATMENTS OF ADHD:

REVIEW OF POSTMARKETING SAFETY DATA IN THE

PEDIATRIC POPULATION ......................... 171

 

      Kate Gelperin, M.D., M.P.H.

 

CLARIFICATION QUESTIONS ...................... 190

 

                    A G E N D A

LUNCH ........................................ 211

 

OPEN PUBLIC HEARING .......................... 211

 

SPONSOR PRESENTATIONS ........................ 328

 

BREAK ........................................ 362

 

REVIEW OF COMMITTEE QUESTIONS

COMMITTEE QUESTIONS AND DISCUSSION ........... 362

 

      Robert Nelson, M.D., Ph.D. (Chair)

 

ADJOURN

               P-R-O-C-E-E-D-I-N-G-S

                                       (7:34 a.m.)

            DR. NELSON:  Good morning.  Welcome to the meeting of the Pediatric Advisory Committee.  I'm Dr. Nelson, the Chair, and I'll turn it over to Jan to start our business.  We'll do introductions first. 

            As a quick reminder, you have to push the mic on and off. Let's start with introductions.  We can start down at this end, and keep them brief.

            DR. GAROFALO:  Yes.  I'm Dr. Elizabeth Garofalo.  I'm the Industry Representative, and I am an independent consultant.

            DR. GORMAN:  Dr. Richard Gorman, pediatrician in private practice, and the representative of Professional Healthcare Organizations.

            DR. LESLIE:  Laurel Leslie, Behavior and Developmental Pediatrician at Children's Hospital, and a Health Services Researcher.

            DR. VITIELLO:  Ben Vitiello, National Institutes on Mental Health.

            MS. KNUDSON:  Paula Knudson, Community Representative, IRB Administrator, University of Texas Health Science Center - Houston.

            DR. WARD:  Dr. Bob Ward, University of Utah, I'm a Neonatalogist and Pediatric Clinical Pharmacologist.

            DR. PINE:  Danny Pine.  I'm a Child Psychiatrist from the National Center of Mental Health.

            DR. O'FALLON:  Judith O'Fallon, retired statistician from the Mayo Clinic.

            MS. DOKKEN:  Deborah Dokken, Patient Family Representative.

            DR. DAUM:  I'm Robert Daum, Pediatric Infectious Diseases from the University of Chicago.

            DR. DIAZ:  Angela Diaz, Director of Mount Sinai Adolescent Health Center in New York City.

            DR. MOORE:  John Moore, Pediatric Cardiologist, University of California - Los Angeles.

            DR. NELSON:  Robert Nelson, Pediatric Care, Children's Hospital in Philadelphia.

            DR. JOHANNESSEN:  Jan Johannessen, Executive Secretary, Pediatric Advisory Committee.

            DR. RAPPLEY:  Marsha Rappley, Developmental and Behavioral Pediatrics, Michigan State University.

            DR. HUDSON:  Melissa Hudson, Pediatric Hematology Oncology, St. Jude Children's Research Hospital.

            DR. BIER:  Dennis Bier, I'm a Pediatric Endocrinologist and Nutritionist from Baylor College of Medicine in Houston.

            DR. NEWMAN:  Tom Newman, Child Pediatrician and Professor of Epidemiology and Biostatistics in Pediatrics at UCSF.

            DR. MURPHY:  Diane Murphy, Pediatrician, Office of Pediatric Therapeutics, FDA.

            DR. LAUGHREN:  Tom Laughren, Division of Psychiatry Products at FDA.

            DR. ANDREASON:  Paul Andreason, Division of Psychiatry Products, FDA.

            DR. DAL PAN:  Gerald Dal Pan, Division of Drug Safety, FDA.

            DR. ROBERTS:  Rosemary Roberts, Pediatrician, Office of Counter-Terrorism and Pediatric Drug Development. 

            DR. IYASU:  Solomon Iyasu, Division of Pediatric Drug Development at FDA.

            DR. NELSON:  Thank you, and I'll turn it over to Jan for the Conflict of Interest Statement and Introductions.

            DR. JOHANNESSEN:  Thank you and good morning.  The following announcement addresses the issue of Conflict of Interest with regard to today's discussion of a report by the Agency on Adverse Event Reporting as mandated in Section 17 of the Best Pharmaceuticals For Children Act for Clofarabine, Irbesartan, Sibutramine, and the mixed salts Amphetamine Product, and two, discussion and reports on Neuropsychiatric and Cardiovascular adverse events possibly related to other approved ADHD medications.  This statement is made part of the record to preclude even the appearance of such at this meeting.

            Based on the submitted agenda for the meeting, and all financial interests reported by the Committee participants, it has been determined that all interested firms regulated by the Food and Drug Administration present no potential for an appearance of conflict of interest at this meeting.  In the event that the discussions involve any other products or firms not already on the agenda for which an FDA participant has a financial interest, the participants are aware of the need to exclude themselves from such involvement, and their exclusion will be noted for the record.

            We note that Dr. Jorge Armenteros, Dr. Laurel Leslie, Dr. Cynthia Pfeffer, Dr. Daniel Pine, Dr. Ben Vitiello, Dr. Robert Moore are participating in the meeting as Voting Consultants, and that Paula Knudson is participating as the Acting Voting Consumer Representative.  We would also like to note that Dr. Elizabeth Garofalo has been invited to participate as a Non-Voting Industry Representative, acting on behalf of regulated industry.  Dr. Garofalo is an Industry Consultant.  Dr. Richard Gorman is participating as the Non-Voting Pediatric Health Organization Representative acting on behalf of the American Academy of Pediatrics.  With respect to all other participants, we ask in the interest of fairness that they address any current or previous financial involvement with any firm whose product they may wish to comment upon.  Thank you.

            DR. NELSON:  So while Solomon is making his way to the podium, let me just make a quick comment. You'll notice, members of the Committee, that we don't have a lot of time for questions.  I'm going to ask that as these presentations are being done, you write down your questions on the assumption that maybe they'll be answered by the next speaker, rather than taking time after presentations, and then we'll hopefully get done what we need to get done in an efficient manner.  And I'm also going to ask the FDA folks to try and stay on time, as well, since we'll be expecting that from everybody.  Solomon.

            DR. IYASU:  Good morning.  I'm going to introduce the Adverse Event reporting under BPCA.  This will be the subject of discussions for the first one hour, and then later, as well.  As you know, we've done several of these presentations in the past.  Almost 50 drugs have been reviewed under BPCA.  Of course, this activity is mandated under Section 17 of the Best Pharmaceuticals for Children Act, which mandates that for drugs that have been given exclusivity, that during the one-year period after exclusivity, any reports of postmarketing adverse events would be reviewed and then presented to this Committee for their review and any recommendations.

            Of course, most of the reports that we are mandated to discuss here come from the database of all adverse event reports that were received by the FDA.  This has a long history which started in 1969; it has almost more than two million reports.  This database contains hundreds of export drugs and therapeutic biologic products, with the exceptions of vaccines. 

            As you know, this is a spontaneous voluntary system.  Most of the reports come from manufacturers, but there are also reports that come from healthcare professionals, consumers, and patients.  More than 90 percent of all those reports that we have in the AER system come from manufacturers, because they're required under the law.

            Just to give you some background, the definitions that we use for such reports is defined under the law.  It does not require that the reporting needs to be -- that the adverse event needs to be causally related and proven before reporting.  Any adverse event, whether or not considered drug-related, is to be reported to the AER system, so I think accidents, intentional overdose, any adverse events occurring from abuse or drug withdrawal calls for action.

            Also, to just update the Committee, and for those who are new to this area, unexpected adverse drug event is also defined under the law, and it's defined as an event not listed in the current labeling for the drug product, including events that may be symptomatically or pathophysiological related to a labeled event, but differ because of greater severity or specificity.

            Again, there is a regulatory definition, just to give you some background, that a serious adverse event is any event occurring at any dose that results in any of the following outcomes, and these outcomes are death or life-threatening adverse event, hospitalization, or prolonged additional hospitalization, persistent or significant disability or incapacity, any congenital anomaly or birth defects, or others that may require some intervention, so there is a regulatory definition for serious adverse event.

            Of course, one has to assess these reports as they come, and there are many factors that effect whether there's a causal relationship between a report  and the assessment.  And key among these factors that we have to look at FDA are whether there is a temporal relationship between the event and the drug, that the event occurred after the drug is a strong indicator that there might be some relationship.

            If we have, of course, information about those events regarding the challenge or re-challenge, meaning that the AER or the adverse event subsides when a drug is discontinued, or it reappears when a drug is re-administered, is also suggestive of a relationship.  If we see a dose response in this report, that's also another suggestive information that might help us understand whether there's a causal relationship or not.

            Again, we look at the biologic plausibility, looking at prior knowledge about the PK and the pharmacokinetic actions of these drugs.  We also look at animal clinical studies, and any laboratory evidence that may be part of the report that we get.

            Another factor that we look at is whether there is a known class effect, that a drug belongs to a class of drugs that has been proven to have a certain effect that we're looking at.  And very important consideration has to be given also to underlying disease and concomitant drugs, because many of these reports that we get are highly confounded by underlying disease that may be exhibiting the same adverse event that we're looking at.

            Now there are several strengths and also limitations to the AER's database, so when we look at postmarketing reports, one has to be very careful  that it includes all drugs that are marketed in the United States, and, therefore, it's a very large sweep of what's going on.  A simple, inexpensive system provides for mostly early detection of safety signals, especially if they are rare adverse events that are serious.  For example, anaphylaxis, liver failure, or plastic anemia, and serious events like that. 

            There are also some important limitations.  Under-reporting is one of the key limitations of the system because they are spontaneous reports.  And the extent of under-reporting may vary from drug-to-drug and over time.  The quality is variable, and because the numerator, which is events, uncertain in terms of numbers, the denominator also in terms of exposure is also uncertain, so often it's very difficult to quantify the risk of these drugs with respect to adverse event.

            Now often the gold standard for looking at causality between an adverse event and a drug is the randomized control trials.  They are, of course, the best for establishing causality and provide a non-biased estimate of the risk of a particular drug with respect to a suspect drug.  So especially very important to have comparative data from these kind of studies to assess when the events under consideration have a high background rate.  But, of course, RCTs also have their own limitations.  They often are short in duration, and thus have a very small sample size and, therefore, they may not pick up rare adverse events.  And often we pool safety data across many different randomized trials to improve the precision and power to detect such events.  But, of course, there are limitations to doing that because the different RCTs that we pull together may have different methodologies that may limit our ability to detect some of the events. 

            And also, another important feature is that RCT's have this more or less select population, and are homogenous, and what you would expect to see in daily clinical practice; therefore, it drives the ability of the risk estimates that we get from RCTs may not apply to daily patient population.  Therefore, there are some limitations even to RCTs.  Of course, not finding an association from an RCT does not rule out the safety issue when you have a preponderance of reports, so it's a vicious cycle that you have to --if you don't get information that is confirmatory, and have you have a preponderance of reports, then you have to be concerned.

            Therefore, today we'll continue our practice of presenting the adverse events under BPCA, and we'll provide you a review of the safety events during the year.  And as appropriate, we'll also look prior to the one-year period that's mandated by BPCA to review the adverse events that are reported to FDA when it's warranted, and that we have some serious adverse events prior to the one-year. 

            We also provide you information on the drug use of the particular drug that we're looking at, first for out-patient, as well as for in-patient use.  We also, for context, provide you a summary of the clinical, pharmacology, toxicology reviews of the exclusivity studies.  We provided the drug label, published literature, responsive materials, and presentations, so that you have a comprehensive set of information to look at.

            As we've done in the past, we'll have -- some drugs are going to be discussed in an abbreviated fashion when there's no new safety concern, some are going to be standard presentation when there are unlabeled new safety concerns, and then we'll have drugs that have in-depth presentation, because there is a safety concern that we'd like you to look at.

            Today we have four drugs that are scheduled for BPCA safety review.  Clofarabine and Irbesartan will have an abbreviated report, because we don't feel that we have concern regarding safety for these two drugs, just from the review that we've done.  Sibutramine will have a standard presentation.  We'd like to give you a little more, because there's been extensive reviews of cardiovascular, as well as fetal toxicity effects of these drugs and, therefore, we'll have two presentations on this so that we have a comprehensive history of what the state of knowledge is about Sibutramine regarding these two issues.

            And then the last drug that will be discussed today on the schedule out of BPCA is Adderall, mixed amphetamine drug.  It's providing an in-depth presentation of this as part of the post exclusivity -- as part of the session on the entire safety concern of all ADHD medications later today.

            I'd like to acknowledge the many offices that have helped with all these reviews, and our first presentation, I'll just get right to it, will be on Clofarabine.  Dr. Larry Grylack from the Pediatrics Division will present adverse event reviews for Clofarabine.  Dr. Grylack has been a medical officer in the FDA for more than three years.  Dr. Grylack.

            DR. GRYLACK:  Thank you, Dr. Iyasu.  It's an honor to be here again this morning presenting to the Advisory Committee, and apologies to the residents of the Pacific and Mountain time zones for the early hour.  This is an abbreviated presentation of the Adverse Event Review for Clofarabine.  The drug is marketed as Clolar for intravenous injection.  Its therapeutic category is anti-neoplastic in the sub-category of purine nucleoside anti-metabolite.  The sponsor is Genzyme Corporation.

            The indication in the Clolar label is the treatment of patients 1-21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens.  Pediatric exclusivity was granted for Clolar in patients 1-21 years of age on July 14^th, 2004, which was prior to the marketing approval date of December 28^th, 2004.  Of note is that Clolar did not have prior marketing approval for any age.

            The in-patient, out-patient, and sales databases used by the FDA document no use of Clofarabine.  Also, the Children's Oncology Group database reported no usage.  The sponsor estimates 200-300 uses per year.

            The FDA Office of Drug Safety's Adverse Event Search covered the period from the time of market approval, December 28^th, 2004, until August 14^th, 2005, which was the one-year post-exclusivity date.  There were 12 unduplicated pediatric adverse event reports, eight of which were domestic reports.  Of the 12 reports, four were deaths, and five were hospitalizations.

            Details of the four deaths that occurred in patients receiving Clofarabine during the exclusivity review period are presented on this slide.  One patient suffered a cardiac arrest after an episode of  aspiration and treatment with airway suction occurring 48 hours after the fifth dose of Clofarabine.  The patient had a history of cardiac dysfunction, and post-mortem exam revealed cardiac fiber hypertrophy.

            The second death was associated with tumor lysis syndrome, resulting in multi-organ failure one day after the start of Clofarabine treatment.  The third death was described as being caused by progressive disease one month after the diagnosis of capillary leak syndrome occurring within 24-hours of the first dose of Clofarabine.  The fourth death reported was due to a cardiac arrest associated with an error in medication not being used for the treatment of the leukemia.  This death occurred seven weeks after treatment with Clofarabine.

            This completes the post-exclusivity adverse event reporting as mandated by the Best Pharmaceuticals for Children Act.  Most adverse events are currently labeled or would not be unexpected in association with a disease, or with the concomitant treatments received by the patients.  The Food and Drug Administration recommends routine monitoring of Clofarabine for adverse events in all populations.  We would like to know whether the Pediatric Advisory Committee agrees.

            Finally, I'd like to acknowledge all of these individuals from the Office of Drug Safety, Office of New Drugs, and the Office of Clinical Pharmacology Biopharmaceutics who provided reports which contributed to my presentation today.  I would also like to acknowledge Denise Pica-Bronco who has admirably filled Kristin Fucas' role of coordinating our Advisory Committee presentations within the Division of Pediatric Drug Development.  Thank you for your attention.

            I would like to next introduce one of my colleagues, Dr. Alan Shapiro.  Dr.  Shapiro is a Pediatric Infectious Disease Specialist with a Ph.D. in Biochemistry.  His past research includes work in immunology, infectious diseases, and molecular pharmacology.  He has also had training in Pediatric Nephrology and Medical Genetics.  Dr. Shapiro has been with the Division of Pediatric Drug Development for over two-years working as a medical officer.  Really, the FDA should give him more than two-years credit considering all his many talents, training aspects.  Dr. Shapiro.

            DR. SHAPIRO:  Thank you, Larry.  Now I'd like to discuss the adverse events for Irbesartan.  Irbesartan, also known as Avapro, is an anti-hypertensive in the Angiotensive II receptors class.  Its sponsor is Sanofi-Synthelab.  Its indication is for the treatment of hypertension alone or with other anti-hypertensive agents, also for the treatment of diabetic nephropathy in patients with type II diabetes and hypertension.  Its original market approval was September 30^th, 1997, and exclusivity was granted on September 16^th of 2004. 

            To summarize, no pediatric adverse events were reported to AERS during the year following exclusivity.  We did find a raw count of four adverse events, three serious, since market approval.  When we did a hands-on review of these adverse events, we only found one unique adverse event report.  That consisted of a patient with urticaria and erthema multiforme minor in a seven year old clinical trial participant who had a vial respiratory infection.  Urticaria and hypersensitivity are described in the product label.