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 14th, 2004, which was prior to the marketing approval date of December 28th, 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 28th, 2004, until August 14th, 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 30th, 1997, and exclusivity was granted on September 16th 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.

            Okay.  The use of Irbesartan in pediatrics is small, only about 3-4,000 prescriptions per year, and represents only 0.1 percent of the total prescriptions.  Now going on to the clinical trials.  In the dose ranging trial, pediatric patients with hypertension done for pediatric exclusivity, the sponsor failed to show a dose response relationship.  Only a small treatment effect on blood pressure during the randomized placebo controlled withdrawal phase of the trial was observed.

            Based on these studies, Irbesartan does not appear to be useful in the treatment of hypertension pediatric patients aged six years and above, despite receiving doses that are equivalent to a plasma concentration seen in adults. 

            Going on to the history of the pediatric exclusivity for Irbesartan, a written request was issued in 1998, and then we received a submission of pharmacokinetic data in February of 2000, which resulted in a labeling change in May of 2001. 

            Final submission of exclusivity studies in 2004 resulted in a proposed labeling revision in October of 2004 that would remove the pharmacokinetic data from the label because the pediatric indication was not approved. I should mention that this labeling change is now in the final process of being finalized.

            Now to conclude, this summary of Irbesartan of adverse event reports is presented in abbreviated format, that there are no concerning safety signals.  The use in the pediatrics population is small, and with a few adverse events reports.  This completes the adverse events reporting as mandated by BPCA.  The FDA recommends routine monitoring of Irbesartan for adverse events in all populations.  Does the Advisory Committee concur?

            I'd like to acknowledge members of the Office of Drug Safety, and the Office of New Drugs for their help in preparing this presentation and for their guidance.  Thank you.

            DR. NELSON:  Should we go ahead to the Sibutramine?

            DR. IYASU:  Yes.  The next presentation is adverse event reports for Sibutramine.  There are two presenters. Dr. Eric Coleman, who is from the Division of Metabolic and Endocrine Drug Product; his background includes residency training in internal medicine, and fellowship training in the areas of metabolism and nutrition.  He joined the Division in 1995, and has been a medical team leader since 2000.  And the second presenter is Dr. Hari Sachs.  Dr. Hari Sachs is a Medical Officer in the Division of Pediatric Drug Development.  She is a Clinical Professor at George Washington University, and continues to practice pediatrics.  And both these presentations will be on Sibutramine.  First, Dr. Eric Coleman.

            DR. COLEMAN:  Thank you and good morning.  I'm going to spend about 10 minutes to give you a very brief overview of the regulatory history of Sibutramine, with a focus on the agency's response to a citizen's petition that was filed back in the spring of 2002. 

            Sibutramine is trade-named Meridia, and this is a norepinephrine and serotonin reuptake inhibitor that was approved for the treatment of obesity in adults in 1997.  In trials of one-year duration, the placebo subtracted weight loss was roughly 3-5 percent, and the principal safety concern with Sibutramine has always been its effects on blood pressure and pulse.  The average changes in blood pressure are on the order of 1-3 millimeters, certainly not staggering, but there are subsets of patients who experience much larger increases in blood pressure and pulse. 

            Because of this concern, when the drug was approved, the labeling did include warnings that the drug could substantially increase blood pressure in some patients.  And, therefore, all patients treated needed to have regular monitoring of their blood pressure and pulse.  Furthermore, given that the drug does have some pathomimetic properties, it was recommended that patients with a history of coronary artery disease, stroke, arrhythmia, CHF, not receive the drug. 

            In June of 1999, the agency issued written requests for pediatric studies. One was a standard pharmacokinetics investigation, and the other was a 12-month placebo controlled trial, which I believe you'll hear more about from Dr. Sachs.  Briefly, this study involved 450 adolescents with body mass indices of at least two units above the mean for the 95th percentile.  The primary efficacy end-point was a change in BMI.  And again, given the concerns about the blood pressure and the pulse, there were subgroups of patients who underwent ambulatory blood pressure monitoring, as well as echo cardiography evaluation.

            Skipping to a different topic, in March of 2002, the Italian Ministry of Health temporarily suspended the marketing license for Sibutramine because of the death of a second young woman who was taking the drug for weight loss.  Shortly after that in this country, FDA received a citizen's petition requesting that we take the drug off the market due to its unfavorable cardiovascular profile.  And a year or so after that, that petition was supplemented with another petition that said there may be concern for fetal toxicity, so we addressed these two issues the best we could, and I'll discuss that.

            Before I get to that, the Europeans, at least in this case, were much quicker than we were.  In June of 2002, just three months or so after the original event in Italy, the EU regulators got together and re-evaluated the available data, and concluded that the risk benefit profile for Sibutramine was still favorable, and they recommended that the drug be re-instituted back in Italy, which it was.  Meanwhile, back here reviewers from metabolic and endocrine were working with reviewers from the Office of Drug Safety, focusing on reports in AERS that had to do with cardiovascular toxicity and fetal toxicity. 

            Our first focus was to look at the number of deaths in AERS.  That certainly is the most objective end-point.  And from the time frame, November of `97 through August of 2003, there were a total of 54 domestic deaths reported to AERS.  Thirty of these deaths apparently involved a cardiovascular event.  I've showed this figure because I think it tells you quite a bit.

            This shows the reports to AERS on the Y Axis by calendar year, and quarter of calendar year.  And you can see that the reports of death to AERS were relatively high the first two years post-marketing, and then there's a rather dramatic decrease in the number of reports.  And then you see this staggering increase in 2002.  It turns out this coincides with the negative publicity that surrounded the activity in Italy, and in this country.  The numbers gradually decrease down after this, but this is not an unusual finding when there's a lot of press about a drug.  There were quite a few lawyer-driven reports in here, I would imagine. 

            Turning to cardiovascular events, we again focused our attention on serious, non-fatal cardiovascular events, same time period - 1997 through 2003.  There were a total of 224 domestic non-fatal CVD events.  These events were many and varied.  I've listed some here, viral cardiomyopathy, MI, A-Fib, hypotension, cardiac valve disease, just to name five.  The important thing to remember is the reporting pattern for these events was very similar to the pattern for deaths.  The rates were highest in the first two years after marketing, which is not unexpected.  There was a dramatic decrease after that.  And then following the negative publicity, we see a major spike in the reports of events.

            Now as many of you know, passive drug safety surveillance systems, such as AERS, are most reliable for picking up serious previously unrecognized rare events.  Aplastic anemia would be a good example.  These systems are not well suited, however, to assessing whether a drug increases the risk for commonly occurring adverse events in the population for which the drug is approved.  And this is clearly the case we are in with Sibutramine and cardiovascular disease.  Given that the drug does have some patho medic properties, it's not inconceivable that it would increase some people's risk for cardiac disease.

            At the same time, obesity itself is a risk factor for cardiovascular disease, so trying to determine causality from a database like this is extremely difficult, if not impossible.  Fortunately, there is an ongoing trial called the Sibutramine Cardiovascular Outcome Study, or SCOUT, which is a randomized placebo-controlled trial involving roughly 9,000 obese patients who are at high risk for cardiovascular events.  And weight loss and CVD events are two of the primary outcomes of interest.  This is an event-driven trial, so it's difficult to say when it would be completed, but it may take up to five years.  But if it is successfully completed, it will no doubt provide the rigorous assessment of Sibutramine's safety profile.

            Just quickly turning to fetal toxicity, again, the folks in ODS combed through AERS looking for terms that could be related to fetal toxicity.  The time span for that search was November of `97 through October of 2004.  There were a total of 34 domestic reports of pregnant women exposed to Sibutramine, and of those 34, five were actually reported as specific birth defects, three of which were involving the cardiovascular system. 

            Now we know from the pre-clinical data that were conducted, the trials conducted, studies conducted before the drug was approved, that there was no signal to suggest that Sibutramine was toxic to the fetus or that it was teratogenic, so we do have animal data going back before the drug's approval that does not raise any suspicion that this would be a problem.  We also did a literature search, and found a handful of reports where women had been exposed to Sibutramine during pregnancy, and they reportedly delivered healthy infants.  So all together, we felt that Sibutramine's current pregnancy Category C was an appropriate designation that did not need to be changed based on the information that I just discussed, and I show you here the actual language from the Sibutramine labeling.

            And finally, although the Agency denied the citizen's petition to take the drug off the market, during the review process we did note, and this is not unexpected, that there were patients who reported cardiovascular events, who apparently had a history of heart disease, or arrhythmia, or stroke, and clearly those are not the people that you would want taking this drug.  So Abbott Laboratories, the manufacturer of Sibutramine, did implement some risk management steps to try to enhance more appropriate use of the drug.  And these measures, again, were geared towards reinforcing the need to monitor blood pressure and pulse in all patients who take the drug, and also to try to limit its use in patients with known coronary artery disease.  I won't go through this list, but again, this lays out the time-line and some of the actual steps that were taken involving labeling changes, Dear Healthcare letters, doctors, and some alterations in the way the medication is supplied, so that people are less likely to get multiple months of drug at one time, and I think I'll leave it at that.

            DR. SACHS:  Good morning, everybody.  Sibutramine, or trade-name Meridia, is an anti-obesity agent that's marketed by Abbott.  It was originally approved in 1997, and exclusivity was granted in 2004 for trials in adolescents.  The mechanism of action is similar to that of SSRIs.  This is a norepinephrine, serotonin, and dopamine reuptake inhibitor, and that becomes real important.  Indicated for the treatment of obesity in adults, along with appropriate diet for patients with a body mass index over 30, or for a lower BMI if there is risk factors, such as diabetes, or dyslipidemia, uncontrolled hypertension that are present.  The adult dosage, as Eric mentioned, was 5-15 milligrams per day. 

            Now as Dr. Coleman has shown you, there's been a lot of review of both the efficacy and safety of Sibutramine, starting with an Advisory Committee in 1996, and some reviews by the Office of Drug Safety for cardiovascular and fetal toxicity.  This was actually updated again in 2004, and that brings us to today where we'll look at the adverse events once again, specifically in pediatrics. 

            To put that in a little context, we're going to look quickly at the use.  And prescriptions for this class of agents has actually been decreasing over the past three years.  Sibutramine use accounts for about 10 percent of the total drug use, of which only 1 percent is pediatric, approximately 4,000 prescriptions.  Most of the use in children is in adolescents with the diagnosis of polycystic ovaries or obesity. 

            We're going to look real quickly at the trials that were performed for exclusivity.  And there were two trials, pK and safety study, and an efficacy and safety study.  The pK study was a single-dose study that was performed in a sub-population of about 90 adolescents.  It found that the pK parameters for Sibutramine and the active metabolites were similar really to that of - between adults and adolescents.  The efficacy trial was a placebo-controlled trial of obese adolescents that had appropriately elevated body mass index.  The primary end-point for the trial was the absolute change in body mass index. 

            When the trial was actually reviewed in detail, the zero height measurements revealed that there might be some concerns about the reliability or accuracy of the height measurements, since approximately 12 percent of patients lost height.  And for that reason, since the height is so essential for determining the body mass index, and that's the primary end-point, it was felt there was no conclusions that could be drawn from the trial, and the labeling was changed to show that data are inadequate to recommend use in adolescents.

            Now when you think of this, please remember when we look at the trials for exclusivity, that is done before there is a really in-depth review of all the data.  The trial, as Dr. Coleman mentioned, looked at cardiovascular safety.  There was ambulatory blood pressure measurements performed on a subset of adolescents, and despite the fact that the patients did not get medication on the day of treatment, there was a modest increase in blood pressure noted, as well as an increase in treatment emergent hypertension.  But as you've heard, there is a bolded warning in the label which states that there can be a substantial increase in blood pressure and heart rate in most patients, and the need to monitor patients that are having therapy.  The echocardiography findings did not raise any concerns or detect any valvular anomalies in the over 100 patients that it was performed on. 

            Now since this agent is related to the SSRIs, there were some psychiatric adverse events noted in the trial, and so labeling was changed to reflect that there may be a potential risk of psychiatric adverse events, and the mechanism of action and the need to monitor patients is detailed.  So as a result of the studies performed for exclusivity for pediatric use, section has been changed.  This is the labeling in full, and it briefly says that the efficacy in adolescents who are obese has not been adequately studied.  There's data about the trial, the psychiatric adverse events, the need to monitor the patients, and then the labeling concludes that it is inadequate to recommend use.

            We'll look briefly at the safety labeling, which is pertinent for the pediatric patients and the adverse events that were seen since approval.  As I mentioned, there's a bolded warning about the potential risk of increased blood pressure and heart rate.  There's also a warning to avoid use in patients with cardiovascular risk factors, and to exclude secondary causes of obesity. 

            Cautions also describes that seizures might occur, and to use cautiously in patients with bleeding diathesis.  And as Dr. Coleman mentioned, this is a pregnancy Category C drug, which is based on the fact that there may be adverse effects on the fetus in animal studies, but there's limited data on this.

            Since market approval in 1997, there have been almost 6,000 total adverse events, of which 1,000 of these are serious, and 118 were deaths, although only five of these deaths were in pediatric patients.  Remember, these numbers include duplicates, and when we look at the data, we often find there's a lot of duplicated reports. 

            Now the five deaths in children were related, two of them were cardiac, and three of them were related to pre-term.  And as was mentioned, there was a very detailed analysis of all of the adverse events, including deaths, which didn't show a pattern.  There were 24 unduplicated serious non-fatal adverse events since market approval.  Nine of these were associated with overdoses.  There was one case each of Qtc prolongation, which occurred during the exclusivity period, and I'll talk about that momentarily.  One case of a seizure, non-insulin-dependent diabetes, granulomatous uyeitis.  And again, there were some congenital anomalies that were noted.  As we've mentioned, the underlying events you can see may not be specifically labeled, although some of them are certainly related to labeled events.

            Now during the pediatric exclusivity period, there were approximately 150 total reports, of which 140 were serious, and there were 18 deaths in all ages, but no pediatric deaths.  The one pediatric adverse event was a 14-year old patient who, during clinical trial, had Qtc prolongation.  He had a baseline abnormality on his EKG, but the Qtc did rise above 450. 

            So in conclusion, the labeling for this drug has been updated after the exclusivity studies.  The one-year review did not really reveal any new pediatric adverse events, or repeat pediatric adverse events.  There's been multiple reviews by the Office of Drug Safety and the Division, which doesn't really show any increased cardiovascular or fetal risk.  You've heard about the SCOUT study, which is ongoing, to formally evaluate the non-fatal and fatal cardiac events in patients.  And we propose monitoring this drug for one-year, just because there was only one event during exclusivity period, and a small number, if you all concur. 

            Once again, I'd like to thank all the folks who participate in these reviews.  There's a lot of folks behind the scenes. 

            DR. NELSON:  Thank you.  Do we have comments from sponsors?  Okay.  Hearing none, we have three questions, and why don't we just go through them one-by-one and address any particular questions that people may have.  And the first is for Clofarabine; the recommendation is routine monitoring.  So is there any discussion or questions?  Judith. 

            DR. O'FALLON:  I'm not sure whether I'm reading this correctly, but it looked to me like there's been only seven and a half months of observation since the thing went out on the market,  and that the Children's Oncology Group hasn't reported any yet who are on the study, so it seems to me that we have a small sample.  This is the one where the exclusivity occurred before the thing went out on the market by about five months, and I just wonder if that gives us a big enough sample.  That's the only issue.  It had a number of deaths, and so on.

            DR. GRYLACK:  You're correct, Dr. O'Fallon, about the unusual juxtaposition of the marketing approval and exclusivity.  As to whether that's a sufficient period of time, I can't say for sure.  I don't know whether anybody from the Office of Drug Safety or Oncology want to comment on that, but certainly that would be a concern, especially since the usage, and the usage is just an estimate by the sponsor at this point, is limited due to the nature of the indication.

            DR. O'FALLON:  This is a small sample issue, and if you're really looking for signals of rarer adverse events, the smaller the sample, the less chance you have of getting them.  That's what my concern is.

            DR. NELSON:  I guess it would be useful to know if COG has any plans to incorporate this in trials, because if they don't currently, then the usage is going to stay very low, and we may not know that at this point.

            DR. MURPHY:  We did talk to them.  Solomon, do you remember if they mentioned any -- because this very low use, we did call them to see if they had any additional data.

            DR. IYASU:  I think the information we got from them was currently there are no open studies, so they were not able to provide us information on use of this medication in pediatric patients.  So the only information we have about use is from the sponsors, which is an estimate based on the sales data that they have. 

            With respect to the question about the small sample size in AERS, when we say we're going to do additional monitoring or returning it to routine monitoring, it does mean that the Office of Drug Safety is going to monitor, just like for any adverse events for a long time, as far as the reports that are coming to the FDA.  The difference with other drugs that we've looked for an additional year is that we do even intense or in-depth look at the adverse events for an additional year, because we have a concern that is not being adequately answered by the numbers that we see in the AERS system, so it doesn't mean that it falls off the radar screen when we say we'll look at it.

            DR. NELSON:  Thank you, Solomon.  So let me just ask if there's anyone who would disagree with routine monitoring for this particular drug at this point, which routine is actually as intense as it always is.  In the interest of time, I'm not going to take a roll call.  I'll just note for the record that the only individuals, apart from the members of the Pediatric Advisory Committee, who are voting in this section are Paula and Bob, since the consultants for the ADHD portion have not been screened for conflict of interest surrounding these issues, for the record.  So I'll note that that is unanimous in agreement there.

            The next is the Irbesartan.  Any comments or discussion about that issue?  I'll just make one note about the label.  I know we've had discussions on this in the past about what information goes in when there is no pediatric indication.  I would ask that at least the FDA consider the possibility that the information on the top slide on page 18 be in the label, which is quite helpful to tell the pediatrician that, in fact, it's not been shown to be useful.  I know that at times putting negative data in labels is felt to sometimes suggest that people ought to use it, but I think that -- I doubt this information would be found anywhere else if it's not in the label.

            DR. SHAPIRO:  I'd like to comment on that.  The pharmacokinetic data is being pulled from the label, but in the proposed labeling it's going to say Irbesartan in a study at a dose of up to 4.5 milligrams per day once daily did not have a lower blood pressure effective in pediatric patients ages 6-16 years of age.  So essentially, there is going to be information in the label describing that it was studied and that it was not effective.  We're just pulling out the pharmacokinetic data because we don't feel -- it doesn't get the indication.

            DR. NELSON:  Well, thank you.  That clarifies it.  Bob.

            DR. TEMPLE:  That reflects a general commitment to put the negative results as they occur into the pediatric sections or the indication section.  One doesn't want to overstate the negative.  Sometimes absence of a positive doesn't really prove something, but it will say as truthfully as possible what's been found or not found.

            DR. NEWMAN:  Just to say that I didn't hear a mention of the sample size of the study going on the label, so probably the best thing to do would be to give the point estimate in the 95 confidence interval for the main effect on blood pressure, so the person reading the label can tell how much actual data there was addressing that question.

            DR. NELSON:  I seem to recall you make that point every meeting we have, Tom.  Any other comments on Irbesartan?  So I'll ask again the question, the negative, anyone who would disagree with returning this to routine monitoring?  So seeing none, I'll note that the vote is unanimous for that recommendation.  And now on to Sibutramine.  Comments, questions from the Committee?  Tom?

            DR. NEWMAN:  I notice that once again we have medication that was granted exclusivity based on a study that FDA on further review decided was inadequate.  And Dr. Sachs mentioned that the exclusivity decision was made before they reviewed the data in depth, but just I think this is troubling, and maybe they need to review the data in depth before they grant exclusivity, or revoke the exclusivity or something, but it does seem troubling to give exclusivity and then have the FDA say that the trial wasn't adequately done. 

            DR. MURPHY:  As you know, we recognize this issue, and we think that it is problematic.  And we can't revoke the exclusivity, and actually it's sort of, by the time you do it they've gotten most of what they need, so the issue is developing an approach which - in the re-authorization, maybe, Congress will reconsider that - where they could still get exclusivity even if there's a negative finding, but that we have more time before we have to make that assessment.  And I think the Europeans are moving in a direction in which they are going to have more time to do that, so I think it might be something for us to consider, also.

            DR. NELSON:  Other comments?  John.

            DR. MOORE:  One concern I have is related to  presumably this one slide that really talks about the results of adverse events in fetus.  Two of the adverse events are hypoplastic left heart syndrome patients, and just a quick calculation, I would expect one HLHS patient to arise in about 10,000 unselected pregnancies, so I'm wondering if this is something that is a concerning signal.  I don't know what the estimated use in pregnant women was.  I know it's warned not to use it in pregnancy, but I suspect that there may be an issue there, there could be.

            DR. NELSON:  Bob.

            DR. WARD:  John, I saw the same thing, but there are so many issues that I think also have to be addressed that may not be recognized about familial association of hypoplastic left heart, or Turner Syndrome, or things like that, that I think the current approach of continued intensive monitoring is more justified than taking an action on limited information presented here.  I also wanted a clarification.  I assume that myoplastic left heart syndrome is what we would refer to as hypoplastic left heart syndrome.  Is that correct?

            DR. SACHS:  This was a foreign report, and that's what it says, so I can't confirm that or deny it - don't know.

            DR. NELSON:  Well, for the purpose of our discussion, I would point out that the recommendation is, in fact, the monitoring continue at the higher level of scrutiny, so hopefully over time some of this will become clearer.  In the interest of time, I'd just ask if there is anyone who would disagree with continuing more intensive monitoring for this particular drug, which I assume would then come back to us at some point in the future with a report.

            DR. MURPHY:  I think if that is what you would wish, it might be helpful to say, based on X number of more cases or a period of time, just give us some idea, because you've done that in the past, of when you would like us to come back, if that's where you're going on this.

            DR. NELSON:  I mean, I guess I'm comfortable leaving that open to some judgment.  I mean, it depends when the SCOUT study is done and when data comes in.  I mean, some of it depends on the accumulation of data, which would be hard for me to say in the abstract, 12 months, 18 months, 24 months.

            DR. MURPHY:  That's the sort of thing I wanted you to say.  It's not a year or two years.

            DR. NELSON:  I'm sure Tom would want a confidence interval with perhaps some of -- 

            DR. MURPHY:  You want us to come back after we have additional data, particularly from the SCOUT and additional reporting that we think might help us assess this.

            DR. WARD:  Could we ask that any cardiovascular events be described in as much detail as possible, and maybe be investigated in more depth, especially as part of this SCOUT study.

            DR. NELSON:  Other comments?  So again I'll ask you in the negative, anyone have any objection to more intensive monitoring over the next year or two, depending upon as data comes in?  So I'll note that the vote is unanimous on that, as well.  And that brings us now to ADHD.  Diane.

            DR. MURPHY:  My task is to first take you back to June of last year, and then to bring you back to today, to help you transition to the focus on the  treatments for ADHD. 

            We're going to be asking you to talk about risk, so just to remind everybody that there is - this is double negative, Dr. Temple.  I understand that, but that there is no drug without some risk, but that an untreated condition also carries risk.  A successful treatment depends upon many things, but these are some of the things that we will be focusing on because the FDA and the panel cannot impact all of these, but we certainly have other academic groups or organizations that might help us make sure that we have proper diagnosis.  The job of making sure we have the right dose and the therapy lie with the sponsor and FDA, and what we're going to focus on today is our knowledge about adverse events adequately expressed; are there better ways of expressing it, or do we need to do anything about it.  In other words, an appropriate communication about risk is what we are asking the Committee to address today.

            So back to June 2005 - some of you weren't here, but many of you were.  And at that time, the FDA brought forth for its review under Section 15, Concerta, and we expanded it to the other methylphenidates at that time.  We said we had identified two possible safety concerns with the methylphenidate products, which were the psychiatric and cardiovascular events, and that we intend to make labeling changes, but that we wanted to examine all, and at this time we said stimulants, but we meant any of these products that are being used to treat ADHD.  And that we asked you to basically advise us if you were in agreement that we do that, because we did not want to direct people improperly from one set of products to another until we had looked at all of these products.  So then we were examining the post-marketing reports, and we would come back to you in early 2006, and I think we qualify March as early 2006. And that at that time, for the cardiovascular events, we said the Agency believes it's not yet possible to determine whether they are causally associated.  We are pursuing additional means to better characterize the cardiovascular risks for all the products approved for ADHD, and we propose that we obtain additional data to help guide us, and we're going to update you today on where we are with this issue.

            Now in your background package, instead of sending you everything from June again, what we tried to do for you is summarize the psychiatric and neurologic events for the methylphenidate products that were in your package, because those were the ones which we had the most extensive summary for you, so that you'll find one table in there that is a repeat from June.

            Today's update on pediatric safety, this is a summary of all the data.  It's not in sequence with the speaker, so what you're going to get is the review of the AERS data for Adderall XR during the one-year post-exclusivity.  You're going to get -- you received and will have presented to you in a condensed form the review of the AERS data for psychiatric events for most products used to treat ADHD, including additional reports requested from the sponsor. 

            What we're trying to tell you is we tried to get as much information as we could.  We went back to the sponsors, the Division of Psychiatry and Office of Drug Safety, sent letters to the sponsors, asked for additional information.  That information was submitted, and it has been analyzed, and so that is in your packet, and will be reviewed.  And in that process, there is a review of the sponsor's submission of psychiatric adverse events from 100 ADHD clinical trials in response to this request, so again, we've tried to maximize the amount of information we can provide you, and a review of the cardiac adverse events from AERS for the ADHD products.  And we will be talking about possible future studies to assess cardiac risk.  So that is our update that you will be hearing today.

            And your job is to assess the potential psychiatric cardiovascular risks with the use of products to treat ADHD in the pediatric population, with the best information that we can provide you at this time; to advise FDA on how best to communicate risks so the physicians and parents can make informed decisions.  This is really the crux of where we're trying to go.  And advise FDA on how best to address risk for all the therapies used to treat ADHD to avoid inappropriate switching to products for which we have less safety information, so we'll be asking you to look at all of these products.

            Now the questions - I am not going to read these in detail, but basically the preamble, if you will, that because these products have been shown to be effective when used to treat children who have been properly diagnosed as having ADHD, there will continue to be a need for access to these therapies.  You have received information on potential cardiovascular and neuropsychiatric risks associated with the use of medications to treat ADHD in children.  This information included adverse events from spontaneous reports and clinical trial data, the current labeling, and FDA's plans for additional studies on cardiovascular risk. 

            In consideration of this information, we're asking you to address the following questions concerning psychiatric and cardiovascular adverse events.  And we have broken up the questions into two sections; the psychiatric adverse event sections - and I'm not going to read them because they will be read to you by the Chair as you go through them - and the cardiovascular.  It's the same set of questions addressing those adverse events. 

            And I want to thank all of you very much, and I particularly want to comment that I know not only is there a lot of information to read, but a number of you have had to cancel other commitments and to make time in your busy schedules, and we sincerely appreciate your efforts to be here today and to advise us.  Thank you.

            DR. NELSON:  Perfect.  Thank you, Diane.  Our next presentation is going to be on labeling.  And I might point out to the Committee that this might at times seem to be a dry topic but, in fact, the label is the primary mode of communication, and the questions we've been asked to address is precisely communication, so take notes because we'll be talking about the labeling at the end of the day.

            DR. MURPHY:  And I was supposed to introduce Dr. Rosemary Roberts, who is a pediatrician and Board  Certified in Pediatric Infectious Disease, has been at the Agency I won't tell how many years, Rosemary, but is basically one of the founding mothers, if you will, of the pediatric program at FDA, has an extensive experience in not only pediatrics, but in the regulatory milieu, which we need to develop these products.

            DR. ROBERTS:  Thank you very much, Diane, for the nice introduction.  Good morning, everyone.  And yes, they gave me the dry topic, so now, just when you thought you knew how to attempt to read one of our labels that are pages long, I'm going to tell you that the labeling in its format and its order are being completely changed; so, hence, where will the safety information be in the new format of the physician's labeling?

            Okay.  Well, first of all, just some simple definitions.  The label is the written printed material, graphic material on the immediate container of the product, whereas labeling includes not only the label, but all the written and graphic material that goes with the product.  So if we look here at Strattera, the label is specifically what is on the immediate container, and then what you see in the back is the fine print physician's package insert.  Who knows what labeling will look like as we move into the electronic age? 

            Now labeling is to be a summary of essential scientific information needed for the safe and effective use of the drug.  It is to be informative, accurate, and not to be promotional in tone, nor false or misleading, and based on data derived from humans, wherever possible.

            Now a little bit of background as to how we came to the new physician's labeling.  Previous labeling regulations date back to 1979, and over the two decades from `79 into the early 21st century, there was increasing amount in complexity of drug information that was being put into the labeling.  So the goal was to have more informative and accessible labeling, resulting in better risk communication and management.  And in order to do this, the process included focus groups, a National Physician Survey, public meeting, and written comments.  And armed with all this information, a group of people at the Agency worked on the proposed rule for Physician's Labeling that was issued in December of 2000 and then the final rule, which was published in January of this year.

            Now there are certain innovations that I want to make you aware of.  There's a highlights section, where it's just going to the very short bulleted statements about key sections of the new labeling.  There's a table of contents, what an original idea when you have something that's that long.  But not only is there a Table of Contents, but you will be actually hyperlink to the direction section that you want to read. 

            There will be a section that identifies the recent major changes in the labeling, and it will also indicate the original date of approval within the United States.  So this is an example of a fictitious drug, and I'm going to use this fictitious drug to highlight the safety areas as I go through this.  But as you can see, there is -- at the very top it says that this is limited information, and you will have to go to the full prescribing information as you move on.

            Now this is the old format of the labeling.  You're probably familiar with this.  The first thing you see is the chemical structure, which for most of us doesn't do much for us, and we usually don't spend a whole lot of time there, nothing against chemists.  Okay.  So on this highlight, these are the things that you're going to see when you first open up either a hard copy or the electronic copy of the labeling.  So at the very top it's going to say that this is limited information. 

            I'm going to introduce the drug Imdicon or Cholinasol.  Now this particular drug is not going to meet what labeling should. It's not going to be a summary of essential scientific information needed for the safe and effective use of the drug, because there's no data at all behind it.  However, it is going to be useful for demonstrating what this new labeling is like.

            Imdicon is an imdinicine diphosphate antagonist platelet aggregation inhibitor.  It's indicated for reducing the risk of thrombotic stroke whenever there's been precursors of thrombotic stroke within the individual, or they have had a completed thrombotic stroke.  And it's also indicated for reducing the incidence of sub-acute coronary stent thrombosis. 

            You can see for this particular drug it was approved in 2000.  There is a boxed warning.  You will see the recent major changes there on the left-hand side of the screen under the box, the indication in usage and the dosage in administration.  As we move to the right-hand side, the dosage forms and strengths, bulleted contraindications, warnings and precautions, adverse reactions, where to report suspected adverse reactions as we're trying to encourage more people to report through the MedWatch system, the drug interactions, and use in a specific population.

            You will also note, for instance, if you look at the warning which, is probably the easiest to read from a distance, under netropenia agranular cytosis, the first bullet, it says 5.1.  That tells you that if you want to read the full prescribing information on that, you go to Section 5.1 of the labeling.  Okay.

            Now this is the Table of Contents.  This is going to be the order in which you see the information in the labeling.  So as you can see, the boxed warning is at the top, you immediately come to indications and usage, the dose that you want, the dosage forms and strengths, and then you start into the safety information.  Once you know what the drug can be used for, how it's to be administered, then the contraindications, warnings and precautions, and adverse reactions.  So here's the Table of Contents you will be able to take, and if you have this in electronic format, click on warnings and precautions and immediately be hyperlinked to that section, so much easier than scrolling down or trying to find the right page or reading one of these that's very long.

            Okay.  For contraindications, for all of you who concentrate on numbers, I want you to know that the Section 201.57, which is the labeling section of our Code of Federal Regulations, now has been reordered, so that, indeed, contraindications is falling in this Subsection C-5.  Contraindications are to describe those situations in which the drug should not be used because the risk of use clearly outweighs any potential benefit.  These are to be known hazards and not theoretical possibilities.

            Now the other thing, there is a very good guidance that was actually a draft guidance that was put out and is available to you that talks about each of these sections.  And its contraindications are divided up into observed as well as expected reactions.  And these would be expected reactions based upon what we know about the drug class or the drug pharmacology, or there are certain clinical situations where you would highly suspect that a product such as this one, which is used to prevent clotting, if you had a patient with severe hepatic impairment, they are more likely to have bleeding problems and, therefore, this drug is, indeed, contraindicated in people with severe hepatic impairment. 

            And from our fictitious drug, Imdicon, the contraindications are not surprisingly in those that have hemtopeioitic disorders or a history of thrombotic thrombocytopenic purpura or aplastic anemia, those with hemostatic disorders or active bleeding, and those with severe hepatic impairment.

            Moving on to warnings and precautions - again, this is divided into observed and expected, and it would include clinically significant adverse reactions observed in association with the use of a drug for which there is reasonable evidence of a causal association between the drug and the adverse reaction.  The causal relationship need not have been established, and I've underlined observed because this means that they have been observed, and I've underlined causal because that's a new word that's been introduced into the Code of Federal Regulations from our previous.

            Now, so what kind of observed reactions would fall into warnings?  Well, if it's a serious adverse reaction.  Now serious, fortunately they didn't change the definition of serious.  It's still where the outcomes would be death, some kind of life-threatening adverse event where a patient had to be hospitalized, or if they were in the hospital, they had to extend their hospitalization, congenital anomalies, et cetera.

            What are otherwise clinically significant adverse reactions?  These are adverse reactions where it would require discontinuation of the drug, where one would have to make a dose regimen adjustment in order to use the drug safely or there would be a significant effect upon patient compliance.  For instance, if you had a drug that had a photosensitivity reaction and you're going to prescribe it for a person who works outside all the time, well, you may want to reconsider that.  That person may stop taking that drug because of their job, so try to look for another drug, or a product that interferes with a laboratory test. 

            Now, then there are adverse reactions which can be expected to occur with a drug based upon observations from other members of the drug class, or the animal studies.  These would be serious, or otherwise clinically significant adverse reactions that either would be based upon what is known about the pharmacology, chemistry, or the drug class, and therefore it's likely that an adverse reaction could occur, or animal data raises substantial concern for the adverse reaction in humans.

            Other factors that need to be considered for placement of adverse reactions into this section would be the indication.  For instance, if you have a self-limited condition where you have adverse reactions such as alopecia or severe nausea, you may want to consider putting that in this section because that would potentially lead to a person considering discontinuing this drug because they have such a self-limited condition; whereas, if it was a chemotherapeutic agent, those kind of issues may not warrant putting it into this section of the labeling.

            Also, the incidence, if there's a high incidence of the particular adverse reaction or if there -- you could actually manage or prevent the adverse reaction through some kind of specialized patient monitoring or titration of the drug, et cetera.  So here's an example of the adverse reactions that went into the warning section for the fictitious drug, Imdicon.  And as you see, there's neutropenia at a 2.4 percent incidence.  It also tells you it may occur suddenly.  It will typically resolve within one to two weeks of discontinuation.  This is very important information to know that if you discontinue the drug, you can expect it to resolve.  And then the second bullet talks about how to monitor for the particular hematologic adverse reactions.  Again, you can see that you're then referred to Section 5.2 of the full prescribing information. 

            Now the boxed warning is simply a subset of warnings, and it's where there is information that we want to highlight for the prescriber, and therefore it is put in a very prominent place within the labeling and within a box.  And when should one use a boxed warning, or when do we contemplate using a boxed warning?  If the adverse reaction is so serious in proportion to the potential benefit from the drug that it is essential that the adverse reaction be considered when one is assessing the risks and the benefits of using the drug.  So again, it goes back to the benefit risk equation, and where does that lie?

            The serious adverse reaction that can be prevented or reduced by appropriate use of the drug to be put in this section or drugs that are approved with restrictions to assure that there is safe use in either distribution or use restriction. 

            Ordinarily, information that goes into the boxed warning is based upon human clinical data.  However, serious animal toxicity can be enough to introduce it into a boxed warning.  So again, this just shows you the highlighted boxed warning.  This is not the full boxed warning.  This is only bulleted highlights from that section.  And that, again, from our example from the Imdicon, it has information on how to monitor for the hematologic adverse reactions, tells you when to discontinue Imdicon, and the adverse reactions for which you would want to discontinue the drug. 

            Now, how do we go about knowing when considering a boxed warning?  And it really is a balancing act.  It's balancing the risks of the drug versus the benefit of the drug.  And I want you to concentrate on this and think about it because it's a very serious situation that we consider with a great deal of knowing that the consequences of what the black box or the boxed warning can lead to, consequences for patients, consequences for physicians, consequences for sponsors, so we don't take it lightly. 

            It is a multi-layered process, and by that I mean internally we involve our statisticians, toxicologists, medical reviewers, safety reviewers, clinical pharmacologists, every discipline that's appropriate within the Agency.  We often bring it to groups such as yourself, external advisory committees, for input.  It's ultimately a consensus decision.  It's not a unanimous decision usually, but it's a consensus decision, and it's a very iterative process in which the sponsor plays a role.

            And here are resources that are on the FDA's website, it talks to you about the new labeling.  There are several fictitious drugs there to give you a handle on how some of the new labeling will look, and hopefully to help us and to help sponsors as we try to put labels in the future into this new labeling.

            I want to thank you very much for your attention.

            DR. NELSON:  Thank you, Rosemary.  The next presentation is by Paul Andreason, who is Acting Deputy Director of the Division of Psychiatry Products at CDER.

            DR. ANDREASON:  Thank you very much.  This morning I'd like to bring you up-to-date on what's been going on in the Division in products that are used to treat Attention Deficit Hyperactive Disorder.  Just as an update, the June 30, 2005 meeting we discussed Concerta in the BPCA review, and in the discussion we came to the conclusion that even though many of these adverse events were known to the psychiatric community, they perhaps were not well communicated to other prescribing communities, such as the pediatric and general practice groups.  And that we would look at psychiatric adverse events in more detail, with the hope of talking about this today, which we will.

            Just to outline some of the things that have happened since June of 2005, and I was not completely aware of just how busy we've been, Canada returned Adderall XR to the market on August 24th, 2005 after removing it in September of 2005.  Then the randomized clinical trials for the psychiatric adverse events for all treatments, a review of those was designed and letters were sent to the sponsors in September of 2005 with a deadline of November 1st for getting that data in to us. 

            Then in October, Pemoline was removed from the market.  In December of 2005, we held a Psychiatric Drug Advisory Committee for the review of methylphenidate transdermal patch, and they recommended approving it, and we completed our review of that and issued an approvable action on the 23rd of December, 2005. 

            In January we requested a labeling update that warned about use in patients with known cardiovascular defects or stimulants.  This was language that was already in the Adderall XR labeling, and this was the same type of labeling that had been in there prior to Canada removing it from their market.  And when they placed it back on the market, it contained that labeling that we already had.  We sent that updated labeling request to the makers of all stimulants.  And that's already actually incorporated into the Concerta labeling, if you look at their website now.

            In March, actually March 3rd of 2006, the results for the review of the randomized clinical trials for the psychiatric events was filed in our Division file system.  Thank you to the Office of Drug Safety people for doing that.  And today, here we meet for the Adderall XR BPCA review and presentation of those psychiatric adverse events that we planned to study.  And I would like to say that that was a large task, and I'm really proud of the folks that did that, because it was no small feat.  And then tomorrow we meet on Modafinil, and its potential use in the treatment of Attention Deficit Disorder with the Psychiatric Drugs Advisory Committee. 

            For those of you who have not seen the labeling for cardiovascular risk and structural cardiac defects, this is what it says, sudden death and pre-existing structural cardiac abnormalities is the section title, or the subsection title.  Sudden death has been reported in association with CNS stimulant treatment at usual doses in children with structural cardiac abnormalities.  Although some structural cardiac abnormality alone may carry an increased risk of sudden death, stimulant products generally should not be used in children, adolescents, or adults with known structural cardiac abnormalities.

            Now if you go and look at all of the existing labeling for the stimulants that are currently on the market, you will notice that there are some differences where risks are placed in labeling, or whether they're mentioned, or what kind of data is there.  That has to do with several factors; first of all, the age of the product, and what kind of data was available or required for the approval of that product at the time, and the breadth of the program.  The products for which we have the most data are those that produced information for us as the result of a written request. 

            In the package for the Committee today, we have a line-by-line, column-by-column comparison of the cardiovascular risk language, but generally speaking, what the stimulants say is that these drugs should be used with caution in patients with hypertension and tachycardia, cardiovascular or cerbrovascular disease, or cardiac arrhythmia, that blood pressure should be monitored, as well as pulse, and that modest increases in pulse and blood pressure have been noted with their use.

            For the psychiatric adverse events, I kind of divided these out for the purpose of illustrating the differences of the drugs over time.  In yellow, you'll see examples of labeling for the more recent products, and in, I suppose that's purple, you'll see the oldest drug -- excuse me -- for yellow the newest, and purple the oldest.  And the adverse events that are focused on in labeling generally revolve around psychosis, agitation, and anxiety. 

            Now for the amphetamine-containing products, Adderall XR is an example of one of the new ones, Dexedrine is an example of the oldest one -- this is what you see.  In Adderall XR you have a warning section that talks about psychosis, clinical experience adjusted in psychotic patients, administration of amphetamine exacerbates symptoms of behavior disturbance and thought disorder.  And then the purple section is not only in Adderall, but it's actually in the Dexedrine labeling, too, word-for-word.  And then you go on to see some psychiatric symptoms listed in the table of commonly occurring adverse events. 

            Now some of the concern has been what does the labeling say about toxicity and usual doses.  I think most people are aware of the psychiatric cardiovascular events that occur in overdose, but some of the concern that has been raised not only in the June 2005 meeting, but since then, is about these risks that may occur, or what are the potential risks of these occurring at usual doses.

            In the Dexedrine labeling, under the overdose stage, in the overdose section it says, "While toxic symptoms occasionally occur as an idiosyncracy at doses as low as 2 milligrams, they are rare with doses of less than 15 milligrams", and then it goes on to say that, "30 milligrams can produce severe reactions."  Now Dexedrine is the amphetamine, the active ingredient in the mixed salts of amphetamine, so roughly if you double the dose here, that would be the Adderall XR dose.  So that gives you an idea of what the therapeutic index is here. 

            The Adderall XR labeling says "toxic symptoms may occur idiosyncratically at low doses."  So the information is there, but not necessarily as accessible as maybe one might have it.  Again, here's the Adderall XR overdose section, starts out by saying "individual patient response to amphetamine varies widely, toxic symptoms may occur idiosyncratically at low doses."  However, this is in the overdose section.

            The Dexedrine labeling, even though it's the oldest, is amazingly data-rich.  "Individual patient response to amphetamines varies widely", and this is the same phrase that I just read to you, but it goes on to say, "30 milligrams can produce severe reactions, yet doses of four to five hundred milligrams are not necessarily fatal."  And then it goes on to talk about some animal data, and what the manifestations of overdose may be. 

            For the methylphenidate-containing products, this is kind of the same breakdown.  I'm comparing here Concerta versus Ritalin.  Again, there are sections on need for comprehensive treatment program, stating that the drug alone is not an adequate treatment for Attention Deficit Hyperactive Disorder.  Again, there's a section in the Concerta labeling about warnings of psychosis, and toxic psychosis has been reported.

            Now this was a piece of confusion before that many people felt that toxic meant overdose; whereas, toxic psychosis is a term of art in psychiatry, meaning that it's not functional psychosis necessarily caused by a psychotic disorder, but by a substance or something introduced into the body.

            And then in the patient package insert for Concerta, it talks about risks of increased blood pressure and psychosis, and talk to your doctor before taking Concerta if you have -- and then it lists the symptoms.  These are some more comparisons between Concerta and Ritalin.  Concerta is contraindicated in patients with marked anxiety, tension and agitation, since the drug may aggravate these symptoms.  And again, in the patient package insert this is outlined.

            There's one statement in the Ritalin labeling that is not in the Concerta labeling.  However, I don't think it necessarily adds that much.  "Patients with an element of agitation may react adversely, discontinue therapy, if necessary."  And then we move on to atomoxetine, a non-stimulant, and this is the information that's in that labeling.  There is actually a boxed warning for suicidal ideation.  And there is a Med Guide that is also part of the atomoxetine labeling. 

            The warning sections, it talks about the symptoms that have been reported, including anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, or psychomotor restlessness, hypomania, and mania.  And then a statement on aggression, call your doctor if treatment emergent, and it talks about the incidence that it occurred at. 

            Now one of the things that came out of the February 5 meeting, or as we discussed the February 9 Drug Safety and Risk Management meeting, was that some people felt that perhaps there was some confusion about whether or not atomoxetine was being considered by the Committee as a stimulant or not, and that there may have been some confusion about nomenclature.  The amphetamines and methylphenidate products are accepted as central nervous system stimulants.  Atomoxetine is marketed as a non-stimulant.

            Modafinil is listed as a wakefulness promoting agent.  It has some, but not all, the properties of stimulants, and I just wanted to quickly go through some of those comparisons.  Amphetamine blocks, reuptake and norepinephrine and dopamine into the presynaptic neuron and increases release of norepinephrine and dopamine.  That dopamine, they say, comes from the reserpine-insensitive cytoplasmic pool, as opposed to the reserpine-non-sensitive granular pool, and in animal studies it increases locomotor activity in mice and rats.  Amphetamines have been extensively abused, tolerance, extreme dependence, psychological dependence, and severe social disability have occurred with them, and there are reports of subjects who have increased the dose to many times the recommended therapeutic doses in their abuse.  Abrupt cessation following prolonged high dose results in a withdrawal syndrome of extreme fatigue, mental depression, and it is a Schedule II non-narcotic. 

            Methylphenidate also blocks reuptake of norepinephrine and dopamine in the presynaptic neuron, and increases release of norepinephrine and dopamine.  Again, it releases dopamine from the granular reserpine sensitive vesicular pool, and it, too, increases locomotor activity in mice and rats.  Chronic abuse has been documented, and it can lead to marked tolerance and dependence, and careful supervision is required during withdrawal from abusive uses.  Severe depression may occur.  It also is a Schedule II non-narcotic.

            Modafinil in vitro binds to the dopamine reuptake site and causes increased extracellular dopamine, but there is no increase in dopamine release.  There is increased locomotor activity in animal studies, but it has no effect on the norepinephrine system.  Modafinil's reinforcing is evidenced by its self-administration in monkeys previously trained to self-administer cocaine.  In humans, Modafinil produces psychoactive and euphoric effects, and it's a Schedule IV controlled substance.

            Finally, atomoxetine produces selective inhibition of the presynaptic norepinephrine transporter, or SNRI, blocks reuptake of norepinephrine.  It does not stimulate release of dopamine or norepinephrine, and it does not increase extracellular dopamine.  It has minimal affinity for either the serotonin dopamine transporters, or other neurotransmitter systems.  It does not increase locomotor activity in mice and rats, and drug discrimination studies in rats and monkeys were inconsistent at showing stimulus generation between atomoxetine and cocaine, and there's no evidence of symptom rebound or adverse event suggesting a drug discontinuation or withdrawal syndrome, and it is not a scheduled substance.  So that is kind of an overview on the differences between the drugs that are accepted as stimulants and others that kind of have not necessarily been grouped into that category.

            Thank you very much.  I'd like to introduce Dr. Marsha Rappley from Michigan State University College of Medicine.

            DR. RAPPLEY:  On February 9th, the Drug Safety and Risk Advisory Committee met to produce recommendations to the FDA about how best to study the serious rare cardiovascular and cerebrovascular events associated with medications used to treat Attention Deficit Hyperactivity Disorder.  Three of us were present, three of the current Pediatric Advisory Committee were present and participated in that meeting; myself, Dr. John Moore, and Deborah Dokken.  I'm going to provide a very brief summary of our view on how that meeting transpired.

            The FDA presented background on the medications, and the discussion quickly moved to strengthening the warning associated with the use of these medications.  The three of us expressed concern about how quickly that discussion shifted to the warning that would be appropriate for the use of these medications, and that it occurred at the expense of an in-depth discussion of the actual risk in children and adults, how that risk differs, and how best to convey that risk to families and physicians.

            A vote was called, a yes/no vote to either support or not support the black box warning for these medications in the use of ADHD.  And among the three of us, our vote was split.  There was one vote in favor of that black box warning, and two votes not in favor of that black box warning.  All three of us felt that that vote was called without discussion of content of that warning, or what the wording might be in such a warning, and that there was brief discussion that this black box warning is the highest level of warning that can be associated with a medication approved for use by the FDA. 

            Further comments from the three of us include from Dr. Moore, that the risk and the benefit of these medications and treatment of ADHD, particularly for adults, has not been well-defined.  From Ms. Dokken, that today's further discussion about the best way to convey the level of risk to families and physicians is extremely important.  And from myself, that what happened at the previous meeting, I believe is a legitimate concern about the increased use of these medications being confused with the actual risk of the medications themself.

            Now I'd like to invite both Ms. Dokken and Dr. Moore to add additional comments, at your pleasure.  Thank you.

            DR. NELSON:  Thank you, Marsha.  We're ahead of schedule.

            MS. MURPHY:  We note it. 

            DR. NELSON:  Well, what I'd like to recommend, because I'm sure we've got a lot more things to do, is we might as well take our 15 minute break now, but what that will mean is instead of starting again at 9:50, I've got 9:22, so how about if we start at 9:35.  We'll just shorten it a bit, so be back here at 9:35 instead of 9:50.

            (Whereupon, the proceedings went off the record at 9:22 a.m. and went back on the record at  9:37 a.m.)

            DR. NELSON:  So we could begin to start taking our seats.  While Dr. Vitiello gets himself prepared, I have two announcements.  So both announcements are actually directed to our esteemed audience.  For those individuals who had pre-registered prior to the closing deadline for making comments during the open public hearing, we do need you to still let the folks at the front desk know that you're here.  So if you didn't actually sign in, make sure you do that so we know that, in fact, you're here.  And the second is, there are some people that are standing in the back.  They're certainly welcome to keep doing that if that's their preference, but if you've got a seat next to you that's empty and filled with your briefcase or whatever, you could make room if they'd like to sit down.  There does look to be plenty of extra seats.  Those in the back are welcome to keep standing, as well, depending upon your back.

            So our next speaker is Dr. Ben Vitiello, who's with the National Institute of Mental Health.

            DR. VITIELLO:  Thank you.  My task here is briefly to summarize the efficacy of stimulants in atomoxetine in the treatment of Attention Deficit Disorder before we embark, actually, in talking about the safety issues.

            The focus will be on children, and adults for that matter, age six and above.  Even though amphetamines are actually marketed and indicated also for children age 3-6, the data in pre-schoolers are much weaker in some respects, so my presentation refers to subjects age six and above.

            A word about Attention Deficit Disorder.  It's a condition that is characterized by developmentally abnormal, persistent and pervasive level of inattention, hyperactivity, or impulsivity that are usually apparent before 7 years of age, that impair school performance, interpersonal relationships, are often co-morbid with other conditions, and they can lead to academic failure, increased risk for delinquency, increased risk for accidents, car accidents, in particular, and increased overall medical cost.   This does not mean that all children with Attention Deficit Disorder are doomed to have a life of failure, but on average as a group, children who have Attention Deficit Disorder are at greater risk for this negative outcome than peers who don't have Attention Deficit Disorder.

            Attention Deficit Disorder is a clinical diagnosis, even if there is a biological substrate for it, of course, but there is no diagnostic marker that can be used for making the diagnosis.  So it's a sort of labor-intensive sort of time consuming diagnosis that requires careful documentation and examination of a patient, collection of information from the patient, the parent, the teacher.  It requires a comprehensive assessment to rule out other possible causes of symptoms.  It also includes a comprehensive physical and neurological examination. 

            It is estimated that at least 5 percent of school-age children meet the criteria for Attention Deficit Disorder.  A higher rate, however, has been reported, so some people believe that the true estimate is more about 6-7, rather than 5.  It's more common in boys.

            Now there are different treatment for Attention Deficit Disorder, so there are choices.  For instance, there is behavioral therapy which is an effective treatment of Attention Deficit Disorder, and then there are a number of pharmacological agents, of  which amphetamines, methylphenidate and atomoxetine are approved officially by the Food and Drug Administration.  Other drugs, like bupropion, Modafinil, Clonidine or Guanfacine, or Tricyclic Antidepressant have some evidence of efficacies, in some cases also good evidence, even though it's less strong stimulants for sure, but they do not have an indication at the moment for the treatment of Attention Deficit Disorder.

            Stimulants are drugs, as has been already pointed out in the previous presentation, that stimulate the central nervous system, they increase alertness, attention, they decrease fatigue, they decrease and focus motor activity; and, therefore, they decrease hyperactivity.  They increase goal-oriented activities, improve performance in a variety of tasks, decrease also appetite and sleep, and can cause euphoria; and, therefore, can be abused. 

            The efficacy of stimulants in the treatment of Attention Deficit Disorder is very well documented by numerous placebo-controlled studies using both crossover, which is within subject the design, or parallel-group design, and this is true for both methylphenidates and a variety of amphetamine products.  The efficacy has also been confirmed by several meta-analyses, so in some way in evidence-based medicine, the strength of the evidence is usually ranked from 1-5, where one is the highest, and five is the weakest.  And the efficacy of stimulants in Attention Deficit Disorder certainly meets the highest standard for evidence.  Strong evidence from at least one systematic review of multiple well-designed randomized clinical trials.

            In this particular study that was funded by the National Institute of Mental Health, and also the Department of Education and other federal agencies, more than 200 children age 7-9 suffering from Attention Deficit Disorder Hyperactive and Inattentive  type combined, were randomized to receive a sequence.  Each subject received placebo in three different dosage of methylphenidate, and the teacher and the parent scored blindly the symptoms of Attention Deficit Disorder.  The higher the score here, the more is the severity of attention deficit symptoms.  You can see there is a dose effect curve that is evidenced particularly with the teacher scores, but also with the parents.  To say that of all the children who entered into the study, four subjects did not tolerate methylphenidate and they had intolerable side effects; and, therefore, they had to be discontinued and were not included in this analysis.  It's about 2 percent of the patients, so the rate of intolerable side effects in this large sample was 2 percent.

            In this particular study of -- so, yes, it can characterized with effect size which is the magnitude of effect of methylphenidate versus placebo expressed in standard deviation units is 1.3 if we use the teacher scores, and it is .6 if we use the parent.  So the fact is certainly moderate and large actually, a large effect size if you use the teacher.  Response rate, 77 percent of the children were responders to methylphenidate, and 12.5 percent on placebo.  The remaining 10 percent didn't respond to either, so the non-response to methylphenidate is 10 percent roughly, and 12.5 response also on placebo.

            The number needed to treat in order to add one extra patient who improves to the one that would improve on the control condition, in this case placebo, is about 1.5, which is one of the highest in medicine, in general, not just in psychiatry, but in medicine.  If you consider that the ceiling is one, because you cannot go better than that, so it's really at the top in terms of discriminating between placebo and active medications.

            The same conclusion you can reach by using parallel-group design.  The previous data were within subject design, this is parallel-group design, this is study supported by industry where about 300 children were randomized to receive placebo or methylphenidate, and the effect size using teacher ratings is .8, a large effect size, and .9 using the parents scores.  And, therefore, the number needed to treat in this particular group is 3.3.  It varies somewhat because of a definition of improvement changes somewhat from one study to another, but still the number needed to treat is very favorable.

            If we look at amphetamines, we pretty much get the same result.  And, in fact, there is no evidence that methylphenidate is any different to amphetamines with efficacy, so they are considered to be sort of equivalent in terms of magnitude of efficacy.  So in this particular study, which is a parallel-group design, short term about three weeks, about 60 patients were randomized to amphetamines, mixed amphetamine salts or methylphenidate, and the primary outcome were the teacher ratings.  And you can see, this is a measure of inattention and over-activity.  This is the placebo.  This is the methylphenidate and this is the amphetamine, and clearly the amphetamine, and also the methylphenidate are better than placebo.  This is course of aggression and defiance that are not really part strictly speaking of Attention Deficit Disorder, but they are often associated with Attention Deficit Disorder, and there is an effect on that, too, even though somewhat smaller.  These are teacher ratings, and these are the parent ratings. 

            In this other study, also very large study, also supported by industry, about 600 children are using a parallel-group design, were randomized to receive fixed doses of amphetamines, 10, 20 and 30 are placebo, and teachers and parents rated the symptoms.  And you can see that this is a level of placebo, and there is also a dose response curve relationship with the linear with amphetamine, as we have seen also with methylphenidate. 

            The results in adults are less extensive, because there are much fewer studies in adults, both with methylphenidate, with amphetamine, than with children.  However, the conclusion seems to be the same. In this study in adults, about 150 patients with Attention Deficit Disorder, parallel-group design, placebo controlled, effect size 1.4.  The response rate was 76 on methylphenidate, and 19 percent on placebo, number needed to treat 1.4. 

            For amphetamines, smaller sample size in this case, a response rate 70 percent on amphetamines, 7 percent on placebo, number needed to treat 1.6.  So the signal is detected in adults as it is in children, and with the same magnitude.

            The therapeutic benefit emerges quickly basically 20 minutes after the first dosing persist as long as the medication is administered and disappears if the medication is discontinued.  Basically, all children, even if they're treated extensively, when they are switched to placebo they represent the same symptomatology of Attention Deficit Disorder.  Stimulants, they suppress symptoms, of course, may not eliminate them for good.

            Atomoxetine is another drug that has proven efficacy in Attention Deficit Disorder.  In this study that was supported by the maker of atomoxetine, Eli Lilly, 171 children were randomized to a parallel-group design versus placebo, and the outcome were Attention Deficit Disorder symptom rated by the clinician, the parent, and the teacher, effect size 0.7, response rate 59 percent on atomoxetine, and 31 percent on placebo, number needed to treat 3.6.

            This other study, about 300 adults, parallel design, goes up to 60 milligram a day, outcomes, rate and scales by the clinician this time, effect size more modest.  This is a small effect size, still statistically significant. 

            There is an interesting study that is not published yet that was presented last year at a Psycho Pharmacology Conference sponsored by NIMH, which directly compare atomoxetine with a preparation of methylphenidate in about 500 children with Attention Deficit Disorder, which also included a placebo group.  And the doses were I think  a fair comparison, a fair amount of methylphenidate, and a good dose also of atomoxetine, which is quite important when you do this type of comparison.  The response rate of 56 percent on methylphenidate, or in this case atomoxetine 45 percent, the placebo 24 percent, OROS was statistically significant better for atomoxetine.  And this study was supported by Eli Lilly, which is the maker of atomoxetine.

            The multi-modal treatment of Attention Deficit Disorder was a study conducted in the 90s, and was publicly funded by NIMH, Department of Education, NIDA, other federal agencies.  And it's remarkable because you compare different treatment strategies for the treatment of Attention Deficit Disorder in children age 7-9.  And the conclusion was that careful use of medication - one of the conclusions, careful use of medication, I would say intensive use of medical, so at fairly high doses, is more effective than behavioral therapy. In fact, the number of children with events over months of a study, so it was not short-term, was long-term, 14 months, randomized study that were optimally controlled in their Attention Deficit Disorder symptoms was 56 percent on medication, and 34 percent on behavioral therapy. 

            These are some results of MTA study.  For instance, the fact on an attention score rated by the parent or by the teacher, this is time as expressed in day, but this is the last point, is 14 months basically, so a little longer than one year.  These are the symptoms, and so the lower the score, the better the trial with respect to the outcome.  You can see that there's two conditions that are medication management or medication plus behavioral therapy in combination are better than behavioral therapy alone according to the parent, and according to the teacher.

            If we look at this other outcome, which is hyperactivity rated by the parent, but the same result you will get from a teacher, you get the same response, the same result; meaning that the medication, either alone or in combination with behavioral therapy is better than behavioral therapy alone or the community control. That was the comparison in this study.

            And interesting enough, also, the social scales of a child as rated by the teacher improve.  In this scale, the higher the score the better, of course, so there is an improvement in social skills that is higher on the medication compared with the other conditions.

            And also, I think even more interesting, if you look at other symptoms that have nothing to do with Attention Deficit Disorder, so-called internalizing symptoms such as anxiety, moodiness, self-esteem, they tended to improve, meaning the symptoms tend to decrease with the medication, so the efficacy of the medication is just not limited to the core symptoms of Attention Deficit Disorder, but extend and apply to a variety of other symptoms that the children have.

            In conclusion, there is strong evidence that pharmacotherapy with the drugs that we have considered improve a patient with Attention Deficit Disorder with respect to symptoms of hyperactivity, impulsiveness and inattention, which are the core symptoms of Attention Deficit Disorder.  And also, there is an effect on defiance and aggression, that are often associated with Attention Deficit Disorder.  There is an improvement in interpersonal interaction and social skills, in general.  The results are an effect on academic work in terms of amount of academic work that is done, completeness, and accuracy.  However, an effect on academic achievement such as school grades, has not been demonstrated.  Actually, that was one of a few outcomes, probably the only outcome that was included in the MTA, Multi-modal Treatment of Attention Deficit Disorder, where there was no treatment effect.  This is maybe due to the fact the school grades have such large variance that is not really amenable to pick up a treatment effect, so it could methodological effect.  But the reality is that still we don't know whether successful treatment of symptoms of Attention Deficit Disorder translate into a better outcome, a better prognosis for the child as the child becomes an adult.  So we still don't know if treatment really is able to change the negative outcomes of Attention Deficit Disorder that will lead to academic under-achievement, occupational under-achievement, in general, higher rate of accident, and higher medical cost.  And since I'm involved in research and I like to divide research in different chapters, I would say the first task which was to show the effectiveness of treatment of a short-term base was achieved back in the 70s and 80s, and well documented later.  But the treatment is effective in the long-term with chronic use.  This was very well documented in the 90s, and MTA played a major role in that.

            The challenge now is to try to design studies that can address this question: Does treatment lead to distal benefits?  And again, this is the challenge, I think, for researchers right now.  Thank you.

            DR. NELSON:  Thank you, Ben.  The next presentation is by Susan McCune.  Susan is a neonatalogist who is in the Division of Pediatric Drug Development at the FDA.

            DR. McCUNE:  Thank you, Dr. Nelson.  Good morning, ladies and gentlemen of the Committee.  Thank you.  I am going to present today the one-year post-exclusivity adverse event review for Adderall XR.

            This slide gives you an overview of my talk.  First, I'm going to give you a little background information about Adderall XR, but then I'm going to briefly describe the clinical trials for the initial approval in adults and children 6-12 years of age, and then again briefly the clinical trials that were done for exclusivity in the adolescent population.  I'm then going to switch gears and talk about the Adderall XR use information, and finally, we're going to talk in some detail about the adverse event reports for Adderall XR in the one-year post-exclusivity period, which covers October 28th, 2004 through November 28th, 2005. 

            In terms of background drug information for Adderall XR, Adderall XR capsule contain dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate.  The therapeutic category is that of central nervous system stimulant.  The sponsor is  Schier.  The indication for the use of Adderall XR is treatment of Attention Deficit Hyperactivity Disorder, or ADHD.  The original market approval for Adderall XR was October 11th, 2001.

            Of note, Adderall was originally marketed in 1960 under the trade-name Obetrol.  It was then approved to treat ADHD and narcolepsy in 1996.  Pediatric exclusivity for Adderall XR was granted on October 28th, 2004. 

            In terms of some background information on Adderall XR, you've heard some of this information already from Dr. Vitiello, and Dr. Andreason.  The mechanism of action of Adderall XR in ADHD is unknown;  although, like methylphenidate it is thought to block the reuptake of both norepinephrine and dopamine, and the diagram here shows only dopamine, but should also show norepinephrine, blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron, and increase the release of these monoamines into the extraneuronal space.

            In addition, there are known peripheral actions that include elevations of both diastolic and systolic blood pressure, and weak bronchodialator and  respiratory stimulant actions.  In terms of the drug delivery system for Adderall XR, each capsule contains two types of drug-containing beads designed to give a double pulse delivery of amphetamines allowing for once daily administration. 

            If you look at the drugs to treat ADHD, and once again, you've heard this this morning from a number of speakers, but I'd like to put them into categories for you.  This is based on the clinical practice guidelines that were published in 2001 in pediatrics.  In addition to the drugs that you see here, we need to add dex methylphenidate which is phocalin into the methylphenidate category.  And as you've heard this morning, Amodafinil is an additional drug.  So in terms of the stimulants which are identified as first-line treatment, there are the methylphenidates, there are the amphetamines, and as you heard this morning, Pemoline has been taken off the market.  They are described as non-stimulants, the atomoxetine, and in addition, there are second-line treatments, including the antidepressants, the tricyclic antidepressants of bupropion, and these are not approved for ADHD treatment.

            Today in my talk, I'm going to focus on Adderall XR.  I'm also going to give you some information about Adderall, and just as a clarification, although it's classified here as intermediate acting, it would be considered a short-acting drug.  In terms of looking at the literature and what are described as adverse events for Adderall XR, this is from Dr. Rappley's paper in The New England Journal from 2005.  And the side effects of Adderall XR include appetite suppression, weight loss, stomachaches, headaches, irritability, possible growth inhibition, exacerbation of psychosis, exacerbation of tics, mild increase in blood pressure and pulse.  And the drug is contraindicated in patients who have cardiovascular disease, hypertension, hyperthyroidism, glaucoma, drug dependence, or use of monomenoxidates inhibitors. 

            Now we're going to talk for just a brief minute about the clinical studies that were done for Adderall XR initial approval.  These trials involve the double-blind randomized placebo-controlled parallel-group study of 255 adults.  In addition, a double-blind randomized placebo-controlled parallel-group study of 584 children age 6-12 years.  An additional classroom analog study of 51 children age 6-12 years was compared to placebo.  In all of these studies, there was demonstration of significant improvement in patient behavior.

            In looking at the exclusivity studies that were done for Adderall XR, the clinical trials in adolescents involved a pK trial of 17 adolescents who were less than 75 kilos, and 6 adolescents greater than 75 kilos.  A double-blind randomized multi-center parallel-group placebo-controlled study of 327 adolescents age 13-17 years.  There was a primary cohort of 287 patients who weighed less or equal to 75 kilos who were randomized to a fixed dose treatment for four weeks.  This treatment included placebo, 10 milligrams, 20 milligrams, 30 milligrams, or 40 milligrams once daily of Adderall XR in the morning.  A secondary cohort was also studied, including 40 patients who weighed greater than 75 kilos.  And these patients were randomized to a fixed a treatment for four weeks of either placebo, 50 milligrams, or 60 milligrams once daily of Adderall XR. 

            The primary efficacy variable was the ADHD rating scale for total scores for the primary cohort.  Improvements in the primary cohort were statistically significantly greater in all four primary cohort active treatment groups compared with placebo.  However, there was not adequate evidence that doses greater than 20 milligrams per day conferred any additional benefit. 

            Following the studies for exclusivity, additional information was added to the label.  The studies for pK were defined in the clinical pharmacology section of the label.  The clinical studies were documented for adolescents in the clinical study section, and the dosage administration section was altered, stating that the recommended starting dose for adolescents who are 13-17 years of age who were diagnosed with ADHD is 10 milligrams per day.  And the dose may be increased to 20 milligrams per day after one week if ADHD symptoms are not adequately controlled.

            In terms of the clinical trials, discontinuation and adverse events for the exclusivity trials, there were eight patients, or 3.4 percent of the patients that were enrolled in the trials that discontinued treatment due to insomnia, depression, motor tics, headaches, light-headedness, and anxiety.  The adverse events that were reported in 5 percent or more of patients in the exclusivity clinical trials were abdominal pain, loss of appetite, insomnia, nervousness, and weight loss.  And 2-4 percent of patients reported accidental injury, asthenia, or fatigue, dry mouth, dyspepsia, emotional ability, nausea, somnolence, and vomiting. 

            Now I'm going to switch gears and talk about the drug use trends for Adderall XR in the period from 2003 to 2005.  The number of prescriptions that were dispensed by retail pharmacies increased from approximately 7.3 million in the pre-exclusivity period - that would be November of 2003 to October 2004 - to approximately 8.6 million in the post-exclusivity period - November 2004 to October 2005.  And this data comes from Verispan. 

            Psychiatrists were the most frequent prescribers at 31.8 percent, followed by pediatricians, who were the second most frequent prescribers at 29.7 percent in the post-exclusivity period.  And pediatric retail pharmacy prescriptions  - in other words, prescriptions for patients zero to sixteen years of age - accounted for 63.8 percent of all Adderall XR prescriptions in the post-exclusivity period.

            I want to take just a minute to walk you through this slide, because you're going to hear this data, I think, again later on in the talks.  Basically, this is a percentage of total prescriptions on the Y axis.  Along the X axis you have three time periods, 2002-2003, 2003-2004, and 2004-2005.  And the Office of Drug Safety examined eight therapeutic classes of treatments for ADHD.  I'm showing you the top three here, which include amphetamine, dextroamphetamine, atomoxetine, and methylphenidate.  There were five other therapeutic categories that were looked at that included dextroamphetamine, dex methylphenidate, methamphetamine, Modafinil and Pemoline, just to give you the total universe of what was examined.  And as you can see, the amphetamine products accounted for approximately 35 percent of use over that time period, and was relatively constant.  The use of methylphenidate decreased slightly over these three time periods, and the use of atomoxetine increased slightly over those three time periods.

            In looking at the category of the amphetamine and a dextroamphetamine combinations that I showed you previously - now this is just a breakdown within this amphetamine, dextroamphetamine combination group - once again, the number of total prescriptions on the Y axis, and the same three time periods on the X axis, and you can see that the majority of use in the amphetamine and dextroamphetamine combinations is accounted for by Adderall XR, a smaller amount by amphetamine salt, and less so by immediate release Adderall.

            Now I'm going to focus on the pediatric adverse event reports for Adderall in the one-year post-exclusivity period.  In terms of all of the reports, these are raw reports in the one-year post-exclusivity period from October 28th, 2004 to November 28th, 2005.  There were 210 total number of reports.  There were 98 reports in the pediatric population.  Please remember that number because I'm going to walk you through that number in a minute, and there were eight deaths and I'll walk you through those numbers, as well.

            For the next few slides, I'm going to give you information about both Adderall XR, as well as immediate release Adderall.  I will refer to Adderall XR always as Adderall XR.  I will refer to Adderall Immediate Release as either Immediate Release Adderall or just Adderall.

            In terms of the Adderall XR review, there were 98 reports that I showed you in the previous slide.  When we did a hands-on review of those reports, it was found that actually 29 of these were related to the Immediate Release Adderall product, and not to Adderall XR.   And so, in going back, the Office of Drug Safety then did a subsequent review for Immediate Release Adderall to make sure that we were capturing all of the Adderall XR reports, as well.  So in looking at the Immediate Release Adderall review, those 29 Immediate Release reports were also captured, of which two were adults.  But in addition, there were three additional Adderall XR reports that were identified in the Adderall review, so if you look at just the Immediate Release Adderall, there were a total of 29 Immediate Release reports, two of which were adult, leaving us with a total of 27 total pediatric Immediate Release Adderall reports in the one-year post-exclusivity period.

            Now if we go back to Adderall XR, we started with these 98 reports.  We subtract the 29 that were related to Adderall, leaving us with 69 reports.  Of those 69 reports, four were adults, 16 were duplicates, and four had no adverse effect that was noted.  Please remember this four, because this will show up again in one of my subsequent slides.  So this leaves us with 45 total reports.  If you add the three from the Adderall Immediate Release review, this gives us a total of 48 pediatric Adderall XR reports in the one-year post-exclusivity period. 

            In the next few slides, I'm going to give you data for both Adderall XR, as well as Immediate Release Adderall.  These are the demographics in the one-year post-exclusivity period.  For both Adderall XR and Adderall, the majority of reports were in the male population.  The majority of patients used the drugs for ADHD or ADD, and the predominant age in which adverse events were reported were primarily in the 6-11 age range, and the 12-16 age range. 

            In terms of the outcomes, you've heard a little bit from Dr. Iyasu this morning that on the MedWatch form, the outcome boxes are checked.  Please note that multiple boxes may be checked on one report, which is why these numbers don't necessarily add up to the totals of 48 and 27.  So in the hands-on review, with Adderall XR there were five deaths, there were two deaths with Immediate Release Adderall, 14 patients required hospitalization with Adderall XR, six with Adderall.  Eight patients reported life-threatening illnesses with Adderall XR, one with Adderall.  Two patients reported disability with Adderall XR, and seven patients with Adderall XR required intervention, and two patients with Immediate Release Adderall.

            Now I'm going to focus on those seven deaths, the five in the Adderall XR, and the two in the Immediate Release Adderall in that one-year post-exclusivity period.  The first was a 10-year old who collapsed at home after 22 months of treatment with Adderall XR, 15 milligrams per day.  The autopsy revealed coronary artery anomalies.  Other family members were subsequently found to have short QT syndrome. 

            There was a 10-year old who experienced sudden death while taking Adderall XR, no other details were available in the report.  There was a 12-year old who took methylphenidate for four years, who died suddenly after running cross country on the first day of Adderall XR treatment at 10 milligrams per day.  There was no autopsy performed.  The mother had a history of ventricular tachycardia.  An 11-year old took Adderall XR, 15 milligrams per day for approximately four months.  Two months after discontinuing Adderall XR, the patient was found unresponsive and could not be revived.  Autopsy listed cardiopulmonary arrest of obscure causes.  At the time of death, the patient was on atomoxetine and bupropion.  Then finally, a 14-year old male who made unusual movements and collapsed at school, he developed ventricular fibrillation, was subsequently hospitalized on full support, but died ten days later.  No autopsy was performed.  He had been on Adderall XR for three years.

            I just want you to note for future presentations by Dr. Gelperin this afternoon, that she will talk about four deaths in the year 2005, and that's because this patient had been off Adderall XR for two months, so her analysis includes these other four patients. 

            In terms of the Immediate Release Adderall, in the post-exclusivity period there were two patients who died.  One was a 12-year old who experienced sudden cardiac death while running.  The patient had been taking Adderall, 30 milligrams per day for five months.  Concomitant medication was atomoxetine.  An autopsy found an unspecified genetic cardiac problem.  And the second case was a 7-year old who died during sleep after restarting Adderall following a summer break.  That patient at autopsy was found to have a bicuspid aortic valve. 

            In trying to put some of the deaths into a little perspective for you, if we go back to January of 1999 through the end of the post-exclusivity period of November 2005, we identified eleven sudden deaths of unknown ideology, six sudden deaths with either cardiac or genetic predisposition, four suicides, and two other.  I want to try to put this in a little perspective because you all have received a number of reviews, and sometimes the numbers overlap, and it's difficult to identify where all these patients are coming from.

            If you look at this timeline from January 1st, 1999 through November 28th, 2005, there was a review by Dr. Gelperin between January 1st, `99 and December 31st, 2003 that identified twelve sudden deaths.  And then I have just told you about the seven sudden deaths that we identified in the post-exclusivity period.  However, when you look at each of these reports, two of these reports in the post-exclusivity period were actually duplicate reports from the previous review, so that means that there actually were a total of 17, as I presented in the previous slide, 17 sudden deaths.  And in the period of Dr. Gelperin's review, there were three suicides noted, there were no suicides that I reported to you in the one-year post exclusivity period; however, there was one suicide in this gap of time between December 31st, 2003 and October 28th, 2004.  And of note, this was when Health Canada took Adderall XR off the market between February 9th, 2005 and August 24th, 2005. 

            Okay.  In looking at the categories of adverse events reported for Adderall XR and Immediate Release Adderall in the one-year post-exclusivity period, there are 52 here, and that's because that includes these four patients lack of effect, and no adverse effect that I told you about before.  So with the Adderall XR, there were 17 psychiatric adverse events, four psychiatric adverse events with Immediate Release Adderall.  There were 15 cardiovascular adverse events with Adderall XR, and 6 with Adderall.  There were five neurologic adverse events with Adderall XR, six with Adderall.  There were three abnormalities in growth and nutrition with Adderall XR, and none with Adderall.  There were two dermatologic adverse events each with Adderall XR and Immediate Release Adderall.  There were three adverse events associated with the respiratory tract with Adderall XR, and then lack of effect, one with Adderall XR, seven with Immediate Release Adderall.  Three other adverse events with Adderall XR, two with Adderall, and no adverse event noted in three cases with Adderall XR.

            Now I'm going to focus solely on the Adderall XR adverse events that I just told you about in that previous slide.  And before I go into any of the rest of these slides, I want you to note that each case may report more than one adverse event, so these numbers here do not necessarily add up to the number here.  And just so you know, underlined events are those that are unlabeled.  So in terms of the 15 cardiovascular adverse events, there were five cases of tachycardia, four chest pain, one prolonged QTC, three arrhythmias, four sudden death, one autonomic dysfunction, and two unspecified cardiac disorders. 

            In terms of the 17 psychiatric adverse events, there were four that described hallucination, seven that described violent behavior that included aggression, agitation, hostility, homicidal ideation or assault, three that described psychosis, four suicidal ideation or attempt, four crying, moodiness and irritability, two paranoia, three insomnia, one nightmares or night terrors, one depression, and two panic anxiety. 

            In terms of the five neurologic adverse events, there were two dyskinesias, one seizure, one depressed consciousness, one leg spasticity, and two tics.  In terms of the respiratory adverse events, there was one patient who had a respiratory arrest associated with severe asthma, one patient that described dyspnea, throat tightness, and one patient with asthma.  In terms of the dermatologic adverse events, one patient described toxic epidermal necrolysis, and one patient described generalized rash and skin exfoliation.  In terms of growth and nutrition, one patient described growth suppression, two patients described weight loss, and there was one case of anorexia.  In terms of the other adverse event reports, there were three; one suspected glaucoma, one increased prothrombin time, and one with extremely high amphetamine levels. 

            So in summary, for the Adderall XR adverse event report profile in the one-year post-exclusivity, there were 48 unduplicated pediatric reports.  There were 14 cases of cardiovascular adverse events, including sudden death.  These are known and labeled, especially in children with structural cardiac abnormalities, as Dr. Andreason told you about earlier this morning, and there are plans for future studies that will be discussed later today by Dr. Graham. 

            In terms of the 15 psychiatric events, these will be discussed in context at the other drugs used to treat ADHD later today by both Dr. Gelperin and Dr. Mosholder.  And in terms of the serious skin reactions, these are not currently in the Adderall XR label.  However, these same skin reactions that were described here are listed under the adverse events with other methylphenidate products in the Concerta label.  And there was one case of glaucoma, and glaucoma is labeled as a contraindication.

            Obviously, this report couldn't have been done without a lot of help from a lot of other people, both in the Office of Drug Safety and the Division of Psychiatric Products, and in the Division of Pediatric Drug Development.  So that's the end of my talk, and now it is my pleasure to introduce Dr. Andrew Mosholder, who is a Child Psychiatrist and Medical Officer in the Division of Drug Risk Evaluation in the Office of Drug Safety.

            DR. MOSHOLDER:  Good morning, and actually, this is the first of two talks I'll be presenting this morning.  And what I'm going to try to do to provide some context for the discussion is provide an overview of the prevalence of use of ADHD medications, and of ADHD in the United States. 

            Okay.  I'll be covering, first of all, some recent survey data from the CDC that was published last September, and also some data that we have from the Verispan prescription drug database.  And just for those of you who were at the February DsaRM meeting, this is very similar to the presentation that I gave there. 

            Okay.  To go first to the CDC survey, this was part of the National Survey of Children's Health.  It was a telephone survey conducted in 2003 and early 2004.  There were roughly 100,000 subjects in the sample ages 4-17 years, and for each subject the parent or guardian in the household responded by telephone to questions about diagnosis and treatment of ADHD for that child.  And the sample was such that they could do statistical projections to the national and the state level, which I'll be showing you in a minute.

            All right.  This is a fairly rich slide, so let me describe it, take a little bit of time to describe it for you.  First of all, we have on the left males, and on the right females.  Going along the horizontal axis out from the center is the percentages, and then the vertical axis is age.  Now you see two sets of bars.  The outer paler blue bars are the percent of subjects who have ever been diagnosed with ADHD, and the inner darker bars are the percent of subjects who are currently receiving a medication for ADHD at the time of this survey.  Now you see that they were able to put statistical confidence intervals on these estimates, so several points to make here.

            First of all, looking at the outer bars which represent the proportion or the percentage of subjects diagnosed with a disorder, you can see that in both girls and boys it increases steadily until say around age 9 or 10, and then tends to level off.  And also, you'll see, it's very obvious that the diagnosis is more common in males than in females. 

            By the teenage years, there's some statistical variation, but one interpretation is that there are relatively few new diagnoses that are taking place in these older years.  And if you average males and females together, that roughly 10 percent of children by the end of the teenage years will have been diagnosed with ADHD. 

            Then looking at the medication, which is the inner bars, you can see that again the prevalence increases until roughly around 10, 11, 12, both boys and girls, and peaks around 9 percent for boys in that age range, and around just under 4 percent for females.  And you can see also that the prevalence of medication tends to decline a bit in the teenage years so that there are by the older teen years a fair proportion of the patients who are no longer receiving the medication. 

            All right.  This map displays by state the prevalence of the diagnosis, lifetime diagnosis.  You can see that there's quite a range from 6 to roughly 10 percent, and also you can see there appears to be some regional variation with sort of a higher prevalence in the southeast, and lower prevalences here in the west. 

            Now this is a similar display, but here we're looking at the prevalence of ADHD medication use.  And again, you can see there's a good range here from around 2 percent up to over 6 percent.  Again, a concentration of more or less here in the southeast, and relatively less use in the west.  And the reasons for these regional variations are not well understood.  So the conclusions from the survey, first of all, there's a high prevalence of ADHD diagnosis and medication use in children and adolescents.  The estimate is 2.5 million children in this age range receiving medication for ADHD, and that is around 4.3 percent of all children in that age group.  And, of course, it's higher for males than females.

            The authors said that with this high prevalence of medication use, it's important to get a better understanding of both the benefits and the risks of medication treatment for this disorder.  And, obviously, the implication here - any risks that we discover about these drugs would have potentially great Public Health impact given the high prevalence of their use.

            There are  regional variations in both diagnosis and medication use, as I said, and medication use peaks around ages 9-12, with peaks being 9.3 percent of boys age 12, 3.7 percent of girls at age 11.  Now there are limitations to this.  Of course, it's survey data, and has the usual limitations of such data.  And also, it's dependent upon parental recall, but nonetheless, I think it gives us some insights. 

            Okay.  I want to turn now to the Verispan data.  This is prescription data from the Vector One National Source, and this is a database that includes data on prescription activity from retail pharmacies from various sources, data is available on prescriber specialty, patient age and gender, and includes roughly 1.8 billion prescriptions annually for 150 million patients, so you can see it's a broad sample.  Limitations, does not provide data on indication or duration of treatment.

            And the drug products are active ingredients we looked at, amphetamine, dextroamphetamine combination, which as you've heard as Adderall and Adderall XR, atomoxetine or Strattera, the D-Ismer of amphetamine which is Dexetrin, the D-Ismer of methylphenidate which is Focalin and Focalin XR, methamphetamine which actually is a prescription drug product but is very rarely used, as you'll see in a moment.  There are various methylphenidate products, and Modafinil, which as you've heard, is under consideration for this indication.  Finally, Pemolin, which has since been taken off the market for petato toxicity, as has already been mentioned.

            This displays by age group the proportion of the total of prescriptions for these drugs.  This was the most recent six-month period for which we had data.  And actually, zero to four it's not -- it rounds down to zero, but there is a very small amount of prescribing for that very young age group, somewhat more in ages 5-9, and about half ages 10-19.  Ages 20-49, maybe a quarter, and then somewhat surprisingly, adults over age 50, up to 10 percent of the use.  And although it's not a topic for this particular committee, at the February meeting, there was concern about this, because obviously for cardiovascular risks this would be a population where that would be of significant concern.

            All right.  This shows the total prescriptions separated by age group, and we see pediatric age group at the top here.  This is the adult use, and then there's a small amount of prescriptions which have unspecified age.  And this covers roughly a three-year period. 

            A few things to notice.  First of all, you can see that for both adults and children, use is increasing.  Looking at the most recent data, you can sort of see visually that about one-third of the total is now used by adults.  And this is per quarter, so this is roughly 2 million prescriptions per month for children, and about one million per month for adults.  And also you see there's a seasonal variation for the pediatric use, and as people probably guessed, these  nadirs correspond to the summer months.  That's not seen in the adult data. 

            Okay.  This is a display of prescriber specialties.  Unfortunately, this is for all ages.  I didn't have it separated out by just pediatric age group, but you can see, as has already been mentioned, psychiatry and pediatrics, the largest portions, just under a third each, some prescribing by other primary care specialties, and then a variety of other specialties with smaller percentages.  And we can imagine that if we had limited it to the pediatric age group, that this would probably have been a larger percentage.  And this is data which Dr. McCune has already showed you in part.  This is the total prescriptions by active ingredient, and you can see this is the total up here for all prescriptions.  And as already been described, it's basically three primary drugs being prescribed, methylphenidate the leading one, followed by amphetamine represented by Adderall, and this is atomoxetine.  Interestingly, you can see that there's a seasonal variation for the first two, but not in the case of atomoxetine.  And then the others, very small percentage of the total.

            And this is just another way of looking at more or less the same data for the most recent six month period, where it was available, of pediatric use by active ingredient.  Again, you can see methylphenidate is the leading one, amphetamine, d-amphetamine representing Adderall, and atomoxetine with about 16 percent, and the others of miscellaneous compounds with smaller percentages. 

            So the conclusions from the prescription data, there's been increasing use of drugs by both adults and children.  As I mentioned, there's roughly one million prescriptions monthly for adults, and two million for children.  If you think back to the CDC estimate of 2.5 million children currently receiving medication, that's in the same ballpark as this, if you figure one prescription per child per month.  It works out to be about two million.  Methylphenidates most frequently prescribed followed by amphetamine, and then atomoxetine. 

            And in closing, I'd like to acknowledge the investigators from the CDC for allowing me to share their data, and also in our Office of Drug Safety, Carol Pamer for her assistance with the Verispan data.  And now it's my pleasure to introduce Dr. Kate Gelperin, a colleague from the Division of Drug Risk Evaluation, and she will be talking about the cardiovascular adverse events.

            DR. GELPERIN:  Good morning.  This morning I'm going to update you on the cardiovascular risk of drugs used in ADHD with a focus on the pediatric population.  I'm going to review the rationale for our safety concerns, talk about MedWatch reports, including sudden death in children. I'm going to discuss some calculated reporting rates, and some information about background incidence of these events, and then briefly just touch on non-fatal cardiovascular events. 

            As Dr. Andreason reviewed earlier today, the amphetamine and methylphenidate are adrenergic agonists, and it is known pharmacologically that increased adrenergic tone can be associated with ventricular arrhythmias and sudden death in some patients.  There is a known effect of sympathomometic  drugs on blood pressure, and that's described in some labeling.  Dr. Andreason has previously described the labeling about cardiovascular risk factors, such as structural heart abnormalities. 

            The relationship between blood pressure and the risk of adverse cardiovascular outcomes is continuous, consistent, and independent of other risk factors based on data from observational studies in adults.  The risks in children are not known. 

            Atomoxetine, the brand name is Strattera, is a selective norepinephrine reuptake inhibitor so it's not strictly speaking classified as one of the stimulants, but I would just call your attention to the current approved labeling for this product, which does include a precaution about effects on blood pressure and heart rate, and does describe in the placebo-controlled clinical trials in children that there was an increase of about 1.5 millimeters of mercury in systolic and diastolic blood pressure compared to placebo.

            There are two publications I'm aware of in children using ambulatory blood pressure monitoring methods.  One more recent one by Samuels, Franco and Wan was published this year which describes 13 subjects with a mean age of 12-1/2 years, who underwent ambulatory blood pressure monitoring, both on their usual stimulant medication, and placebo, using a placebo-controlled double-blind randomized crossover design.  There were nine males and two females, six of them were on methylphenidate, four were on amphetamine, and one was on dextroamphetamine.  Eleven patients had paired ambulatory blood pressure monitoring studies that were considered to be of sufficient quality for a full analysis. 

            After a three-day run-in followed by a 24-hour monitoring period, the subjects crossed over to the alternate therapy repeated ambulatory blood pressure monitoring.  The subjects demonstrated elevations in both hemodynamic parameters derived from ambulatory pressure monitoring on active drug.  Total diastolic blood pressure and waking diastolic blood pressure were significantly higher on active treatment.  Total heart rate was significantly higher on active treatment.  The authors point out that the rate pressure product, which is the product of systolic blood pressure and heart rate, which is an index of myocardial oxygen demand, was higher during active treatment, and the effects of this over long periods of time is just not known in children.

            Very few long term studies randomized control double-blind trials have been done in children.  Dr. Vitiello reviewed the multi-modal studies, and there is a Swedish study which also was a long-term study of amphetamine.  However, these studies, and in addition, there are long-term extension trials which do not have a comparator arm in some cases, or in other cases they are open label, that do have some information about blood pressure.  However, targeted cardiovascular outcome trials have not been done.

            A review of MedWatch cases that was done for the PBCA review did suggest potential cardiovascular signal, but these data were not considered to be conclusive.  The non-fatal cardiovascular reports include syncope, chest pain, myocardial infarction, stroke, arrhythmias.  However, the cases are often not well documented.  There have been sudden death reports, and I'll tell you a little bit more about these. 

            Last June there was a Pediatric Advisory Committee discussion about these cardiovascular and psychiatric adverse effects, and the Committee considered that the FDA should pursue additional means to better characterize the cardiovascular risks for all drug products approved for ADHD. 

            I'm going to tell you about some calculated reporting rates from MedWatch reports, but I want to mention the limitations of reporting rates.  As Dr. Iyasu mentioned earlier this morning, there is considered to be under-reporting of spontaneous reports in the United States; however, the extent of this is not known, but it results in a numerator that is not reliable. 

            In addition, the denominator is not reliable.  It's based on projected drug utilization numbers, so this is not an incidence.  And a comparison of reporting rates to a background incidence, or even between drugs, is really only a rough estimate.  And, of course, with spontaneous reports there may be confounding, there may be other drugs on board, there may be pre-existing conditions.  However, the presence of other drugs and pre-existing conditions does not necessarily rule out that the drug in question has contributed to an adverse effect, so the Office of Drug Safety has conducted searches of the adverse event reporting system, safety database, we call that AERS, and we used a definition of sudden death in our review that has been used by the World Health Organization, which is that death occurred immediately or within 24 hours of an acute collapse.

            In our analysis, we excluded cases in which the death was caused by a multi-drug overdose, because we felt this would not be relevant to the usual therapeutic use of the drug.  We also excluded all cases in which drug abuse was reported, and we excluded cases in which death was most likely caused by something else.

            For a perspective, I'd like to call your attention to the published incidence rates for pediatric sudden death in the United States.  A review of this topic was done in 1996 by Liberthson and published in The New England Journal.  It includes data on 469 sudden deaths from nine studies of large populations.  The rate of sudden death in these populations ranged from 1.3 to 8.5 per hundred thousand patients years, with males consistently out numbering females.  In two-thirds of the cases, a specific cardiac cause was identified.  Extrapolation of these data suggests that each year several thousand Americans under the age of 20 years die suddenly from cardiac disorders.

            For ages 1-30 years, the most common cardiac causes of sudden death including myocarditis, hypertrophic cardiomyopathy, coronary artery disease, congenital coronary artery anomalies, conduction system abnormalities, mitral valve collapse and aortic dissection. 

            This slide was shown previously at the February Drug Safety Advisory Committee meeting, and is based on work that was done by my colleague, Dr. Lourdes Villalba, who is a safety reviewer in the Division of Psychiatric Products.  These reporting rates cover the time period between 1992 and February 2005.  You also received information in your background package for a consult that had been prepared by me prior to this consult with reporting rates for a five-year period.  And you can see that the reporting rates per hundred thousand person years for this larger time period are actually comparable to the five-year period that we had previously looked at.

            Of note, however, atomoxetine was not included in that earlier review, because that drug was only approved in November of 2002.  So, for instance, in this slide there are only two years of data for atomoxetine included. 

            Although the calculated background rates that you see in this slide do not appear to exceed the published incidence rates based on death certificate reviews, this is not completely reassuring because the extent of under-reporting is not known.  For instance, if FDA has received 10 percent of potentially relevant cases, then the reporting rate would be approximately equal to the published incidence rates.  However, if FDA has received only 1 percent of the true number of cases, the reporting rate would exceed the published rate. 

            This slide describes to you some of the characteristics of the 13 cases of pediatric sudden death for that 12-year period in which amphetamine or dextroamphetamine was considered a suspect drug.  In all 13 cases, the suspect drug was identified as either Adderall or Adderall XR.  The ages of the patients ranged from 7-16 years, and they were all male.  The dosage ranged as you see, and the duration of therapy ranged from one day to eight years.  Autopsies were done in 11 cases, and the autopsy findings included things like aberrant origin of coronary artery, idiopathic hypertrophic subaortic stenosis, bicuspid aortic valve.  In three cases, the coroner stated that there was an unexplained increase or a toxic amphetamine level in a child who had been taking apparently normal doses. 

            Cardiac hypertrophy was described in three cases.  A heart murmur had been reported on history in three cases, a maternal history of ventricular arrhythmia was described in one case, and there were no relevant autopsy findings in five cases.  Ten of these 13 cases, there were no concomitant medications reported.

            With regard to the 11 cases identified of pediatric sudden death in that 12 year period in which methylphenidate was considered a suspect drug, the ages ranged from 9-15 years.  There were seven males, and there were four females.  The brand name of the product was Ritalin in seven cases, and Concerta in four cases.  The doses ranged as you see.  The duration of therapy ranged from two months to ten years, and an autopsy was done in seven cases.

            In two cases, there was reported a congenital cardiac malformation along with concomitant quantity in  therapy.  In one case there were multiple abnormalities, including heart hypertrophy and tricuspid valve anomalies.  In one case there was cardiac small vessel damage, cardiac hypertrophy and obesity, and in one case there were unexplained toxic levels of methylphenidate, and this was nine days post-operative.  One subject had a history of syncope and there were no pertinent findings reported in five cases.  In six of these cases there were no concomitant medications.

            With regard to the three atomoxetine cases reported in that 12-year period, the youngest child was 2-1/2 years old, and the oldest was 12 years old, two were male and one was female.  The duration of therapy ranged from six weeks to four months, and an autopsy was done in all three cases.  One autopsy found toxic levels of a different drug, Olenzepine, and this may have caused the death.  In one cases, lymphocytic myocarditis compatible with a viral infection was found at autopsy, and in one case peribronchioloar chronic inflammation was found.  In none of these three cases were structural heart abnormalities noted.  In two of the cases, there were no concomitant medications. 

            This slide attempts to update for you so that we can bring this information up to the most recent time possible, just for the calendar year of 2005, so these reporting rates are going to include two cases which were actually included in Dr. Villalba's reporting rates which did go up to February of 2005.  The reason this was done is just to apply - we now use a different vendor which is Verispan, and so to use the drug use data that was available, the numerator was selected to be the year 2005.  So for the drugs of interest, you can see the count of cases for methylphenidate - there were two, for amphetamine there were four, and for atomoxetine there were four, and the corresponding reporting rates we believe are probably not meaningfully different from the previous reporting rates.  However, I don't mean to say that these are completely reassuring numbers.

            I will just briefly describe the cases, although you really have already heard about these from Dr. McCune.  And as she mentioned in the amphetamine reporting rate, the case where the child had stopped the amphetamine two months prior to death and was actually taking atomoxetine and Buproprion at the time of death was not included in this reporting rate because the drug had been stopped two months prior to death.

            The ages ranged from 10-14 years, with a mean of 11.5 years.  There were three male and one female.  The brand was Adderall XR in three cases, and Adderall  in one.  The dose is 15 milligrams total daily dose in two cases, 30 milligrams in one case, and not reported in one case.  Duration of therapy ranged from five months to three years.  Autopsy was done in two cases.  One the report stated that the coroner found a genetic cardiac problem which was not further specified.  The other case, the finding was coronary artery anomalies.  There were no concomitant medications in two cases.

            For methylphenidate there was very little information with the two cases that were reported.  And atomoxetine, the four cases ranged in age from 6-11 years.  They were all male.  The duration of therapy ranged from three days to a few months.  All four had autopsies.  One showed cardiomyopathy and valvular disease, one showed brain herniation, one stated cardiopulmonary arrest of obscure causes, and there were no concomitant medications in two reports.

            This pediatric sudden death case report, I think, highlighted for us the risk of a child with previously undiagnosed severe structural heart abnormality starting therapy with a stimulant, and that this 13-year old male who had previously been healthy and involved in sports was started on a 20 milligram dose of Immediate Release amphetamine, and he did collapse at his computer in the late afternoon, and the autopsy showed idiopathic hypertrophic subaortic stenosis. 

            The non-fatal cardiovascular events are under review, but in a five year period for amphetamine, you can see they included things like syncope, arrhythmia, myocardial infarction.  For methylphenidate, similar types of events, and for atomoxetine, these events are currently under review.

            In summary, I would just state that we have many challenges in risk assessment of this issue, the acute versus chronic effects of the drugs, the different background risk for the different age groups, and the unknown effect of confounders.  I'd like to introduce to you Dr. David Graham, who is our Associate Director for Medicine and Science, and he's going to tell you about the FDA plans to study these issues.

            DR. GRAHAM:  Good morning.  I will spend the next few minutes talking about studies that we have in mind to investigate further the question of cardiovascular risk with drugs used to treat Attention Deficit Disorder.  Just sort of summarizing what's gone before, within the Office of Drug Safety, I think it's safe to say our Bayesian priors are that these drugs probably do increase cardiovascular risk.  The question then really is, by how much, and are there factors that could predict who might be more likely to have this happen?

            The distinction in our mind between a stimulant and a non-stimulant is, in our view, probably immaterial to the question of cardiovascular risk, because all drugs increase norepinephrine levels within the synapse.  And we know very well, and if you look at any cardiovascular textbook, increased adrenergic tone is associated with arrhythmias and sudden death, and so we think that all three of these drugs should be considered together as a group, and the distinctions I think are more a red herring than anything else.

            Just to give you a little background, we have an epidemiology contract program that replaces a previous cooperative agreement program we've had that enables us to do epidemiologic studies in population-based settings.  So these aren't clinical trials, they're observational studies.  They use automated healthcare data, but we do have the ability to go back to medical records.

            We currently have four programs that are funded covering about 23 million covered lives.  One of the problems with these types of databases are turnover, and so in terms of trying to look at chronic use of a therapy over time, the turnover within these health plans gets in the way of our being able to follow people because they disappear from the health plan.  An employer changes the health insurance for the family and they disappear from the data set, and so you can see the turnover varies at one year between 8-30 percent depending on which of the various plans we're talking about.  And then for the five-year turnover it's 25-80 percent.  This year we have funding of $1.6 million for databases.  Next year that funding drops to less than a million dollars. 

            To investigate this question, we queried our four databases to see was it possible to go forward with a more in-depth formal epidemiologic study.  The design that we employed was in section cohorts, so these are new users of these products, so there's a period of time that we see before they get their first prescription.  And you can see the study periods that we've included, and the drugs of interest are the three major ADHD drugs that we're considering.  And we'll be looking at two components, children and adolescents, and then adults, as well.  And the rest of my talk will focus on the pediatric age group. 

            Our primary outcome of interest is sudden cardiac death, then acute myocardial infarction, cerebrovascular accidents, and arrhythmia are also important to us. 

            This just gives you a little detail about the population that we'll be hopefully doing the study in.  We have a base population of about 7 million children  under the age of 19, between 1-19 years of age, and that covers about 45 million person years of observation time.  For each of the three drugs that we'll be studying, you can see the number of patients that we have, about 200,000 children on methylphenidate or amphetamine, and a smaller number with atomoxetine.  And then the number of person years of time on drug that we have within each of these cohorts.  So these are fairly large cohorts, but as you'll see, they may not be large enough to resolve uncertainties at the level we would like.

            For all three drugs across the databases, the proportion of drug that's used in males is about is about 73 percent.  This slide describes the persistency of use of these products over time, so this is a description of duration of use of products over time.  And you can see for methylphenidate and amphetamine that the median duration of use is somewhere around seven or eight months within the database that we have, and that about 10 percent of patients have use that goes on beyond about 18 months.  For atomoxetine, the curve is shifted towards shorter durations of use.  That is, in some regards, an artifact of how long the drug has been on the market.  But what it does tell you is that in terms of looking for risk as a function of time on drug, that the denominator at risk gets very small with prolonged durations of use. 

            Background rates for sudden death were summarized by Kate in her presentation.  This is just to give the Committee an idea of what we think we're dealing with, which is that these are uncommon events, and so that poses unique challenges in trying to study something in an observational database.  But it also means that the ability to study this in a clinical trial is probably nil.  And you can see now that we have uncertainty about what these background rates are for sudden death between one and nine per hundred thousand per year.  For myocardial infarction, the range is even greater depending on the study that's been done.  And then for cerebrovascular accident, there we have a number of different studies that have all come up with about the same rate, so we think that in terms of certainty of background rates, our background rate for cerebrovascular accident is probably the one with the greatest certainty. 

            With this feasibility study we queried the database of these four health plans to see how many children they had with a primary diagnosis, hospitalized diagnosis with the different outcomes that we're interested in, so there's no replication of children in these slides.  It was the first, the primary diagnosis.  You can see that we had about 17 children with myocardial infarction, another 17 with other hospitalizations for ischemic heart disease, 14 with cardiac arrest, 49 with stroke, and 245 with arrhythmia.  This is both superventricular and ventricular arrhythmias, but it was the primary discharge diagnosis for those hospitalizations.

            If we look for any diagnosis within the hospital discharge, not only the primary but also secondary discharge diagnoses, we have 24 children with a diagnosis of myocardial infarction, about 90 with a diagnosis of stroke, and about 450 with a diagnosis of cardiac arrhythmia.  Two hundred and forty one deaths were reported within this cohort, but as I'll show you in the next slide, that is a gross under-estimate of what the actual number of deaths probably were.  First off, these deaths occurred at any time after entry into the inception cohort, and so you could have somebody who's entered the inception cohort, is on the drug for six months, and then is still in the database after that but isn't taking the drug any more, and they died subsequently, so we don't know if the deaths are while they're on drug or off drug.  These deaths could be from any cause, not just from cardiac causes. 

            For two of the sites, the deaths that we had were based on in-hospital discharge diagnoses only.  Or one site, we have no information on deaths, and for one other site we included both in-patient and out-patient deaths because they have linkage to death certificates.  So when we go on to do our study, we will be looking for both in-hospital and out-of-hospital sudden deaths, and that will require that we go to the National Death Index, and that we seek out death certificates on all subjects that died.

            The next five slides I'll go through quickly.  I'll explain the first one, and then members of the Committee want to look at them at their own leisure, they can.  But these are power curves that give a sense of what types of risk ratios we might be able to detect based on the background rates that we're dealing with, and the number of subjects that we have to work with in the study.  And so what this slide shows is it's looking at acute myocardial infarction in children.  And if you remember, the background rates there went between 1-20 per hundred thousand per year, so these power curves are predicated on a background rate of about 15 per hundred thousand per year.  And what this slide shows is that if you go to the previous slide where we showed the size of the cohorts, we have a total of 400,000 children who are on any of these drugs.  I mean, 400,000 person years, 399,000 person years on the drug, and so if you went over to the 400 and go up, you can see that we had a lot of power to detect even relative risk of two, if we look at all drugs combined together.  But if we wanted to look at individual drugs, for example, we want to look at atomoxetine where we have about 40,000 patient years of use, you can see that we really only have power to detect a relative risk of somewhere around three or four.  So this is just to give you an idea of what we're dealing with.

            And this slide is for stroke in children where background rates were three of 100,000 per year.  And then this is another way of calculating power, which is the way it's done in clinical trials, where a study is powered based on the number of outcome events that you'll experience.  And so this, you can see, you can use this slide to see well, we need X number of events to determine the relative risk of a given magnitude. 

            Another way of looking at an observational study, or any study for that matter is - one way is what relative risk can we detect with what degree of confidence?  Another way to approach it is what level of risk can we exclude with a given level of confidence, it's sort of basically capping the risk to say that we can't tell you exactly what the risk is, but we can tell you that it's unlikely to be greater than some number.  And so the next two slides show what those power curves look like in terms of the power to exclude a variety of relative risks.

            This slide tries to summarize what the previous five slides were dealing with in terms of what we believe the power is in our study to detect particular relative risks for sudden death, myocardial infarction, stroke in children by individual drug, and then combined.  And so you can see that at the end of the day, there'll still be some level of uncertainty in what we can only hope for, probably, with the studies that we're proposing is, is that we'll detect, if they're there, relative risks that are relatively substantial, but the relative risk itself may be substantial, but the absolute risk may still remain relatively low.

            Some additional power considerations I think that we need to be aware of is that we don't know what the background rate is for sure, especially say with myocardial infarction, with sudden death.  And so based on the information we have, as I've circled in red here, it's possible that for myocardial infarction that we may have more cases than one would expect.  We may have less cases than one would expect.  And then again, we also have the problem, we don't know if these events happened while on drug or off drug, so these are things that need to be finalized in an in-depth study.

            So I'd like to leave the Committee with a couple of caveats.  One, this feasibility study we're talking about very preliminary results.  The purpose of the preliminary feasibility study was to see whether there's enough information there for us to go forward with an in-depth study.  We believe there is, and we're in the process of trying to design the study to go forward. 

            Definitions of exposure in outcome we used are relatively crude here, and they haven't been validated; although, acute myocardial infarction has been well validated in adults and the positive predictive value of a primary diagnosis of AMI is about 95 percent.  Our power calculations are crude, and a lot of that has to do with the uncertainty about what background rates are.

            At the February Drug Safety and Risk Management Advisory meeting, one proposal came up during the committee discussion about forming an observational echocardiographic study of patients who have been on these various drugs for varying durations of use.  I think the committee was probably thinking more about doing such a study in adults than in children, but the same study design could be applied with children, as well. 

            Generally, what they were talking about was within a large healthcare database, identify patients on these drugs for varying durations of time, select suitable untreated patients, and perform echocardiography on them.  And look to see what the left ventricular wall thickness is, what there contractility is, and then other measures that the echocardiographers could tell us would be important, perhaps predictors of various cardiovascular outcomes.  So to give you an idea of what that might look like, taking our preliminary feasibility results and looking at the curve, the contour of duration of use, you could see at six months you'd sample people who were on the drug for six months at that particular time, bring them into a lab, do cardiography on them.  You take people at 12 months, at 18 months, at two years, and do the same thing, and then what you basically have is sort of a time series study, not on a given individual being followed chronologically over time, but it's a cross sectional prevalence study over time of what echocardiographic changes might be.

            So in summary, I think we have some concern about the potential for cardiovascular risk with these drugs.  There's a very high prevalence of use of these drugs in children, and so the Public Health impact could actually be of importance and meaningful.  Sudden unexplained death is our primary interest, and will also be the most difficult to study. 

            Our feasibility study has showed that we have substantial exposure time, and that the study is feasible to do.  We have limited statistical power to detect relative risk below about 2, but the number of arrhythmia cases struck us as being particularly high. None of us being pediatric cardiologists, we didn't know whether that was something to worry about or not, but that was the primary discharge diagnosis.  We're now in the process of obtaining cost estimates for carrying out the study, but our budget is very limited, and we're looking for ways to fund the study.  And then these are the members of the study team from FDA and the various sites, research database sites that we've used to do the study.  Thank you.

            DR. MOSHOLDER:  Hello, once again.  And the next two talks we're going to be changing topics now, and we'll be talking about neuropsychiatric adverse events with drugs for ADHD.  And I'll be starting with a presentation of clinical trial data, and then Dr. Gelperin will present post-marketing data.  So for my talk, I'll describe the background of this project.  You've already heard a bit about it this morning.  And then I'll be focusing on clinical trial data regarding these events, and I'll have a few comments to make about some literature reports.

            Okay.  Just for orientation, this is a list of the currently approved products for ADHD, and I won't read all of them, but in general, you can see we have amphetamine, which as you've heard is Adderall, Adderall XR.  There are a number of methylphenidate products, including extended release preparations, Concerta, Ritalin LA, atomoxetine, or Strattera.  The  D-ismer of methylphenidate represented by the Focalin products.  There's a D-ismer of amphetamine which is Dexedrine, and then as you see, there's some other methylphenidate products.  And then finally, there are two products for which this indication is pending, Modafinil, which will be discussed tomorrow, and also for methylphenidate, there's a methylphenidate transdermal system, a skin patch, for which we also had data.  Although that's not marketed, so, of course, there's no post-marketing data. 

            Just to give you the background on this project, the BPCA review for Concerta last year, which was presented to this Committee, and a comparable review for other methylphenidate products identified psychiatric adverse events as a possible concern.  The review concluded that labeling regarding these events could be improved, and in June this Committee recommended that these adverse events be examined with an eye towards improving the product's labeling regarding these events.  And so, accordingly, the Division of Drug Risk Evaluation undertook a review of clinical trial and post-marketing data regarding psychiatric adverse events with these drugs.  And this involved, as you've already heard, requesting information from the sponsors, and we asked for both post-marketing and clinical trial data.  And we included the sponsors with pending applications, as well as approved applications for this indication.

            And we focused on four categories; first of all, psychosis or mania, and we can get into a little bit why we grouped those together, but I think just to state it briefly, as a practical matter because it's very difficult to distinguish within the data whether these were psychotic disorders or manic bipolar-type events.  Secondly, suicidal ideation and behavior.  Third category was aggression and violent behavior, and then we also had a miscellaneous category where we asked for serious adverse events, but these data won't be discussed today. 

            For the post-marketing analysis, the time frame was from January 1st, 2000 forward, and Dr. Gelperin is going to present the post-marketing data in the next talk.  And this presentation will focus on the clinical trial findings.  So turning now to the clinical trial analysis, the purpose was to characterize the adverse psychiatric events observed in ADHD clinical trials with an emphasis on these three categories, as I mentioned.  And to determine the rates of these events by pooling the data, primarily by development program, but also data for all methylphenidate oral products. 

            And the information requests that went to the sponsors, which I mentioned previously, for the clinical trial data, the sponsors were asked to perform a text string search of their adverse event databases using both preferred terms and investigator verbatim terms, and searching for terms representing events from these categories. 

            After that, the sponsors were asked to enumerate these events according to exposure, age group, gender, and trial, to provide brief clinical descriptions of the adverse events identified in the search, also to provide descriptions of the clinical trials included in the analysis, and all the sponsors responded, and we were able to review and aggregate the data, and I'll be presenting the findings.

            The products we included, this by now is getting to be a familiar list, I think, but basically methylphenidate, we had Concerta, Medidate CD, and Ritalin LA, atomoxetine, Adderall XR for amphetamine, and for d-methylphenidate, Focalin and Focalin XR.  For the pending applications we had the methylphenidate transdermal system, and Modafinil.  We did receive adult data, although this is described in the written report, which is in the briefing package, but I won't be presenting it in this slide presentation.

            Okay.  To characterize first the clinical trial data sets, this display is for the double-blind portion of the development programs only, and it shows the number of patients randomized both to drug and placebo.  And you can see that in general, there were several hundred subjects in these development programs, and the one notable exception, atomoxetine, had a considerably larger sample size, and followed by the Adderall XR development program.  And these were all pediatric patients, by the way.

            Now this is a similar look at the data, but here we're looking not at numbers of patients, but at person years of exposure.  And as people know, a person year would be one patient taking the drug for one year, or it could be two patients taking a drug for six months, as an aggregated measure.  And you can see that here, atomoxetine has by far the largest exposure when measured in this way.  Part of the reason is that this includes a long-term relapse prevention trial data. But I think you can also see that for some of the products, the actual exposure times were relatively short, just 20-30 years of aggregated person time in double-blind studies.

            Okay.  Now let's look at the numbers of events for these three categories, the next three slides I'll be showing you that.  And starting with the psychosis or mania events, and this display - this is rates of the events for hundred patient years, and you'll see that the products are displayed here.  And this is aggregated, all the oral methylphenidate products were pooled together here.  And a couple of things to notice.

            First of all, there are very few events, a total of 13 events across all double-blind trials that fit in this category, so that's number one.  Number two is, despite that, you'll notice that all 13 events occurred on active treatment, and there were zero on placebo, so that's unlikely to be due to random chance, suggesting some effect of the drugs.  And then you see actually the highest individual rate applies to the methylphenidate transdermal system, with four events, and the others, as you see.

            Looking now at suicidal events, once again - well, let me add first of all, there are no completed suicides in these trials.  And most of these events were ideation rather than actual attempts.  You see once again, there were not many such events, that's a total of 17.  And then you also see that for a couple of products, there appears to be an imbalance relative to placebo, Modafinil at the highest rate per hundred  person years.  And then also, atomoxetine an imbalance relative to placebo, and the sponsor has done an analysis of that, which I'll present in a few minutes.  And then apart from those, there was one event with Adderall XR, and one on placebo in the methylphenidate study. 

            And then the third category, aggression - and here we see actually there's far more events, much higher frequency both on placebo and on drug.  One point to make is, you can see just looking at the placebo, there's some variability from development program to development program, as far as the placebo rate, suggesting there's some differences in ascertainment, and perhaps population studied.  Secondly, looking at this, you'd be hard-pressed to say that there's much evidence that the drug treatment is actually reducing aggressive behaviors in these subjects; although, intuitively one might think that treating ADHD might reduce aggressive behavior in kids, but in these adverse event data, that didn't really seem to be the case.  There's only one, in fact, Modafinil, where the rate was numerically lower for active drug.  And with methylphenidate transdermal system, actually the rate was considerably higher, although this did not reach the customary level of statistical significance.

            Okay.  It's of interest to look at the placebo group, because this is a large sample of ADHD patients without medication.  And in aggregate, there  are almost 4,000 representing over 400 patient years of exposure.  As you might expect, these are predominantly males and pre-adolescents.  And as I mentioned, the absence of any psychotic or manic events in this group was notable.

            For suicidal events, the rate was just under one per hundred of person years, and those of you familiar with the antidepressant pediatric trial analysis, this is a much lower rate than the rates we were seeing in that meta analysis.  Of course, this is a different indication, and also, it tends to be a younger population.  And aggression events, as you see, were far more frequent than the other categories.

            Okay.  The next two slides, I want to show you Lilly did their own analysis of two of these categories for atomoxetine.  And first, this is the suicidal events.  And these findings are actually reflected in the Strattera labeling.  And you see that they use two categories of events; one, suicidal events using an FDA definition, and a second one using Lilly's own definition.  And this was indications not limited to ADHD, so it's a slightly different set of studies.  And also, this did not include the long-term studies that I mentioned, so it's a little different pool of studies from the data I showed you a couple of slides ago.  You see, there is this imbalance with six events on atomoxetine, zero on placebo, and then with the other definition, it's seven versus one.  And you can see the P-values, this one did reach the customary level of statistical significance. 

            Interestingly, the adults really not much of a difference between drug and placebo in frequency of these events.  So this finding, as I said, is mentioned in the Strattera labeling. 

            Also, for aggression, similarly, Lilly looked at these events, and you can see there is a slight excess relative to placebo in terms of frequency.  And, again, that is now described in the Strattera labeling.  And for comparison, this was a methylphenidate active control group, which is somewhat lower. 

            All right.  This is a rather dense slide, but it's just to present the open label data.  And this, I guess in a sense, sort of compensates for the relatively short duration of the double-blind studies.  You can see that with longer exposure time, we've picked up events in most of the categories for these drugs.  And I'll be coming back to the psychotic mania events in a minute.

            So what are the limitations of these data?  Well, first of all, the small sample sizes, and the short duration of treatment, as I've described.  And also, the small number of events made any estimates of the rates relatively unstable.  It's possible there's lack of consistency across trials with respect to ascertainment and reporting of these events by investigators.  There's a possibility of misclassification of cases.  The case definition and search terms, we can't be certain that they had adequate sensitivity and specificity.  And I should add that Lilly was the only sponsor that in their own analyses actually adjudicated the event reports. 

            So just to summarize the findings, for aggression events, it was more frequent with drug than placebo for methylphenidate, patch, Ritalin LA, and atomoxetine.  And again, there's little evidence from these data, at least, that the drugs are successful in reducing the rate of aggressive events. 

            For suicidal events, there is an imbalance for Modafinil and atomoxetine relative to placebo.  As I mentioned, the atomoxetine finding is statistically significant, and is part of the labeling now.  And for the psychosis and mania events, as I mentioned, we had 13 events, all of them happen to -- in the double-blind trials, all of them happen to curve on active treatment.  And in open label treatment, you can see that there was some frequency with all of the products, and the highest percent was the methylphenidate transdermal patch.

            And this is just to provide some examples of some of the more clinically significant events from this category.  There was one 8-year old treated with Modafinil, and a 9-year old treated with atomoxetine.  Both of those children were hospitalized.  Two other cases with Adderall XR, the methylphenidate patch were not hospitalized, but the drug was discontinued by the investigators.  And in this case, the child on Modafinil had a previous history of psychotic symptoms which had not been elicited at the time of enrollment into the study.  So that's just to illustrate the types of events that were in these categories.

            Some more comments on the trials, many of these trials were of short duration, and also in terms of the patient population, many enrolled subjects previously known to respond to drugs in the class so that these factors limit the utility of these trials for determining the drug product safety profiles.  In particular, if children known to respond adversely to the drugs in a class are excluded from the trials, then that, perhaps, maybe not be generalizable to the population for this indication.

            And then just to close, a few brief comments on some literature reports.  I have these two slides.  This first one is case reports, and you can see there is one case series of six.  These were adults, but six patients admitted to the same psychiatric hospital in a three-month span with psychosis thought to be related to Dextroamphetamine, and that caught the author's attention, so they wrote it up as a case series.  There is description of two children who developed what is termed toxic hallucinosis on methylphenidate, and similarly, another case series of three children with visual and tactile hallucinations on methylphenidate.  And a report of a 13-year old female who was described as having typical amphetamine psychosis with Adderall treatment.  And then some publications that had sort of more systematic data collection.  Cherland and co-authors did a chart review of 98 child outpatient's diagnosed with ADHD, and treated with stimulants, and they found that 6 percent developed psychotic symptoms.  That's a much higher rate than what was seen in the clinical trials I just described.  And Dr. Gelperin is going to have some more comments on this.

            Similarly, for atomoxetine, a case series of 153 sequential pediatric outpatients, the incidence of mania was 6.5 percent.  Again, higher than what was seen in the clinical trial population.  And again, Dr. Gelperin is going to mention that.  And then there was a placebo-controlled randomized study of amphetamine with divalproex sodium in patients who had pediatric ADHD and bipolar disorder.  It was a very small study, but it was interesting to note that none of the 30 subjects had worsening of mania when they were receiving concomitant Valpro-8 plus the amphetamine.

            So I'll stop there, and I want to acknowledge, first of all, the sponsors who provided their clinical trial data, and also the people who assisted at the FDA.  And with that, it's my pleasure to bring back again Dr. Kate Gelperin, who's going to talk about the post-marketing data for psychiatric adverse events.

            DR. GELPERIN:  Thanks, Andy.  Today, I'm going to tell you about the results of an analysis of psychiatric adverse effects during drug therapy of ADHD.  I'm going to talk about the methods that we used for the case review and the analysis.  I'm going to talk about the MedWatch reports that reviewed the three main categories that Dr. Mosholder had discussed.  I'll talk a little bit about clinical implications, and what might be some conclusions. 

            The post-marketing safety information was requested from the manufacturers of these drugs, and they performed an analysis of each case that they identified in the searches that we described for spontaneous or literature reports that they had received since January of 2000.  There were four broad categories of psychiatric adverse events.  This discussion today is not going to include the miscellaneous category.  And a high level analysis of patient characteristics and potential risk factors for psychiatric adverse events was completed.  By "high level", I mean that the cases received the initial hands-on review, and the characteristics were entered into Excel spreadsheets.  These data were summarized using SAS and are analyzed as we'll discuss today.  However, additional in-depth analyses could also be undertaken for, for instance, more clinical review of individual cases.

            At the same time, the FDA Office of Drug Safety undertook a search of the AERS safety database for the same time period, and the identified MedWatch cases were assessed by a team of reviewers in the Division of Drug Risk Evaluation.  The reports were classified into the categories, and each report could qualify for more than one category.  For instance, a child could exhibit aggressive behavior and have hallucinations, so that case would count in two of the categories.

            The hands-on review of the MedWatch reports identified duplicates, and reports which were considered to be of very poor quality, or were highly unlikely to be related to the drug of interest, and they were excluded from the analysis.  The criteria that we identified up-front to look at the characteristics of these reports, since they were quite large in number, were adapted from Neuron Ho and a publication that was originally intended to describe a rating system for individual cases, and has since then become really incorporated into post-marketing drug risk assessment as some of the cornerstones that Dr. Iyasu also described to you to help to sort through the questions about post-marketing data, and really make the most of the individual case reports that come to us spontaneously.  So, for instance, we looked at are there published case reports that might be consistent with a causal association?  What's the temporal association?  Did the events improve or resolve when the drug was stopped?  Did the events recur when the drug was re-administered?  That's the positive re-challenge, and that's one of the hallmarks for post-marketing causality assessment of spontaneous reports.

            The cases were also assessed for alternative factors that could cause or contribute to the adverse event, such as concomitant medications, drug abuse, or a pre-existing condition with similar signs or symptoms.  We also considered whether the case was confirmed by a health professional or originally reported by a health professional.  We examined various demographic factors and other potential risk factors that our colleagues in the Division of Psychiatric Products were interested in, such as were there seizure disorders in these patients, was there a psychiatric history other than ADHD?  Was there a family history of serious psychiatric illness?  And in the time constraints today, I'm really going to just be able to give you just a very high level overview.

            These are the search terms that we were interested in for the category of psychosis or mania.  Hallucinations of any type we were interested in, events that were coded as psychotic disorder or acute psychosis, paranoia, and mania. 

            Now I want to orient you to this slide, because you'll see this format again.  Okay.  So the drug names, you've seen these numerous times today, and I am going to use generic names.  I'm going to use the name amphetamine to refer to all branded or generic amphetamine or dextroamphetamine products, either short-acting or long-acting, that would include Adderall.  It would also include Dexedrine.  Atomoxetine is the brand name Strattera.  I'll be referring to it as atomoxetine.  Methylphenidate, these numbers include all brands, all formulations currently marketed, such as Concerta, Ritalin, both short-acting and long-acting. 

            This drug, Modafinil, the brand name is Provigil, is in a gray box because it is not currently approved for ADHD.  It is, however, currently approved for narcolepsy.  And so the sponsor was asked to send us the information about the narcolepsy patients, and we found that there is some small amount of off-label use in ADHD, and so these numbers are included here for completeness, but I'm really going to focus in the time that we have on the currently approved drugs.

            Also, I am presenting to you the results of the FDA AERS analysis.  You did receive in your background package a 90-page document that goes into excruciating detail of the sponsor's analysis and the FDA analysis.  And I'm happy to say that on all of the points worth mentioning, that were pretty much in agreement, so today I'm going to tell you about the numbers from the FDA analysis. 

            These are for the category psychosis or mania.  These are the non-excluded cases, which means we thought they were of sufficient quality to be included in our analysis today.  I will also point out to you that there's an N, which is the count of cases, and we are not attempting to use reporting rates or to otherwise try to assess the frequency of the occurrence of these events, either relative to other drugs that are used in this condition, or relative to expected rates for a variety of reasons, we did not feel that would be appropriate.  So even though these numbers look different, we are not making a conclusion based on that at this time.

            Patient age, you will see that the majority of the reports of psychosis or mania for the drugs currently approved for ADHD were in children and adolescents, predominantly male.  Fewer than a third typically had another psychiatric history, and we were surprised, there were very few with drug abuse on board, and very few with overdose, and very few with seizure disorder. NR means that that information was not reported.  That could mean that it didn't happen, it could mean that it did happen but the reporter forgot to tell us. 

            Sort of the same setup with the drugs, but some different attributes that may help us to understand whether we think there's a drug relationship here.  We wanted to look at how many of these reports are case reports from published medical literature, and we found that yes, there are some.  How many get better when the drug is stopped?  Well, maybe a third to a half.  Now in many of these cases, they may have ultimately gotten better, but at the time the case was reported, they hadn't gotten better yet, so this number should not be taken to mean that these are the only ones who got better when the drug was stopped.

            Positive re-challenge is the gold standard for post-marketing causality assessment.  That means the drug was stopped, the event went away.  The drug was given again, and the event came back.  And we did have cases of that sort.  Many of the cases did not have concomitant medications on board which would be potential confounders, and it was also striking that almost 90 percent of cases across the board did not have a prior history of a similar psychotic event.  Medical confirmation was obtained in half to three-quarters of these cases.

            I'll just comment that the Modafinil patients were typically older, they were adults, typically treated for narcolepsy and there was some occurrence of psychosis related events. 

            I'm just going to give you a couple of examples of cases to give you a sense of what are we talking about.  This is an amphetamine case from published literature, Journal of the American Board of Family Practice in 2002.  A 12-year old female who developed hallucinations after five weeks of therapy with 10 milligrams a day of amphetamine for the inattentive type of ADD.  She was on no concomitant medications.  She didn't have much in the way of family history or medical history.  The amphetamine was stopped and Clonazepam was started PRN for agitation.  However, she got much worse, and four days later she really was having visual hallucinations, command auditory hallucinations, and tactile hallucinations of bugs crawling under her skin.  She also displayed waxy flexibility, and she was admitted to the hospital.  She was kept free of medications and she returned to her baseline within seven days.  She was fully evaluated and a tox screen was negative, so the authors concluded that this was an amphetamine reaction, even though the dose was not excessive, and she was discharged home on no medications. 

 

            This is a report from the sponsor describing a 6-year old male who was started on 100 milligrams a day of Modafinil for ADHD who experienced visual hallucinations after a single dose, and they did resolve when the drug was stopped.  There were no concomitant medications.

            This is a report from the sponsor which describes a 7-year old female who received 18 milligrams a day of atomoxetine for ADHD.  Within hours of taking the first dose, the patient started talking non-stop and stated that she was happy.  The next morning the child was still elated, two hours after taking her second dose she started running, stopped suddenly and fell to the ground.  She stated she had run into a wall, but there was no wall there.  The atomoxetine was stopped, and this report did not include the outcome of the events. 

            This report is a methylphenidate case from published literature from The Journal of Neurology from 2004.  A 12-year old boy with cerebral palsy, low normal intelligence and a combined sub-type of ADHD was treated with 10 milligrams a day of methylphenidate, and his attention improved.  However, one morning he was observed crawling on the floor complaining that roaches were surrounding him.  This phenomenon appeared two hours after his dose, continued for two hours, and then disappeared with no intervention.  Methylphenidate was stopped; however, his school performance deteriorated, and so the methylphenidate was resumed.  However, the hallucinations immediately recurred and were stopped, and three years of follow-up have been uneventful.

            So the question is, how often do such things occur at usual doses?  So Dr. Mosholder showed you, for instance, the proportion of patients in open label long-term extensions from the clinical programs, and all of those rates were less than 1 percent with the exception of the methylphenidate patch.  Interestingly, this chart review, which is actually the only similar information I could find in published literature for stimulants, describes the experience at an out-patient clinic in Canada from the years 1989 to 1995.

            In that five-year period, of 192 children who were diagnosed with ADHD, 98 were started on stimulants, most received methylphenidate.  Of those, six developed psychotic symptoms, and so giving us a frequency of around 6 percent.  One hypothesis is that since only half of the children with the diagnosis were treated, perhaps these children are somehow more severely affected, so maybe this is the upper bound.  So maybe, we might think that the rate is somewhere between under 1 percent, up to 5 percent, or 6 percent. 

            This is for atomoxetine, a publication in The Journal of Pediatrics from the year 2004 of pooled data from out-patient settings in Colorado and Minnesota.  The author is a pediatric psychiatrist.  He described a total of 153 sequential patients treated with atomoxetine, of whom a third developed unwanted psychiatric symptoms.  Of that third, however, 80 percent did have a past history of mood symptoms, so again, we may be talking about a more severely affected population, or perhaps some additional co-morbidities.  Of these, ten children developed symptoms severe enough to be considered mania, three requiring hospital admission, and three incarcerated in juvenile detention centers. 

            So what are the findings?  We found no risk factors that could account for the majority of reports.  For instance, drug abuse was not a common feature, and the vast majority of these reports did not have a history of a similar psychosis-related condition.  There were positive re-challenge cases identified, and many cases had a positive de-challenge.  This may not be a rare occurrence based on the published case series, and to some extent, even from the clinical trial experience. 

            A large proportion of these cases do involve young children, and in our review of the narrative, it was striking that often the young children were describing various insects, bugs, snakes, and worms with a combination of visual and tactile hallucinations, which we haven't seen described elsewhere.

            So the labeling, I'm including here just for your reference.  Dr.  Andreason told you a bit about this earlier, and you will be asked to look at this and advise us later.  But to summarize, the current approved labeling for drugs with the ADHD indication does not clearly address the risk of drug-induced signs or symptoms of psychosis or mania, such as hallucinations in patients without identifiable risk factors, or occurring at usual doses.  So this is a setting where there's no previous psychosis, and there's no overdose.  Current labeling does not address importance of stopping drug therapy in patients who develop signs or symptoms of psychosis or mania.  And we will ask for your advice later today.

            Now on to aggression or violent behavior, these were the search terms that we requested, aggression, anger, hostility, homicidal ideation, and even murder or imprisonment.  This is the similar format that you've seen.  And again, you can see that the predominance of the reports is in children and adolescents, predominantly male.  Psychiatric history in a quarter to nearly a half, although some of these were fairly soft conditions.  Drug abuse, interestingly, in very few, overdose in relatively few, and very few with seizure disorders. 

            Published literature for methylphenidate and atomoxetine during this five-year period, I wouldn't  be surprised if we expanded our search dates, maybe we would find something for this.  Positive de-challenge in some cases, positive re-challenge cases were identified, many with no concomitant medications, although for some reason, the atomoxetine group seemed to have more concomitant medications on board. 

            We were a little surprised, given ADHD diagnosis, that the striking majority of cases reported that they didn't have a prior history of aggression or violent behavior, so we're not sure what to make of that.  And many of these cases did have health professional confirmation.

            So the findings, most cases were classified as non-serious, although about 20 percent were considered life-threatening or required hospital admission.  There were some juvenile incarceration cases.  Most of the reports did involve children and adolescents, and we did not identify any specific risk factors that could account for most cases, such as drug abuse.  And there were some positive re-challenge cases.

            With regard to the labeling, the amphetamine and the methylphenidate products don't currently have labeling about aggression at the usual doses.  However, the Strattera label does have that, as was discussed previously. 

            On to suicidality, these were the search terms that we requested, suicidal, depression, gunshot wound, intentional self-injury, non-accidental overdose, self-injurious behavior, self-injurious ideations, self-mutilization, suicidal ideation, suicide attempt, and completed suicide.  We did have some completed suicides in the post-marketing data unlike in clinical trial data where there were no completed suicides. 

            Similarly, for the approved drugs, we did find that a large proportion of these cases were in children and adolescents, male predominance.  For these suicidal ideation and suicidal behavior cases, maybe there were a few more with some other psychiatric history reported.  Drug abuse was, perhaps, a little bit higher than on the previous slides, but still not in a majority.  Overdose in many of these was actually the method of the suicide attempt or behavior, very few were seizure disorder.  Published medical literature, yes, for atomoxetine and methylphenidate - again, if we opened up the dates and looked further, maybe we would find something more for that.

            Positive de-challenge in a little more than a third of the cases, and there were some positive re-challenge cases.  The majority had no concomitant medications, and the majority again did not have a prior history of similar events.  Many cases were from health professionals. 

            So the current labeling for the amphetamine and methylphenidate products does not include any information about suicidality.  We felt that a possible causal association between stimulant therapy and suicidality couldn't be ruled out on the basis of our analysis.  With regard to atomoxetine, we felt that the results of the post-marketing review were consistent with the association that is already clearly described in the labeling.

            So to summarize, suicidality has been identified as a potential safety issue for atomoxetine and that information is conveyed in the labeling.  A causal association between other drug therapies of ADHD and suicidality could not be ruled out on the basis of our analysis.  We recommend further evaluation, such as a clinical expert case review, for some of these cases that were identified regarding a possible co-occurrence of undesired psychiatric effects that perhaps could contribute to suicidal ideation or behaviors in vulnerable patients.

            With regard to aggression or violent behavior, numerous post-marketing reports have been received, most in children and adolescents with a male predominance.  We did not identify any specific risk factors which could account for the majority of the cases that we identified, and these data suggest that some cases, aggression or violent behavior may be drug-induced.  The Committee will be asked to discuss any labeling implications later today.

            With regard to psychosis or mania, we found that signs and symptoms of psychosis or mania, particularly hallucinations, can occur in some patients with no identifiable risk factors at usual doses of any of the drugs currently approved to treat ADHD.  Based on published case series rates, and to some extent the clinical trial data, this may not be a rare occurrence.  No risk factors were identified, which could account for the majority of reports of psychosis-related events.  For instance, drug abuse was reported in two cases. 

            The predominance in young children of hallucinations, both visual and tactile involving insects, snakes and worms, we think deserves further evaluation.  The Committee will be asked to discuss any labeling implications of these findings later today.

            We'd like to thank the manufacturers of the drugs discussed today for providing timely and comprehensive safety data for these analyses, and our colleagues in the Division of Psychiatric Products.

            DR. NELSON:  Thank you.  And let me commend all of our speakers for doing what I was highly doubtful could in fact occur.  Everyone stayed on time, amazing.

            Now the second point is, we're scheduled for lunch at 12:25.  We were scheduled for 10 minutes of clarification questions.  We don't necessarily need to take 25 unless we want to.  I'll point out at least for the Committee, we have box lunches coming in.  The only reason to give a longer lunch break is the people in the audience, I suspect, do not and might want to try to get back at 1:00 on time, so we'll see how much time you need to take for that.  And I will also, before opening up for clarification questions to our speakers, is to point out to the Committee that everybody that has presented, it's my understanding, will be here during our discussion this afternoon, so there should be no need to get their insight into the questions themselves.  All we need to do is focus on informational aspects for the moment, because they'll still be available to us this afternoon.  So with that, just open for clarification questions about any of the information that we've been presented this morning.  I'll start keeping a list.  John, you're first, then Judith, and then -- 

            DR. MOORE:  A question for Susan McCune and Dr. Gelperin.  One year post-exclusivity adverse event for you on Adderall, well, the Adderall XR and Adderall both, you mentioned seven cases total, I think.  And then Dr. Gelperin, in what I think is the same data, mentioned only four cases of sudden death.  Could you two kind of reconcile that for us?

            DR. GELPERIN:  Yes.  I know Dr. McCune tried in her beautiful slide with the Xs and the Os to explain this, but it's minutia of post-marketing report counting.  The issue is that two additional of the cases that were presented by Dr. McCune were previously reported in the prior time period, but because of the conventions of searching for the BPCA, the safety evaluator who did those searches did not exclude those cases from her analysis.  However, I felt that it was not reasonable to include them in the reporting rates when they were already included in the reporting rates for the other time period.  And then the third case, as we mentioned, is the one where the amphetamine was stopped two months prior to the death, and the child was actually on Strattera and Buproprion at the time of death.  That could have been -- you could go either way with that, I agree, but we decided not to include it in the reporting rate.

            DR. NELSON:  Judith.

            DR. O'FALLON:  In all the data that was presented about the efficacy, which I found very helpful, there was one that was mentioned that the efficacy rating was done on the basis of the clinician.  And that one kind of blew my mind, so I wondered how is it that the clinician can assess efficacy?  I understand what the parents are doing, I understand what the teachers are doing.  I don't understand quite what the clinicians are doing.

            DR. NELSON:  Ben.

            DR. VITIELLO:  The clinician basically collects information from the patient, and when it is available from family members, and so makes a determination based on that information.

            DR. NELSON:  But I assume that they were blinded to treatment assignment in those studies.  Right?

            DR. VITIELLO:  Yes, that goes without saying.  It was a double-blind assessment. 

            DR. NELSON:  Dan.

            DR. PINE:  I have three quick questions for Dr.  Mosholder.  First of all, for the adverse events data in the randomized controlled trials, I didn't see statistics for the mania in the stimulants versus placebo, the 13 versus zero.  Could you give either an odds ratio, risk ratio, lower bound confidence interval, something like that?

            DR. MOSHOLDER:  Yes.  I did that sort of back of the envelope on my own.  I didn't put it in the report, because it's a little unsatisfactory to do that sort of crude pooling without a formal meta analysis.  I think it was out to three decimal places, but I didn't make note of that.  To really do a more precise meta analysis and I'll defer to the people who are more expert in statistics, I thought that the data here were too sparse, and you'd be left with a lot of zero cells, and you'd have to make corrections for that, so I just sort of didn't go there.  But it would have been -- if you just crudely pool everything together, I think the P-value is out to three decimal places, but I don't have that, unfortunately, on me at the moment.

            DR. PINE:  And what about a point estimate on an odds ratio or risk, did you -- that's all right.

            DR. MOSHOLDER:  Yes.  Well, that would be undefined because of the zero for placebo.  You could put a confidence limit on the rate difference, but I don't have that. 

            DR. PINE:  So the second question was about the data on aggression, and I wondered the degree to which you had available ratings that were obtained during the study of aggressive behavior, because obviously, most of the studies would obtain those.  And it would be important and interesting to see if those data look similar or not to spontaneous reports of aggression; so do you have those data?

            DR. MOSHOLDER:  I did not for this analysis, although I will say that in Lilly's analysis of aggression, they did look at some of the efficacy rating scales which included items relevant to aggression.  And I don't think there was much of a finding either way, but it is my impression that some of the standard efficacy ratings used in these trials has such items, and maybe not all of them did, but you're right - that would be another way to -- and to be fair, these trials were not designed to look at aggression as an end-point in itself.  It was simply observing aggression counted as an adverse event, is the way I looked at it.

            DR. PINE:  And then the last question concerns an opportunity to either query the data set or query the companies for some inconsistencies in some of the case reports of hallucinations or psychosis.  So, for example, I notice that a couple of them that you showed were listed as psychosis, but then were listed as not serious, which seemed a little curious.  Was there any opportunity to try to clarify that discrepancy, or figure out why that appeared like that?

            DR. MOSHOLDER:  Certainly, that could be done. I didn't have all the information or the time to delve into all of the cases, but I guess you're raising the question of how could you have a psychotic event and not consider it serious?  Well, that's up to the investigator and the sponsor to see if it meets the regulatory definition for serious.  I think the other point is that the distinction - a lot of the events clearly could have fit into more than one category, and that someone having command hallucinations to do self-harm, that could be counted either as a psychotic event or a suicidal event, and so in a certain sense, some of these distinctions were a little arbitrary. 

            DR. NELSON:  Bob Ward.

            DR. WARD:  I had a couple of questions for Dr. Gelperin.  In the suicidality slide, if I recall that table correctly, about 35 percent had a prior history of suicidality, either ideation or attempt, and roughly 45-50 percent were not reported.  So if you took away the absence of data, the majority would have a prior history. 

            DR. GELPERIN:  Okay, just looking.  Are we talking about slide -- 

            DR. WARD:  I don't know what your slide numbers are.

            DR. GELPERIN:  Oh, okay.

 

            DR. WARD:  Put your slides up, maybe we can tell.

            DR. GELPERIN:  Can we put slide 28 back up?  Okay. 

            DR. WARD:  It was a table, it was in that same format you had been presenting for several of the data tables.

            DR. GELPERIN:  Right.

            DR. WARD:  Oh, I think I saw it.  It was the one that had - yes, okay, right there.  Back one.  There.  When I scanned through there, it looked like other psychiatric history yes, for almost all, unless there was an absence of data, not reported.  Correct?

            DR. GELPERIN:  This was -- so each individual case was assessed either by the sponsor or by the FDA review panel.  And then a yes or a no, or a not reported could be the answer.  So this tabulates the answers, and typically in a post-marketing spontaneous report, it's like if somebody were telling you a story.  The things they remember to tell you, you hope they're remembering the important things, but they might forget some important things, or they might stop talking to you before they tell you the important things.  So that's why not reported is a big category.

            DR. WARD:  It is a big category.

            DR. GELPERIN:  Sometimes what that means is that if it were really important, you might think that someone might have mentioned it.  So, for instance, this is the FDA analysis you're looking at.  If it wasn't stated, we said it was not reported.  Some of the sponsors actually in their analysis kind of made the leap that if some -- that they wouldn't forget to say oh, by the way, this person has schizophrenia, and now they're suicidal. 

            DR. WARD:  What I would, I guess, prefer to see you address would be if you take away those where we don't have data, it's not reported, it would appear that the predominant number of these cases had some prior psychiatric history reported.

            DR. GELPERIN:  So 45 percent -- 

            DR. WARD:  If you just took them out of the analysis all together if they didn't have any report, at least that's the way I would have to deal with it in the absence of data.

            DR. GELPERIN:  Okay.  So, for instance, let's look at atomoxetine.  So roughly a third stated there was another psychiatric history.  I can tell you that those were typically things like oppositional defiant disorder, obsessive compulsive disorder, but for some reason, the sponsor also decided in some analyses to include things that were sort of softer.  So it's not -- that shouldn't be taken to mean that these were DSM-4 criteria, psychiatric diagnoses.  Some of them were pretty soft things that just weren't part of the ADHD spectrum.  But I actually thought your question was really on the next slide, which was how many reported a previous history of a similar event.

            DR. WARD:  No.  Actually, it pertained to that previous slide.

            DR. GELPERIN:  Oh, the other psychiatric history.

            DR. WARD:  Yes.  The majority, for whom we had data mentioned or not mentioned, that there was a large percentage that had a prior psychiatric history, and that we know that ADHD may be a component of multiple behavioral and psychiatric spectrum disorders.

            DR. GELPERIN:  Actually, for the post-marketing reports that would not be the correct conclusion, because the only reports in this category  - so there's another one that would have said no.  There would have been a no, and that would be a report where the reporter stated specifically there was no other psychiatric history.  So not reported means they didn't say that, no means they said there was no other psychiatric history, and yes means they provided some other psychiatric history.  So you could not conclude that the majority probably had other psychiatric history.

            DR. WARD:  Then the column we're discussing atomoxetine, the no would be 1 percent?

            DR. GELPERIN:  That's right.

            DR. TEMPLE:  Kate, that's the point he's making, that where you have information it's almost always yes.  In other words, for the first one, you have information on 90 percent of patients, and apparently they said no in 10 percent.

 

            DR. WARD:  Right.

            DR. TEMPLE:  So, I'm sorry, you have information in 55 percent, 45 percent of the 55 percent is yes, 45 percent didn't say anything.  I think that's the point you're making.

            DR. WARD:  Yes.  Thanks, Bob.  Yes.

            DR. TEMPLE:  Where you have information, it's usually yes.  Now then you have to figure out what the no reports mean.  Your thought is that it's probably no, otherwise they would have reported it.  But that may or may not be the case. 

            DR. NELSON:  So I've got Dr. Daum, and then Dr. Armenteros.  Robert.

            DR. DAUM:  Thank you.  So my question is also for Dr. Gelperin.  I was hoping for some clarification with the category of aggression or violent behavior. I'm sorry for asking that question back to you, but that's where I'm proceeding.  It seems to me that there's quite a wide range of behaviors there, from aggression, however that was defined, all the way to murder.  And that those behaviors may or may not have different weights in terms of their social acceptability, to say the least.  So when you get to the slide where there's challenge and de-challenge data, can you give us more information?  I mean, would someone actually commit a murder and then was re-challenged?  I don't mean it facetiously, but -- 

            DR. GELPERIN:  No.  That's a great question and that was really what I was alluding to when I said our time constraints were such that what you were hearing about is just such a high level, but there's obviously layers and layers in these data.  I can actually answer your question specifically with regard to the pediatric re-challenge cases for atomoxetine.  So there were 12 such cases in which a positive re-challenge occurred. I don't have a slide for this, but I can just tell you that they were all classified as non-serious.  They were -- the Medra PTs were aggressive for four, anger for seven, and hostility for one.  It was considered to be an exacerbation of a pre-existing behavior in one case, and it was not in 11 cases.  There was no drug abuse in 12 cases, and the age ranged from 4-14 years, with a mean of 9.6 years.  Six were males, four were females.  There were no concomitant medications in four of the cases, and the daily dose of atomoxetine ranged from 10 milligrams to 60 milligrams.  Five of these were healthcare professional reports, and seven were consumer reports. 

            DR. DAUM:  Can I try to probe a little more for what I'm after.  Can you tell us a little more what hostility means in this context, and what anger means, because I'm sure no one in this room would ever be accused of being hostile or angry, but why were these reports filed for hostile or angry behavior?  It must have been pretty impressive.

            DR. GELPERIN:  Actually, it's quite striking the number of reports that have been filed for atomoxetine in this category.  The vast majority are non-serious reports, but many of them are from healthcare professionals.  And we actually don't know why this is happening, but for somebody to pick up the phone or to tell the sales rep, or to -- it means that somebody in the United States decided that the drug company and FDA should know that their child started hitting somebody and didn't do it before. 

            Now let me give you another example of a positive re-challenge case that is a more serious case, and shows the overlap, and perhaps gives a sense of how the co-morbidities may occur.  This was a consumer report, but it's the mother of a 9-year old boy who reported that her son started hitting people and cutting himself, and he was hearing voices after a few weeks of treatment with Adderall XR for ADHD.    The mother decided on her own to stop the medication and the events resolved.  However, the physician advised that she should restart it when school started because the boy needed it.  The dose was then increased to 15 milligrams daily one month later, and the events returned, so that's a positive re-challenge.

            Seraquel was added to the child's treatment because of the auditory hallucinations, however, the child worsened and was admitted to a psychiatric hospital.  So I think that gives you a sense of the vast majority of these cases are non-serious.  Also, for post-marketing spontaneous reports, the quality of the information is not like a published case report.  We are basically listening to a mother who's telling us something.  Did she get it right?  I don't know, but it's my job to listen to what she's telling us.

            DR. NELSON:  Jorge.

            DR. ARMENTEROS:  Don't go too far.  Actually, pertaining to the same topic.  I believe the ascertainment and the search terms used included, as you mentioned, a wide range, some of which are pretty serious.  But perhaps one, and I wonder if you had the opportunity of looking at it, is more simple and maybe  mediating some of this, which is agitation.  That could actually be a component behind the most common episode that you described.  Any thoughts about the possibility of looking at that?

            DR. GELPERIN:  The most common component of what?

            DR. ARMENTEROS:  What I was saying is that the possibility of looking at agitation in the process of evaluating your aggressive repertoire. 

            DR. GELPERIN:  I think that's an excellent point.  And really, I would almost make a plea that additional analyses should be done, because if you look at our time frame, the Committee asked us to do this analysis only a little more than six months ago, and so it takes a long time to get the sponsor, the data searches, the Excel spreadsheets.  I mean, a thousand cases had to be reviewed by groups of people who are expert in this, but it was really - I would call this a high level analysis, where we selected using the Neuron-Ho criteria, we selected key points to help us assess the quality of the information, but I think that the clinical analysis, and in-depth analysis of these issues - and, in fact, I really wonder whether something like the multi-modal, or some of the trial data could be sort of plumbed a little bit further to really help us out with understanding the rates and maybe co-morbidities. 

            DR. NELSON:  Tom.

            DR. NEWMAN:  A question for Dr. Mosholder.  I'm wondering what the miscellaneous serious adverse psychiatric effects were, and if you know the distribution between the drug and placebo groups, what those were?

            DR. MOSHOLDER:  Yes.  Unfortunately, this will be a very brief answer, because I don't have those data really analyzed.  I think some of the serious events were actually more in the behavioral realm, but were coded, for example, as personality disorder or something like that.  And I have to say, too, one complication was that some of the sponsors misunderstood that we only wanted serious outcome, regulatory serious outcome so that in some cases we got almost all psychiatric adverse events fitting any of the miscellaneous criteria, regardless of whether they were serious, so that was a little overwhelming to try to sort through, so I don't have those data.

            DR. NEWMAN:  You don't know whether there were more with drug or placebo.

            DR.  MOSHOLDER:  No.  And actually, the miscellaneous category really spanned quite a range from tics to insomnia, so I wouldn't even want to -- I would want to parse that out before I started comparing frequencies. 

            DR. NEWMAN:  One other quick question, the suicidal events, do you have a feel for how many of them were ideation versus attempts or behaviors?

 

            DR. MOSHOLDER:  Most of them were -- I can't give you the exact number, but most were ideation, and fewer attempts. 

            DR. DIAZ:  In the adverse event reports for Adderall XR, there are two cases reported of disability.  Can you expand, describe what those were, please?

            DR. McCUNE:  You're talking about the two cardiac events with cardiac disability?

            DR. DIAZ:  Yes.

            DR. McCUNE:  Yes.  Those were actually two patients that had underlying cardiac disease that actually had adverse events associated with cardiac surgeries. 

            DR. NELSON:  Ben, I'll give you the last question before lunch.

            DR. VITIELLO:  More of a question, was just a comment.  Since the issue of hostility and aggression has come up, clinical trials indicate that there is a treatment effect on that, but in the treatment decreasing, hostility and aggression, that actually is statistically and clinically significant effect, which indicates that these events of aggression and hostility that has been reported are really idiosyncratic episodes that occur against the mean, which is actually the opposite effect, that these drugs at the group level, they decrease hostility and aggression.  This is sort of an important thing to keep in mind. 

            DR. NELSON:  Thank you.  We're scheduled for lunch.  One o'clock is when the open public hearing occurs, and just so that everyone is aware, we have I think 42 people who want to speak to us, so we will start at 1:00.

            DR. JOHANNESSEN:  I'd also just like to add that if you are pre-registered as an open public hearing speaker and you haven't checked in at the desk to get your number, you need to do that.  The other thing is that we're bringing lunch just for the Committee, so we'd certainly appreciate it if you'd leave them alone during lunch and let them have a little peace and quiet.  I think the press office people are here, and they're going to be arranging things for after the meeting.  Thank you.

            (Whereupon, the proceedings went off the record at 12:25 p.m. and went back on the record at  1:01 p.m.)

            DR. NELSON:  So if we could start to begin to get organized and I'll start to describe our process.

            (Pause.)

            So as I mentioned, this is going to be the start of our open public hearing.  I know I have to read something before, right?  It's right here.

            Now I'm going to describe the process briefly, and then I'll read the statement that I need to read before the open public hearing.  As you can tell by the slide up front, we have 42 people who are going to speak to us this afternoon.  If you divide that into the amount of time, it's basically three minutes each.  We'll have people assisting the order and everyone, I gather, has a number. 

            There's also a timer up there which will be green for two and a half minutes and then turn yellow for 30 seconds.  At three minutes, the microphone is off.  Now one could say is that fair?  Well, from a distributive justice point of view with 42 people, yes.  We'd like to give you as much opportunity to get your points across within your three minutes.

            So let me read the statement before we open our public hearing and then Jan will take over in terms of calling up people and we'll be operating whatever slides people have from up here.

            Both the Food and Drug Administration and the public believe in a transparent process for information gathering decision making.  To ensure such transparency at the open public hearing session of the Advisory Committee Meeting, the FDA believes that it is important to understand the context of an individual's presentation.  For this reason, the FDA encourages you, the open public hearing speaker, at the beginning of your written or oral statement, to advise the Committee of any financial relationship that you may have with the sponsor, its product or if known, its direct competitors.  For example, this financial information may include the sponsor's payment of your travel, lodging or other expenses in connection with your attendance at the meeting.  Likewise, FDA encourages you at the beginning of your statement to advise the Committee if you do not have any such financial relationships.  However, if you choose not to address this issue of financial relationships at the beginning of your statement, it will not preclude you from speaking.

            DR. JOHANNESSEN:  So we're ready for speaker number one.

            DR. DILLER:  Let me know when I can start.  I have no financial considerations to take into account here.  I'm a behavioral developmental pediatrician.  My name is Lawrence Diller who has prescribed Ritalin and other stimulants for nearly 30 years.  I've never been against medication.  Yet, I applaud the courage of the previous Advisory Committee in broadening the discussion of the use of stimulants in our country beyond the cardiovascular consequences.

            The majority's recommendation for a black box warning was also meant to express their concern about the 1 in 10 11-year-old boys taking drugs like these in this country, and that many children have a serious psychiatric disorder requiring medication. 

            Indeed, in our country, Ritalin and Adderall have become lifestyle drugs, performance enhancers, rather than solely a medical treatment.  To that end, even though the risk of sudden death are minimal to existential, these drugs have to be extremely safe if we are giving them to children who are generally very normal and healthy.  And indeed, the historical record of 70 years suggests that they are. 

            Nevertheless, their over-use highlights an ethical, not medical dilemma, because stimulants are not the moral equivalent to helping parents and schools address the needs of these children.  But I must alert you to the real and present danger of prescription stimulants.  For years, I and a few others have been deeply worried about the risks of prescription stimulant abuse especially in teens and young adults.  Now in the February issue of Drug and Alcohol Dependence, we have the first hard data on the misuse and abuse of prescription stimulants.  Based on a 2002 Government survey, this data has been vetted by the Drug Enforcement Administration.

            Twenty-one million people over the age of 12 have illegally used prescription stimulants at least once.  Three million have misused prescription stimulants alone.  Of those, approximately 1 in 10, or 75,000, between the ages of 12 and 25, have gone on to meet DSM-IV criteria for addiction or drug abuse. 

            The use of prescription stimulants are growing the fastest in the adult population, so these numbers are probably larger in 2006.  Seventy-five thousand prescription drug addicts dwarf the current cardiovascular casualties.  These numbers represent the fourth episode in our history of a doctor prescribed stimulant abuse epidemic.  And if our previous experiences are any guide, then several years from now you are likely to look back at this time with regret, chagrin and anger.

            Those who do not study history are condemned to repeat it and you may remember the graffiti on the walls of the San Francisco Haight-Ashbury in the late 1960s, "speed kills."  We must immediately address this new Ritalin abuse epidemic in our teens and young adults, with much tighter controls on prescription and diversion to this population.  At the same time, we need a rational policy for the use of these drugs with a much smaller group of pre-teens who can and do benefit from Ritalin safely.

            Thank you.

            DR. JOHANNESSEN:  Thank you.  Is speaker two here?  This is Douglas Tynan.

            DR. TYNAN:  Right.  Slides, please.  Thank you.  Good afternoon, my name is Douglas Tynan and I have no other sponsors.  I'm the Director of the ADHD Program at the Nemours Pediatric Clinics in Delaware.  I am a child clinical psychologist.  I also chair the current task force on stimulant medicine use established by the Delaware House of Representatives.

            There have been serious concerns in the First State regarding prescription of stimulant medicines for ADHD.  According to the Federal DEA 2002 Report, Delaware has the second highest use of amphetamines and fifth highest use of methylphenidate.  Last year's national phone survey of children's health indicates 7 percent and 3.5 percent of girls in Delaware were medicated for ADHD.

            Next.  Because of the trend of higher use of these medicines, the Delaware House of Representatives established a task force to study the patterns of treatment of ADHD in Delaware of school-age children.  We've included parents, educators, public health, law enforcement, health and mental health professionals who have reviewed research and clinical literature, interviewed families, school personnel and national experts.

            We have determined that simply curtailing discussion of ADHD medicines in schools is not a practical solution, that we need to do more.  Our task force has recommended so far prescription monitoring in the State of Delaware; the Department of Education to establish specific guidelines on how to refer a student needing an evaluation; the Department of Ed. to continue its goal to educate all school personnel and training teachers in behavior modifications for the positive behavior support program from the U.S. Department of Ed.; health insurers provide full benefits of evidence-based behavioral therapies and psychological diagnostic testing as part of mental health benefit packages; and the schools' health and mental health providers to work collaboratively to address any communication barriers that interfere with treatment.

            Nemours is one of the nation's largest pediatric subspecialty groups.  The practice is moving forward to address this issue.  Nemours has developed -- next slide -- as part of the electronic medical record an electronic prompt for pediatricians to use the full AAP criteria, including history, documentation of problems, web-based questionnaires and documentation of impairment before making a diagnosis.  The AMR also provides parent information, not only on medicine, but on behavioral strategy support groups and education interventions.

            In addition, a second Nemours program, HRSA-funded program addresses this issue by placing clinical child psychologists in medically under-served areas in the State to provide assessment and psychotherapy services for these children.

            Initial data from our integrated care program shows a 35 percent drop in diagnosis after one year.  The rapid increase, the number of children, particularly younger children treated with medicine, does need to be examined closely.  However, we're trying to limit what schools say to parents or frightened parents will not be sufficient control of the trend.  Our State Task Force has determined the only solution is to develop comprehensive multi-modal treatment programs to address behavioral problems and encourage families to access and utilize all evidence-based therapies, not just medication as suggested by the Surgeon General's Conference in 2001.  We, at Nemours, at attempting to do that for thousands of children we serve in Delaware and Florida.

            Thank you.

            DR. JOHANNESSEN:  Thank you.  Speaker number three, Dr. Lawrence Greenhill.

            DR. GREENHILL:  My name is Lawrence Greenhill.  I'm a child psychiatrist working at the New York State Psychiatric Institute doing treatment research for the safety and efficacy of medications used to treat attention deficit hyperactivity disorder in children, adolescents and adults.  I am the chairman of the Work Group on Research at the American Academy of Child and Adolescent Psychiatry.  This organization strives to raise the standards of care and ethical methods in clinical trials and in medication.  The organization also supports the FDA Advisory Panels and their efforts to better characterize the safety of medication treatments and we appreciate the broadcasting of tables, slides and all information on the website which helps practitioners and families.

            This is important because untreated ADHD children can be highly impairing both for the patient and their family.  Patients and families need to know about effective treatments for ADHD as well as full knowledge of their adverse events. 

            In order to help practitioners and their families, I'd like to pose three questions for the Advisory Panel to consider.  First, how does one base clinical decisions on infrequent, but severe adverse events and do these infrequent events require new practices for the practitioner?  I've seen the pendulum swing from the use of spontaneous patient interview methods which under-report the adverse events in small clinical trials to now the full disclosure of every adverse event from the unreliable post-marketing system, no matter how rare. 

            A full review of all infrequent, cardiovascular, neuropsychiatric events makes it difficult for families and physicians to determine the balance of benefit versus risk when seeking treatment.  Professional organizations, including the American Academy of Child and Adolescent Psychiatry and the American Academy of Pediatrics, now publish practice guidelines for practitioners to set a standard for care.  They ask practitioners to weigh all common adverse events when they're making their treatment decisions.  How then do we weigh the infrequent and rare?

            My second question is can the Panel recommend to the pharmaceutical industry and FDA to agree on standard methods for collecting safety information so that infrequent moderate and severe adverse events in the real world settings get more reliably detected.

            My third question is that I would like to ask the Advisory Panel if they would recommend the FDA better specify which groups are at risk for specific adverse events and if that is known.  In the last hearing which was the February 9th hearing, they voted by a narrow margin, 8 to 7, to recommend black box warnings.  And that's quite controversial because they didn't specify whether it was for children or adults.

            In closing, I'd like to add that my travel to this meeting has been supported by the American Academy of Child and Adolescent Psychiatry,

            DR. JOHANNESSEN:  Thank you.  Next speaker is number four, Dr. Adelaide Robb.

            DR. ROBB:  I have slides.  I'm here on behalf of the ACAP and the National Institutes of Neurologic Diseases and Stroke to talk about the safety data from an NINDS-funded study called Quantity and an ADHD Treatment that was conducted at Universities of Buffalo, Cincinnati, Pittsburgh and Rochester.  Next slide.

            I'm the head of the DSMB for that study.  There were 122 children, ages 7 to 12, who were diagnosed with ADHD and no comorbid medical problems.  Next slide.

            They were either assigned to methylphenidate, clonidine, methylphenidate plus clonidine or a placebo.  Next slide.

            And they were titrated up to final doses over the first eight weeks in the study and left on maintenance dose for the second eight weeks in the study.

      Next slide. 

            Cardiovascular parameters and side effects with the Pittsburgh Side Effects Rating Scale were collected.  The mean dose of methylphenidate in the methylphenidate-only group was 30 milligrams.  The mean dose of clonidine in the clonidine-only group was 0.24 milligrams of clonidine and then in combination  they had .23 milligrams of clonidine and 25 of methylphenidate.  Next slide.

            And these are some of the more common side effects divided by whether patients had clonidine or no clonidine and the most common ones in the clonidine group were nervousness, sleepiness, fatigue and headache.  Next slide.

            And several patients in each of the groups had more serious SAEs meaning that the symptoms were present more days than not for most of the day over the course of a week.  Two people withdrew early, one for chest pain and tachycardia on methylphenidate, although the physical exam and electrocardiogram were within normal limits and a second patient withdrew for a mild elevation in QTc of 440 milliseconds who was on combination methylphenidate and clonidine.  The EKG showed left ventricular hypertrophy by voltage criteria only.  Echocardiogram was normal.  Next slide.

            And I just wanted to talk about the changes in parameters which are not listed up there.  In the placebo group, pulse dropped by 1.2 beats per minute.  Systolic blood pressure went down by 2 millimeters in mercury; diastolic by 1.3; methylphenidate dropped blood pressure by 1.1 millimeters of mercury and for systolic; 2.1 for diastolic.  Heart rate also dropped, 0.3 beats per minute.

            Clonidine dropped heart rate the greatest, down 6.8 beats per minutes, dropping blood pressure systolic by .9 and diastolic by 1.2.  Combination therapy, so both meds together, heart rate dropped by 1.6 beats per minute; 2.8 millimeters of mercury systolic and 1.0 diastolic.  No patients had elevations in blood pressure or elevations in heart rate except for the one patient mentioned previously and in terms of psychiatric side effects, people on placebo, 7 percent had irritability, sadness and tearfulness; 13 percent on methylphenidate; 19 percent on clonidine, and 12 percent on combination. 

            THE COURT:  Speaker number five, Dr. David Fassler.

            DR. FASSLER:  Thank you.  My name is David Fassler.  I'm a child and adolescent psychiatrist from Burlington, Vermont.  My travel to today's meeting has been supported by the American Psychiatric Association where I serve as a trustee-at-large.

            As you've heard, ADHD is a common disorder of childhood and adolescence, affecting 3 to 5 percent of all young people.  Half of the people with ADHD continue to have signs and symptoms well into adulthood.  We have solid research evidence demonstrating the efficacy of treatment, including treatment with medication.  However, no one medication works for all children or adults.  Fortunately, there are a number of medications which physicians can and do use to treat this condition.  Although they are generally well tolerated, all treatment interventions have risks and potential side effects.

            We also know that appropriate intervention for ADHD actually saves lives, specifically, treatment reduces the risk of serious accidents, including accidents which lead to head injury and permanent disability.  Research also demonstrates that treatment significantly reduces the risk of substance abuse in adolescents.

            As we learned at last month's hearing, the FDA has received reports about a small number of patients who experience serious heart-related problems while taking medication for the treatment of ADHD.  Today, you've reviewed data concerning reports of possible psychiatric reactions to these medications.  You've also heard that there's significant limitations to our analysis and interpretation of data derived from clinical trials and post-marketing reports.  And you've heard that most patients can and do take these medications without significant difficulties or complications. 

            However, any side effects need to be taken seriously.  For this reason I fully support the call for more research on both the safety and efficacy of medication used in the treatment of ADHD.  I also support the call for updated labeling language and for the development of med. guides and FAQ sheets, specific to these medications.  Physicians and patients need and deserve as much information as possible in order to make fully-informed decisions about treatment options.

            However, I would urge the FDA to exercise caution with respect to new warning labels.  Regulatory decisions must be firmly based on a careful review and understanding of the underlying science.  Precipitous actions can have unintended and detrimental consequences. 

            Let me end with a few specific suggestions.  First, I would encourage you to support more large-scale multi-site studies with long-term follow up.  The results of such studies will give us the information we need to more accurately address many of the issues and questions which have been raised today.

            Second, with respect to the med. guides, I urge you to present any information about potential risks in a balanced context with appropriate information about efficacy and the benefits of treatment.

            And finally, with respect to monitoring, I urge you to avoid mandating specific schedules.  Instead, I'd suggest that the frequency of on-going contact should be based on the clinical needs of the patient.

            Thank you for the opportunity to share these comments.

            DR. JOHANNESSEN:  Speaker number six, Mr. Kendrick Moxon.

            MR. MOXON:  I'm a civil rights attorney, specializing in litigation concerning informed consent regarding psychiatric treatments and an advisor to CCHR.

            Parents have been sold the concept that their children were endangered from ADHD and must receive medication and deceived with a claim that these drugs are safe.  The entity largely responsible for promulgating this dangerous philosophy is the pharmaceutical front group, CHADD. 

            More than a decade ago, CHADD was criticized by the DEA because of its close association with the pharmaceutical interests.  Nothing has changed.  In fact, it's gotten worse.  In Fiscal Year 2001-2002, CHADD received over $500,000 from pharmaceutical companies whose drugs it praises.  The next year, it received $674,000 from those companies.  Next year, it received over $900,000.  Last year, it received over $1 million from its pharmaceutical benefactors.  As a result, CHADD contemptuously refers to any treatment other than psychiatric drugs for ADHD symptoms as alternative treatments that should be distrusted and it identifies ADHD drugs as effective and characterizes their side effects as mild and short-term.  Yet, CHADD never tells parents that many children on those drugs have died or taken their own lives.

            The hearings on cardiovascular harms, CHADD representative, Dr. Christopher Griffith, even had the audacity to blame teenage pregnancy on the failure of teenagers to take ADHD medications.  With all due respect to CHADD's medical advisor, I suggest perhaps he missed the class in medical school where they taught the real reason for pregnancies.

            CHADD also makes misrepresentations to parents.  One of the frequently asked questions on CHADD's website is, "My child started taking medication and has developed tics.  What do I do?"  It answers this question with a marketing statement.  "A relatively uncommon side effect of psycho-stimulant medications is the unmasking of latent tics and involuntary motor movements.  Psycho-stimulant medications can facilitate the emergence of a tic disorder in susceptible individuals."  Misrepresenting that these medications unmask a condition widely known to be caused by the drugs is like punching a person in the mouth and then claiming the punch unmasked a loose tooth.

            CHADD has opposed every single effort to inform parents of the dangers of its sponsors' drugs.  Yet, parents have a right to full and impartial knowledge of a potentially lethal drug given to their children.  At the least, this Committee should issue warnings to help counter-balance CHADD's marketing campaign which endangers the lives of children and misleads parents over the risks and efficacy of these drugs.

            Thank you.

            DR. JOHANNESSEN:  Thank you.  Next speaker, number seven, is Ellen Liversidge.

            MS. LIVERSIDGE:  Good afternoon.  I have no financial information to divulge.  I am a member of the Alliance for Human Research Protection, a parent, and a speech pathologist in an elementary school where we regularly give the Connors ADHD Rating Scale on boys, always boys, tell the parent the child tests positive for ADHD and suggest they take the report to their pediatrician.

            Schools, as I see it, are the pipeline for ADHD diagnoses and I recommend that the FDA, perhaps in concert with the Department of Education, must require that real risk and benefit information be provided to each parent at that meeting, who is given this recommendation by the authority figure that their child's school represents.

            I reviewed the United Nations Convention on the rights of the child.  Forty-one tenets ratified by every country in the world except the U.S. and Somalia, and number 33 stood out.  It said "the Government should protect children from dangerous drugs."  It looks as if we are not doing a good job, so it's just as well that we didn't sign.

            I would like to refer to the Vanderbilt study just out showing that 2.1 million children are taking off-label, atypical, antipsychotic drugs, over half of them for ADHD.  Those drugs are not on the table today, but I feel that it is worth mentioning them. 

            The State of Louisiana, apparently, brought suit against Eli Lilly and Janssen Pharmaceutical for alleged unfair business practices by misleading doctors into believing these drugs were safe for children, even though they are not FDA approved.  How the suit turned out and whether more states have brought some more suits is not known to me.   But it figures that the industry would go after the third vulnerable group available:  first, people with mental illness; second, the elderly; and finally, children.

            What will the FDA do with these drugs which carry another warning of diabetes, hypoglycemia and death?  Will it wait for more diabetes and death in children?  And why are these drugs not on the table today?

            In your packet is the harrowing story of a mother who was pressured by her sons' schools to putting them on ADHD drugs.  Over the years they were on and off 12 psychotropics.  The children doubled their body weight on Zyprexa and suffered until their parents weaned them off, causing 18 side effects.  She says, "we will always live with the realization that, as their parents, we were an instrument of delivery in the poisoning of our two little boys.  I pray that your children will never be turned into mindless" --     [Audio shut off.]

            DR. JOHANNESSEN:  Thank you.  Next speaker is number eight, Dr. Sam Goldstein.

            DR. GOLDSTEIN:  Good afternoon.  I am an Assistant Clinical Professor at the University of Utah School of Medicine and editor of the Journal of Attention Disorders.  For the record, I'm neither employed by, nor contracted with any pharmaceutical company, nor do I receive funding for research from such companies.

            My travel expenses for this meeting are being reimbursed as part of my noncompensated service as an advisor for the group, Children and Adults with ADHD.  The opinions offered today, however, are mine alone.

            The FDA Center for Drug Evaluation and Research is committed to ensuring the safety of approved drugs.  The CDER is also committed to strong and sound science.  In its publication, FSO1-3, the CDER notes that its mission depends more than ever on a solid cadre of experienced, highly qualified and dedicated professionals.

            Today, the important work of this Committee is to examine the cardiac risks of stimulants for individuals appropriately diagnosed and treated for a number of conditions, including ADHD.  I remind the Committee that stimulants are also approved to treat narcolepsy.  They've become a mainstay as cognitive enhancers during the recovery process from traumatic brain injury, as well as in the early stages of progressive dementia.

            Millions of individuals in the United States rely on these medications to maintain and improve the quality of their daily lives.  As such, the work of this Committee is critically important.  My simple message to you is to keep that in mind, the examination of potential health risks for those taking stimulant medications.

            In my accompanying statement, I provide background citations concerning the health risks of stimulant use.  I urge Committee Members to read the original citations and as the CDER mandates, rely on experienced scientists to explain and interpret these data.

            My opinion as a lay person, treating provider, journal editor, author or individual researcher should be heard, but assigned significantly less importance in this evaluative process than empirical science.  This is the mandate of the FDA and of your Committee.

            It is important for you to not address issues beyond the scope of this designated assignment.  It is not this Committee's charge to evaluate the risks versus benefits of medication treatment for those with ADHD, nor the potential risks posed by a legal diversion to the general population.

            It is critical that you avoid the seduction to dictate social policy concerning the treatment of developmental disorders in children, send messages about prescribing practices to physicians, about marketing to the pharmaceutical industry or for that matter, convey personal opinions or beliefs to the FDA governing body.

            I also urge you to avoid issues or topics that may advance the personal agendas and ideologies of particular individuals or groups.  You must avoid be manipulated into examining the ideology, definition or existence of ADHD.  Your work should not turn into an intelligent design debate in which established science and fact are attacked through opinion and a convoluted pseudo-scientific process.

            Our goal should be for physicians, families, educators and Government officials to work together to curb diversion, misuse, and abuse of medication.  We must adhere to treatment standards.  Finally, we must continue to work together to understand and appreciate the potential --

            [Audio shut off.]

            DR. JOHANNESSEN:  Thank you.  The next speaker is number nine, Christine Limbers.

            MS. LIMBERS:  I'm Christine Limbers.  I'm a doctoral student in clinical psychology at Texas A & M University.

            Patient-reported outcome instruments are used as effectiveness endpoints for new medical products or interventions in clinical trials.  Because some treatment affects such as internal states such as pain and fatigue can only be known by the patient, self-report has become the gold standard in PRO assessment for adults and older children in clinical trials.

            However, given the misbelief that young children are not capable of reliably and validly self-reporting on matters of their health and well being, children under the age of 10 have not been consistently afforded the same level of opportunity to self report their health-related quality of life in clinical trials.  And parent proxy report is often used to monitor the effectiveness of a treatment on children's health-related quality of life.

            The purpose of my presentation today is to demonstrate that children as young as five years old are capable of reliably and validly self reporting when asked with an age-appropriate, child-friendly instrument.

            For this presentation, I will be focusing specifically on data from 11,410 healthy and chronically ill children, ages 5 to 18 years, who have completed the 23 item Pediatric Quality of Life Inventory.  Examining the internal consistency reliability of children's response on the PedQL for each age group from 5 to 10 years, the Cronbach alpha values are all above .84, demonstrating that children as young as five years old are able to reliably self report on their health-related quality of life.

            Next.  Using the known groups validity method, we demonstrate the construct validity of child self report for each age group, including children as young as five years old.  Children with a known chronic health condition report significantly lower PedQL scores than healthy children.

            Next.  The problem with relying on parent proxy report is that parents have consistently been shown to misspecify their children's health-related quality of life in comparison to their children's perceptions.  Even with moderate to good agreement, which is the case from looking at these interclass correlation values, between child and parent report, there still exists a great degree of measurement error that increases the likelihood of incorrectly concluding an intervention has resulted in nonsignificant differences between groups.

            Next.  The last slide demonstrates the responsiveness of child self report in detecting changes in children's health-related quality of life and a clinical trial involving children ages 5 to 18 undergoing chemotherapy.  In this particular study, the largest hemoglobin response is demonstrated in children ages 5 to 7 and consistent with these findings, it was only in this age group of 5 to 7 year olds that children self reported significantly higher health-related quality of life scores.

            In conclusion, the above data demonstrates that children as young as five years old have the capacity to reliably and validly self report on matters of their health and well being when given the opportunity to do so with an age-appropriate measure.  Based on this evidence, we propose that children should be afforded the same rights as adult patients, that is, the gold standard for patient reported outcome is the patient.

            Thank you.

            DR. JOHANNESSEN:  The next speaker is Winni Johnson.

            MS. JOHNSON:  Hi.  My name is Winni Johnson and I'm the mother of children and adolescents living with Attention Deficit Disorder.  Thank you for allowing me to speak to you today.  I came from Cincinnati, paying for my own transportation and hotel expenses.  I am not receiving any public funds.

            I have 11 children, 1 biological daughter, 6 adopted daughters and 4 adopted sons.  Many of my children came to us with special needs resulting from Fetal Alcohol and maternal substance abuse.  Six of my children are being treated with medication for their ADHD.  Psychologicals and support systems, including talk therapy, helps manage their symptoms.  Physicians closely monitor their physical and mental health.

            My 11 children range in age from 11 to 28.  Six of them have taken medications to help manage their Attention Deficit Disorder for several years.  My family's struggle with Attention Deficit Disorder began about 15 years ago when our oldest son, Andrew, showed serious learning problems.  He had trouble reading and his handwriting was horrible.  He couldn't sit still in class and had trouble making friends.  Although he couldn't pay attention in school or participate in a conversation without interrupting, he could spend hours glued to a TV or playing video games.  School was very frustrating for Andrew, but he was clearly very bright, great auditory learner and remembers most of what he hears.  I wanted my children to reach their full potential, so I went in search of answers.

            We began with vitamin therapy and that touted natural cause as a cure, but were not effective.  After a complete psychiatric evaluation, Andrew started to take a prescribed medication to treat his ADHD symptoms.  There was a dramatic and immediate improvement.  He had the same personality, but was able to function normally in and out of school for the first time.  The ADHD medication, together with talk therapy, helped Andrew make it through the elementary and high school years.  After he began taking the ADHD medication, he started his behavioral coaching.  Andrew passed a strict admissions test and was admitted to a top academic school.  Two years later, he transferred to the School for Creative and Performing Arts, specializing in theater technology, lights, sound and scenery.  Today, he is following the same path at Ohio University where he's also active in student organizations.

            I hope you all can imagine the pride I feel as his parent when the same child once told me, "Mom, you have no idea what it's like to be smart and stupid at the same time."

            When I heard of the proposal to put an FDA black box warning on many of the medications used to treat ADHD, I became very concerned that other parents may avoid seeking help.  All medication, including psychiatric medications have side effects.  Both stimulant and non-stimulant ADHD medications have been effective aids to our family.  If a child has Attention Deficit Disorder and has been prescribed medication by a licensed physician, the parents should be aware of the side effects, and should not fear for something that has a low chance of occurring.

            All medications should be managed by physicians.  Collaboration with physicians helped with our adopted daughter, Molly, to better manage her ADHD symptoms.  Molly was adopted at the age of 4 from Russia.  The staff at her orphanage told us she was mute and mentally --

            [Audio shut off.]

            DR. JOHANNESSEN:  Thank you.  The next speaker is number 11, Dr. Peter Breggin.

            DR. BREGGIN.  Hi, I'm Peter Breggin.  I'm a psychiatrist and an independent researcher, obliged to no one. 

            I've given you my 1998 peer-reviewed article which is the most extensive review of adverse effects from stimulant medications still available, although it's been slightly updated in my more recent books.

            At the least, there should be five very important considerations worthy of black box status.  One, cardiovascular, it's obvious, others will talk about it.  Two, these drugs cause depression and they cause obsessiveness.  Children on these drugs in studies that looked carefully, up to 50 percent will have lethargy, apathy, tiredness, sadness, crying.  And one study out of NIH that looked at it found almost 50 percent of obsessive disorders on the drugs, caused by the drugs.

            The combination we know of depression and obsessiveness, leads to suicidality.  In animals, the equivalent extensively studied is loss of spontaneous behavior and obsessive behavior.  Obviously, this looks good in an over-controlled classroom.

            Number three, mania and psychosis.  The rates you'll find are much higher than usually admitted to.  Most mania we now see in children is induced, if not all virtually, is induced by stimulants and in particular, SSRIs.

            Four, dependency and abuse.  The Ritalin label, the methylphenidate product labels are behind the -- we compared Adderall and the amphetamine labels.  They need to be updated.  Ritalin is equally as addicting and abuse-prone.

            Five, brain damage and dysfunction.  Take a look at my paper.  Even by 1998, multiple studies showing brain changes that were persistent, brain damage in both children and adults.  And don't be fooled by those who would blame brain damage on ADHD, rather than on the drugs the kids are taking when we've even got the rat studies to tell us that it's the drugs the kids are taking.

            Again, take a look at my 1998 peer-reviewed article.  There's a lot of science for all five of these kinds of warnings and just, in general, it's time for us to take more responsibility for our children.  We really need to teach them.  We need to discipline them.  We need to take the roles that traditionally have helped children grow up and stop foisting off the problem on the mythical ADHD.  We need to retake our kids.

            Thank you.

            DR. JOHANNESSEN:  Thank you.  Next speaker, number 12 is Dr. Carol Watkins.

            DR. WATKINS:  Hi.  I'm a psychiatrist, child, adolescent and adult in private practice.  I don't take financial compensation from pharmaceutical companies.  I drove myself down here today.

            Besides my private outpatient work, I've spent my hours consulting to schools and group home settings.  During the past two decades I've worked with children, adolescents and adults and families affected with ADHD and related conditions and during those years I gave birth to a son with fairly severe ADHD.  And I remember the day that I, supposedly an expert in child mental health, in particular with schools, sat in the parent-teacher conference in tears as the staff told me my four and a half year old child was in danger of being expelled from pre-school.

            My own family experience made me more humble about what we could achieve.  It also made me want to learn more about the practical ways that multi-modal treatments work together.

            I've been active professionally in CHADD and OCTA in an effort to give back, in exchange for the support I received when I was in need.  Stimulants, mainly amphetamines and methylphenidate have been around for over 50 years and have been used in millions of children and adults.  They're not perfect drugs and they really do have potential side effects.  I see stimulants like neighbors who live next door to you for the past 40 or 50 years.  You know when  you can depend on them and you know they have quirks and some significant weaknesses and you know they don't get along with a few of your other friends and there's some parties where they're just not going to fit in.

            Newer medications and treatments are like people who have just moved into the neighborhood.  They may look great, but you have to be a little more cautious in your dealings with them. 

            When we consider the potential side effects of the stimulants, we need to look at the long-term consequences of ADHD itself.  Studies have shown children with ADHD are more likely to have injuries, illnesses, asthma, interpersonal problems.  Adolescents with ADHD are more likely to be suspended from school or have serious car accidents.  And adults with ADHD are more likely to have employment difficulties or spend time in jail. 

            When I evaluate an individual for ADHD, I usually use several sessions.  The initial history may raise questions that require more outside data or physical tests.  For children, the school nurse can also help follow vital signs and check lists since frequently the times the meds are at their peak are when they're at school, not when they're seeing me.

            And after I initiate treatment, I continue with close follow up, monitoring and evaluating as to how things go.  I think I also like to enlist the child in understanding about potential side effects and understanding and helping me monitor things.  There are actually picture books that cover some of these issues.

            Several years ago I discovered a major insurance company in Maryland had decided to reimburse for medication and not psychotherapy for ADHD.  I've called several physicians' organizations and I called the CHADD.  All these organizations enthusiastically supported the need for --

            [Audio shut off.]

            DR. JOHANNESSEN:  Thank you.  Our next speaker is number 13, Barbara Hawkins.

            MS. HAWKINS:  My name is Barbara Hawkins.  I have no financial ties with anyone except my husband.

            I am the parent of an 18-year-old daughter who was diagnosed at five with ADHD.  We've had many struggles and challenges over the years.  Fortunately, we've received excellent medical care and advice and support from other professionals.  Our daughter's pediatrician from the age of 2 just happened to have a post-M.D. fellowship in pediatric behavior.  He was thorough, cautious, conservative in his use of medicines.  Our daughter was carefully monitored and the dosages of stimulants, as well as changes in the stimulants we were using, were adjusted periodically throughout her childhood and into her adolescence.

            We were told possible side effects of the medicine and the need to carefully titrate the medicine to gain the full effect.  Since he was her primary care doctor, he was familiar with her other medical needs and handled those in conjunction with treating her for the ADHD.  He also referred us for counseling when that was necessary and provided the school information on the impact of the ADHD on her learning.

            It is extremely difficult to raise a child with ADHD.  We struggle with some issues to this day.  As a senior in high school, my daughter faces time management and organizational problems.  She continues to have problems with short-term memory which impacts her success in math.  Sleep problems, so common with those with ADHD, impact her attendance.  Without the stimulant therapy, I cannot imagine how much more difficult this would be. 

            My daughter was lucky to have no underlying medical conditions that precluded the use of stimulants and she responded well to the medicine.  All parents would prefer not to use medicine.  Many are terrified to do so.  I believe that accurate information on side effects is necessary and certainly should be updated when that's appropriate.  I do not believe that the information available to us today justifies adding a black box warning and doing so will certainly make parents much more fearful.

            Untreated and mistreated ADHD leads to serious consequences.  I cannot tell you how many parents I've spoken to at parent support groups who have heard all of the inaccurate negatives about medicine and simply will not even consider it for their child.

            Unless and until there is solid, concrete evidence that a stimulant is to blame for serious side effects, I would urge you to reconsider the black box warning.

            Thank you.

            DR. JOHANNESSEN:  Thank you.  The speaker is number 14.  Katy Warren.

            MS. WARREN:  Hi.  Thank you for the opportunity to come here today.  My heart, for over 20 years, has been in serving and encouraging high school and junior high youth to keep hold of their dreams.  This is why I've had the passion to come here.  I'm currently 29 years old.  Before my graduation from high school, advanced honors program in 1995, I was respected by my high school for my high school and extracurricular activities and was nominated for Who's Who in American High School Students.  I'm also a 2001 mechanical engineer graduate of Texas A & M University.  And I also was selected among 20 engineers in the entire department to be involved in the George Bush College of Government and Public Science, a special leadership program.

            But upon my gradation from Texas A & M, I was also privileged to join Pinnacle Honor Society, a society that awards students who have disabilities for their wonderful work at undergraduate and graduate studies.  Given the gifts that I'm blessed with, I hope to use them in future with neuroscience and acoustical engineering and helping also to uncover Attention Deficit Disorder.

            I've been blessed with wonderful doctors over the years, neurologists, psychiatrists, neuro-psychotherapists and other doctors that have really helped me through these times.  Additionally,  I also had a brain tumor which the cause of the seizures was known before I was diagnosed with ADHD and started receiving treatment.

            Additional disorders have complicated them due to my brain tumor and they've had to include anti-seizure medication, one of which has recently been determined to cause chronic pain, fibromyalgia due to the common anticonvulsant and various other anti-convulsants used with children, is known to cause these conditions and have higher fatality risks for both children and adults.

            I'm also, through my family, my wonderful family, I had a wonderful mother.  She got her degree in medical technology and was able to help me through the difficult times.  It was great.  She also got me, through my doctor, to Scottish Rite Hospital in Dallas and confirmed that I had ADHD and ADHD alone, not including learning disabilities, not to mention that I was having seizures.

            They did a wonderful job with me, tested my IQ to find it highly gifted.  And my parents tried the  natural way, but eventually they found out that we've got to turn to medication.  So that's when I started taking methylphenidate --

            [Audio shut off.]

            DR. JOHANNESSEN:  Thank you.  The next speaker is Dr. Fred Baughman, for 15.

            DR. BAUGHMAN:  Today in the United States nearly one child in five is on some psychiatric medication, clearly something is wrong.  I've been a neurologist and child neurologist for 35 years, making disease/no disease diagnoses daily.  I have discovered and described real diseases, something biological psychiatry has never done.

            If there's gross microscopic or chemical abnormality, a disease is present.  There is no such thing as a psychiatric disease.  Psychiatric drugs appeared in the '50s.  Psychiatry and big PhRMA married and gave birth to the chemical imbalance lie.  In 1970, Lipman of the FDA argued hyperkinesis is a medical syndrome.  In 1994, Lieber of the FDA confessed no pathophysiology has been delineated.  At the 1998 Consensus Conference, William Kerry concluded ADHD appears to be a set of normal behaviors.

            Swanson and Castellanos reviewed the MRI brain scan research concluding ADHD subjects have, on average, 10 percent brain atrophy.  I challenge Dr. Swanson.  Why didn't you mention that virtually all of the ADHD subjects were on stimulant therapy and that this is the likely cause of their brain atrophy?

            Caught in the lie, the Consensus Conference Panel confessed "we do not have an independent valid test for ADHD.  There are no data to indicate that ADHD is a brain malfunction."  That in '98 with the epidemic at well over 4 million.

            In '02, Weinberger of the NIMH claimed "major psychiatric diseases are associated with objective changes", but could not reference a single proof."   In '02, the ADD Commission of Holland determined that the Brain Foundation's claim that ADHD is an inborn brain dysfunction was misleading and enjoined them to stop.

            In '03, Irish authorities prohibited GlaxoSmithKline from claiming paroxetine works by bringing serotonin levels back to normal.  While the FDA's Goodman acknowledged that such claims go too far, he had the gall to suggest this is reasonable shorthand for expressing that this is a chemically or brain-based problem, saying any psychiatric diagnosis is a brain-based problem that medications are normalizing function is an anti-scientific pro-drug lie.  There's nothing more despicable than a physician who knowingly tells normal patients that they are diseased for profit, yet this has become standard practice throughout medicine and at the FDA as well.

            All health care agents and --

            [Audio shut off.]

            DR. JOHANNESSEN:  Thank you.  The next speaker is Dr. Grace Jackson.

            DR. JACKSON:  Hello.  I'd like to thank Dr. Jan Johannessen for his courtesy and professional assistance.  My name is Dr. Grace Jackson.  My discloser is I have been an expert witness on behalf of a nonprofit organization in Anchorage, Alaska named the Law Project for Psychiatric Rights and I've been an invited lecturer on seven occasions in the United Kingdom. 

            If I could have my first slide, please?  It's been bothersome to hear that there remains controversy about a connection or possible connection between stimulant medications and cardiovascular problems.  My points here today have to be limited.  I could make many, but this will be focused upon cardiovascular effects and neurovascular effects.

            Next slide, please.  As early as 1977, Drs. Vernon Fischer and Hendrick Barner wrote a letter to the editor of JAMA, the Journal of the American Medical Association, in which they documented the cardiomyopathic changes which were evident in the left ventricle of a patient who was undergoing coronary bypass surgery, after she had received Ritalin for four and a half years.  The unusual stacking of membranes that you see, they're stained positively for sarcoplasmic reticulum.  This was in 1977.  It was curious to Fischer who wondered if there was any possible connection between methylphenidate, Ritalin, and the cardiac abnormalities that were seen in this patient's left ventricle and consistent with her enlarged heart.

            Next slide, please.  So Fischer teamed up with Henderson and this was then--17 years later--published a paper in which they did just this.  Let's see if there is, in fact, a causal effect.  And they did experiments which include oral exposure of normal doses in mice, as well as the intraperitoneal injections which are usually discounted because of the route of administration.

            Next slide, please.  What they observed here is on the left, a slide which shows the sarcoplasmic reticulum where the lemallations, the abnormal membrane deposits in the left ventricle of the human from 1977 and in the middle of the screen, the same kinds of deposits, accumulating in the ventricle of the mouse, and then on the right, in other species, demonstrating the same kinds of pathological findings in rat.

            This seemed to them to be a confirmation that the cardiomyopathy, that enlarged heart that was seen in the human back in 1977, was indeed consistent with the causal effect.

            Next slide, please.  Significance.  These abnormalities developed quickly.  They were persistent in low doses, had the same effect as high doses.

            Next slide, please.  Clinical implications, more studies are needed.

            Next slide, please.  This is from the Strattera website, Eli Lilly  which states that Strattera is a nonstimulant, the only nonstimulant approved for the treatment of ADHD.

            Next slide, please.  This is from the FDA's website saying the same thing.  Strattera is the only nonstimulant approved for ADHD.

            Next slide, please.  This is the anatomical therapeutic chemical classification system used by the World Health Organization, ATC.  This is actually available on the internet.  You can check it.

            Next slide.  According to the World Health Organization, atomoxitine is listed as N06V substance which is a centrally-acting sympathomimetic, that is, a psycho-stimulant used for ADHD.  You also see on this same list modafinil N06VA07, classified by the World Health Organization --

            [Audio shut off.]

            DR. JOHANNESSEN:  Thank you.  The next speaker is Tamar Osterman.

            MS. OSTERMAN:  My name is Tamar Osterman.  I'm the mother of an 8-year-old boy with ADHD.  He takes 27 milligrams of Concerta and 10 milligrams of Ritalin daily.  As a parent, the diagnosis and treatment of ADHD has been humbling.  My husband and I set limits and expectations and provide a stable and loving home.  I don't feed my kids processed foods that come in weird colors and my child has been tested for food and environmental allergies.

            When Jonah was in kindergarten, he began doing things that never happened at even two years of age.  He wrote on walls, cut his clothes and broke things because a tool was at hand.  He pulled down his pants at school, more than once.  He talked incessantly at school and made odd noises.  But his Connor Scale was within normal range and he was and continues to be a very strong student.

            I took him in for a physical exam.  We discussed he had severe sleep apnea which can cause ADHD symptoms, so he had a tonsillectomy.  I put him in therapy to see if there was an underlying psychological or emotional problem.  We worked with his teachers to create incentive programs and manage his behavior and imposed consequences.  Everything helped, but not consistently or sustainably.

            By the spring of first grade, his behavior was clearly outside the norm for boys his age.  A second Connor put him well within the ADHD range.  At the urging of his psychologist we tried medication.  The effect has been tremendous.  We have peace in the household.  He is productive and appropriate at school and at home.  We continued in therapy from which he was recently discharged to work on social issues.  He sees his pediatrician every three months for weight and heart checks and his school has been a terrific partner in our efforts.

            If every child's case were managed as well as my son's, maybe we wouldn't be here today.  The standard of care for ADHD kids should have three components.  One, regularly monitoring by their primary care physician.  Two, a conservative approach to drug therapy.  And three, supplementary behavioral and therapeutic modes to support the medication regime.  Medication is an important tool in the tool box of ADHD treatment.  Used properly and strategically, it makes the needed difference in many children's lives.  It did for mine.

            DR. JOHANNESSEN:  Thank you.  Next speaker is number 18, Dr. David Stein.

            DR. STEIN:  I'm Dr. David Stein.  I'm a professor of psychology at Longwood University, a consulting investigator with the Bureau of Criminal Investigation, Virginia State Police, and I'm also the author of five books on treating children without the use of medication.

            The risks of psychiatric drugs in the bodies of children and teenagers are well documented and need no further elaboration from me.  I wish to address two issues that are intertwined:  one, the validity of ADD and ADHD as diseases; and two, effective alternative behavioral treatments that reduce reliance on drugs.

            My behavioral cognitive treatment methods have been awarded by the American Psychological Association, the International Center for the Study of Psychiatry and Psychology, and at the Ritalin Litigation Conference.

            Currently, popular behavioral treatments were acknowledged to only have an initial 44 percent treatment efficacy rate, which rapidly declines at the 1998 NIH Consensus Conference.  They are predicated on the belief that ADD, ADHD children are diseased and handicapped and are therefore designed to focus on preceding stimuli which offer excessive cue-ing, assisting, reminding and warnings.  Of the thousands of studies using CAT scans, MRIs, PET scans, not one can be replicated or used at the clinical level.

            The following is a quote from Russell Barclay, the modern initiator of the disease zeitgeist and the primary designer and model of almost all popular behavioral treatment approaches.  "Misled by research reports that lab measures have found differences between ADHD and non-ADHD children and by the fact that ADHD is a biologically-based disorder, many parents ask for medical tests to confirm the diagnosis of ADHD.  At present, there are no lab tests for measures that are of value in making a diagnosis of ADHD, so blood work, urine analysis, chromosome studies, EEGs, MRIs, CAT scans, should not be used routinely in the evaluation of ADHD."

            He later stated, "ADHD may simply represent a human trait and not a pathological condition, in most cases."  And another statement, "This means that ADHD should not be considered some grossly abnormal condition.  In fact, it is a condition not qualitatively different from normal at all."

            Therefore, the assumption of disease or handicap may be erroneous and may make children even worse.  What a terrible thing it is to tell a child that he has a psychiatric disease when in reality no such evidence exists.  No psychological test exists and no medical test exists.  If a child is made to believe he or she has such a disease, then every life decision for education, for marriage, for career, and for having family will be predicated on this falsehood.

            In addition, the excessive helping advocated by the false disease assumption only makes children increasingly dependent on others and on external cue-ing.  They become helpless. 

            In addition, currently popular treatments violate many behavioral and learning principles.  They are poorly designed and theoretically, they should not work and realistically, they --

            [Audio shut off.]

            DR. JOHANNESSEN:  Thank you.  Speaker 19 has withdrawn.  Speaker 20, Dr. Darrel Regier.

            DR. REGIER:  Good afternoon.  I'm Darrel Regier, a psychiatrist, an epidemiologist and formerly at the National Institute of Mental Health, now with the American Psychiatric Association where I'm the Director of Research.  No pharmaceutical or other outside funds were used in conjunction with my testimony to this Committee.

            I will highlight three points in my statement.  First, let me emphasize that ADHD is real, highly prevalent and consistently found in up to 7 percent of school-age youth and about 4 percent of adults.  ADHD is potentially a disabling condition that can impair academic and employment performance and serve as a precursor to substance abuse disorders.

            Second, we know that the treatments for ADHD are indisputably effective.  The federally-funded MTA Study demonstrated 65 percent of youth responded to combined methylphenidate and behavioral interventions as opposed to a 25 percent response rate in community-based treatment as usual.  Improvements in combos showed significant decreases in ADHD symptoms, reductions in ineffective parenting and improvements in academic achievement.

            Any potential pharmacologic intervention, including medications for ADHD must be prescribed judiciously.  A physical examination and a thorough assessment of the person's personal and family cardiac history must precede prescription to stimulant medications with on-going periodic monitoring.

            My third point concerns the need for accelerated research:  on the prevalence and course of ADHD across the lifespan, on cardiac and other general medical risks that co-occur with the disorder and on treatment and outcomes, including long-term treatment benefits and risks.  We lack accurate national information on need, unmet need and actual treatments provided for ADHD in children and adults. 

            To this point, we urge the FDA to pursue the original objectives of the previous panel and avoid the use of black box warnings as expressions of FDA, consultant and personal opinions about the most appropriate and prevalence and treated prevalence rates as the basis for allegations of inappropriate prescribing.

            The risks of limiting access to valid and effective treatments clearly is heightened when the FDA has asked to use non-research standards for warnings and also finds itself pressured from individuals and organizations which deny the very existence of mental disorders for whom no conceivable benefit exists, balanced against the potential risks of treatment.  In this context, the plural of anecdote is certainly not data.

            What should be our next steps?  First, NIH-supported epidemiologic research in this area and in child health, more broadly, is vitally needed. 

            Second, all physicians must have fully transparent access to existing clinical safety and efficacy data on all classes of medications used to treat ADHD. 

            And third, on the part of our profession, we must and will more strenuously disseminate and ensure implementation of --

            [Audio shut off.]

            DR. JOHANNESSEN:  Thank you.  The next speaker, number 21, is Dr. Ravenel.

            DR. RAVENEL:  I'm a pediatrician here at my own expense, with 36 years combined experience in academic and private practice to share some comments regarding concerns on widespread diversion and risk for dependence, even among the conventional use of traditional stimulants and the risk for suicidality and adverse cardiovascular events related to a newer stimulant, atomoxitine.  We've heard previously it is actually classified by the World Health Organization as such.  This information comes from published data, clinical experience reported to me by full-time pediatric behavioral developmental specialists and pharmaceutical company doctors. 

            Prevailing informed consent overstates the supposed effectiveness of stimulants, while failing to disclose and understating drastically adverse effects.  A recent study reported a drug and alcohol dependence suggests that abuse and diversion of traditional stimulants has risen dramatically.  An estimated 9 percent of the entire population of the United States, aged 12 years and older, have used stimulants non-medically during their lifetime and among them, 2.59 million have misused stimulants for ADHD exclusively.

            One can calculate from the data in the article that some 27 percent of those 12 to 17 years old have become dependent upon the medicine.  Although marketed as a nonstimulant, as we said, Strattera is a stimulant in action and in World Health Organization classification.  It's therefore not surprising that adverse cardiovascular effects included in the package insert from Eli Lilly have been described by clinicians increases of heart rate of 25 beats per minute or more, a rate of 110 or more were found in 3.6 percent of treated subjects, compared with 0.5 of placebo.  Elevated systolic blood pressures in two or more occasions and 8.6 percent of treated subjects compared to 3.6 placebo. 

            Full-time pediatric developmental specialists have repeatedly described occurrence of clinical tachycardia in treated subjects with prompt resolution of discontinuance and recurring with treatment again. 

            An evidence-based alternative, non-medical model for the nature of ADHD and proposed alternative approach has been described.  I have published an article, available on the internet of which members have been provided a copy, as well as an effective behavioral approach as described by Dr. Stein in his published research.

            Stimulants certainly may have a place for treatment in some ADHD subjects, but prevailing informed consent should be modified to reflect the lack of data of long-term effectiveness as well as the adverse effect potential.  A trial of non-medication management with an effective non-reward-based approach should be attempted before resorting to powerful drugs, not as an afterthought or given token lip service as is the usual practice.

            Thank you.

            DR. JOHANNESSEN:  Thank you, Dr. Ravenel.  Next speaker, number 22, is Dr. Sullivan.

            DR. SULLIVAN:  Let me start by prefacing my remarks with that I have no financial disclosures to make.

            Thank you for the opportunity to provide comments to the Pediatric Advisory Committee and the Food and Drug Administration.  My name is Dr. Thomas Sullivan.  I'm a pediatrician with 36 years of clinical experience treating children.  I'm here today in the official capacity representing the American Academy of Pediatrics. 

            Attention Deficit Hyperactivity Disorder, ADHD, is a real disease.  It causes significant impairment in many children and adults.  A careful and accurate diagnosis of ADHD should be made prior to starting stimulant medication. 

            The American Academy of Pediatrics developed guidelines for the diagnosis of ADHD in children ages 6 through 12 years, which can be referenced for this age group.  The AAP has also developed guidelines for the treatment of ADHD which notes that people suffering from impairment from ADHD, there are effective treatments including the prescription of stimulant medications.  Reports that have been received by the FDA point to the possible increased risk of cardiac events in people being treated with stimulants.  The American Academy of Pediatrics urges the FDA to pursue further studies to determine whether or not stimulants actually cause these problems and whether these problems occur more frequently in people on stimulants than in other people.

            One way to identify and follow the children and youth with ADHD in order to evaluate their treatment and side effects of the prescribed drugs would be through a national registry.  Until studies of unanswered questions about cardiac side effects, the AAP agrees it would be prudent to revise the labeling of stimulants in such a way as to alert clinicians to the possible cardiac side effects, particularly in people with known structural cardiac defects.  Such labeling should be consistent across all stimulant preparations.

            Rather than a black box warning to highlight these concerns, the AAP recommends that the FDA require manufacturers to send a letter to physicians letting them know the findings that led to the revised labeling and to further studies on the safety of stimulants.  The AAP also advises that appropriate and consistent labeling about potential psychiatric side effects be developed and adopted by all manufacturers of stimulants.

            Clinicians and their patients must weigh the potential risks and the potential benefits of treatments with stimulants, of other available treatments and of nontreatment. 

            On behalf of the American Academy of Pediatrics and its 60,000 members, I want to thank you for your attention.

            DR. JOHANNESSEN:  Thank you.  Next speaker, number 23, is Jim Paicopolos.

            MR. PAICOPOLOS:  My name is Jim Paicopolos.  I'm a parent.  I come here first as a parent and to tell you how my son became a victim of Adderall and how my nephew, Daniel, also became a victim and had to undergo open heart surgery as a direct result of taking the medication Adderall XR. 

            My son Nicholas developed tachycardia.  He's a little bit more fortunate because he started to complain about chest pains and when I first told the doctor about the chest pains what ended up happening was the doctor ignored me.  I took my son to another doctor and sure enough, he had tachycardia.  I sent the letter to the doctor and the doctor still kind of ignored it, so then I sent a letter to the Medical Board, then the doctor took my son off the medication.          My son was diagnosed by a neuropsychologist and two psychiatrists because of disagreement between my ex-wife and I with regards to the medication.  He was diagnosed, given every possible, conceivable test stating that my son had ADHD.  This is my son's report card, straight As in conduct, Honor Roll student, made the National Honor Society, not taking any medication whatsoever and no therapy.

            I strongly believe that there should be a black box warning regarding the dangers to children from the use of amphetamines and other stimulant medications.  In my practice as a school psychologist I have spoken to countless parents who have told me how their children were affected by that medication, how they couldn't sleep at night, how their children lost weight.  One child looked like a concentration camp survivor and I told his mother that.

            My son lost 19 percent of his body weight, developed a rash all over his body before they decided to change his medication, in addition to what I've said before.

            So what I'm recommending here is that in addition to the black box warning that further research be done to determine what kind of effects do that and that every doctor who notices an adverse event occurring in a child would have to mandatorily report it, other than voluntarily report it to the FDA.  Because that's not happening right now.  From all the parents that I've spoken to and from speaking -- hearing from one group of parents to another, these adverse events aren't coming forward. 

            When I spoke with Shryer Corporation  about the medication problems my son was having, they said that Adderall doesn't cause any kind of side effect.  It was all in my head, and that I should refer all these questions back to my pediatrician.

            I don't feel that a pharmaceutical company is responsible when they go around telling parents that there's no side effects when there absolutely are and they're hiding them, because that's the only way I can see there hasn't been any.

            When I looked through the studies, like the MTA Study, the MTA Study was based upon one group versus another group taking medication, not one group and a placebo, so that medication, that whole study is completely flawed.

            [Audio shut off.]

            DR. JOHANNESSEN:  Thank you.  The next speaker is Dr. Todd Gruber, number 24.

            DR. GRUBER:  Good afternoon.  I'm Dr. Todd Gruber, Medical Safety Director for Novartis.  I'd like to thank you for the opportunity to speak to you today about the Novartis ADHD medications.

            Ritalin was the first methylphenidate product for the treatment of ADHD.  Approved by the FDA in 1955, it has a long record as a safe and effective medication for the symptoms of this disorder.

            For more than 50 years, Ritalin has helped patients and their families lead more productive, healthy lives.  It is the most studied drug for ADHD and patient exposure amounts to more than 8.4 million years of patient treatments.

            Other methylphenidate products have now been available generically for many years and in recent years, methylphenidate has been introduced in several long-acting preparations from Novartis and from other manufacturers.  We would also like to point out that although methylphenidate products and amphetamine-based ADHD medications are in the same class, methylphenidate has some pharmacologic differences from amphetamine-based ADHD medications and some of the other ADHD medications.  Considering this, there may also be differences in the adverse event profiles of the medications.

            ADHD is a complex disorder with many treatment considerations including comorbidities that can complicate its diagnosis and treatment.  Published research has shown that there's a high prevalence of other psychiatric conditions in ADHD patients.  Compared to the general population, ADHD patients have higher rates of depression, oppositional defiant disorder, conduct disorder, bipolar disorder, anxiety disorder and other psychiatric diagnoses.

            Novartis is committed to patient safety for all of its products.  Novartis reviews its global, safety database on an on-going basis.

            With regard to psychiatric events, among patients taking methylphenidate products, Novartis has recently reviewed data from our clinical trials in our global safety database and submitted findings to the FDA.  Based on our review, we believe our methylphenidate product labels accurate reflect the kinds of psychiatric events observed in patients taking methylphenidate during clinical trials and in clinical practice.

            We welcome the opportunity to work with the FDA to ensure that the information in our product labels is as clear as possible and we'll continue to review our global safety database and we'll take steps to address any new information and notify the FDA of any updates.

            Thank you.

            DR. JOHANNESSEN:  Thank you.  Julie Zito.

            DR. ZITO:  Julie Zito from the University of Maryland, working in psychiatric pharmacoepidemiology.  I have federal funding and no pharmaceutical research funding and I appreciate very much the Panel's tedious and tough and tortured work today to try to understand this very complex question.

            I have three points to share quickly.  First, broad-brushed black box warnings on all ADHD products, regardless of their clinical pharmacology, based on incomplete and sometimes inaccurate MedWatch reports with varying doses, unknown combinations and different post-marketing assessment periods, is really inadequate science to make the case.

            Clinicians need clarification of the benefits and risks of stimulants and black box warnings simply aren't enough.  I say this because like many of you, I am concerned about stimulant safety, particularly the amphetamines.  But like the boy who cried wolf, the Panel needs to consider what will happen following the many, many black box warnings that have been based on these data from a passive, post-marketing surveillance system.  I suggest confusion, polarizing viewpoints, initial press hysteria, but then what?  Well, we have really no idea what changes in prescription practice may come from these and no way to assure that better treatment is going to occur, unless we mandate studies to clarify the benefits and risks of stimulant use after marketing.

            Second point, the U.S. does not now have the national infrastructure to do just that, so drug safety after marketing still remains weak.  And that's when we need the large numbers of patient exposures to get to the drug which would give us the opportunity then to learn about the safety of the drug relative to other marketed products and this would occur in real world patients, the people who are far more complex than the clinical trial volunteers.

            The system is virtually the only way we will really learn the risk of rare adverse drug events, like suicides and deaths.

            Third point, a national mandate to develop an active PMS, post-marketing surveillance program in a prospective clinical monitoring system requires the will, the funding and the cooperation of all the major stakeholders -- I said stockholders -- that's a Freudian slip -- for a sustained effort to measure the incidents, measuring incidents of treatment-emergent drug events.

            Why bother?  Because clinicians really need to learn what does generalize from clinical trials and what does not.  Make no mistake, it's a tall order.  So families, consumers --

            [Audio shut off.]

            DR. JOHANNESSEN:  Thank you.  Next speaker is Vera Sharav.

            MS. SHARAV:  Slide.  Next slide.  FDA finally confirms that approved ADHD drugs cause psychosis, aggression and violence in children.  As with antidepressants, pain killers and sleeping pills, FDA approval is synonymous with dangerous, not safe and effective. 

            Violent behavior induced by these drugs is a danger to both self and others, including school mates. 

            Next slide.  A dubious diagnosis, as you have heard described over and over again by those who don't have a stake in the system.

            Next slide.  Meta-analysis of all ADHD studies worldwide found no evidence demonstrating clinical efficacy, no evidence that drugs improve academic performance or risky behavior and no evidence of long-term safety.

            Next, please.  Are drugs helping kids graduate from difficulty staying on task to psychopathology?  The most important finding of this review is that signs and symptoms of psychosis or mania, particularly hallucinations can occur in some patients with no identifiable risk factors at usual doses of any of the drugs currently used for ADHD.

            FDA's review, however, does not include all drugs prescribed for ADHD, the most toxic being the atypical anti-psychotics.  Therefore, this panel does not have adequate information to appreciate the full scope and magnitude of the severe drug-induced harms suffered by children treated with ADHD.  In fact, 2.5 million U.S. children have been prescribed anti-psychotics in 2002, more than half for ADHD and other unapproved conditions.  Now anti-psychotics all carry black box warnings.  The hazards include hundred pound weight gain in a little child, insulin resistance, diabetes, heart disease, early death.

            Next slide.  Anti-psychotics, we're told, by prominent psychiatrists, are widely used, mostly for aggression, driven by the number of children being diagnosed with bipolar disorder.  Now historically, this is rare in children, but now bipolar is highly prevalent, only in the U.S.  We are seeing an increasing number of very young children, ages 3 to 7 with frank symptoms of the bipolar disorder.  Many of these young patients have been treated with stimulants and antidepressants.  Now the observed link between spiraling ADHD drug use and epidemic bipolar among U.S. children is alarming.  No other country in the world allows the health of its children to be sacrificed to increase the wealth of an industry.

            [Audio shut off.]

            DR. JOHANNESSEN:  Next speaker is Alan Jones.  Do you want me to leave these slides up for you?

            MR. JONES:  We will continue.  One in 10 children, age 2 to 5, had obvious signs of psychiatric illness such as ADHD, fact or fiction?  Next slide.

            Brandon, the bipolar bear, you might notice is a marketing effort to bring the reality of -- down to where a child can grasp it.  Next slide, please.

            But we have to remember, people, that the consequences of psychiatric drugging are very real.  Let's remember there are real children being harmed.  Some have been killed.  Others are scarred for life.

            Aliah Gleason was a victim of school mental health screening.  A normal, happy child, she was drawn into a four-month nightmare, forced institutionalization and forced drugging.  She was placed on a total of 12 drugs, many at the same time.  After legal intervention, she was returned home, weaned from all medications, lost the weight she gained on medications and resumed her normal life.  Her story can be told and can be read in Mother Jones Magazine.

            Next please.  Joseph Woolsten says if you or I were on that regimen, we would have a lot of trouble attending to work or school.  We don't have any idea what that combination of medicines does to a developing child.  They may have a number of long-term side effects.  The polypharmacy we are seeing is unregulated.  None of these polypharmacy cocktails have been studied.

            Next slide, please.  Another mother, Leslie Darr had two children medicated with Zyprexa, Trileptal and Adderall after an initial diagnosis of ADHD and failure of the ADHD drugs.  Sadly, her story is not unique.  It involves her family.  It could be any family in the United States.

            Next, please.  What's to be done?  Action is needed to protect the life and safety of children from indiscriminant, mostly off-label prescription of psychoactive drugs for ill-defined behavioral symptoms.  Action is needed to protect the safety of the school mates who might be at risk.  This Committee has a moral duty to recommend a risk minimization action plan for all these drugs.

            Next, please.  The Alliance for Human Research Protection urges action to minimize risk for children.  Mandatory restrictions on access to these drugs, mandatory registry for doctors who prescribe these drugs, contraindication for psychoactive drug cocktails or at least a warning that polypharmacy has not been tested for safety and is therefore experimental.  No advertising of these drugs for psychotic behavior.  Require physicians to provide parents with a copy of FDA-approved label and med. guide,  required signed, parental informed consent.

            Next, please.  I'll close with some slides from the Texas Children's Medication Algorithm Project.  These are educational materials prepared for our children.  The youngster goes to the doctor and gets his special medication.  Now he takes his medicine every day.  Does anybody but PhRMa remember Joe Camel? 

            Ladies and gentlemen, the FDA has failed to protect our children from unbounded marketing of psychotropic drugs.  Change at the FDA will not come from the top down.  It will come from you people.  It will come from responsible advice flowing upward through the FDA.  Please follow the courageous leaders of the Drug Safety Advisory Committee to vote for immediate decisive measures to protect the children of this country.

            DR. JOHANNESSEN:  Thank you.  Next speaker is Clinton Libby.

            MR. LIBBY:  My name is Clinton Libby.  Next slide. 

            I am here today as a volunteer member of Able Child, a national nonprofit organization comprised of parents greatly concerned with the issues of psychotropic drugs being prescribed to our children and the erosion of full, informed consent. 

            The Secretary of Health and Human Services is required to promulgate to the broadest consumer audience a toll-free number for receiving reports of adverse events for Section 17, Adverse Event Reporting on the Best Pharmaceutical for Children Act, a recent amendment to the Cosmetic Act.

            I'm sure that the members of this Committee know what MedWatch is, but does the American public know?  The data that I'm going to present will illustrate the reporting system is unknown and therefore fails to provide the statistical data that this Committee needs in order to determine the efficacy and safety of ADHD drugs as mandated by the Cosmetic Act.  Without complete data, a black box warning will at least disclose already known adverse events. 

            On March 12, 2006, I asked people along the Washington Mall if they knew about MedWatch.  Out of 150 signed declarations, representing 25 States and the District of Columbia, 147 or 98 percent had no idea of what MedWatch was.  Four hundred to 500 additional people all declared ignorance, but would not sign the survey.

            Guesses included a television program, a fallen down can't get up medical device, and a medical stock newsletter.  I am submitting to the Panel the methodology of my survey along with copies of the signatures obtained.

            After my testimony last month to the Drug Safety Committee, a representative from Novartis asked me if the deceased children's names that I read into the record had MedWatch reports filed in their behalf.  How can this Committee or the drug manufacturers determine the safety and efficacy of ADHD drugs, as required in the Cosmetic Act, if adverse events are rarely reported?

            Irregular data collection adulterates the scientific process and method and endangers the public safety.  The data needed to judge safety and efficacy has not been adequately collected since MedWatch has not been justly marketed or mandated.  We must protect our children and ensure public safety through the collection of accurate, statistical data.

            Parents, educators, and the general population need to know about MedWatch in order to utilize it.  The current death-related evidence alone should determine a black box warning label.  Per current federal regulations, Title 21, Section 50.25, full, informed consent requires a description of any reasonably foreseeable risks or discomfort to the subject.  When side effects include suicide, death, psychotic behavior, we must inform parents that they can make a fully educated decision.

            I call to this Committee on behalf of the parents that make up Able Child to mandate MedWatch reports for the pediatric population in order to reach the broadest possible audience, as required in Section 17, and to black box warn the public of the risks associated with using these drugs.

            Thank you for your time and consideration.

            DR. JOHANNESSEN:  Thank you, next speaker is Dr. Moira Dolan.

            DR. DOLAN:  Hi.  I'm a medical doctor, licensed in the State of Texas.  I'm Executive Director of the Medical Accountability Network which is an organization of health care professionals seeking to instill ethics and integrity in the field of medicine.  What a concept.

            In medicine, we deal with science, use the science in order to give informed consent so the physicians, patients and dispensing practitioners can actually work as a team together to really weigh the risks and benefits of our treatments.  ADHD describes a wide spectrum of behaviors with no known biological cause or correlant.  

            Every single one of the drugs used to treat ADHD are described by the drug manufacturers and distributors themselves as having an unknown mechanism of action, including this quote from the package insert from Adderall, "there is no conclusive evidence regarding how the effects of this drug relate to the condition of the central nervous system."

            Likewise, for Strattera, "the mechanism of action by which atomoxitine produces it effects in ADHD is unknown."  Untreated behaviors characterized as ADHD are not fatal.  Any studies pretending to show that have actually been subject to statistical corruption.  These drugs are therefore not life saving, yet treatment of ADHD can be fatal.

            I'm sure you're no doubt aware of the extensive post-marketing studies of the stimulants as well as Strattera that have shown the children who are being drugged for daydreaming are found hanging by their shoelaces in the school bathroom. 

            How is it that these devastating drug effects only emerged as profound problems in the post-marketing studies?  Take a good look at the FDA's own critique of the gross flaws of the Adderall pre-approval studies, for example, Study 301, the placebo washout period was only one week.  The entire duration of the study was only three weeks.  Study 201, no legitimate control group.  Placebo in each drug dose was only given for one week. 

            Here's the tragedy, most commonly, the emerging psychoactive drug effects are interpreted as more mental illness.  So you end up with the situation documented in Texas when the Comptroller's Office reviewed the drugging of children in foster care.  It was commonly found that these children are on up to a dozen psychoactive drugs at once.  Add to that the very well-documented fantastic rate of diversion of these drugs for abuse.  Here you find the exact same path of LSD, methaqualone, ecstacy, rohypnol and the date rape drug, GH --

            [Audio shut off.]

            THE COURT:  Thank you.  Our next speaker is Dr. Thomas Kobylski.

            DR. KOBYLSKI:  Good afternoon.  I have no financial disclosures, save one.  I've taken time out of my practice to be here.  I've lost money.

            I'm here today as a practicing child and adolescent psychiatrist for 20 years, currently on clinical faculty at Georgetown, as well as president of the Child and Adolescent Psychiatric Society of Greater Washington.

            Ironically, we are having to set up a couple of projects where we're trying to work with the local mental health professionals and pediatricians to help the growing unmet mental health needs of children.

            I appreciate your role here and I'm glad that I'm on this side of the room here today.  In my practice and training as a psychiatrist medications was always secondary to any other psychotherapeutic, behavioral and other interventions that were mentioned here today and I take seriously our Hippocratic Oath.

            Like other people that have discussed, especially the families, I've had hundreds of experiences where stimulants have made a world of difference in a child's and family's life.  Honestly, I have had situations, although not common, where stimulants have worsened anxiety, mood, thinking and behavior.  Fortunately, I have not had any adverse cardiovascular responses.

            Regarding the first do no harm rule, I can only state what a parent told me this morning when I was talking to them about the potential response of a black box warning.  She works in another government agency.  She told me that, and to quote, "if such a warning prevented one child with ADHD from the very likelihood of clinical benefit that we have received in our family, then that is harm."

            Thank you and good luck with your decision making.

            THE COURT:  Thank you.  Next speaker, number 31, Senator Curtis Bramble.

            SEN. BRAMBLE:  Thank you.  Good afternoon.  My name is Curt Bramble, Utah State Senator speaking on behalf of citizens of Utah and also on behalf of Georgia State Senator Nancy Schafer who couldn't be here today because the Georgia Legislature is currently in session.

            I'm here because of the problems we face in the state level that are essentially based on the inadequate disclosure of the potential problems dealing with the side effects of stimulants.  A 2003 study published in Scientific Review of Mental Health Practice stated that the use of psychostimulants increased over 700 percent of the 1990s and that the rate of school-based administration of Ritalin was synonymous with the prevalence of so-called ADHD.

            On April 27, 2004, the FDA conceded that one of the most common side effects of drugs used to treat ADHD was psychotic behavior or psychosis.  The following are just a few of the many tragic stories involving heinous crimes committed by individuals under the influence of drugs to treat ADHD.

            Now this is anecdotal information, but I think it's important to note.  In May 1999, 15-year-old T.J. Solomon, entered Heritage High School in Georgia, opened fire injuring six students and then threatened to kill himself until an Assistant Principal disarmed him.  He had been taken a drug used to treat ADHD.

            In February 2003, 12-year-old Cory Clevenger molested and sodomized a 4-year-old girl in a wooded area near his home.  He had been taking a drug for ADHD.

            In May 1997, 18-year-old Jeremy Strolmeyer raped and murdered a 7-year-old girl in Nevada.  He had been taking a drug for ADHD.

            And in 2001, Steven Bingham, a truck driver from Utah, was convicted in the sexual assault of an 8-year-old girl he had kidnapped.  Bingham had no prior criminal record, but he was taking a drug used to treat ADHD.

            These tragic stories are about real people whose lives have been ruined by taking drugs used to treat ADHD.

            Since the FDA stated almost two years ago that such drugs are dangerous, why hasn't this Agency taken measures to safeguard the American public including safeguarding our children?  Of equal concern is the mixed message that we are sending our kids.  First, we proclaim just say no to drugs.  But then we say take your Ritalin, take your Adderall.  These are the same drugs on the street that are called speed.

            Most disturbing has been the Agency's lack of initiative.  Full disclosure and immediate warnings are needed to protect our children.  Such warnings, not only within the FDA's responsibility to the American public they're what is expected, they're what is demanded of the Agency, at least by my constituents.

            In the absence of an effective response from the FDA, numerous state legislators have found it necessary to introduce legislation to protect the public.  If the FDA was doing its job, these bills would not be necessary.  The introduction of this type of legislation really begs the question of why are we spending so many millions of dollars, if the FDA is unwilling or unable to do its job.

            Hopefully, questions about the safety of these drugs can be addressed by requiring full and complete disclosure of the potential risks associated with the use of drugs treating ADHD.

            Thank you for your time and consideration.

            DR. JOHANNESSEN:  Next speaker is Dr. Glen Elliot.

            DR. ELLIOT:  I appreciate the opportunity to speak before the Panel.  My name is Glen Elliot.  I am head of the Children's Center at Langley Porter which is where child and adolescent psychiatry is housed at the University of California, San Francisco.  And I am, myself, a child and adolescent psychiatrist.

            I'm speaking today on behalf of the multi-modal treatment of ADHD which actually is a fully federally-funded study that began in 1989 that has been looking at children over the past number of years to look at different kinds of treatment for ADHD and what long-term responses there might be to that.

            As part of that study, this is what I'd like to talk about today, we have been monitoring cardiovascular effects and have some data that goes over about six years at this point that we wanted to present to the Panel in your deliberations.

            What are presented here are two slides, one of two measures, one of which is pulse rate and the other which is blood pressure.  What you can see on the lefthand side, to give you a little orientation are four different measures of baseline and then at two, three and six years with several groups. 

            We have -- part of the sample came to this study without having been previously treated with methylphenidate and we are able to look at children who were randomly assigned initially and for the first 14 months to either no medication treatment or behavioral arm or to medication and then follow those children who stayed in that arm, that is stayed on medication for a full six years or stayed off of medications for the same period of time.  And then at Year 2, we added another group which were what we call local controls.  These are children matched for age, gender and school to our sample that we have been following subsequently as well.

            What's shown on the pulse rate is that what's well known for children, these kids started at age 7, to less than 10 and are about 6 years older than that.  The pulse rate gradually drops over time.  It looks as if by Year 2, the pulse rate stays up a little bit with the group that's treated with Ritalin, that's the far left, but it follows the other two controls, that is, ADHD kids not treated with medication, but with normal controls in subsequent years.

            On the right hand side are blood pressure measures for the same periods of time and the same groups.  The bottom part is diastolic pressure and the top part is systolic pressure.  Again, as is well known as kids get older their blood pressure gradually increases, particularly systolic.  The effects are not statistically significant across the treatment groups.  There are effects, however, by age, as one would expect.

            Thank you very much.

            DR. JOHANNESSEN:  Thank you.  The next speaker is Cynthia Wainscott.

            MS. WAINSCOTT:  Good afternoon.  I'm Cynthia Wainscott with the National Mental Health Association, the country's oldest and largest nonprofit organization addressing all aspects of mental health and mental illness.

            I am also here as the grandmother of Jessica. 

            National Mental Health Association applauds your efforts to ensure the safety of America's children, youth and families.  We, too, are deeply committed to ensuring the availability of the best treatments for the millions of children who have mental illness.  Safety is paramount in treating all illnesses.  However, it is important to not let the discussion about ADHD medications overshadow the public health crisis of untreated mental disorders in children.

            In this nation, if you don't remember anything else I say, remember this, only one third of the children in need of mental health treatment receive it.  And even fewer get appropriate treatment.

            Many of the initial reactions to the black box warning on SSRIs resulted in a public health scare and discouraged much needed treatment.  Please don't let this happen again, putting millions of American children at risk.  We ask the FDA to consider the potential negative consequences of imposing a black box warning on medications before additional needed research is conducted and reviewed.

            Specifically, we are concerned that a black box warning would make people hesitant to seek much needed treatment, not only for ADHD, but for other conditions as well.  The way you present information will be key to avoiding this, whatever you decide.

            As we all know, there must be a strong partnership between parents, treatment providers and children when determining appropriate care.  NMHA believes it is essential that families make informed decisions about medical care, only after having been given the best available information regarding the benefits and the risks of medication and other forms of treatment.

            According to a nationwide survey NMHA conducted in 2005, families with teenagers diagnosed with ADHD strongly believe that treatment leads to improvement in school and at home.  Both parents and teens involved in the survey credited their treatment in the form of medication, counseling, and/or behavioral therapy with contributing to better grades in school, higher self-esteem and improved social relationships and enhanced participation in extracurricular activities.

            We have heard that there is no such thing as ADHD.  We have heard there is no evidence that treatment works.  I've seen it in my family.  Jessica did not choose this illness.  It is not something somebody made up.  She didn't read about it in a book.  It came to her and it came to her through genetic link very clearly.  I can go back four generations.

            Pat statements about ADHD not being real are hurt by this grandmother as an assault on a very heroic 16-year-old girl who has fought through many difficulties and is now on the A-B Honor Roll, who has friends --

            [Audio shut off.]

            DR. JOHANNESSEN:  Thank you.  Our next speaker is Dr. Judith Rappoport.

            DR. RAPPOPORT:  I have no financial interest in these proceedings.  I am a child and adolescent psychiatrist who is at the moment chief of the Child Psychiatry Branch at the National Institute of Mental Health.  I also have had a part-time practice over the last 30 years and I am the author or co-author of over 25 double-blind studies that involve a placebo with stimulant and often a comparison drug.

            The first thing I want to say is that these are among the most safe and effective medications we know, that I don't recognize many of the presentations that have gone before me with hundreds and hundreds of children and their families that I know.  One of the things that's clear is the relative quality of life of these children in their school, with their peers, with their families when on stimulants compared to placebo. The meta-analyses I read all show a major effect size with little comparable.

            I want to focus on the stimulants because in terms of efficacy while sometimes other drugs are better than placebo, nothing touches the stimulants and I might add parenthetically I always thought Strattera was a tricyclic and not a stimulant and classify it that way myself.

            The impact of limiting the stimulants is likely to lead to use of second tier drugs which have both less efficacy and possibly more chronic toxicity.  I want to stress the word "chronic" because a piece of information out of that simply excellent report that was created for this Committee meeting that I would very much like to see is the timing of many of the adverse effects.

            I've been teaching the use of stimulants in medical schools for over 20 years and it has been known for more than 20 years that on rare occasions, just as this report documents, children can get excited, over-excited and irritable, agitated.  On rare occasions can have brief psychotic episodes and the stimulants, this go away as soon as you discontinue the drug.  These are very often surprisingly affected dramatically by just switching to a different stimulant and people often try that simply because they are the safer drugs than compared to everything else.

            I'd like to add while it's very much evidence that impulsive behavior is a high risk predictor for abuse, on the other hand there is very little evidence that having been prescribed a stimulant in childhood is a risk for abuse and in fact, three of the four studies clearly show that that's not the case, that that impulsivity isn't the occasion.

            While I feel strongly of the use of behavior therapy, it's particularly effective for associated and oppositional behavior and conduct disorder behavior and I think most behavior therapists would admit that it's somewhat less effective for motor restlessness and inattention which are the core deficits.

            Thank you very much.

            DR. JOHANNESSEN:  Thank you.  The next speaker is Gayle Ruzicka.

            MS. RUZICKA:  Good afternoon.  My name is Gayle Ruzicka and I'm here to speak in behalf of Utah Eagle Forum.  Phyllis Schaffly, president of National Eagle Forum has stated, "the real issue here is the fundamental right of parents to decide what medical treatment is appropriate for their children."

            However, parents cannot make an informed decision if they do not possess all the necessary information.  A 1995 Drug Enforcement Administration report states, "methylphenidate is a central nervous system stimulant and shares many of the pharmacological effects of amphetamine, methamphetamine and cocaine.  The side effects of cocaine, amphetamine and methamphetamine are addiction, irritability, restlessness, auditory hallucinations and mood disturbances, including psychosis, mania, violent behavior and more."

            The same side effects are attributed to psycho-stimulant drugs such as Ritalin, Concerta, Adderall and others, yet parents when told that their child has ADHD and needs a stimulant drug are not informed of those side effects and thus cannot make an informed decision.

            While the validity of ADHD is not in question today, it is still worth mentioning that parents are not informed that the diagnosis of ADHD is highly subjective and not rooted in science.  Loving parents, who want what's best for their children, will agree to a regimen of mind altering addictive and dangerous drugs, not knowing that they might be opening Pandora's box.

            When a child commits a heinous crime as a result of being under the influence of psycho-stimulant drugs, not only is their future destroyed, their parents are left heartbroken and wondering what went wrong in the rearing of their child.  But the blame should only be laid at the feet of those who fail to disclose the risk associated with so-called treatment.

            The side effect of those drugs are already known by the FDA and yet the Agency still has not taken the necessary action to protect American families.

            While I'm glad to see this Advisory Panel address this issue, it is clear that this should have happened long ago.  Today, you cannot change the past and save families who were deceived, bring back to life the children who have died or free those who are in jail as a result of crimes committed under the influence of these drugs.  But today, as a member of this Panel, you have the chance to do the ethical thing and to set things right.  You have the chance to protect families from this point on by ensuring that parents are told the truth so they can make fully informed decisions. 

            The strongest warnings must be issued, not only through the black box, but also by the doctor who would recommend that the child be drugged and by the pharmacist who would fill the prescription.

            It is the only ethical decision that can be made today.  Anything else --

            [Audio shut off.]

            THE COURT:  Thank you.  The next speaker is James Swanson.

            MR. SWANSON:  My name is James Swanson, I'm a professor of pediatrics at University of California Irvine.  I've received support from several pharmaceutical companies, in particular, McNeil Pharmaceutical and Novartis and Cephalon and UCB and a few others.  I have support from the National Institutes of Mental Health in the National Institutes of Child Health and Human Development and NIMBS for some of my research as well.

            The multi-modal treatment study of ADHD and the pre-school ADHD treatment studies are multi-site studies whose purposes are to evaluate long-term effects of stimulant medication. 

            If you go to the next slide, I just wanted to emphasize that there's a strong interest in the evaluation of safety of stimulant medications among the investigators of these studies.  And if anybody doesn't believe that, you can ask me afterwards and I tell you more about it.  And there is strong support from NIMH and the group of investigators to report side effects when they are present.  And I'm going to do that today.

            Next slide shows how we study growth in these studies.  We did it with measures of height and weight in kilogram and centimeters, but we also used standardized measures from the CDC norms.  On the growth curves you can see here under normal growth an individual stays on the same growth curve.  On the right, you see the height which I'll emphasize today, because I don't have time to talk about weight.  And you can see two points on the growth curve.  Under normal growth, the child stays on the same growth curve and I've listed some percentile and Z scores on the right that show you what the growth curves are for percentiles.  The heavy one is 50th percentile and a zero Z score.

            The next slide shows that for normal growth, the Z score remains constant over time when repeated measures are taken. 

            The next slide is for the PATS, the Preschool ADHD Treatment Study.  This study took dense measures of growth, get good precision of measurement.

            The next slide shows that this study started with non-pharmacological treatment and a titration during this time, standardized growth was above average, but remained constant.  The maintenance phase of this study, next slide, shows over the year, the standardized growth decreased.

            The next slide shows that decrease was about .26 standard deviation units, about 7.5 percentile units, about a centimeter and a half less growth than would be expected otherwise.  In other words, 5 centimeters instead of 6.5.

            The next slide shows the MTA study.  We previously reported in the MTA results at the one year and the two year points.  This is the six year data.  The next slide shows that there were naturalistic subgroups differing in treatment.

            The next slide shows that the growth suppression or reduction was bigger at two years than at six years.  At that point it's about --

            [Audio shut off.]

            DR. JOHANNESSEN:  Thank you.  The next speaker is Dr. Read Sulik.

            DR. SULIK:  Good afternoon.  I'm Dr. Sulik. I'm a pediatrician and a child and adolescent psychiatrist in the State of Minnesota.  I'm president of the Minnesota Society of Child and Adolescent Psychiatry.  I'm also the parent of an adolescent with ADHD.

            Next slide.  My disclosures today, the expenses for the travel to this meeting are being reimbursed by the organization CHADD.

            Next slide.  I have a three-fold purpose for testifying today.  The first is to emphasize that ADHD is a chronic medical condition that has potentially devastating consequences, socially, behaviorally and emotionally on children and adolescents, as well as their families.

            Next.  Medications are not always, but are often a critically necessary component of treatment for ADHD.

            Next.  When potential risks involving medicine are identified, there are ways to educate us health care providers and inform us of how to improve monitoring without inhibiting access to care.

            Next.  ADHD is prevalent among children and adolescents, as indicated by multiple epidemiological findings across communities and countries.

            Next.  ADHD may include not only symptoms of inattentiveness, hyperactivity and impulsivity, but children with ADHD may be unable to self-regulate appropriately and therefore may have poor control over their behaviors and their emotions.

            The negative redirection and the negative social feedback that a child with ADHD experiences increases emotional suffering.

            Next.  When ADHD is present, but it's untreated and poorly managed, the child may suffer emotionally and experience impairment and functioning.  This can alter the course of development for children and this ultimately can have negative lifelong effects.

            Next.  The goal of ADHD treatment then is to relieve suffering and maximize functioning in all areas including improved relationships of parents, teachers, peers and siblings, decreased negative and impulsive risk-taking behaviors, improved academic performance, decreased associated mental health problems and improved self-regulation.

            Next.  Comprehensive treatment of ADHD should involve implementing structured protocols of physical, social and clinical interventions, including medications when appropriate and regular routine follow-up care and monitoring.

            Next.  Children with ADHD and their families must have appropriate education about ADHD and their treatment and access to appropriate care, treatment and monitoring.  It's important to know that primary care physicians are most often the first step in the assessment and the treatment of ADHD.

            Next.  Follow-up visits must include monitoring for improvements and symptoms and functioning and assessing for common medication side effects, adverse events and safety.

            Next.  Improved monitoring then would include increasing the primary care provider's access to education and also to consultation with child and adolescent psychiatrists and other health care professionals to get appropriate information on assessment and diagnosis, treatment --

            [Audio shut off.]

            DR. JOHANNESSEN:  Thank you.  The next speaker is Sharon Kientz.

            MS. KIENTZ:  My name is Sharon Kientz.  And I am here today to give an educator's perspective on the ADHD Ritalin epidemic.  I'm a retired teacher, a current school trustee, and the grandmother of a 17-year-old grandson who after 11 years on psychiatric drugs will never be healthy and whole.

            The public schools are the primary facilitators of childhood entry into the psycho- stimulant drug market.  The process begins in a regular classroom with a teacher, unable to deal with a nonconformist child.  A referral is made to the school psychologist.  The child is tested, a diagnosis made and a label attached.  The next easy step is finding a physician willing to prescribe a psychotropic drug.  A common test to label a child is the SNAPRDSM3 which rates 46 normal behaviors as not at all, just a little, pretty much and very much.  This totally subjective test determines a child's future.

            I taught kindergarten for 21 years and never saw a child outside the broad, normal range of wiggles and attention.  ADHD did not exist the first 12 years of my teaching career and then in the late 1980s, it became the explanation of every behavior difficulty for which Ritalin became the panacea.

            I have witnessed the complicity of the public school system in this epidemic at the county level.  In January of '05, I attended an ADHD conference sponsored by Fresno County Office of Education.  The speaker, Susan Barton, presented as truth the fallacious theory of ADD as a real neurobiological genetic disease.  This conference was attended by 60 special ed. teachers and psychologists, all of whom totally bought the speaker's fraudulent presentation and all of whom were eager to bring the message back to their schools.  One hundred ninety thousand students in Fresno County are at risk from this presentation.

            When he was in first grade in 1994, my grandson was a normal, energetic boy, who was having difficulty learning to read.  His teacher identified him as ADD and told his mother that he could not succeed in school without Ritalin.  She took him to a psychiatrist named Dr. Warren Vaughn who prescribed Meleril for him.  After my furious interference, the Meleril was discontinued and he was prescribed Ritalin and Cylert.  At age 12, he was diagnosed bipolar for which a cocktail of Wellbutrin, Serzone, Imipramine and Lithium was prescribed.  For the past two years he has taken Risperdol and Strattera.  All of these drugs have caused severe neurological and psychological effects including mania, despondency, sleeplessness, tremors and increased heart rate. 

            This once exuberant 6-year-old has become a shuffling, struggling to focus, unable to concentrate, academically failing, chemically lobotomized mental patient who believes his brain is broken and he cannot live without the drugs.  Remember this nightmare started in a public school classroom with a teacher's diagnosis.

            With the psychopharmaceutical industry --

            [Audio shut off.]

            DR. JOHANNESSEN:  Thank you.  The next speaker is Mr. Lee Spiller.

            MR. SPILLER:  Thank you very much.  My name is Lee Spiller and I'm from the Citizens Commission on Human Rights of Texas.  I guess we're here because we really do need to warn kids.  In case work, we see a lot of this.  A kid goes on a drug, something happens, something is wrong.  Heaven forbid it would be something wrong with the treatment.  Instead, it gets treated like an emerging mental illness.  He gets a drug.  And then things go wrong.  And then he gets another drug.  We're not discontinuing the drugs.  And the Texas Foster Care System, the doctor that testified earlier talked about seeing kids on as many as 13 meds.  We had case workers testify that kids were on 17 meds.

            We really do need to warn people.  We can't stop with the black box because I think you all know that at the end of the day whatever you come up with there's going to be a team of people that will try to mitigate it.  So we've got to figure out how to have a warning that will keep warning no matter what they do with it on Madison Avenue.

            The only strategy I can think of is a black box coupled up with a risk map.  I gave you all a handout.  I'm just going to read this into the record and I'll probably run out of time, but "black box signs and symptoms of psychosis or mania, particularly hallucinations can occur in some patients with no identifiable risk factors at usual doses of any of the drugs used to treat ADHD."  That's for your all's review.

            Suicidal actions have been reported in relation to some drugs used to treat ADHD and so on.  And then the risk map part comments where you have a patient sign that in the doctor's office.  It's on a form.  It can't be downplayed.  And then you follow it up and the pharmacy with another form acknowledging that they've been warned.  And every time they refill their prescription they get reminded, just like people get reminded when they get prescribed Accutane or thalidomide.

            The idea is to help kids.  I really don't think that you all want to hurt kids.  So it's a matter of how do we communicate and I really thank you for being here and I hope we can get it done.  Thanks.

            DR. JOHANNESSEN:  Thank you.  The next speaker is Mr. Bruce Wiseman.

            MR. WISEMAN:  Good afternoon, ladies and gentlemen.  My name is Bruce Wiseman.  I am the U.S. President of the Citizens Commission on Human Rights.

            Parents are being misled and children are being harmed and in some cases destroyed because the FDA has turned a blind eye to pharmaceutical marketing strategies that do not fully disclose the life- threatening risks associated with ADHD drugs.  These sophisticated feel-good marketing ploys target kids with everything from cute cartoon characters to coloring books and CDs, while parents are snared by glossy brochures and reassuring websites which forward lies and misinformation.

            One company's cutesie website, "Science Made Simple" states that ADHD is a medical condition linked to a chemical imbalance in the brain.  This is a lie.  There are no tests available for assessing the chemical status of a living person's brain and it is well known and understood that there are no chemical imbalance tests for ADHD.  APA President Steven Sharfstein has publicly acknowledged that there are no lab tests that can determine a chemical imbalance and the U.S. Surgeon General has admitted that the etiology of ADHD is unknown.

            Another pharmaceutical's ADHD marketing site states as fact that stimulant medications are not addictive when used as directed.  Yet, Dr. Nadine Lambert of the University of California at Berkeley followed 492 children for 26 years, half labeled with ADHD and half not.  Her report to the NIH says and I quote, "this study has provided evidence that childhood use of CNS stimulant treatment is significantly and pervasively implicated in cocaine dependence as well as in lifetime use of stimulants and cocaine."

            And still another's kid-centric marketing brochure which, while it includes a recently mandated warning about the risk of suicidal thoughts does not warn of actual deaths, yet the company is well aware of the information in the report written by Britain's Medical Health Care Regulatory Agency on December 9, 2005 and recently released by court order which reveals 130 cases of suicidal and self-injurious behavior in one month, approximately 20 of which were accomplished suicides.  The report also disclosed 766 spontaneous reports of cardiac disorders and 172 of liver injury.  Yet, the first thing one encounters on this firm's website is the drug is safe and effective.

            I could go on, time allowing, but the all too obvious bottom line is that the pharmaceutical industry, awash in their billions of child-drugging revenue will not police themselves.  The FDA must set aside its industry-favorite bias and begin to do their job: protect the American consumer.

            A moratorium should be ordered on these drugs immediately.  Failing that, a black box warning must be ordered for all ADHD drugs so that parents and children are fully and truthfully informed about their life threatening risks.

            Thank you.

            DR. JOHANNESSEN:  Thank you.  The next speaker is Jacqueline Bessner.

            MS. BESSNER:  Leeann Marie Bessner, age 15, 108 pound high school sophomore, always laughing and joking around, a popular, stunningly beautiful girl, an amazing athlete.  She loved basketball and baseball.  She was a natural.  She used Dad's baseball glove, "the weapon", we used to call it.  The fans would always joke about how big that glove was and she was so tiny.  She ran the bases like lightning.  She played varsity basketball.  She wore number 42, just like her dad which I will point out I am speaker number 42, coincidentally, today.

            We never missed a school play, a baseball or basketball game.  We clipped every newspaper article for her scrap book.  She will not run another base or shoot another free throw or tease her little sister or share memories with her own children because on October 9th, she took her life.  Leeann came to me last spring and wondered if she had ADD.  She described a hard time concentrating in class.  She struggled with her school work.  We agreed and decided to have her tested after summer break. 

            In August, Leeann was tested for ADD by a licensed counselor, as well as for depression, which is routine.  There was no depression, but she is diagnosed with ADD.  A recommendation is sent to our family doctor and Leeann is put on Concerta.  I am told the side effects are weight loss, sleeplessness and upset stomach.  She starts with 18 milligrams.  She comes to me, she's not feeling any improvement.  I call the physician.  The dose is doubled to 36 milligrams on September 18th.  Leeann took her life at approximately 2 a.m. on October 9th.  I found her that morning hanging from her loftbed with a belt tied around her neck.  She had intentionally strangled herself.  Amongst my screams, I recall her beautiful brown eyes partially open.  She's dead.

            After Leeann's death, we found a note Leeann had written to a friend about a week prior to her death.  She describes Concerta as her depression medicine, how much weight she had lost.  She cannot sleep at night and she was so sad.  She stated that she had made a recent attempt on her life, but was afraid to push out the chair.  The letter was never sent to her friend.

            Imagine for just one moment that this is your son or your daughter.  Imagine what we live each day.  Imagine discovering that the FDA had hearings last June for the suicidality of this medicine, three months before my daughter was ever prescribed it, but nothing was ever done.

            You had the power to save our daughter's life last June, but you did nothing.  Leeann would have made the honor roll for the first time this year, for the first time in several years, but what a price to pay with her life.

            This is Mr. Frog.  She loved frogs. 

            DR. JOHANNESSEN:  Thank you.  I guess in drawing to a close our public testimony before we turn to the sponsor's presentations just two quick comments.  Certainly the diversity of viewpoints expressed, I think, impresses at least me and perhaps other members of the Committee of both the controversy and on-going complexity of the diagnosis and treatment of ADHD and all the various social and clinical issues that are involved in terms of school systems, off-label practice, psychiatric practice, behavioral practice, abuse and diversion, a big set of issues.

            But I think more importantly, I appreciate the willingness of those who've testified about their own individual experience to come to take us from the statistics to the reality of individuals, whether it's been individuals who have been helped by medication or those who have been hurt, as we've heard from others and be willing to share both their personal experiences as parents and as individuals, so I thank you for coming and sharing that with us, to put a face on the statistics.

            So I'd like to at least take a five minute break while we get organized for the sponsor presentations and then we'll get back to our business.  Thank you.

(Whereupon, the above-entitled matter went off the record at 3:08 p.m. and resumed at 3:18 p.m.)

            DR. NELSON:  The agenda before us for the rest of the afternoon are sponsor presentations and then discussion and we'll take a short break again between sponsor presentation and discussions.  And at this point I'm not giving any predictions as to when we might end, but we'll see.  I have my hopes.

            So are we ready to go with the slide presentation off of the computer from the podium?  Is that all set?

            First up is McNeil.

            DR. STARR:  Dr. Nelson, Committee members, members of the FDA and invited guests, I would particularly like to thank the families that came today to share their experiences, both positive and negative.

            Good afternoon.  My name is Lynn Starr.  I'm a behavioral pediatrician and ADHD has been the focus of my career.  On behalf of McNeil, I wish to thank you for the opportunity to share with you today our data on Concerta.

            ADHD is a biologic disorder, was described in the early 1900s and has been recognized under various names since the 1950s.  Since then, it has been extensively studied.  ADHD is not a benign disorder.  Untreated, ADHD can result in severe consequences.

            The standard of care for ADHD includes a combined approach of pharmacotherapy and behavioral interventions.  Stimulants, including methylphenidate and Concerta are the mainstay of pharmacotherapy for ADHD and have proven benefits.

            Today, we will review the safety data for Concerta in the context of its benefits in the treatment of ADHD.  Concerta is an extended release formulation of methylphenidate.  It is designed to allow once daily dosing to achieve a 12-hour duration of effect.  The active ingredient in Concerta, methylphenidate, is metabolized primarily to alpha phenyl piperidine acid, known as PPAA, which has little to no pharmacologic activity.

            Concerta was approved for use in 2000 for children and in 2004 for adolescents.  Methylphenidate has been in use for more than half a century.

            ADHD is estimated to affect roughly 4.4 million children or up to 7 percent of school age children in the United States.  Similar prevalences have been reported worldwide.  Care has significantly improved over the last decade, due in large put to implementation of comprehensive management guidelines, expert clinical recognition and the availability of therapies as proven clinical benefits.

            According to the DSM-IV, the core symptoms of ADHD are inattention and/or hyperactivity and impulsivity.  For a diagnosis of ADHD to be established, the symptoms must cause significant impairment in functioning and must be inappropriate for the individual's developmental stage. 

            It is now recognized with up to 50 percent of children with ADHD will carry these symptoms noticeably into adulthood.  Comorbid conditions are commonly seen in individuals with ADHD.  These comorbidities may affect the assessment of ADHD and complicate the evaluation of adverse effects and response to treatment.  Children, their families and society, pay a high price for untreated ADHD.  Children with ADHD struggle with friendships and social interactions, have academic difficulties and tend to more accident prone.

            As young adults, they are more likely to be involved in traffic accidents.  In addition, they are at an increased risk of developing substance use disorders and tend to do so at a younger age.

            ADHD is the most well-studied disorder is child psychiatry with more than 400 clinical trials and 4,000 published scientific articles to date.  Methylphenidate has demonstrated improvement in many clinical studies in reducing core symptoms of ADHD and oppositional behavior, decreasing emergency room visits, decreasing the risk of developing substance abuse as well as early onset of substance use and decreasing symptoms of overt aggression.

            Concerta specifically has been shown to improve accuracy and productivity in seatwork, improve core symptoms of ADHD, decrease driving errors and decrease disruptive, negative and defiant behaviors.

            I would now like to turn our attention to a discussion of adverse event reporting, starting with cardiovascular data.  It is important to note these cardiovascular events in the context of their occurrence in the general population.  Here, we see the general population background rates for various cardiovascular events.  The limitations of these rates has been discussed earlier today.  Based on these data, and the data we will now review, we consider the rates of cardiovascular adverse events observed with Concerta to be either consistent with or lower than the rates observed in the general population.

            As you can see in the Concerta double-blind clinical trials database which is comprised mainly of pediatric patients, there were no instances of sudden death, myocardial infarction or stroke.  The one subject with hypertension was an 11-year-old male who received 54 milligrams of Concerta and experienced elevated blood pressure, an increase 1 millimeter of mercury over maximum systolic numbers in the normal range.  The patient was also taking fexofenadine hydrochloride.  No actions were taken and the case resolved spontaneously.

            Our open label clinical trials included 2,800 children, adolescents and adults.  There were also no instances of sudden death, myocardial infarction or stroke.  Elevated blood pressure was noted in 20 cases.  These elevations were coded as hypertension, defined as blood pressure measures over the 95th percentile for weight, age, and gender on any given visit.  This effect is consistent with the known pharmacologic effects of this class of medications and their current labeling.

            Our post-marketing database also shows a small number of adverse events and low incidence rates when estimated over approximately 3.5 million person- years of use.

            In conclusion, the low rates presented for cardiovascular events continue to support the favorable benefit to risk profile of Concerta in the treatment of ADHD.  Current labeling recommends monitoring of blood pressure in patients taking Concerta, especially those with hypertension.

            A recent labeling change has been undertaken to address sudden death and preexisting structural cardiac abnormalities.

            I will now turn to a discussion of psychiatric safety.  I will share with you data from the Concerta double-blind and open-label clinical trials.  We consider the open-label data to be valuable since they allow us to calculate an estimated rate for the occurrence of adverse events.  I will also present reports from post-marketing data as well as background population rates where available.

            The first category of interest includes symptoms of psychosis and mania.  It is difficult to find direct comparisons.  The background rates for bipolar disorder, manic episodes and schizophrenia are shown here.  When we searched our double-blind database for events that matched the terms broadly classified as psychosis/mania, there were no instances of these events in any of the patients who were treated with Concerta.

            Our open-label findings are represented here and reflect very low numbers consistent with background rates.  Rates calculated as per thousand patient-years were also consistent with background rates.  The majority of these children were already on methylphenidate immediate release prior to enrolling in the open-label trial.  Some were continuing from the active drug arm of Concerta double-blind study.  It is important to remember that these represent reports of individual symptoms and do not necessarily constitute a diagnosis of psychosis or manic disorder.

            Cases broadly classified as psychosis mania in our post-marketing database totalled 160 with an estimated rate of 4.6 per 100,000 person-years, which is quite low.  Again, these reports represent individual symptoms and do not necessarily constitute a diagnosis of psychosis or manic disorder.  Please note that for post-marketing events, the data received by McNeil are supplied to the FDA.  The FDA may also receive notification of cases in their adverse events reporting system which may not be reported to McNeil.

            The second category of interest is aggression.  The Centers for Disease Control and Prevention Survey reports that approximately 33 percent of older adolescents, grades 9 through 12, have been in a physical fight in the year preceding the survey.  For younger adolescents, the CDC has also reported that approximately 60 percent of children in grades 6 to 8 have been involved in some form of fighting behavior.

            Our double-blind clinical trial database revealed no events classified as anger, aggression or violent behavior.  In our open label trials we found 53 events.  Of these events, five aggression events were deemed to be serious.  The incidence rate is 37.9 per 1,000 person-years.  The FDA has estimated the incident rate for aggression and violent behavior in placebo-treated subjects across the ADHD double-blind trials to be 70.6 per 1,000 person-years.

            In our post-marketing database, data from 219 cases of aggression or violent behavior resulted in a rate of 6.3 per 100,000 person-years.  To put these numbers into context, the exposure is estimated to be approximately 3.5 million person-years of treatment.  It should be noted that comorbidity such as conduct disorder and oppositional defiant disorder carry their own risk of aggressive behavior and can play a role in some of these cases.  We also know that based on a meta-analysis of 28 placebo controlled trials, stimulants demonstrate efficacy in reducing aggression.

            The low rates presented here for psychosis/mania and aggression continue to support the favorable benefit-to-risk profile of Concerta and appear to be consistent with what would be expected in the general population.  The patient section of the current labeling describes symptoms of psychosis as possible side effects of Concerta.

            Additional information about psychosis is provided in the physician's section of the labeling under indications and warnings.

            Now I will turn to a discussion of suicidal ideation and behavior.  To briefly review the Concerta data, we found no cases of suicidal ideation in behavior in our double-blind clinical trials.  When broken down by subcategories, we found no instances of completed suicide, attempted suicide, suicidal ideation depression or psychotic depression in the Concerta double-blind trials.

            Our open-label clinical trials also revealed no cases of completed suicide, suicidal ideation and behavior events are few in the rates when calculated for 100,000 patient-years are far below the expected rates.  There were 121 reports of suicidal ideation or behavior in the post-marketing database which will be further discussed by Dr. Jacobs, a consultant who we have asked to review our database.

            Dr. Jacobs is a noted suicide expert and an associate clinical professor of psychiatry at Harvard Medical School and is currently the chair of the American Psychiatric Association Practice Guidelines on Suicide.

            DR. JACOBS:  Thank you, Dr. Starr.  In understanding suicidality in the pediatric population and addressing the post-marketing reports, it's important to understand several issues.  First, definitions.  One must focus on whether or not the event is accompanied by an intent to die.  This is specifically relevant for suicide attempts and ideation because there can be varying degree of clinical significance.

            The category of self-injury has particular relevance in the young population because it could be mischaracterized as suicidal behavior which generally, it is not.  This is relevant for pediatric clinical practice and for the interpretation of post-marketing reports.

            The second issue is prevalence.  Let me start with suicide.  The smallest, but most important circle here.  It is the third leading cause of death in young people.  The larger circles represent the prevalence of ideation and attempts as indicated by the CDC Youth Risk Behavioral Survey.

            As you can see, it's quite large; 16.5 percent for ideation; 8.4 percent for attempters.  I've calculated an estimated number based upon the population for the CDC's actual number for completed suicide for ideation and attempters which you can see is quite large and this is for the population 10 to 19.  For 15 to 19, these numbers would be half.  The self-injury category has its own prevalence.

            The message here is that you have a lot of ideation, a lot of attempts, many more in relation to completed suicide indicating that there's a broad range of degree and clinical significance.

            Third is risk factors.  Over 90 percent of young people who commit suicide have a psychiatric illness including ADHD.  There are a number of reasons for increased suicidality in the ADHD population.  First, background prevalence which I've mentioned.  Second, there is evidence of a direct association between ADHD and suicide.  A recent study revealed three times the general population.  There are overlapping symptoms which are seen in suicidal youngsters such as impulsiveness, disruptive behavior, irritability, parent-child communication issues and trouble with the law.  And also and finally, there's a significant association between ADHD and comorbid psychiatric illness.  Depression, conduct disorder, substance abuse and bipolar disorder, all of which are associated with suicide.

            When I analyzed the 121 cases, this is what I found:  75 were non-suicidal and these were characterized as kids who scratched their wrists, picked at their skin and took one or two or three extra doses of Concerta.  And what's important about that in an ironic way, it's proof of lack of response of dose response because these kids had no subsequent adverse event or behavior or suicidal ideation.  There were also many cases of self-injury.  There were 21 cases of suicidal ideation; 18 suicide attempts; and 11 hospitalizations.  There were 7 fatal outcomes, which I'll discuss.

            There were five suicides.  Three pediatric, two adult in the ADHD population.  In the non-ADHD, there were one overdose, a poly-drug overdose and one misintentional use.  All of the suicides had contributing factors such as comorbid diagnoses, concomitant medications. 

            In the pediatric group, as I said, there were three suicides, so I did a comparison of observed suicides versus expected rate.  The expected number was calculated by multiplying the rate of suicide in the general population times the exposure of the Concerta population.  It is clear that the observed cases were significantly less than the expected, even accounting for under-reporting.  If one did this for ideation and attempts, the expected numbers would be in the hundreds of thousands.

            Next slide.  Obviously, a very important category are challenges and re-challenges.  There were three re-challenges.  In that category, there were no hospitalizations, no suicide attempts, two confounders.  Of the 15 de-challenges, there were two suicide attempts, 9 had confounders, 1 negative re-challenge which meant that a young person had taken Concerta, had made an overdose, but was given Concerta back and nothing happened.

            In conclusion, two-thirds of the cases were non-suicidal events.  The majority of cases of suicidal ideation and attempts were not in the severe category and can be explained by multiple alternative explanations.  The de-challenge and re-challenge cases were few in number and did not contain any suicide attempts.  And most importantly, the observed cases of suicide were significantly less than expected, particularly in a population with known risk for suicide.  Given my understanding of youth suicide, principles of causation and my review of the cases, these data do not support a causal link between the suicide events and Concerta.

            DR. STARR:  Thank you, Dr. Jacobs.  In conclusion, the data support a favorable benefit risk profile for Concerta.  Having said that, at McNeil, patient safety is our first priority.  Like the FDA, we take these questions seriously.  That is why we are committed to working with the FDA to utilize the new physician labeling rule to further clarify and better organize the information contained in our current labeling, to continue to analyze the available data and work with leading experts to evaluate the best methods for advancing the study of ADHD and its treatment and to enhance our current educational efforts to ensure that physicians, patients and their families make informed decisions.

            We look forward to this Committee's guidance into this process and at this time we welcome your questions.

            Available to assist in answering your questions today in addition to McNeil and Johnson & Johnson staff are the following experts:  Dr. Stephen Farone, Dr. Douglas Jacobs, Dr. Mark Lerner, and Dr. Thomas Spencer.

            DR. NELSON:  Thank you.  And let me see if there are any questions from members of the Committee concerning this presentation.

            I understand you'll be here through our discussion as well in case those arise later.

            Tom, we can always count on Tom for questions.  Go ahead, Tom.

            DR. NEWMAN:  You can count on me.  Just a comment or clarification.  The zero out of 300 and something looks a bit reassuring, but when I look at Dr. Mosholder's table it's 12.7 person years of exposure in the Concerta group, so it looks like this is a trial that lasted a total of about two weeks.  Is that right?  And if so, then not having any events in two weeks is I think somewhat less reassuring which is zero out of 310.

            DR. STARR:  I think that probably for a really good discussion of person-years, I would ask our statistician to kind of come up and help to clarify that. 

            Camille, can you come up to the front table?

            We had a number of short-term trials, three to four weeks, and then just a couple of longer trials, so let me ask Camille to respond to that question.

            MS. ORMEN:  From McNeil.  Our person-year exposure for the double-blind studies was just a little under 1400 person-years.  For the open label, it was 3.5 million person-years, estimated.  I'm sorry, for the open label it was -- that's correct, 1400 for the open label.

            DR. NEWMAN:  So the double-blind person- years was how many?

            MS. ORMEN:  No, I'm sorry, that's not correct.  The double blind was 14 patient-years.

            DR. NEWMAN:  Because it says here 12.68 which would be about a two-week study, right?

            MS. ORMEN:  That's correct.  The double-blind studies ranged from two weeks to four weeks.

            DR. NELSON:  If there's no other questions, we'll go on to the next sponsor presentation.

            DR. ALLEN:  Thank you.  My name is A.J. Allen.  I'm the medical director for Strattera at Eli Lilly & Company.  And I'm going to get into quite a bit of data and scientific methods in a moment.  I want to first thank the Committee for hearing us and also to the FDA for the help they've provided with preparing for this presentation.

            I'd also like to just stop and pause and think about why we're here.  We're here because we're all concerned about patients.  I think this is true of everybody and in particular, I wanted to just note on the public comments I heard a lot of different things, too.  I heard some stories of personal courage and some stories of tragedy and my heart goes out to those that have lost loved ones.

            I do want to emphasize I also heard that ADHD is a medical condition that's real.  It has significant comorbidity and needs treatment.  All treatment options have benefits and risk.  Some of those are expected and unexpected, but the fact is, it's true for all options.  The goal should not be in labeling and for us to inform -- it should be to inform patients and families about the benefits and risks so they can make a decision, but it should not be to scare patients and families and it should not be to create a system out of fear that really ends up denying patient care or preventing treatment.

            I also heard that clinicians know their patients well and they're the ones that are going to be able to make the best decisions about patient needs and we shouldn't tie their hands.  I think it's clear there's need for more research on ADHD and its causes and treatment options.  We support that and in addition, the mental health system for children is certainly strained and whatever is done we would hope that it would not make this problem worse.

            I also heard that people were saying that because there's uncertainty about the cause of ADHD that this isn't a real disorder.  The fact is that science is about uncertainty to different degrees.  Richard Feynman is a Nobel Prize winner.  He knows about science.  The fact is the vast majority of the data supports the reality of this disorder.

            Now I want to get into methodology for atomoxetine trials.  Most of the data from these trials came from prior to our marketing approvals, so we did not exclude patients due to past experience on our medication.  In addition, we did not exclude patients based on past experience with stimulants unless there was a stimulant medication in the trial.  It there was a stimulant medication for ethical reasons, we excluded patients who would not respond or who had had a significant adverse event.

            Our trials required a diagnosis of ADHD of any subtype and we had -- there should be an "a" here, a minimum symptom severity support at baseline.  The trials allowed common comorbidity with the exception where trials where there was a stimulant, as I noted before, and we ruled out contraindications in those that were in the label and we had three trials that specifically looked at comorbidities.  One comorbidity in ADHD and anxiety; ADHD and depression; and ADHD and tics.  You have those as poster presentations in your packets, so I won't be going over those.

            I'm going to skip the adult piece here.  We did exclude patients who had seizure psychosis, history of mania or were suicidal at the time of being seen.

            In terms of clinical trial data, this is really derived from Dr. Mosholder's table.  What I've done is added all the methylphenidate products including demethylphenidate and modafinil, you can see double blind exposure, open label exposure and total and you can see how atomoxitine compares with the other drugs in terms of exposure.  I've also calculated the approximate days of treatment in each of those studies, although I'll note that's rough.

            I would also note that our principles of medical research requires that we disclose our trial data.  As I said, you have posters in your packets from some of our presentations.  We do presentations at meetings and try and provide this out that way.  We also do peer-reviewed publications and we do put our data on lillytrials.com as part of the PhRMA guidelines.

            I also should note that the presentation I'm giving today will be available via the FDA's website eventually. 

            Shifting to post-marketing events, this is the Lilly Code of Conduct around post-marketing events.  The bottom line here is that everybody at Lilly is required to read this, sign it and agree to it and they are going to report events, not necessarily whether they think these events are due to the drug or not, but based on the fact that they heard about them.  Okay?  So there's no suspicion of causality that goes into this process.

            We also have in terms of how we get events, we bring them in through a number of different causes.  You have the Lilly Answer Center which is where most of these consumer adverse events come in. You have some that come in via our sales reps, from health care providers.  You have some where health care providers call us directly.  I don't know how many of these would be present if you didn't have or if you had a different system of marketing the drug than what we have or a different approach, but this is what our data is.  Presumably, some of these would drop out if we were not actively marketing the drug.

            Some limitations of post-marketing events.  There's differences, because of the methods I just noted, there may be differences between companies and methods and efficiency of collecting events.  There's also differences based on medication history.  Older medications are not going to have as many adverse events reported via the post-marketing system as our newer medications.  And clinician experience is going to play a role in that as well.

            Many events are sketchy.  That's been noted before.  We've also -- one of the other things is you don't have a control group, so you really don't know about developmental changes that may occur over time and that's an important consideration and you have multiple confounding factors that may come into play.

            I wanted to just pause and also note there was some discussion about putting risk in context, relative risk versus the absolute risk.  This is just to give you some numbers on absolute risk regarding different types of -- odds of death from different causes of injury from the National Safety Council, including the proverbial "struck by lightning."

            In terms of post-marketing events, the bottom line is these are important, but imperfect pharmaco-viligance tools.  The efficiency of collecting these events depends on the medication of the company.  The cases are often difficult to assess.  There's a need to compare background rate of events to the relevant population, not just the general population and all risks need to be put in the appropriate context.

            I want to shift now briefly to the pharmacology of atomoxitine.  Dr. Andreason touched on some of this, so I'm not going to go through this.  This is finding data for atomoxitine and psycho stimulants to the norepinephrine dopamine  transporters.  This gives you a summary right here that there's quite a difference between the different drugs.

            This is from an animal model of ADHD where young animals are lesioned with a neurotoxin 6-hydroxydopamine.  What you see here is when give saline to these animals, there's no effect on their movement, but when you give atomoxitine it decreases the movement.  In sham animals that haven't been treated, there's no real effect of saline on movement, but you do see a slight decrease with atomoxitine, you see a stimulant effect with stimulants.  It would go up.

            This is from a study looking at substance abuse liability.  The main point here is that in terms of how these drugs are experienced subjectively, stimulants produced liking effect whereas atomoxitine really is not differentiated from the placebo and this happened -- these are desipramine which is a tricyclic antidepressant.

            This is a different scale that just really looks at subjective effects related largely to stimulant medications.  You can see stimulants are perceived as stimulants and atomoxitine is not.

            Now I presented that data also because we have some data, the question of cardiovascular adverse events, you've heard the data that's in our label.  The mean pulses in that doesn't cover the effects in terms of orthostatic changes and what you see here in this study is one hour after dose, so near the peak level for both the stimulants and for atomoxitine, you're going to see a marked orthostatic difference with atomoxitine which you don't see with the stimulants.  In particular, you have a higher blood pressure when you're lying down with atomoxitine.  When you stand up, blood pressure drops and to keep you standing up, your heart rate goes up to maintain your pressure.

            I want to shift now to suicidal ideation and behavior.  This is a general statement.  We've done this analysis a number of ways, so I'm going to use a general outline and method.  You use a text string search of database fields, of visits that cover a particular window of time.  The reason these are highlighted is because depending upon the method or the particular analysis, these text strings databases or the window of time may vary and that can lead to some of the different results from one study to another.

            You take out the clear false positive hits.  You prepare the data for review.  You can either review raw data or patient summaries.  You have clinicians review those using predefined criteria in the case of suicidality, all of these whether it's Lilly's or the FDA's are based on the Columbia University categories and then you do a statistical analysis.

            This is the analysis that Dr. Mosholder presented earlier.  I'm not going to go into this in detail, except to note that there were no suicides in this analysis and there were five cases that were identified as suicidal ideation and one case that was identified as suicidal behavior.

            We can go into the cases if you'd like.  They're actually in the poster that you have provided as in the briefing materials.

            We more recently have looked at the relative risk of atomoxitine versus methylphenidate.  A disadvantage to atomoxitine would be in this direction if the boxes were over here.  What you see is essentially there's no difference to relative risk here, it's .52, so we can't distinguish something based on our comparative trials using the same methodology we used in our earlier analysis. 

            This really just summarizes what I just went through so I'm going to skip this slide in the interest of time.  In terms of psychosis and mania, the general methodology outline really can be applied to any psychiatric adverse events.  What we saw, I think, with the, at least and this is partly due to the variable data from different sponsors, also it's due to the lack of time that the FDA had.  They really focused on, as I understand it, the analysis consisted of looking at the text string search that was done and then doing a statistical analysis, tallying up the cases. 

            We actually have gone through and taken a look at some of the cases in the double-blind placebo- controlled area and the reason we did this is because there's a number of phenomena that may be reported clinically as hallucinations, that really may not be hallucinations or psychosis in young children.  For example, imaginary friends, hypnogogic hallucinations which are a phenomena that occur as you're falling asleep, images that you may see at that time or as associated with migraine headaches, images of loved ones who have recently died, obsessive/compulsive thoughts, flashbacks from post-traumatic stress disorder and so on.

            I wanted to go through two of the cases to give you an illustration of this.  This is one of the four patients that was in Dr. Mosholder's analysis, a 12-year-old male had described as seeing hallucinations.  This was described as a mild severity adverse event, just lasted one day and the patient continued in the study and actually after about a year, not quite a year, discontinued due to lack of efficacy at that point in time.  Of interest, this patient was described as also having tiredness, decreased sleep and some cloudy thinking and it's possible that what we're seeing here, given the mild nature of the duration and these associated phenomena, his hypnogogic hallucination.

            This is a case of actually, a case that we felt was a psychotic event, a child that was 9 years old.  After 212 days on therapy and this was in an extension study that while double blind, it was double blind to dose.  Everyone was receiving atomoxitine.  They had an event of psychosis.  It was severe severity, unknown duration.  They ended up being discontinued from the study and hospitalized, but one of the things we don't know the final outcome on this, but we did learn that the patient was sexually assaulted earlier in the study and so it's possible that this child had post-traumatic stress, although we do think this -- we feel fairly comfortable calling this psychosis.

            Also, we would note that we did -- we have looked at an at-risk population, ADHD with comorbid depression in our clinical trial that you have in your packet.  We did an analysis using the Young mania rating scale, using objective criteria to try and identify cases of mania.  And what you found in this is two cases in the atomoxitine group, two cases in the placebo, essentially no difference between these two.  Again, I think this emphasizes the importance of controlled data.

            We also, I'm not going to make too much of this, this is an open label case series, but there has been a report now of some kids with atomoxitine benefitting from treatment of their ADHD when there's comorbid bipolar disorder when they're on some sort of a mood stimulus stabilizer.

            Again, I've kind of covered all of this.  I think the bottom line here is that you really have to look at these cases in the clinical trials carefully to be sure whether or not they may be true hallucinations or not.

            Aggression hostility, I'm not going to go through the analysis in detail.  I will note that we have done this analysis for cases where we had atomoxitine and stimulants in the same trial and that analysis, the relative risk ratio --  here it is -- is .96.  So we could not distinguish between atomoxitine and methylphenidate in those controlled trials.

            Bottom line is we at Lilly, we feel that ADHD is a real medical condition.  There's significant morbidity.  It needs treatment.  It's important to put the benefits and risks of all treatment options, including no treatment, in context.

            Patients and families need to be informed, but the goal should not be to try and scare them or create such a burdensome system of consent that you're actually going to limit their access out of fear. 

            Clinicians know their individual patients are in the best position to direct their treatment as needed, particularly when evaluating some of these adverse events. 

            Strattera, we feel, is generally safe and effective for the treatment of ADHD.  I didn't go through the data, but there's substantial data supporting that, in the trials that have been presented and we're committed to continuing to study Strattera's benefits and risks and appropriate labeling.

            Thank you and I'll be around for questions now or also after at the break.

            DR. NELSON:  Thank you.  Let me see if the Committee has any specific questions about this presentation.

            Bob?

            DR. WARD:  This is certainly not my area of pediatric medicine, but both presentations have shown almost a log-fold lower frequency of adverse events than would occur in the general population.  Is this selection?  What would you propose as explanations?

            DR. ALLEN:  That's a good question.  I think there probably is an element of selection coming into clinical trials.  It's a factor there.  What I've heard from investigators and I hope I'm quoting them correct, is that they generally are going to avoid patients that are in the more severe category, the more extreme category for ethical reasons, not necessarily because they're trying to skew the trial, but because when you're doing a double-blind trial, you don't want to put somebody that you're not sure what the treatment is going to be if they're really sick in that trial.  So I think there is some bias that way.  Now there may be other factors that come into play, but that, I think, certainly plays a role.

            DR. NELSON:  Thank you.  So what I'd like to do is before the Committee starts their general discussion with the question is just to take a 10-minute break and we'll start at 5 after 4.

(Whereupon, the proceedings in the foregoing matter went off the record at 3:55 p.m. and went back on the record at 4:06 p.m.)

            DR. NELSON:  So now, the committee I guess gets to talk.  Now, it's certainly my hope that we can be done around 6:00-ish.  But, you know, the last train to Philadelphia is 10:00, so I'm happy to stay later.  So we'll see how it goes.

            So let me call your attention to the questions, and I'm going to read the preamble and then go through the first set of questions, and then just make a couple of quick comments to get us into the discussion, and hopefully help us organize our thinking and the conversation that we'll have.

            These are the same questions that Diane presented initially.  There was a preamble, and I think the preamble, to remind you, starts off with the notion that the products have been shown to be effective to treat children who have been properly diagnosed as having ADHD.  And that the notion is that  there will need to be continued access to the therapy.

            But we've heard a lot about potential adverse effects or risks in both the cardiovascular and neuropsychiatric areas that are potentially associated with these medications.  And the information included adverse events from spontaneous reports, clinical trial data, current labeling, and FDA's plans for additional studies on cardiovascular risk.

            So with all of that information that we were given this morning, and the information that we've heard this afternoon both from our guests during the open public session as well as from the sponsors, we then have these questions.  So for the psychiatric adverse events, the questions are the same for both.  I'm going to read the questions and then suggest a way to organize our discussion.

            What are the important messages you think should be conveyed to physicians and parents regarding these potential risks?  In your discussion, please comment on the strength of the evidence relevant to the identified risks.  As appropriate, identify differences among drug products.

            The second question is:  are the messages about these potential risks being adequately communicated through current labeling?  Third, if not, what additional information or changes should be made to the label?  Or I should say labeling, since I'm assuming it wouldn't all fit on the package itself.  I was listening, Rosemary.

            And number four, what other mechanisms should be employed to communicate these potential risks to practitioners, families, and patients?

            So as I look at these questions, I see them as falling into three general areas.  The first question is:  how do we interpret the data?  And so we had a lot of data presented to us, and the first question is:  what is the data?  What are the data saying to us?  How do we interpret that data?  If we're going to say something, what do we, in fact, say?  So that's the first question.

            The second two are really related.  It's, how do we, within the framework of the FDA labeling, try to foster and improve informed consent, both on the part of practitioners and parents as they struggle with the decision whether to use or not use these medications in particular instances.  So is what's happening now good?  And if not, how could it be improved?

            And then, the fourth question is sort of a blue sky question of saying, well, what else should we do?  We heard a lot of possible suggestions around things such as registry, risk management strategies, informed consent, etcetera, etcetera, etcetera, some of which are outside of the purview of FDA jurisdiction, some of which might be within their purview.  So the fourth question is sort of a blue sky, what else should happen?

            So my suggestion is we do try to stick with them in that order.  If I start hearing blue sky as we're talking about data, I'll caution you to save that, and then our next conversation should be how that impacts on labeling.  And then, we should finally then tackle the sort of blue sky question. 

            The questions are the same both for neuropsychiatric risks and cardiovascular risks.  So hopefully when we get to the second set, which would be cardiovascular, we could perhaps shorthand our references back to the first if, in fact, there are similarities as we go along.  Or there might be differences.

            So having given us that orientation, I guess at this point the floor is wide open for people who want to wade into the interpretation of the data as a first step against sticking with, in this case, the psychiatric adverse events, risks, outcomes that we've heard about, and keeping cardiovascular towards the ‑‑ after that.

            DR. DAUM:  Can I ask a favor before we really start getting into this?  Maybe ask Dr. Andreason to review very briefly what is on the labels right now. 

            DR. NELSON:  You have that really nice little table. 

            DR. ANDREASON: And you have the table that ‑‑

            DR. NELSON:  That was cardiovascular.

            DR. ANDREASON: ‑‑ was cardiovascular, if you're ‑‑

            DR. NELSON:  Do you have a slide that you can recall somewhere?

            DR. ANDREASON:  I can pull the slides back up, or we can just go over the labels that you have questions about.  It turns out that the more current ones are more inclusive, the oldest are the least inclusive, and then others fall somewhere in between.

            DR. DAUM:  If there's a couple of slides that you could briefly orient us for this part of the ‑‑ crucial part of the discussion, that would be very helpful.

            DR. ANDREASON:  Yes, sure.  Just if you hit that link there, and say enable macros, please.  There you go.  And scroll down.  It should be ‑‑ right there.  Go back up there.

            Yes.  This is for the amphetamines.  And then, after this set of slides, it talks about the methylphenadine-containing products. 

            That's ‑‑ no, go back up.  But that's ‑‑ I don't have a table that shows them like I did with ‑‑ like we have for the cardiovascular events.  So if you took ‑‑ I mean, there's a couple of ways that you could go about this.  You could take what is in the most current for both the methylphenidate and the amphetamine-containing products and work from those, and say ‑‑ and use those as kind of the model to work from, I think would be a reasonable thing to do.

            DR. TEMPLE:  Well, put up a recent one, so they can look at it.

            DR. ANDREASON:  Certainly.  Okay.  If you go to the Concerta one that has the psychosis language ‑‑ right there.  Yes, here we go. 

            DR. MURPHY:  So what he has done, just to make sure that ‑‑ he has taken the different parts of the labeling under warnings, what there is, and what it says under adverse events, and tried to put different places in the ‑‑ extracting from the label the different places what is said under each of those places.  So for Concerta, this is the example of what's in the label right now.

            DR. ANDREASON:  That's correct.  Everything on this slide is in the Concerta labeling.  What is in purple is what is in the Ritalin labeling, but none of the yellow is.

            DR. TEMPLE:  But, for example, you'll note that the warning on psychosis says that in psychotic patients the drug can make it worse.  It doesn't say that in people without a history of psychosis it can give you one.  So someone might think that maybe it should have that. 

            Now, the phrase there that says toxic psychosis has been reported, toxic psychosis has been reported ‑‑ we talked about this in June.  I live with this every day ‑‑ not psychosis but the labeling.

            (Laughter.)

            Toxic psychosis is a term of art in psychiatry, which means it's a psychosis ‑‑ it's not a functional psychosis.  It's psychosis that is brought about by schizophrenia or bipolar disorder.  And I think that the confusion there was that people were reading that and saying, "Well, that's psychosis in overdose." 

            And so what we felt we wanted to clear up was that either toxic psychosis didn't necessarily mean an overdose, or we could say psychosis has been reported in overdose, and say at some rate or rarely or at whatever, you know, the data showed with usual use, or at usual dosages, or usual recommended therapeutic dosages.

            Yes?

            DR. O'FALLON:  Is the term "treatment" emergent?  I mean, that was the one that was sort of talking to me, and I'm not an M.D.

            DR. NELSON:  Let me just get some organizing thoughts here.  I saw a few hands go jumping up.  Dan and Tom. 

            Let me ask an orienting question here.  In the cardiovascular presentation, we heard the plausibility that this could be a class effect, because whether you increase it on the sending end or stop it on the receiving end, in increasing the concentrations the bottom line is you had an increase in autonome tone. 

            Is that ‑‑ so there was at least a plausibility in terms of mechanisms suggested there where it would be a class effect, whether you would call it a stimulant or a non-stimulant.  I didn't hear any statement like that in this context. 

            So what are your thoughts as to whether we should be looking at this sort of drug by drug by drug?  Or I heard some suggestion that that would be the case, particularly for ‑‑ I'm going to mispronounce it ‑‑ the "A" one, atomoxitene.

            So should we be parsing the data differently from your view, or should this be a class, and we could then look at what the class labeling ought to look at in different areas, assuming we come to an interpretation of the data?

            DR. LAUGHREN:  I thought the most compelling data with regard to the specific event psychosis was from the control trials that Dr. Mosholder presented where you had psychosis events occurring across all of the programs, as I understand it pretty much, at least across amphetamines, methylphenidate, and I believe atomoxitene, and none in the placebo. 

            And so there were 13 events across sort of those class of drugs in patients getting drug, none in the placebo. 

            PARTICIPANT:  Tom, you didn't have it with every single entity.

            DR. LAUGHREN:  No.

            PARTICIPANT:  But you had it with all three molecules.

            DR. LAUGHREN:  You have it with all three molecules, basically.  Okay.  So I misspoke.  I guess we didn't have it.

            DR. NELSON:  Just to remind us, I've got his slides up here I think, so maybe just call our attention to the right ‑‑

            DR. MOSHOLDER:  Oh, yes.  Thank you.  Yes.  You see that Adderall, there were no events in this category, the double-blind portion of the trial, although there were some in the open label.

            DR. TEMPLE:  So, I mean, in some ways we want you to think about both of those things.  I mean, we face the dilemma of whether to think of something as class effect or as related to the single drugs all the time, and you're faced with limited data most of the time in trying to do that. 

            So, I mean, you know, it would be hard to say there is proof, but we're going to have to decide one way or the other.  So you're supposed to help us.

            DR. NELSON:  Tom?

            DR. LAUGHREN:  If I could just make one additional statement.  I guess it's true that there were no psychosis events in the double-blind, the placebo control trials, with amphetamine. 

            However, again ‑‑ and this may be a place where looking at the individual cases, and looking at ‑‑ at the histories of patients, at the lack of history of any psychosis, and then seeing treatment-emergent psychosis occurring in relation to drug going away when you take it away, might in combination with clinical trials data be fairly compelling for this particular event, since psychosis is not an expected event, really, very commonly in this population.

            It's not like aggression or suicidality where those events are very common in this population.  Psychosis is not.  So that it ‑‑ I think it's going to be important to discuss these separately.

            DR. WARD:  Does that apply for the co-morbid conditions as well?  I'm worried about our looking at one aspect of their total psychiatric status, yet ignoring maybe a bigger aspect.

            DR. LAUGHREN:  Well, I think ‑‑ and, again, there are other experts here at the table, but I think co-morbid depression, co-morbid conduct disorder, they are very common in ADHD.  Co-morbid psychosis is not so common.

            DR. NELSON:  I've got Dan, Tom, and then Marsha, unless Dan says something Marsha wants to respond to, before we go to the statistician.

            DR. PINE:  So I guess I want to amplify on some of the comments that Dr. Laughren was just making.  So, first of all, I would agree that at least the first thing that caught my eye is the zero versus 13 in the randomized control trials.  And I think that's something that really requires very careful scrutiny, number one.

            Number two, I would agree with pretty much everything that Dr. Laughren just said, that part of the reason that I think that deserves careful scrutiny is that by and large those are not really expected adverse events in this population, particularly garden variety kids that are likely to be involved in those trials.

            But perhaps most importantly, one of the reasons that it requires careful scrutiny is the rarity of it.  And the rarity of those kind of events is important, because of what it says about the data, number one.  But it is also important to point out that most people seen and evaluated and working with eight- and nine-year old or ten-year old children have not seen very many cases of acute psychosis.

            And there were hints in the data that raised some concerns to me that what one person might be calling psychosis might not be what another person would be calling psychosis.  And I think that before we get too carried away I think it's going to be very important to have a very good sense about what exactly we're talking about in terms of the nature of the events, because some of the vignettes were convincing and concerning, and others of them really weren't.

            And, you know, given the small numbers, we could be telling quite a different story, depending on the richness and the specificity of the data.  So I'm concerned that some of the events are not what I would necessarily classify as psychosis or mania, having seen it before.

            DR. NELSON:  Tom, I pulled up your slide.  I don't know if ‑‑

            DR. NEWMAN:  Yes.  This is actually in answer to Dan's question earlier.  I just used the data that was in Dr. Mosholder's Table 4 to enter the total person-years of these drugs and the mania and psychosis events.  And, first, the 13 versus zero is a little bit misleading, because there was about twice as much exposure, twice as much person-years, or twice as much time exposed with the active drug.

            But if you look where it says incidence rate difference, that would be I think the thing ‑‑ if I were going to make a decision for a patient that would be most clinically relevant, that means for every, you know, 100 patients treated for one year, there will be 1.6 extra episodes of psychosis/mania, or whatever it is that was being reported.

            And the confidence interval is there.  You can see down there by the P values that it's statistically significant, could probably say a one-tail test of .002, or a two-tail of .0039. 

            So I think the first question is, is this relationship causal?  And the answer is probably yes.  We already know that, you know, from the challenge to challenge it is very likely that this causes this problem in some people. 

            And then, if you're trying to estimate the magnitude of the effect, we have this 1.6, you know, per hundred person-years, which for all the reasons Dr. Mosholder stated is probably an underestimate, because these are people who, you know, had already been on the drugs and had already tolerated them.

            And many people in the open label portions of these trials often start them and discontinue them.  So this seems like kind of a low estimate, and the two studies that were shown ‑‑ I think one was like five percent, one was six percent ‑‑ and just case series, and maybe those are a little high, because maybe the reasons why people decided they wanted to review their last hundred cases is they saw two or three in a row and said, "Gee, we'd better report this."

            But something on the order of probably two to five percent might be a reasonable estimate for the risk of ‑‑ two to five per hundred person-years of treatment for the risk of some sort of psychosis or mania.

            DR. TEMPLE:  That's 10 times the observed rate.

            DR. NEWMAN:  No, that is the observed rate.

            DR. TEMPLE:  The observed rate was one in 600.

            DR. NEWMAN:  No, I'm saying per hundred person-years ‑‑

            DR. TEMPLE:  Right.

            DR. NEWMAN:  ‑‑ and this is the observed rate is 1.6 per hundred person-years.

            DR. TEMPLE:  Right.

            DR. NEWMAN:  I mean, most of these trials were really short, like a couple of weeks, and so if you don't ‑‑

            DR. TEMPLE:  Okay.  So you're converting it to exposed persons.

            DR. NEWMAN:  Yes.  That's what this analysis does is just adds up all the person-years, divides them ‑‑ the number of events into the number of person-years of exposure.

            DR. NELSON:  Now, in fairness, Tom, that doesn't necessarily address the question of whether these are apples and apples or whether the term "psychosis" or "mania" is actually ‑‑

            DR. NEWMAN:  Right.

            DR. NELSON:  ‑‑ including a number of other things, which is very difficult to know.

            DR. NEWMAN:  That's true.  But also, this method of ascertaining events which is do a tech search of the database looking for certain words, I think ‑‑

            DR. NELSON:  Would underestimate.

            DR. NEWMAN:  ‑‑ would underestimate, yes.

            DR. NELSON:  Let me go to Marsha, and then Jorge.

            DR. RAPPLEY:  I agree with Dr. Pine's comments that we were presented with scenarios that suggest some things that might not really be psychosis.  But I was also struck by Dr. Gelperin's description of the theme of some of these psychotic hallucinations, and it reminded me of what we see with alcoholism or other sort of metabolic conditions that result in hallucinations.  And I just wondered if some of the psychiatrists would speak to that.

            DR. NELSON:  Would you like to speak to that?  I could go to Jorge first, unless you want to ‑‑ Jorge, go ahead.

            DR. ARMENTEROS:  Well, I guess a very elemental problem here is we are throwing around the term "psychosis" very loosely.  Normal children, you know, could have hallucinations and they have been described.  They don't have to have any psychiatric disorder to have those experiences.

            It is really under the, you know, psychiatric term and, you know, a very well-defined disorder that we start thinking about them as a psychotic process.  What we tend to see, actually, when, a child develops what I will then call a psychosis as a result of the treatment with a stimulant, it has to look really like a hallucination for real.  We're talking about true experience that's out of the realm of normal, not quite, you know, perhaps an odd behavior.

            So it may look like a person that's very intoxicated, but I never thought of, really, a very intoxicated person with alcohol as actually having hallucinations that commonly.

            I think we have a problem, because the labeling talks about psychosis, and we are ascertaining psychosis/mania.  I think that's a very dangerous ground to walk, because we may be coming to terms with some ideas and conclusions that may not be completely correct.  So I am ‑‑ I mean, we are even discussing the ‑‑ whether this frequency is real or not, and so forth.  And at the same time, we are starting with what appears to be a very confusing term. 

            So I'm concerned about that.  I think it would be very hard to really pinpoint it the way it is presented to us.

            DR. NELSON:  Go ahead.

            DR. JOHANN-LIANG:  Yes.  I'm speaking from the Office of Drug Safety, and, you know, given all the caveats of the post-marketing assessment of these cases, and, you know, the ‑‑ what do these all mean, but there was a tremendous amount of work that was done to try to sort of organize all of the reports that have come into us by, you know, Dr. Mosholder, Dr. Gelperin, the whole team from our division.

            And one thing that does seem to stand out, although because of the organizational purposes it was lumped as psychosis/mania, and that's how it was looked at.  There is a message that we want to make sure that it gets through, that it doesn't get lost, is that of all the sort of high-level analysis that was done, the one thing that does seem to stand out, that these children who go on these drugs do ‑‑ we read case upon cases of these children who do experience these hallucinations, whether you want to ‑‑ you know, it went under this category, because that's how it was organized.

            And it does appear, based upon, you know, all the different sort of puzzles that we had that we put together, that this adverse event seems to be over and beyond just unmasking of, you know, what the child was going to do these events anyway.  I mean, there is really no prior history of any of these events.  The kid gets started on the drug and then experiences these tactile and visual hallucinations ‑‑ case upon case that we've read.

            So that is something that really stuck out to all the reviewers looking at these post-marketing reports that have come in.  So I think you need to consider the post-marketing reports that have come in, you know, in the context of the clinical trial data, which were more short ‑‑ shorter term, where it really was more events for the active arm versus no events on the placebo, together with these cases that we have reviewed in the patients on trials.  So you need to keep that in ‑‑

            DR. NELSON:  Bob?

            DR. WARD:  I'm struck again, though, with the magnitude of use of these medications in that post-marketing period.  And if ‑‑ as the psychiatrists describe for us, if there is a range of childhood behavior and experiences, that can look like a psychosis, or it can be hallucinations that are self-limited. 

            I don't want us to use a medical term, because we don't have another term for it.  I would be happy at calling it just hallucinations, then, if that's ‑‑ if that's really what it's called, rather than coming to the conclusion of a psychiatric diagnosis of psychosis.

            DR. JOHANN-LIANG:  It's a good point.  We were struck mainly by those hallucination cases, but there were cases of mania and other variety of cases as well.  So, I mean, it's hard to say it's just that.  What I think is an important message is that it's ‑‑ what we felt was that this is was drug effect, or what ‑‑ you know, on top of other baseline co-morbidities.

            DR. MURPHY:  Bob, I think that's perfectly fine.  I don't think anybody here would disagree.  That if that's the place that you're seeing this, then that's what we think you all think you need to call it, because I think both the control trials and the post-marketing, they got that same message. 

            If you look at hallucinations, and then particularly in the post-marketing where you saw those dechallenge/rechallenge cases ‑‑ and we tried again to put all of the methylphenidate ones together for you.  If you go through, you'll see that hallucination is in there.  And, again, that's what they tried to do today for you on the post-marketing, again during the trials.

            So we were trying to focus that when we lumped them all together, and then you sort of sift it through, that word ‑‑ I won't even use ‑‑ that word does seem ‑‑ in that series of descriptors for hallucinations does seem to be the area that we could separate out.  I'm not a psychiatrist, so I'm saying that it would seem that that ‑‑ if that's what you all are considered about, though, is labeling it as something that you don't think it is ‑‑

            DR. WARD:  Also, the magnitude ‑‑ I mean, the millions, literally, of exposures that are occurring, and whether ‑‑ what their reporting could be within the range of a child's normal experiences.

            DR. ANDREASON:  I tend to think that they're probably not within the range of normal.  But what we've got here is another psychiatric term of art ‑‑ psychosis ‑‑ of which hallucinations is a part of.  My guess is as pediatricians you've seen a lot of things that we would call psychosis.

            And a bridge that you might be a little more comfortable with is say you have a child that for one reason or another has had too much diphenhydramine.  They will get a hallucination, visual hallucinations, disorientation.  They will attend to things in the room that aren't there.  That's ‑‑ we would call that psychosis, but you probably see that relatively commonly in pediatrics, and are fairly comfortable with it.

            Another one would be, say, the treatment with prednisone for any number of things.  People will get paranoid oftentimes with that.  Sometimes they will get manic with that.  But those are the types of things that I think that you would see more often in pediatric practice that you probably kind of treat and have never really thought of as psychosis, but we would think as a toxic psychosis.

            DR. NELSON:  Cynthia?

            DR. PFEFFER:  Yes.  I wanted to emphasize something that Dan Pine mentioned, and that is the sense of the rarities of some of these problems that we're trying to grapple with.  And I think we're in the same issue we had ‑‑ when we did discussions of suicidal behavior, too, which was a relatively rare event. 

            And in this type of population, whatever the meaning of the word "psychosis" here is relatively rare.  And the large number of children who have been treated with this medicine ‑‑ and if we looked at the control trials at least, there is still a large number relative to the event.

            And I'm also struck with the way we're trying to define this, that it's not really a clear issue here.  And so what I'm thinking is that, what is the most important meaning to the prescribing clinician, and the meaning to the child and the parents who have to think of making a decision to use the medication? 

            And that is that if our labeling and our other educational methods can be updated periodically, and if we can develop means perhaps with our future clinical trials to consider rare events, and how one begins to study those rare events, and begin to formulate a more standardized methodology, I think in the future we might have a better way of informing.

            But that's not what we have right now.  And it sounds that we are concerned enough that there's something there, there's some noise that seems to be relevant.  And if our labeling can be in a way updated, so our label is dated perhaps ‑‑ and at this present knowledge state, this is what we are saying, and this is what we are highlighting. 

            And we can word it in such a way that it's not an absolute finding, but we're concerned, and that this is a way perhaps of educating a parent to look at benefit and risk.  But there's no doubt for these medications there is a benefit higher than some other medicines we use in child psychiatry, so that the question of risk-benefit that a parent has to decide upon, and the clinician has to educate and discuss, is such that there seems to be tremendous benefit relative to rare events that are occurring.

            DR. NELSON:  I'm going to go to Rich.  Then I've got Robert and Judith.

            DR. GORMAN:  I want to amplify on the discussion about psychosis as a terminology.  I think both pediatricians and the patients that they serve would be better served by terminology that is simple and is actually what the data shows. 

            And I think that using the word "adverse" neuropsychiatric effects, such as hallucinations, headaches, and whatever else we want to put into that laundry list, will allow for future reports of adverse events that appear on the label to be more accurate, because you're absolutely right.  If I overdose somebody on Benadryl or prednisone, I don't report that to the FDA as a manic event, even though they are in toxic psychosis.  But you put down specific episodes.

            And while hallucinations are really pretty common in pediatrics, if you've ever had a child with a febrile illness, you realize they're going to hallucinate occasionally.  You also know that that goes away.  If there could be some reassurance as evidenced from the data that these are self-limited effects, that might also help the pediatrician in their prescribing patterns of these drugs.

            As being different from the other thought that I've heard expressed by people where this unmasks other psychiatric diseases, I don't think that's going to go away when you ‑‑ the other psychiatric diseases are going to go away.  Their symptoms may go away.  But for these hallucinations that seem to be specific, and hallucinations in otherwise well children on medications are relatively rare.

            DR. NELSON:  Robert?

            DR. DAUM:  So the speaker just before you really ‑‑ I'm sorry, I don't know your name ‑‑ really said sort of my overriding view really perfectly.  And I would just like to add or emphasize that I think we're talking about children here who previously did not do this.  And I think that's an important thing to say.  We're talking about children who were previously not hallucinating and not being psychotic.  So that's the first point I'd like to make. 

            The second one is that I totally defer to the psychiatrists here and people with more expertise that many of these kids who we're seeing are psychotic or manic may not be.  But I feel uncomfortable sitting here parsing the data out that the way we've seen them today I don't know how we could pick and choose.

            And I'm going to throw out the idea that some of them probably were psychotic, and that some of them probably just had hallucinations, which you could say is an exaggerated variant.  Or I don't know exactly how you'd put it, but I think language could be constructed to say hallucinatory and possibly even psychotic behavior.

            And I would also emphasize what you said so nicely, and that is that these are infrequent events.  And I think when we get back to talking about blue sky, Scott, and talk about sort of risk-benefit kind of issues, I think that should come back to us, that these are probably low frequency events, and I think we should also acknowledge our uncertainty about exactly how frequent they are.

            So that's what I wanted to say.

            DR. NELSON:  Dan?

            DR. PINE:  This will be a bit of a summary point, and then I'm going to ask Dr. Vitiello to maybe talk about the MTA data a little bit. 

            So I guess, again, speaking as a psychiatrist, I think it does look to be the case that clearly there is some class of unusual adverse ‑‑ whatever you want to call them ‑‑ behavioral, neuropsychiatric, adverse events that we need to think about notifying people about, and that we shouldn't be too overly precise about what they are, number one.

            Number two, one of the advantages of one study in particular, the MTA study, is that a number of the raters had extensive training in thinking about these types of events and observed not a huge cohort, but a cohort of over 400 children over many years.

            And so they would have a sense of both what are the types of unusual behavioral reactions that kids have on stimulants?  And from among those unusual behavioral reactions, which ones would you think of as mania, which ones would you think of as psychosis, and which would you think of as something else?

            So I wondered if maybe Ben Vitiello could talk a little bit about the prevalence of these kind of events over the five years or six years in the MTA study, and were any of them such that the psychiatrists in the MTA study would have classified them as psychosis or mania?

            DR. VITIELLO:  I think the most meaningful is really the first 14 months, because the patients were treated and followed very closely.  So the MTA is about 600 children that were randomized to receive medication or not.  Of about 250 kids who received medication management at relatively high dose ‑‑ I mean, a high dose means at least 30 milligrams a day for a period of 14 months ‑‑ there was one incidence of a child who had hallucinations.

            So we have about 250 children exposed to this treatment for 14 months.  So it's about 300 patient-years.  You have one episode.

            The hallucination disappeared when the drug was discontinued.  The child was so hyperactive that eventually the family agreed to go back on the medication, so it was rechallenged and their dose event didn't come back.  So the child finished the study on the medication. 

            So it's a relatively infrequent event, but ‑‑ and it's not clear if it is causally related, even though it's plausible, because we saw CMS stimulants and we know that intoxication with these agents anyway brings hallucination and delusions.  So there is a plausible mechanism.

            DR. NELSON:  Jorge, you want to respond to that specifically?

            DR. ARMENTEROS:  I want to add something important.  I believe that that is ‑‑ I hope that this conversation is actually not to replace, okay, the actual language that indicates that there could be an exacerbation in those that already have a problem, because this data actually doesn't ‑‑ the data that we were presented has nothing to do with existing cases, because these are all, you know, of course very well described cases that go into the studies.

            So, you know, on the one hand we have this situation we are discussing right now.  But we cannot eliminate completely the possibility of exacerbation when it is already an existing condition.

            DR. NELSON:  Yes.  Later on I was going to get us to drill down into the label itself. 

            Judith?

            DR. O'FALLON:  The first thing I was going to say is I do think we need to present the information to the parents.  Now, I'd like to be thinking about this as a parent, from that point of view.

            The parent would like to know whether this was a ‑‑ whether these problems are something new, i.e. emergent, or whether ‑‑ treatment emergent, or whether they are exacerbation of underlying problems, because ‑‑ and I would think that the doctor would need to know that, too.  But anyway, I think those two things should be presented separately, so that people would have some idea.

            And the other ‑‑ the second thing, though, that's bothering me is the time factor.  Again, as a parent, I would like to know whether something shows up right away.  In other words, I can look for it, and if we get out a month, we're probably relatively home-free, as versus something that could be building up over time. 

            And, again, the study ‑‑ we have so little long-term data available to us from these studies that we really don't have a ‑‑ I don't think we have a very good idea of how many of these develop further down the line, because the studies are so short.  And that's a problem.  You know, the data ‑‑ our design is not ‑‑ based on these designs is not adequate.

            DR. NELSON:  I think when we get to some of the discussion about what we think ought to be done further, maybe we can talk about that.  I'm reminded of the comment I think Dr. Mosholder may have made that these are rare events, which would never come out in any standard clinical trial.  So it gets into the question of other alternatives and approaches.

            But let me see if I could summarize what I've heard so far to just keep this moving along.  People are talking about this psychosis/mania not in a psychiatric meaning, but at least in a popular meaning, as being a real observation, which occurs rarely but appears to be related to a drug signal and not to an uncovering effect based on its comparison to the placebo group, and, therefore ‑‑ and I haven't heard anybody disagree with Tom's redaction on the other data, but whatever number we put to it it's a small number and that that's real.

            So is that a fair summary at least of where everybody ‑‑ you know, the assumptions behind the conversation?  Bob?

            DR. TEMPLE:  I guess what I heard, and I think we could with a little more time but probably  not here, do something about it ‑‑ is figure out whether these are primarily just visual hallucinations and nothing else, or visual hallucinations accompanying something else that looks like a diagnosis. 

            And conceivably, we could do the same thing for the ‑‑ some of the post-marketing data, which I think people were worried about.  And I must say it seems to me that represents a meaningful distinction.  Either way you'd tell people, but you'd want to know what to tell them.

            DR. NELSON:  Right.  So I agree it's still unclear, and it may not be that we could clear it up here exactly how you would parse out what psychosis/mania meant in terms of the phenomenology of what was being observed, apart from its psychiatric use.  If something was going on, that should be described to people, and they should know about it in the course of getting treated with this class of drugs.

            Now, I guess having ‑‑ if that's a ‑‑ you know, we don't have to ‑‑ I'm sure there's a little bit of gray around the margin there, but just trying to name that. 

            My next question before we move to how you communicate that is we were also presented information about aggression and about suicidality.  And I threw up at least the summary slide here that I think ‑‑ or at least one slide that kind of summarizes that from that presentation.  So the question is:  do people feel the data, even if the numbers are slightly different, say pretty much the same thing qualitatively or not?  Start with Dan.

            DR. PINE:  I actually think there's quite a big difference with the aggression data in particular, relative to the other things we were talking about.  And there are two issues, and Ben Vitiello brought them up in the morning.

            One is there is actually quite a rich database that looks at the effect of psychostimulants on aggression in powerful randomized control designs using validated measures of aggression.  And there is pretty good evidence that there are robust decreases in aggression and hostility with psychostimulants.

            And I think it would be not right to look at the adverse event data here without keeping in mind that there is also strong data to suggest that psychostimulants reliably reduce aggression and hostility, number one.

            DR. NELSON:  Can I just challenge you on that for a second?

            DR. PINE:  Yes.

            DR. NELSON:  I mean, that may be true, but that's the other side of the equation.  I mean, just as in SSRIs, no one is denying that they don't treat depression, but on the other hand there was still the drug-related effect of suicidality.  There could be aggression that emerges while a large number of children are treated relative to their aggression at the same time.  Is that not possible?

            DR. PINE:  So I think it's excellent that you brought up the point of SSRIs, because I think it's a very good comparison to make.  Part of the reason that the data in the SSRIs are so concerning is not only that you did have this signal suggesting that there was an adverse behavioral effect, but when you look at the data on efficacy of, you know, the other side of the equation, the efficacy data were really quite weak. 

            So it was not only that some kids might develop suicidal thoughts on SSRIs.  It was that some kids might develop suicidal thoughts, and most kids are not going to be tremendously benefitted from them.

            It's a very different situation here, because while we might have the suggestion that some kids will have an idiosyncratic increase in aggression based on the adverse events data, the magnitude of the effect size ‑‑ and we didn't ‑‑ we didn't review these data here, but the magnitude of the effect size for the reduction in aggression and hostility by stimulants is much larger and much better replicated than the magnitude of the effect of SSRIs on symptoms of depression.

            DR. NELSON:  Let me just push back once more.  So let's imagine, though, I'm a parent with a child who is being put on a stimulant for school performance, lack of concentration, etcetera, etcetera, and not for hostile or aggressive behavior, and then they develop it.  So independent of the efficacy issues, the awareness of the possibility of that as an adverse event in the minds of the parent, so it would strike me that you would want to say both things at the same time, wouldn't you?

            DR. PINE:  I have no problems communicating, and I think in some sense we're obligated to communicate to parents that these events were observed.  I think it would be a mistake to communicate that message without the countermessage that the medications have been very reliably and robustly shown to reduce these very same behaviors that you might be looking out for.

            The other thing that makes the ‑‑ and I don't even like using the word "psychosis/mania" to tell you the truth.  I'd prefer it if we called ‑‑ called it behavioral toxicity.  But the other reason where aggression is really quite different is this is a core feature of the disorder that a lot of these kids have.  So I think that it would not be wise to equate, in some sense, at least my concern with those two issues.

            DR. NELSON:  Okay.  Just as a non-psychiatrist, I'd like to restate what I think you're saying, is that although the data on the risk side may look similar, what's different about it is on the effectiveness side there is good data about the effectiveness in terms of the treatment of aggressive behavior, and, in fact, aggressive behavior is a part of the phenomenology of the condition, of which psychosis is not.

            DR. PINE:  I wouldn't say ‑‑ again, I wouldn't say psychosis.  I'd say ‑‑

            DR. NELSON:  Yes.  I'm using that in a non-psychiatric way.

            DR. PINE:  Which I have a very hard time doing.

            DR. NELSON:  Right.  Laurel, and then Ben.

            DR. LESLIE:  I just want to raise that there are different subtypes of ADHD, so the aggression tends to go along with certain subtypes and not the others.  And so I think it would behoove us to be careful about that.  You could see aggressive signs coming up in attentive kids that do not have the coexisting aggression conduct disorder or defiant disorder type of picture.

            So I think this is a good distinction you're bringing up, Skip, that needs to be thought about.

            The other thing I wanted to say is above and beyond the specifics we say about psychosis, etcetera, one of the messages is if your child has a problem, talk to your doctor about it.  I think first and foremost we've got to make sure that comes up.  Anything new happens with your child, talk to your doctor, because I think some of the stories we heard during the SSRIs and today have been where things have not ‑‑ have gotten delayed going to ‑‑ forward to a physician.

            The same message the FDA group raised for the physicians.  If there's a problem that comes up, these meds are so easy ‑‑ they don't have a long half-life.  Take the child off of it.  See what happens.  I think ‑‑ I think those are messages we don't give out strongly enough, and then you see people starting to add other medications on when it might just be a side effect, that if you switched to a different stimulant or a different class of medication you wouldn't see it.

            So I'd just say in this first question, these two messages of talk to your doctor and try the child off of it and try something else, are really critical before we start laying a lot of other diagnoses on children, where it may just be a side effect of the specific medication.

            DR. NELSON:  Okay.  Ben?

            DR. VITIELLO:  Just a few comments.  I think it's important, the issue of effects, that treatment is likely to improve depression ‑‑ I'm sorry, aggression, and it may happen that some kids can become aggressive.  And I think the practical implication of that message is that if you have a child who has attention deficit disorder and is aggressive before starting treatment, that will not be a contraindication to use of a medication, because the chances are that the aggression will get better.

            So I think it's ‑‑ that comment that Danny was making before has very practical implications.  You don't want to give a message that aggression is a reason to refrain from using a medication, because that will not be appropriate.

            The other comment is that I notice ‑‑ and this is just semantics ‑‑ that the adjectives "rare" and "infrequent" are used sort of interchangeably here, and I wonder if that is correct or there are some definitions from an epidemiological point of view that one can use.  And if such a definition exists, these episodes ‑‑ the incidence or the rate of its incidence is more appropriately called rare, or it should be called infrequent?

            And the third comment is that, going back to the label, what seems to be important here is to revise alerting that these events can happen, and that the medication in this case should be at least temporarily discontinued to see what happens to the symptoms.  That seems to me the bottom line here of our discussion.

            DR. NELSON:  Tom?

            DR. LAUGHREN:  I don't think this slide is the best summary side on the aggression data.  If you go back to slide ‑‑ Dr. Mosholder's slide 17, where you see the actual data, you'll see ‑‑ and I think this is very important to distinguish between the data we were looking at for psychosis, whatever that is, and the data for aggression.  With psychosis there were no events in placebo patients.  Here there are a lot of events in placebo patients.

            And even though there isn't a slight excess for atomoxitene ‑‑ you know, 8.6 versus 5.9 ‑‑ you're really not seeing much of a signal coming out of the control trials for aggression.  I really think that's a more accurate reflection of the data.  So in weighing the ‑‑ you know, the clinical trials data here, I think it's a much different signal than you're seeing with whatever psychosis is.

            In terms of Ben's question about rare and infrequent, these are not very well defined.  One commonly used definition is to consider it rare if it's less than 1 in 1,000, whereas infrequent might be 1 in 100 to 1 in 1,000, frequent being less than, you know ‑‑ greater than 1 in 100.  But it's not something that's very well accepted.

            DR. TEMPLE:  Actually, our labeling rule used to give numbers like that.  But I think we've gotten rid of it in the new rule, because nobody knows what it means.

            DR. NELSON:  Tom?

            DR. NEWMAN:  Yes.  I did ‑‑ the same analysis I did for the psychosis I did for the aggression.  I don't know if you can pull up that slide, but that one is sort of just barely statistically significant.  It's a slightly higher absolute risk, because the aggression is more common.

            And I think probably what is going on sort of ‑‑ how to resolve this discrepancy where there is more reports here ‑‑ I don't have my pointer, but you can see it goes the same way as before, same number of person-years.  It's 83 versus 30 events, and the difference is 3.3 percent, and it looks like, you know, just what the two-tail ‑‑ not quite statistically ‑‑ I've got to be careful here ‑‑ not ‑‑ okay, I've got one here.  I don't want to zap you, though.

            Okay.  So it's not quite statistically significant there with ‑‑ if you use a two-tail test.  And I think probably what is going on is that this isn't people reporting sort of aggression on a scale as part of a research project where if the child was already aggressive you could notice a decrease.  This is people perceiving an adverse event, so this may ‑‑ these are relatively small numbers where my child didn't use to do this and he started doing it.

            So I do think probably both of these happen ‑‑ people who are already aggressive can get better, and a few who weren't aggressive before ‑‑ there are more complaints of emerging aggression in the people on these medicines than on placebo.  But that's different from sort of average aggression.

            DR. NELSON:  So I guess to summarize what I'm hearing as well to then move us to the suicidality question is there are important differences.  There may still be a signal, albeit just barely above the background noise of the condition itself, and that there is an important distinction between aggression as part of the condition where it might be a reason for treatment versus aggression as a treatment emergent phenomenon in a child who ‑‑ that has not been as much a case.  Is that fair?

            DR. TEMPLE:  Yes.  There are also ‑‑ this is from the control trial data, which is obviously most credible.  There also are at least some of the spontaneous reports in which there was the appearance of recurrence on readministration.  I'm not sure how much to make of that.  When it's part of the background, it's not as thrilling as if it's a very rare event.  But that I think was at least some reason that we thought it might be real, at least in some cases.

            So what I hear is that you'd be a little lighter weight on this, because you're not as sure, but you remind people that it's a possibility maybe.  Something like that?

            DR. NELSON:  Well, that there's a signal, but that that needs to be interpreted in the context of the condition and the reasons for treatment, etcetera, in a way that psychosis is not ‑‑

            DR. TEMPLE:  Well, let me ‑‑

            DR. NELSON:  In terms of the effect size, yes.

            DR. TEMPLE:  Well, let me ‑‑ I don't think anybody would say this is a reason, you know, not to use the drugs.  But just at the point we were trying to tell people what can happen, what you should watch for, this is obviously a weaker signal, but I ‑‑ I hear people saying it might be ‑‑ it's something you should still tell people is at least a possibility.  That it can happen to some people, even if it doesn't happen on average or anything.

            DR. NELSON:  Yes, I think ‑‑

            DR. DAUM:  Again, to just clarify, I think it would be important to make the distinction that's been heard before, because if the kid is already being aggressive, it may go away.  And so the language ought to be very soft on this, it seems to me, and say some kids who weren't exhibiting aggressive behaviors before may.  And if that happens, talk to your doctor.

            DR. NELSON:  Just one quick comment.  I'm not under the impression we're going to be able to craft consent form language.  I don't even do that in my IRB meetings.  So I think we've got the drift, unless we feel we need to specify it further, because I want to now move the discussion to suicidality.  But we can ‑‑ you know, Laurel, if you have something you want to make sure ‑‑

            DR. PFEFFER:  I just had a question, because it gets to this already existing versus emergent.  And, again, not trying to craft the language, but there was a statement made earlier that we felt confident enough about the other that we would ‑‑ you suggest we might want to say consider stopping temporarily, because, again, with ADHD, you know ‑‑ in this situation, would you want to have any statement about that or not, depending, again, on whether it was there before or not?  Or you just don't think we should go there because of the level of the evidence?

            DR. NELSON:  Laurel, and then Jorge.

            DR. LESLIE:  This is where I would agree with the gentleman down at the end of the table that's saying onset or severe exacerbation of aggression would mean that you'd want to pull it away.  But making that kind of a clear distinction as opposed to ongoing aggression I think would be important.

            The other thing, just again, I think getting the message out that you don't just do baseline heart rate and respiratory rate, you should look at baseline aggression, baseline insomnia, all the kind of major side effects ought to be looked at baseline, because the number of times I've had people complain about something when it has already been existing and we've been able to document it, it happens quite frequently.

            DR. NELSON:  I'd actually say it would be more important to monitor that than whether their heart rate has gone up by five after they're on the drug.

            Deborah?

            DR. DOKKEN:  Skip, I'm having trouble deciding which is number one and which is number four.  But I wanted to highlight what Dr. Leslie said about messages, you know, and one of them being that parents should ‑‑ if they observe changes in their child ‑‑ and I think this is going to go to other things that we're going to talk about, but whether it's number one or number four when we talk about mechanisms, if we can somewhere put on the table that there's more guidance about, you know, when to go to your doctor, and it goes back to Judith's comment about time frames.

            And, you know, there are some models out there where, you know, good anticipatory guidance for families, you know, can make a difference about both their observations and when they report their observations to their physicians.  So, you know, again, if that's a message or a mechanism, I don't know.  But I just want to ‑‑

            DR. NELSON:  Well, what I'd like to suggest is at least to have the same conversation about suicidality, but then ask the specific question about looking at the things that Rosemary presented about the label, where do you think all this stuff ought to go? 

            If you consider that an informed consent document, where you've got the risks, the benefits, the indications, etcetera, where would this stuff go?  So we'd go to that kind of question.

            So, Tom?

            DR. LAUGHREN:  Just before you leave aggression, can I raise a point for clarification?  Because we're eventually going to have to try and craft this, and I want to make sure that we're conveying, you know, the sense of the committee.  And, again, I want to distinguish between psychosis or hallucinations, whatever you want to call it, and aggression, in terms of giving advice to the prescriber.

            It's fairly easy for psychosis/ hallucinations to leave in the suggestion somehow that you consider backing off the medication if you see it.  It's not so clear how to easily do that in a way that's going to be easily interpreted for aggression, because aggression is not well defined.  I mean, it ranges all the way from getting argumentative or, you having, you know, some sort of a scuffle to some serious aggression.

            And if you're going to put in labeling, you know, "Stop the medication at the first sign of aggression," you know, in a normal child you're going to see some aggression at some point.  So maybe we could get a little bit better clarification of that.

            DR. NELSON:  Sounds like a question for our psychiatric colleagues.  Go ahead.

            DR. HUDSON:  I'm not a psychiatric colleague, but I think this should be in the context of any behavior that is new, an exacerbation of an existing behavior, or a new onset of behaviors, they should consider ‑‑ you know, discuss with the doctor immediately and consider withdrawing medication.  I mean, you can say that globally, and then we could focus on the specific behaviors that we've discussed today.

            DR. NELSON:  So whether any of ‑‑ do you want to try and give more specificity about what aggression might mean, Dan?

            DR. PINE:  Yes, two points.  One point is I get a little nervous the more you're kind of advising practice in situations that are extremely complicated, because, you know, you're going to make a recommendation that might work for 50 percent of the cases, but it's going to be terrible for another 20 percent, and, you know, not the ideal thing in another 30.

            So what I would recommend, I think the message ‑‑ and this is what I've heard from a lot of people ‑‑ is that the problem has been in failure to communicate.  So I think the main thing that would want to be communicated to the public and to physicians is that in this situation there is a need for patients' families to sit down with physicians and to discuss the fact that this is a distinct possibility, that it may be related to the medication, that it may not be related to the medication, and that it really behooves the clinician to think about what's the best thing to do, given that this has happened and not go beyond that.

            DR. NELSON:  Very well.

            DR. TEMPLE:  Could one solve that perhaps by trying to distinguish between a little worse, you know, and not much different from a marked increase compared to previous existence?  And you wouldn't say you have to stop that, of course.  You'd say you might want to think about it. 

            DR. PINE:  I'd be fine with that.

            DR. TEMPLE:  Yes.  Okay.  That's fine.  That's helpful.

            DR. NELSON:  So I guess I'd like to then see what we think about applying this conversation that we've had now to the suicidality question, which has come up.  And, Tom, I don't see a table that you did for that.

            DR. NEWMAN:  Yes, I didn't, because, you know, there were 13 events, and eight of them were with atomoxitene, and four with modafinil.  And it just ‑‑ it didn't ‑‑ so I felt uncomfortable combining everything when 12 of the 13 events were with just these two drugs.  So that's why I didn't.

            DR. NELSON:  Well, I might also point out that the evidence at least in here ‑‑ I mean, this goes to some of the class effect issues, too.  You have a different mechanism of action, but yet the data, because it's obviously bigger and richer, which was I think the point of one of the slides, more patient-year exposures in that one product development than there is in the entire sum of the other stimulants, whether that's just simply what's being seen, and because it's a richer database, or whether it's ‑‑ are there differences or not, I guess as a set of questions. 

            Tom?

            DR. LAUGHREN:  It may be that.  It may also be the fact, as was pointed out by Lily, that for atomoxitene they were not prescreening patients.  For most of the methylphenidate programs, they were looking at patients who had already tolerated the drug, and so you have less of an opportunity to detect something new.

            DR. NELSON:  So in fairness, we should perhaps then consider it a class effect rather than a ‑‑

            DR. LAUGHREN:  Well, I don't ‑‑ fair isn't the issue.  Right is the issue.  I mean, we're not ‑‑ I mean, the way I look at the control trials data is that we're not seeing a signal for any of the drugs other than the, you know, atomoxitene, and that's already labeled.  It has a black box for suicidality, and you're sort of seeing a signal for modafinil.  But I don't think we're seeing a signal in the other programs.

            Why we're not seeing a signal, I don't know.  But I don't ‑‑ I'm not comfortable extrapolating findings from two programs to the other programs.

            DR. NELSON:  Bob?

            DR. WARD:  Do we have post-marketing those surveillance data that would support it in the methylphenidate?

            DR. LAUGHREN:  Well, you've got all kinds of spontaneous reports of suicidality.  The great difficulty is evaluating those when, if you look at a ‑‑ you know, as CDC does every couple of years, they sample 20,000 high school students, and, as you saw, they find anywhere from 15 to 20 percent of so-called normal kids who admit to having suicidal ideas.

            DR. WARD:  That has been my problem with that whole issue all along is that we have two very frequent events ‑‑ ADHD and suicidality in teenagers.

            DR. NELSON:  So basically two and a half million are on it, and 20 percent of them have those ideas.

            DR. TEMPLE:  That includes people who are off it, too.

            DR. NELSON:  Right.  So do other people have any insights to the suicidality issue?  I'm not hearing a lot of enthusiasm about lumping suicidality in with these other two observations. 

            Okay.  That at least ‑‑ and on the previous two, we didn't really discuss explicitly class effect/non-class effect.  Were people in their minds making distinctions between these different products, or putting them all together in their minds about how we should approach it?  Tom?

            DR. NEWMAN:  I think we probably have to put them together as we did before.  I mean, I just ‑‑ I don't think that if we single out one class and put a label on that one, you know, change the labeling, then people shift to the other class, it's just that there's less data with that class, or the sample size was smaller or something.  And I think they are chemically similar.  It's hard ‑‑ I think it would be hard to justify differential labeling for the different drugs.

            DR. VITIELLO:  Still, I think with stimulants ‑‑ intoxication with stimulants leads to psychosis and delusion.  But I don't think intoxication with atomoxitene has such an effect.  So I think pharmacologically, actually, they are quite distinct.

            DR. LAUGHREN:  Yes, I think we think they are pharmacologically quite different.  Dr. Andreason showed some slides earlier, and Lily showed some slides as well.  You know, the action at the neurone is really quite different. 

            I mean, the stimulants all release catecolamines from the presynaptic ‑‑ from the terminal, the ‑‑ you know, atomoxitene is a selective norepinephrine reuptake inhibitor.  And modafinil is ‑‑ has still a different mechanism that is not very well understood.  So I don't ‑‑ I don't think you can throw them all together.

            DR. NEWMAN:  Well, just ‑‑ I'm looking at the ‑‑ you know, in the clinical trial data for the atomoxitene, it was ‑‑ it was four compared to zero.  I mean, there was at least a little hint of a signal.  It's twice as many person-years on atomoxitene, so it's hard.  But, I mean, it looks like there may be something there.

            On the other hand, that one already has a label for suicidality, so maybe people wouldn't switch to that one, because it already has a black box.  I don't know.

            DR. LAUGHREN:  It also has specific language for induction of mania.  In that suicidality warning, it talks about being very cautious if you're going to use it in someone who has a history or even a family history of bipolar.

            DR. NELSON:  Well, I guess with people's permission what I'd like to do is perhaps get Rosemary's slide up, and whether we use the fictional drug or not, begin to just take a look at where people think some of this stuff ought to go.  And since the label is at this point entirely different, and I'm not sure if people ‑‑ are labels being changed or grandfathered in, or how that transitional process is, but putting that aside let's just ask the question about, what would be the best way for practitioners and parents to be able to see this?  Assuming they hopefully read the labeling. 

            Cardiac is the second question.  The whole ‑‑ we'll redo this whole thing for cardiac, hopefully maybe in a little more shorthand.

            DR. TEMPLE:  You probably don't have to consider the specific question of highlights.  If we were to write labeling in the new format, we'd take the pieces from the rest ‑‑ from the main labeling and put them into highlights appropriately.  So you probably don't have to think of that separately.  Maybe you weren't going to, but just ‑‑

            DR. NELSON:  Well, I mean, I guess what's interesting now ‑‑ and part of the motivation at times I think for a black box is to get it up front, independent of big, black, bold letters.  Now, the highlight is now up front, and the highlight, from my understanding, includes everything that's a highlight of the entire label, including a highlight of the black box, which is sort of the mini black box.  It's up there.

            DR. TEMPLE:  Along with other warnings and things like that.

            DR. NELSON:  Yes.  So now there's a lot more information that gets up front in a way that's clearer than it is in the old label where the only thing you'd see at the beginning is the black box, and then you get the chemical structure and you find the indications and warnings somewhere on page 8, by and large in the small print.

            DR. TEMPLE:  All I'm saying is that if you thought something ought to be a warning, if there were highlights, that warning would probably appear in the ‑‑

            DR. NELSON:  So all of that would end up here.

            DR. TEMPLE:  Right.  It would be a highlight.

            DR. NELSON:  But it's worth at least keeping this up as a shorthand for the outline of what it would look like, even though this would be the highlight at the beginning, and then there would be a bigger section later on that would explicate each ‑‑ in more detail each individual point.  Is that fair?  Laurel?

            DR. LESLIE:  I'm just trying to figure out what ‑‑ how warning and precautions and adverse reactions are being used.  So, for example, the neutropenia in this case, there is actually a warning about monitoring for it.  And then, is it down in the ‑‑ yes, it's down in the adverse reactions.  So you'd put it in both ‑‑ you'd put ‑‑ so, for example, would we put hallucinations in adverse reactions, and then up in the warning say, "If this occurred," the whole thing about consider stopping.  Is that ‑‑ so you'd see it as a repetition in both settings?

            DR. NELSON:  Let me just restate what I heard Rosemary say, and then ‑‑ the contraindication would be where you shouldn't use it.  So, in other words, the risks in that population exceeds the benefits to where it shouldn't be used.  That ‑‑ when we get to talking about cardiovascular, that would probably be those with known structural heart disease.

            I would assume there may be some indications here that that would fit, but that's not what we've talked about, whereas the warnings and precaution would be where there has been adverse events that have been seen, such that we've been discussing where causality is a reasonable inference, even if it's not fully established by the RCT, etcetera. 

            And there may be monitoring, then, recommended much as what we have talked about in terms of monitoring for the emergence of aggression.  So that seems to fit, the way at least Rosemary described, the warning and precautions section.

            DR. TEMPLE:  Usually if something ‑‑ if an adverse reaction and its consequences and what you should do are moved to warnings and precautions, it's usually not repeated in adverse reactions.  Although if there were much more to say, you might.  But usually that ‑‑ usually it's not.

            DR. NELSON:  Marsha?

            DR. RAPPLEY:  Thinking about myself and working with patients and going to write a prescription, or hearing my patient describe what they feel as an adverse event, I want to go to my desktop and pull up this page.  And the first thing I'm going to want to know is, how often should I expect this to happen?  And then, I'll move down and look at the other pieces.

            And so a description of patient-years helps me to understand a study, but it doesn't help me to understand the person in front of me and what I might expect or what I might expect in terms of my entire practice.  So I'm struggling with the best way to ‑‑ is there a consistent way that we report incidence in these forms?  And then, again, back to the use of the terms descriptive, rare, and infrequent.

            DR. TEMPLE:  It's pretty consistent, and it's not usually patient-years.  For the control trials that go into the labeling ‑‑ and, you know, these long tables in adverse reactions has all the adverse reactions that occurred at least five percent of the time or three percent of the time and were more common than in placebo.  You'll just see a long list, and the denominator will be number of exposed people.  That's because they were more or less exposed for the same amount of time

            If you try to use the followup data, the long-term followup, then you have to do something to correct for exposure, and then you'll see different analyses, but usually, for better or worse, a fairly crude analysis without taking much into account of exposure.  Now, if it's more complicated things like, you know, heart attack survival, things over time, we are much more likely to look at time of exposure and hazard ratio, and all that kind of stuff.

            Does that answer it?

            DR. RAPPLEY:  Well, I'm thinking about this problem here.  We observed that 1.6 cases per hundred patient-years is what we observed for this "psychosis."  And you estimate it really to be about 2.5.  So if I'm thinking about that, how often ‑‑ like how many times should that be occurring in my catchment of patients that might be 2,000?

            DR. TEMPLE:  We should probably think about that.  For the control trials ‑‑ Andy can correct me ‑‑ they are relatively short, and the exposure is relatively similar.  So you could ‑‑ we probably could give a rate per hundred people started on therapy, and it probably wouldn't give you that much difference of proportion ‑‑ a different number of course.  Probably wouldn't give you that much different a proportion from the number corrected for patient-years. 

            Correcting for patient-years, you know, does help you distinguish between an eight-week study and a 16-week study, which you might want to do, but not necessarily.  Maybe these all occur early.  We don't ‑‑ you know, there's a lot of questions about how best to do it.

            But what we usually do, the most usual thing, is to give the rate, and the denominator is the number of people in the trials, unless you're using, you know, extended data where that won't do.

            DR. NELSON:  Bob?

            DR. WARD:  That sounds like a good distinction between a course of antibiotics and a therapy that is a long-term therapy for a lasting disorder.  And it seems to me that expressing this in terms of 100 patients treated for a year, you would expect this to occur in X number of patients.

            DR. TEMPLE:  To me, it all depends on ‑‑ you know, a lot of adverse reactions are time-related.  That is, they appear in the first week of treatment.  So is it really more truthful to give the rate per number of exposed?  Or rate per patient-year?  Because the rate per patient-year keeps dropping off, because it ‑‑ because they go away.  I don't think there's a good answer.

            But for things that happen sporadically over time, then rate per patient year is probably a better number.  And for anything where the data aren't controlled, where there's no control group, that's really all you can do.  You don't have a comparator or anything like that.

            DR. WARD:  But in the data presented today, we've not had a lot of emphasis or description of the time under therapy before the emergence of these events.  So I would stay away from that.  I understand the distinction, but I would stay away from that with this particular group of labels.

            DR. TEMPLE:  Well, and that's why you saw the data ‑‑ that's why Andy presented it that way, although it did seem to me we ought to go back and look at the 13 cases and see when they occurred, whether they were all early or later.  But that's another ‑‑

            DR. NELSON:  So I guess the question for people to ponder is how best to inform practitioners and parents, assuming both are looking at the label and we can talk about things like medication guides and other things when we get to other mechanisms, you know, other than putting what we've said in warnings and precautions, which seems to be the best place, other thoughts?  Laurel?

            DR. LESLIE:  I just want to follow up on what Marsha is saying, is a busy practitioner will yank this up and look at it.  So if only the common greater than two percent are going to be listed under those adverse reactions, is that the approach?  I just ‑‑ I'm worrying very much about the person opening their PDA and looking at it and saying, "No.  Hallucinations don't happen with this.  It must be something else."

            DR. TEMPLE:  Well, but if you thought that this should go into warnings and precautions, because it's relatively important, then what I said about the usual table in adverse reactions where it's only things over two percent, that wouldn't apply.  That's just how you deal with the vast number of things you get in any given clinical trial.  But if something is more important, it could be in there in the warnings, even if it's one in 10,000, if it's, you know, acute hepatic necrosis, you know.

            DR. LAUGHREN:  Generally, with psychiatric drugs, we put common and non-serious adverse events in the adverse reaction section.  Anything that's at all serious or important we would put in warnings or precautions, which in the new label will be one section. 

            And something that's really serious, where you feel very confident about causality, and you think there's something you can do about it, you might put it in a black box.  But that's a very high level of evidence generally, to put something in a black box.

            DR. NELSON:  Jorge, and then ‑‑

            DR. ARMENTEROS:  You know, from a practitioner's point of view, it's ‑‑ you know, they are not thinking like the FDA.  They are not looking at the paper saying, "Well, this is warnings.  This is adverse events.  So this must be more important than that."  Perhaps a black box, yes, gives you that sensation.  The rest gets all blurry.

            So if there is a concern, and it is going to be some warning and precaution, that's fine.  Leave it there.  Still mention it on adverse events.  The casual practitioner is not dissecting this document as you do.  They are very, you know, quick.  They have pressures, and they need to understand things quickly.

            So I'll be very careful in, you know, conceptually dividing this that fits a profile or protocol ‑‑ the practitioner doesn't go by that.

            DR. LAUGHREN:  To follow up on that, in the new form of labeling, all of the important events, whether they're ‑‑ you know, they're there because they're common and not serious, or they're serious, are all going to be in this highlights section.  They'll all be mentioned there, and then with a reference to where the clinician can go to find more detail about it.  They will all be there in that half a page.

            DR. NELSON:  Bob?

            DR. DAUM:  So I'd just feel bad if the session ended, and I didn't get a chance to say this.  So I'll say it as quickly as I can.  But in the vaccine world, people have gone to ‑‑ to try and make a better partnership between parents and children and providers ‑‑ have gone to information sheets.  And these have been developed, certainly not just by the FDA unilaterally, but mostly by the CDC, but lots of stakeholders have weighed in on developing the language.

            And one of the things it strikes me as an outsider to this issue is that the decision to treat a child with ADHD starts a real partnership that I think I've heard several times we all want to improve between a parent and a child and a provider. 

            And one of the ways that might be really helpful, since I don't think parents really read or understand package inserts, and I don't think physicians do that often either, is to have a more lay language sheet developed for these drugs, and say, you know, "Today we start this partnership, this is the drug we're going to use, this is the benefit we expect, this is the risk we're going to take," and really work at developing the language, certainly not here and now, to make a sheet like that for these kinds of drugs. 

            I mean, I would just like to make a pitch for that, and I know it's not helping with the package insert much, but I think it's needed in this circumstance.

            DR. TEMPLE:  So as undoubtedly you know, a previous committee that considered these matters thought what's called a med guide was a very important thing to do.  They were particularly worried about cardiovascular things, which you're going to get to.  But is that ‑‑ med guides are ordinarily done because there's something important you want to warn people about, or something they can do to prevent trouble, or something like that.

            Maybe you're just proposing a package insert ‑‑ not as scary.  But you think there ought to be something developed for delivery to the patient and the patient's caregiver and all that.

            DR. DAUM:  Yes, I do.  And I would take the model from it, what we do ‑‑ we pediatricians do routinely for vaccines.  And I think those vaccine information sheets have been very successful.  Parents have to read them, and even have to sign them.  And it forms a partnership, it forms an understanding, and they can take it home.  It's simple language, and it details some of the stuff that we're talking about today in pleasant but straightforward language.

            DR. NELSON:  Richard, do you want to elaborate?

            DR. GORMAN:  I'm speaking on behalf of the American Academy at this point.  The American Academy attempted to create such one-page medication sheets shortly after the vaccines blazed that trail of patient education.  They were discontinued about six years later because of lack of interest on the part of practitioners.

            Times may have changed.  It may be time to revisit that again in terms of ‑‑ or maybe the agents we chose to write about first were not the agents that practitioners had the most need of for those handouts.

            DR. DAUM:  Yes.  I'm not talking necessarily about a comprehensive thing.  I'm talking about these drugs for these diseases, because this is a partnership thing.  There's a lot of media stuff, there's a lot of consideration stuff, there's a lot of unclear data, and I think something to take home and mull over and interact over would be really helpful.

            DR. NELSON:  And I guess I would reinforce that.  Personally, a lot of what I heard in the public discussion was the importance of informed consent, and thinking of any ways that that can be optimized.  The med guide would be part of that, and part of the ‑‑ I think it's going to be a tough decision as you go forward what gets into this half-page highlight, because in many ways that's sort of the informed consent document for the physician.

            Probably they might drill down, if they're really interested, into the fine print.  But if there's something that you think they ought to know that might change their decision making one way or the other about whether they would or wouldn't put someone on a medication, that should probably be in the highlight. 

            And if there's anything that a parent would want know that would make them think maybe they wouldn't want to do that, that should certainly be in the med guide, whatever that is.

            DR. TEMPLE:  Would you say, based on the discussion you've just had of the psychiatric problems, that there are things in that category ‑‑ I ask particularly because a med guide ‑‑ the two reasons for med guide are, one, that there's something so troublesome ‑‑ well, you already saw it, but I'll just say it again.  That there's something so troublesome that people need to understand this before they even use the drug.  That's one.

            Or, two, that there is something that, if they knew about it, they can track and follow and avoid major troubles.  Those are the two main reasons for a med guide.

            DR. MURPHY:  We didn't present it to them, Bob, but it's in their handout.

            DR. TEMPLE:  Okay.

            DR. MURPHY:  If you want to look up the differences between med guides and patient medications, it's in your handouts.

            DR. TEMPLE:  Okay.  But those are the reasons that ‑‑ what I said are the reasons that you write a med guide.  Would you say that that threshold has been passed yet for the psychiatric things?  Maybe the cardiovascular things you'll think so, but ‑‑

            DR. DAUM:  In my conception of this, I'm not viewing this as some kind of "take this drug and here are the risks and side effects."  I'm talking more about what ADHD is, why we think your child has it, what can be done about it if we do nothing, what can be done about it with drug therapy.  We're proposing that you have this ‑‑ here are the drugs and here are the good things, here are the problems.

            So I don't know your med guide perhaps as well as I should, but I'm viewing this more as a thing about the illness that we're saying your child has today and the treatments for it, including risks and benefits.  So it's not just a warning, "this might happen," kind of thing.  That's not what I'm thinking about doing.

            DR. TEMPLE:  Well, once you decide to write a med guide for the reasons I gave, it then is supposed to be reasonably balanced.  It doesn't have to be all negative.

            DR. DAUM:  Well, I would hope not.

            DR. NELSON:  We're going to go Marsha, Dan, and then Tom.

            DR. RAPPLEY:  Somewhere ‑‑ and I was thinking in the med guide or the patient handout or the patient-doctor handout ‑‑ we need to say who is at particular risk.  And in this ‑‑ there are vulnerable groups that may be more at risk.  So when we think about the neural behavior or psychiatric side effects, that would include people who have a history of those conditions.  And that might include very young children, or that might include children who have mental retardation. 

            There would be a group ‑‑ there needs to be a place for us to discuss those people who, coming new to this medication, are in a group that we know to be more vulnerable to these side effects.  And there are a few of those around the neural psychiatric behaviors.  And it seems like that whatever it is we hand to parents and we ask the physician to talk about with the parent, it belongs there.

            DR. NELSON:  Dan?

            DR. PINE:  So, again, speaking from the psychiatric perspective, it does seem that there was a lot of confluence of opinion that we needed to do a better job of informing families and physicians and kids.  And I think, you know, based on the criteria that you read, the threshold for a med guide probably has been passed based on the discussion that we had.

            That being said, I do want to come back to this point about getting nervous if you're, you know, regulating practice.  You know, I think issues of adverse effects of medication are one thing, and I think those need to be communicated.  But I think, you know, how to avoid them and what to do about them, those are not really things that we've discussed here.

            And, you know, I think the med guide should focus on informing people of the risks.  What are they?  You know, the second criteria that you laid out I think really applies here.  If people know to look for it ahead of time, they're going to be vigilant, and they're going to catch it when it happens.  That's what it should focus on, you know.

            DR. TEMPLE:  Let me mention one other slightly thorny problem that is yours.  The history is that if med guides don't get attached to unit of use packaging they don't get handed out.  There are exceptions to that.  We've made special arrangements for the non-steroidal inflammatory drugs, because that was very front and center.

            So that's also an unpleasant discovery for the companies, but we'll have to deal with that.  I just thought I'd mention it.

            DR. NELSON:  Tom?

            DR. LAUGHREN:  Yes.  Just to follow up on that, several of these drugs already have patient package inserts, and one actually has a med guide.  It wouldn't be that difficult to write either one of those.  But as Bob pointed out, if it's not a med guide, even if it is a med guide, if you don't have unit of use packaging, it's hard to get these things distributed.  PPIs don't have a very good record of being distributed.  So that's one thing to think about.

            In terms of what goes in it, it doesn't have to be ‑‑ it doesn't have to, you know, tell the clinician what to do to manage it.  It can, you know, focus mostly on what the things are to be concerned about without intruding on the practice of medicine.

            DR. NELSON:  Tom?

            DR. NEWMAN:  Yes.  Sort of related to what the med ‑‑ how the med guide might prevent something bad from happening.  And also, I'm ‑‑ I have been looking all afternoon at these regulations about the box warning and what it takes to merit one.  And the first one is an adverse reaction so serious in proportion to the potential benefit that it is essential that it be considered. 

            And I'm really sort of not there with that, because then these drugs have a lot of potential benefit, much more ‑‑ I mean, it's well documented.  And so I'm not worried about that, but the second one is serious adverse reaction that can be prevented or reduced by appropriate use. 

            And I'd like to ask the people around the table who have much more contact with community physicians who are prescribing these medicines, how common would it be for a child who develops what we think might be an adverse drug reaction to be put on another medicine rather than stopping the stimulants, because that's the thing that I'm worried about.  That's the thing that I sort of want to warn people about is where the med guide would help, where it might even warrant a black box.

            If this is common, where somebody hallucinates and then gets put on an anti-psychotic drug or something, that would really I think be something worth making sure it didn't happen.  But I don't know what community pediatricians do.

            I do know when I see kids in urgent care clinics, some of them from, you know, foster care or the group home, and so on, that I see are on stimulants and a variety of other medicines, and it's kind of scary.

            DR. NELSON:  Jorge?

            DR. ARMENTEROS:  Well, from a psychiatric point of view, if you are giving a stimulant, or if any physician is giving a stimulant, and some of this ‑‑ hallucinations/psychosis/mania/whatever we want to call it ‑‑ occurs, the typical reaction is you stop the medication.  It's not common for that individual, and it's not common.  It may happen, but it's not common, to then go on and add an anti-psychotic.

            So, I mean, it's ‑‑ still, the practitioner is responsible ultimately for all of this.  And I think it is already pretty clear, more or less, what the course of action should be for the most part.

            DR. NEWMAN:  Yes.  And I'm just not talking about best practice, or what should be done. I want to know what really happens out there.

            DR. ARMENTEROS:  What I'm describing is pretty common practice.  What you have described where ‑‑ there could be a group of children with various medications, you know, at the same time.  We may not know how they got there.  It may not be that an anti-psychotic was added for the control of a side effect of a stimulant.  You know, that's ‑‑ I mean, it may have happened, but it's really not the common occurrence.

            DR. NELSON:  Let me just ask a question in terms of time.  At some point I'd like to transition to cardiovascular, and we'll probably have a little more sort of fine tuning of med guide discussion, etcetera, even in that context.  So ‑‑

            DR. JOHANN-LIANG:  Can I make a quick ‑‑

            DR. NELSON:  Yes.  I just want to ‑‑ I'd like to make that at some point.  I don't want to cut off discussion, but just let you know that I want to try to do it.  Go ahead.

            DR. JOHANN-LIANG:  Well, speaking as a pediatrician, not as a psychiatrist, but I think what you were saying ‑‑ you know, you're the psychiatrist, but what I think he was saying ‑‑ it does happen.  We see these cases where children are not properly discontinued from the stimulant, but sort of considered as an unmasking of a psychotic event, and then introduce another anti-psychotic medication, and, therefore, end up with multiple drugs on board.

            So these things do happen in the real world, so that's something to consider, that it's ‑‑ you know, it does happen.  I don't know what the rate is.

            DR. WARD:  That's exactly the issue I wanted to address is that we need to communicate to the pediatrician, who may not be as experienced as the psychiatrist with evaluating the emergence of a psychosis or psychotic-like reactions, or whatever we want to call it, and that somewhere in here I think it would be worth suggesting that in the face of those kinds of reactions that discontinuation of the drug, a trial off the drug, would be a reasonable first step.

            And then, at least from our perspective, I think even though that is to a degree practicing pediatrics for them, I think it is a worthy guide to them, as opposed to the aggression that ‑‑ I think distinguishing between those two is worthwhile.

            DR. NELSON:  Let me go to Richard, and then Laurel.

            DR. GORMAN:  I think suggesting potential avenues of practice such as considering discontinuing the medication sounds like a great suggestion in either a med guide or perhaps even in the label.  I'm going to add my anecdote to how many people get into polypharmacy.  Most ped