M E M O R A N D U M DEPARTMENT OF HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
DATE: August 16, 2004
FROM: Thomas P. Laughren, M.D.
Team Leader, Psychiatric Drug Products
Division of Neuropharmacological Drug Products
SUBJECT: Overview for September 13 & 14, 2004 Meeting of Psychopharmacological Drugs Advisory Committee (PDAC) and Pediatric Drugs Advisory Committee (Peds AC)
TO: Members of PDAC and Peds AC
On September 13th and 14th, the PDAC and Peds AC will meet to consider the occurrence of suicidality in the course of treatment of pediatric patients with various antidepressants. This September meeting is followup to a meeting on this same topic held on February 2, 2004. At the February meeting, the committees were presented with preliminary data on suicidality occurring in clinical trials involving pediatric patients being treated with various antidepressants. The major focus of that meeting was on FDA’s plans for a more definitive evaluation and analysis of these data. The two key aspects of FDA’s plans for evaluation of these data were the following: (1) the classification of suicidality events captured under the broad category of “possibly suicide-related” into more specific and meaningful categories by experts in pediatric suicidality; and, (2) an analysis of patient-level data from these trials that would permit adjustment for potential confounders. The committees generally endorsed FDA’s proposed plan for further evaluation of these data. This additional work has now been completed, and the committees will be presented the results of these analyses.
The committees recommended at the February meeting that, while we were completing our analyses of the pediatric suicidality data, FDA should strengthen the labeling for these products. In particular, there was concern that some patients being treated with these drugs may not be closely monitored for suicidality. There was a consensus of the committees that, whether or not any of these drugs could be shown more definitively to have a role in the induction of suicidality, it would be important to remind clinicians treating patients with any of these drugs to be alert to the emergence of suicidality and to various other symptoms that might represent precursors to suicidality. FDA issued a Public Health Advisory on March 22, 2004, announcing an initiative to ask companies to add Warning statements to address this concern. This new Warning language has been accepted by the sponsors for all of these products.
The new language warns clinicians to observe closely patients who are being treated with antidepressants, for clinical worsening and suicidality, especially at the beginning of a course of therapy, or at times of dose changes. Clinicians are advised to consider changing the therapeutic regimen in patients whose depression is persistently worse or whose emergent suicidality is severe, abrupt in onset, or was not part of the patient’s presenting symptoms. The new language notes that a causal role for antidepressants in inducing such behaviors has not been established. The new warning applies both to adults and children, and is not limited to patients being treated for major depression, but rather, applies to patients being treated with antedepressants for any condition, psychiatric or nonpsychiatric. Clinicians are also advised to observe for the emergence of other symptoms that have been reported in association with antidepressant treatment due to the concern, but not yet proof, for a possible causal link between such symptoms and worsening depression or suicidality. These symptoms include: anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia (psychomotor restlessness), hypomania and mania. The new language also advises families and caregivers of these patients to be alert to the emergence of these symptoms, and to report such symptoms to the health care providers. Finally, the new language alerts clinicians to be particular careful in using these medications in patients with bipolar depression or a family history of bipolar disorder.
The primary focus of our presentations at this meeting will be to provide you with (1) a detailed description of our approach to evaluating and analyzing the pediatric suicidality data, and (2) the results of this work. However, we have also included presentations on related studies, in particular, several pertinent epidemiological studies and TADS (Treatment of Adolescents with Depression Study). Thus, you will hear presentations by both FDA staff and experts in pediatric suicidality from the academic community outside of FDA.
There will be an open public session on the afternoon of September 13th, to provide an opportunity for others in the community to make statements pertinent to this concern about a possible causal association between antidepressant drug treatment and emergent suicidality in pediatric patients.
The morning of September 14th has been reserved for your deliberations on this topic.
The background package for this meeting will include the following documents in addition to this cover memo:
Additional background information on this general topic of antidepressants and suicidality, including documents generated in relation to the February 2nd advisory committee meeting and those developed in association with FDA’s March 22nd Public Health Advisory can be found at the following link: http://www.fda.gov/cder/drug/antidepressants/default.htm. A transcript for the February, 2004 meeting can be found at this link as well.
I would like to draw your attention to some particular issues of interest as you review the package and prepare to answer the questions we will present to you. The data continue to show differences between individual drugs, drug classes, and even across studies within individual drugs, even when the focus is limited to those trials done in patients with major depressive disorder. We have explored a number of possible explanations for such differences, but none has provided a satisfactory answer. Thus, while there remains a “signal” of risk for suicidality for some drugs in some trials, it is important to note that the data are not “black and white” in providing a clear and definitive answer to the question of a link between the drugs and pediatric suicidality. Consequently, we are very interested in hearing comments from committee members on how these data should be interpreted and how these data should be translated into information to guide physicians, patients, and families in the use of these drugs. Now that we have completed our analysis of these data, we would like to move forward to update the labeling of these products to reflect the results from these analyses, and we seek your specific guidance on how best to accomplish this task.
The following are draft questions and topics for discussion at the meeting. These questions and discussion topics may be revised before the meeting.
· Please comment on our approach to classification of the possible cases of suicidality (suicidal thinking and/or behaviors) and our analyses of the resulting data from the 23 pediatric trials involving 9 antidepressant drugs.
· Do the suicidality data from these trials support the conclusion that any or all of these drugs increase the risk of suicidality in pediatric patients?
· If the answer to the previous question is yes, to which of these 9 drugs does this increased risk of suicidality apply? Please discuss, for example, whether the increased risk applies to all antidepressants, only certain classes of antidepressants, or only certain antidepressants.
· If there is a class suicidality risk, or a suicidality risk that is limited to certain drugs in this class, how should this information be reflected in the labeling of each of the products? What, if any, additional regulatory actions should the Agency take?
· Please discuss what additional research is needed to further delineate the risks and benefits of these drugs in pediatric patients with psychiatric illness.
The FDA relies on the knowledge, judgement, experience and wisdom of scientists and practitioners like you to help determine how to move forward and address newly emerging issues related to drug development. We thank you for your time and effort, and we look forward to seeing and hearing from you on September 13th and 14th .