# Presentation: 247282

## Topics Directly Pertinent to Continuing Evaluation of Data from Pediatric Controlled Trials

## Possible Failure to Fully Capture All Events of Potential Interest with Regard to Suicidality

- The first step in the process of evaluation for suicidality was to find events of potential interest.  GSK had developed an algorithm for searching for events possibly representing suicidality in their database, and we proposed a variation of this to other sponsors.  However, this was admittedly a compromise. It is conceivable that certain cases of interest might have been missed by the search methods employed.  The only failsafe approach to identifying all possible events of interest would be to have experts blindly evaluate every case report form for the more than 4000 patients who participated in these trials.  Since that is not feasible, we welcome advice from the committee on possible modifications to the search strategies used for identifying cases that might have been missed.  Additional searches at this point would further delay the analyses of these data, and this needs to be taken into consideration.  However, if the committees feel there are serious deficiencies in the search methods employed, it would be helpful to hear about alternative approaches.

## Approaches to Classifying Events into Meaningful Categories for the Purpose of Further Analysis

- As noted, an important next step is to decide on categories into which events of interest might be classified, along with operational definitions for such classifications.  The approach used by sponsors thus far has been to classify cases first into a crude category of “possibly suicide-related,” and then a further subgrouping of that broader group into a “suicide attempt” class.  Since we are just now beginning to address this question with our outside experts, we would welcome any advice the committees might have on how to classify these events for the purpose of further analysis.

## Patient Level Data Analysis

- Since we are in the preliminary stages of designing an appropriate analysis of patient level data, this would be an opportune time to get feedback on how to approach this analysis.  In addition, you have seen our list of potential covariates for inclusion in this analysis, and we would welcome any thoughts you might have on this list.  If we have left out important covariates, please let us know, since this would be the time to try to gather any additional information that you feel might be helpful in trying to understand these data.

## Topics of Future Interest

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## Ascertainment for Suicidality 

- As we reviewed the descriptive information for the events identified by sponsors as possibly suggestive of suicidality, it became apparent that ascertainment for emergence of suicidality was not optimal.  The case descriptions were frequently sparse and lacking the kind of detail that would ordinarily be useful in assessing whether or not the events might legitimately be considered to represent suicidality.  Of course, these studies were not designed with that goal in mind.  Indeed, patients who were judged to be suicidal at screening were excluded.  Nor did we emphasize such assessment for suicidality in our Written Requests for these pediatric programs.  Furthermore, there is, of course, no fix for this problem with regard to these studies.  However, one of our outside experts will address the issue of how one might develop guidance for more adequate assessment for emergent suicidality in future studies.  We would welcome any advice from the committees on the development of such guidance.

## Future Approaches to Trying to Address the Question of  What Benefits These Drugs Might Have in Pediatric MDD

- As noted, attempts to demonstrate efficacy in short-term trials for these drugs have not been successful, for the most part.  We would welcome your thoughts on how to interpret and understand these predominantly negative results, and also any thoughts you might have on alternative approaches to demonstrating benefits in this population.  An approach often used in expanding information on effectiveness in adult MDD populations is the randomized withdrawal design, in which patients who have responded during open treatment with an antidepressant drug are randomized to either continuation of drug or switch to placebo.  The endpoint in these trials is typically time to relapse, and the success rate for these trials is far higher than the roughly 50% success rate in acute trials in adult MDD.  We would welcome your thoughts on whether or not this design might be useful in evaluating possible benefits of these drugs in pediatric MDD.