1

 

                DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

                       FOOD AND DRUG ADMINISTRATION

 

                CENTER FOR DRUG EVALUATION AND RESEARCH

 

 

 

 

 

 

 

 

 

 

 

 

 

 

                          JOINT MEETING OF THE

 

           CDER PSYCHOPHARMACOLOGIC DRUGS ADVISORY COMMITTEE

 

                                AND THE

 

                    FDA PEDIATRIC ADVISORY COMMITTEE

 

 

 

 

 

 

 

 

 

 

 

                      Tuesday, September 14, 2004

 

                               7:56 a.m.

 

 

 

 

 

 

 

 

 

                          Holiday Inn Bethesda

                         8120 Wisconsin Avenue

                           Bethesda, Maryland

                                                                 2

 

                              PARTICIPANTS

 

      Wayne Goodman, M.D., Chair

      Anuja M. Patel, M.P.H., Executive Secretary

 

      PSYCHOPHARMACOLOGIC DRUGS ADVISORY COMMITTEE

      MEMBERS

      James J. McGough, M.D.

      Jean E. Bronstein, R.N., M.S. (Consumer Rep)

      Philip S. Wang, M.D. M.P.H., Dr. P.H.

      Dilip J. Mehta, M.D., Ph.D., (Industry Rep)

      Lauren Marangell, M.D.

      Delbert G. Robinson, M.D.

      Daniel S. Pine, M.D.

      Barbara G. Wells, Pharm. D.

      Bruce G. Pollock, M.D., Ph.D.

 

      PEDIATRIC ADVISORY COMMITTEE MEMBERS

 

      P. Joan Chesney, M.D.

      Deborah L. Dokken, M.P.A.

      Michael E. Fant, M.D., Ph.D.

      Richard L. Gorman, M.D.

      Robert M. Nelson, M.D., Ph.D.

      Thomas B. Newman, M.D., M.P.H.

      Judith R. O'Fallon, Ph.D.

      Victor M. Santana, M.D.

 

      SGE CONSULTANTS (VOTING)

 

      Norman Fost, M.D., M.P.H.

      Charles E. Irwin, Jr., M.D.

      Lauren K. Leslie, M.D., FAAP

      Steven Ebert, Pharm. D.

      James M. Perrin, M.D.

      Cynthia R. Pfeffer, M.D.

      Robert D. Gibbons, Ph.D.

      Tana A. Grady-Weliky, M.D.

      Richard P. Malone, M.D.

      Irene E. Ortiz, M.D.

      Matthew V. Rudorfer, M.D.

 

      SGE PATIENT REPRESENTATIVE (VOTING)

      Gail W. Griffith

 

      GUEST SPEAKERS (NON-VOTING)

      Kelly Posner, Ph.D.

                                                                 3

 

                        PARTICIPANTS (Continued)

 

      GUESTS (NON-VOTING)

      Samuel Maldonado, M.D., M.P.H.

 

      FDA

      Robert Temple, M.D.

      Russell G. Katz, M.D.

 

      PARTICIPANTS (Continued)

 

      Thomas Laughren, M.D.

      M. Dianne Murphy, M.D.

      Anne Trontell, M.D., M.P.H.

                                                                 4

 

                            C O N T E N T S

 

      Call to Order and Opening Remarks:

         Wayne Goodman, M.D.                                     5

 

      Conflict of Interest Statement

         Anuja Patel                                             6

 

      Opening Comments

         Thomas Laughren, M.D.                                   9

 

      Committee Questions and Discussion                        31

 

      Presentation

         Diane Wysowski, Ph.D.                                 152

 

      Committee Discussion of Questions and Vote               163

 

      Concluding Remarks

         P. Joan Chesney, M.D.                                 402

         Wayne Goodman, M.D.                                   404

 

                                                                 5

 

                         P R O C E E D I N G S

 

                   Call to Order and Opening Remarks

 

                DR. GOODMAN:  Welcome to day two of this

 

      joint two-day session of the Psychopharmacologic

 

      Drugs Advisory Committee and the Pediatric Advisory

 

      Committee being held on September 14, 2004, here at

 

      the Holiday Inn in Bethesda, Maryland.

 

                We are convened to address recent concerns

 

      about reports of suicidal ideas and behavior

 

      developing in some children and adolescents during

 

      treatment of depression with selective serotonin

 

      reuptake inhibitors and other antidepressants.

 

                Our goal is to gather information from a

 

      variety of sources and perspectives to help us

 

      understand this complex situation and ultimately,

 

      to offer the best possible recommendations to the

 

      FDA.

 

                Now, I would like to turn the microphone

 

      to Anuja Patel of the FDA Center for Drug

 

      Evaluation and Research and Executive Secretary of

 

      this committee to read the conflict the interest

 

      statement into the record.

 

                                                                 6

 

                     Conflict of Interest Statement

 

                MS. PATEL:  Good morning.  The following

 

      announcement addresses the issue of conflict of

 

      interest and is made a part of the record to

 

      preclude even the appearance of such at this

 

      meeting.

 

                The topics to be discussed today are

 

      issues of broad applicability.  Unlike issues

 

      before a committee in which a particular company's

 

      product is discussed, issues of broader

 

      applicability involve many industrial sponsors and

 

      products.

 

                All Special Government Employees and

 

      invited guests have been screened for their

 

      financial interest as they may apply to the general

 

      topics at hand.

 

                The Food and Drug Administration has

 

      granted particular matter of general applicability

 

      waivers under 18 U.S.C. 208(b)(3) to the following

 

      Special Government Employees which permits them to

 

      participate fully in today's discussion and vote:

 

      Jean Bronstein, Dr. Joan Chesney, Dr. Wayne

 

                                                                 7

 

      Goodman, Dr. Lauren Marangell, Dr. James McGough,

 

      Dr. James Perrin, Dr. Bruce Pollock.  In addition,

 

      Dr. Philip Wang has been granted a limited waiver

 

      that permits him to participate in the committee's

 

      discussions.  He is, however, excluded from voting.

 

                A copy of the waiver statements may be

 

      obtained by submitting a written request to the

 

      Agency's Freedom of Information Office, Room 12A-30

 

      of the Parklawn Building.

 

                In addition, Dr. Judith O'Fallon and Dr.

 

      Victor Santana have de minimis financial interests

 

      under 5 CFR Part 2640.202 that are covered by

 

      regulatory waiver under 18 U.S.C. 208(b)(2).

 

                Because general topics impact so many

 

      entities, it is not practical to recite all

 

      potential conflicts of interest as they apply to

 

      each member, consultant, and guest speaker.

 

                FDA acknowledges that there may be

 

      potential conflicts of interest, but because of the

 

      general nature of the discussion before the

 

      committees, these potential conflicts are

 

      mitigated.

 

                                                                 8

 

                With respect to FDA's invited industry

 

      representative, we would like to disclose that Dr.

 

      Dilip Mehta and Dr. Samuel Maldonado are

 

      participating in this meeting as industry

 

      representatives acting on behalf of regulated

 

      industry.  Dr. Mehta is retired from Pfizer and Dr.

 

      Maldonado is employed by Johnson & Johnson.

 

                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. GOODMAN:  Thank you, Anuja.

 

                We will be starting off this morning with

 

      a presentation from Tom Laughren who will give us

 

      an overview and also pose the questions, the five

 

      questions to this committee.

 

                Following his presentation, I would invite

 

      questions.  I also think it would be a good time

 

      before we get into the meat of our discussions to

 

      ask representatives from the FDA questions, to

 

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      further interrogate some of the data that was

 

      presented yesterday.

 

                Before we get into the actual discussion

 

      of the questions, I would like us to think of the

 

      questions that were carried over from yesterday,

 

      pose those, and then we will take a short break,

 

      reconvene and start the process of discussing the

 

      questions.

 

                Is that clear?  Okay.

 

                Tom, are you ready?

 

                            Opening Comments

 

                         Thomas Laughren, M.D.

 

                DR. LAUGHREN:  Good morning.  I would also

 

      like to welcome everyone back to the meeting today.

 

      I would like to do a couple of things in my few

 

      minutes here.

 

                First of all, what I want to do is to

 

      briefly review what I think are some of the key

 

      findings from Dr. Hammad's presentation yesterday,

 

      so that you have these in mind as you are

 

      considering the questions before you.

 

                Then, I want to talk a little bit about

 

                                                                10

 

      what I think the data mean and talk about what some

 

      of the regulatory options are as you are

 

      considering our questions, and then I want to go

 

      over the questions and the topics again.

 

                These are the 24 trials that we are

 

      considering. Again, 16 of them were in major

 

      depression, and the other 8 trials were in several

 

      various psychiatric disorders - OCD, GAD, 1 in SAD,

 

      and 1 in ADHD.

 

                Again, just for summary, I think these are

 

      the three contributions that the Division made to

 

      this effort. Again, we went to a lot of effort to

 

      make sure that we had complete case finding.  With

 

      the help of Columbia, we accomplished what I think

 

      is a rational classification of these events, and

 

      we both obtained and included patient level data in

 

      our analysis of the suicidality data again to try

 

      and understand some of the differences both between

 

      trials, within programs and across programs.

 

                These are the outcomes that we looked at

 

      again. The focus of the analysis was on two areas,

 

      the suicidality event data and also on the suicide

 

                                                                11

 

      item data.

 

                For the event data, could we have the

 

      other slide up that we had running yesterday?  Our

 

      primary endpoint, as you recall, was the

 

      combination of suicidal behavior and ideation,

 

      Codes 1, 2, and 6, where 1 was suicide attempt, 2

 

      was preparatory actions, and then 6, suicidal

 

      ideation.

 

                So, that was our primary endpoint, but we

 

      also looked at secondary endpoints, at suicidal

 

      behavior, in other words, Codes 1 and 2, and then

 

      suicidal ideation, Code 6, and then for our

 

      sensitivity analysis, we looked at this larger

 

      outcome including 1, 2, and 6, but also adding in 3

 

      and 10, where again, 3 is self-injurious behavior

 

      where the intent is not known, and 10 is not enough

 

      information.  Again, these are the cases where

 

      there is injury, but it is not possible to tell

 

      whether it's self-injury or other injury.

 

                With regard to the suicide item data, we

 

      looked at two measures about worsening suicidality

 

      on that item or emergence, and these again are the

 

                                                                12

 

      cases where the patients are normal at baseline and

 

      have some increase during the trial.

 

                In terms of our analytical plan, the major

 

      focus was on doing risk ratio analyses, both for

 

      the suicidality event data and for the item data.

 

      In both cases, we looked at individual trials, as

 

      well as for the event data, we looked at various

 

      pools.

 

                We looked at both by drug, we combined all

 

      the SSRIs, MDD trials as a group, we looked at all

 

      of the other indications combined as a group and

 

      also did one pooling which included all 24 trials.

 

      For the item data, we looked again at individual

 

      trials and then a pooled analysis over all trials.

 

                Dr. Hammad put a lot of effort into again

 

      trying to explain the differences that we were

 

      seeing between trials within programs and across

 

      programs, and I just want to spend a couple of

 

      minutes talking about exactly what he did.

 

                He looked for confounding within trials

 

      using both the univariate approach and a

 

      multivariate approach.  There were a total of 17

 

                                                                13

 

      covariates that he looked at.  He was not able to

 

      find any evidence for important confounding in that

 

      search.

 

                He also did stratified analysis to explore

 

      for effect modification.  The three variables that

 

      he looked at were age, gender, and history of

 

      suicide attempt or ideation, so basically, what he

 

      did in each of these is to stratify on these

 

      variables within trials to look to see if there was

 

      basically an interaction.

 

                Again, he did not find any evidence for

 

      that, so basically, what that means is that on

 

      these variables, you find the signal both in

 

      children and adolescents, you find it both in males

 

      and females, and you find it both in those with and

 

      without history of suicide attempt or ideation.

 

                Finally, he looked at 12 trial level

 

      covariates, again, as an attempt to try and explain

 

      the differences across trials using a

 

      meta-regression approach.  Again, that approach was

 

      not able to explain the variability.

 

                Now, I would say that one of the problems

 

                                                                14

 

      in doing these kinds of explorations is that there

 

      is very limited power, you have a very small number

 

      of events.  When you use an eyeball approach to the

 

      data, you can't help but thinking that trial

 

      differences might have made a difference.

 

                I just use the TADS, the fluoxetine

 

      situation as an example.  The company had three

 

      trials.  There was no signal coming from those

 

      three trials.  If you look at the careful screening

 

      that was done to obtain the patients for those

 

      samples, and the exclusions of patients with prior

 

      histories of treatment resistance, and so forth,

 

      and then you look at the TADS sample, which is many

 

      ways was probably more representative of the

 

      community of patients who actually get treated,

 

      there is quite a difference.  Again, as you recall,

 

      in the TADS trial, you see quite a striking signal

 

      for suicidality.

 

                So, even though quantitatively, we weren't

 

      able to tease that out and to explain the

 

      differences using various quantitative approaches,

 

      it is hard to think that that may not have made a

 

                                                                15

 

      difference.

 

                In my next three slides, I am going to

 

      present very briefly some of the data.

 

                What this slide is, is presenting the risk

 

      ratios for various poolings.  So, in this column,

 

      you have the risk ratios on our primary endpoint,

 

      which was suicidality ideation or behavior, 1, 2,

 

      and 6.

 

                In the second column, you have this

 

      expanded sensitivity analysis, 1, 2, 6, plus adding

 

      3 and 10.  The first row is all trials, so this is

 

      a pooling across all 24 trials.  In the second row,

 

      you have the pooling of the 11 trials with SSRIs

 

      and major depression.

 

                Now, there are two things I want you to

 

      notice about this slide.  First of all, in every

 

      case, the risk ratios are around 2.  They range

 

      from 1.7 to 2.2, but they are sort of in the

 

      vicinity of 2.

 

                Secondly, if you look at the confidence

 

      intervals on these risk ratios, in every case, it

 

      does not include 1, so in that sense, it is a

 

                                                                16

 

      statistically significant finding. So, this is the

 

      pooled data.

 

                What I have given you in this slide are a

 

      different set of poolings.  Here, what I am doing

 

      is pooling the individual depression trials in the

 

      7 programs that looked at depression, and these are

 

      the 7 programs listed here.  Every row is a

 

      separate depression program.

 

                What I have given you here, first of all,

 

      is the outcome on our primary endpoint a

 

      combination of 1, 2, and 6.  I have also given you,

 

      in the second column, the outcome on suicidal

 

      behavior, and in the third column, the outcome on

 

      suicidal ideation.

 

                There are a couple of things I want you to

 

      notice about this slide.  First of all, in every

 

      instance where we have events, and we had no events

 

      for Serzone, but in the other 6 instances where you

 

      have events, the risk ratio is always greater than

 

      1.

 

                Now, I want to turn to trying to tease

 

      apart where that overall effect is coming from if

 

                                                                17

 

      you break it apart by behavior and ideation.  Dr.

 

      Hammad made this point yesterday, in three cases it

 

      appears as if the overall effect is coming from

 

      behavior, in three cases it looks like it is coming

 

      from ideation.

 

                So, if you look at Celexa, here is the

 

      risk ratio for behavior, 2.23.  There is nothing

 

      happening for ideation.

 

                If you look at Paxil, again, it looks like

 

      it is coming mostly from behavior.

 

                If you look at Prozac, it looks like it is

 

      probably coming more from behavior than from

 

      ideation.

 

                For Effexor, there is a signal coming from

 

      both, but it is clearly coming more from ideation.

 

      Here, the confidence interval is almost

 

      significant.

 

                For Remeron, it is all coming from

 

      ideation, and from Zoloft, there is nothing

 

      happening for behavior, it is all coming from

 

      ideation.

 

                I am not sure what this means.  As Dr.

 

                                                                18

 

      Hammad pointed out, this may simply be a small

 

      numbers problem, but we are not seeing a consistent

 

      finding in terms of where the overall effect is

 

      coming from.

 

                Finally, what I have given you in this

 

      slide is the data from the individual other 8

 

      trials in non-MDD indications.  As you get into

 

      these trials, the number of events you are dealing

 

      with is very small, and just to illustrate that, I

 

      have put the actual number of events in this slide.

 

                So, in each of these parentheses, the

 

      first one is the number of events for drug, and the

 

      second one is for placebo.  So, you can see the

 

      small number of events that we are dealing with.

 

                If you recall from the previous slide, for

 

      Effexor, we were seeing quite a strong signal for

 

      major depression.  These are two GAD studies.

 

      There is nothing at all happening here.

 

                For Luvox, again, Luvox was only studied

 

      in OCD, there was no depression trial.  Just one

 

      study in depression, only two events.  They were

 

      both happening in the drug group.

 

                                                                19

 

                For the two non-MDD Paxil studies, one in

 

      social anxiety, one in OCD, again, small numbers of

 

      events, but in both cases, they were happening in

 

      the drug group.

 

                The same for the Prozac OCD, just one

 

      event, but it happened in the drug group.

 

                No events for Wellbutrin.

 

                For Zoloft, this is the only case where

 

      the one event is happening in placebo, and not in

 

      drug.

 

                It is hard to know what to make of all of

 

      this, although the one thing that you can't help

 

      noticing is that even though there are a small

 

      number of events, where events occurred, they most

 

      happen on the drug side.

 

                Just to summarize these data, again, if

 

      you look at various pooled analyses, the risk

 

      ratios hover around 2.  They range from 1.7 to 2.2.

 

      In all cases for those poolings, it appears to be a

 

      significant finding.

 

                The signal appears to be coming mostly

 

      from major depression, although perhaps not

 

                                                                20

 

      exclusively.  Despite those findings, there still

 

      are these inconsistencies in this risk, both across

 

      trials, within programs and across programs.

 

                On the other hand, my view is--and there

 

      isn't necessarily one consistent view coming out of

 

      FDA on this--but my view is that this is a

 

      reasonably consistent signal for risk.  You are

 

      seeing it in seven of nine programs.  We don't see

 

      any events in Wellbutrin.  On the other hand,

 

      Wellbutrin was only studied in ADHD, just one

 

      trial.

 

                There is no signal coming from Serzone,

 

      which was studied in major depression.  I am not

 

      sure if that means that Serzone is free of risk or

 

      it simply may mean that the events, the

 

      ascertainment in those programs was not good enough

 

      to pick them up.  I don't know the answer.

 

                One other point that Dr. Hammad made

 

      yesterday, that I want to return to, is a way of

 

      thinking about this risk is in terms of risk

 

      difference, and if you look over all these trials

 

      and estimate what the risk difference is, that is

 

                                                                21

 

      the difference in the risk between drug and

 

      placebo, so you are subtracting the placebo risk

 

      from the drug risk, it is in the range of 2 to 3

 

      percent.

 

                What that means is that again, out of 100

 

      patients treated--this is short term now,

 

      short-term treatment--you can expect 2 or 3 out of

 

      that 100 will have some excess of suicidality above

 

      and beyond what would be in the background that is

 

      due to drug.

 

                As a clinician, what you have to do is to

 

      balance that risk against the perceived benefit.

 

      The problem here, of course, is that we only have,

 

      at least from FDA's standpoint, a demonstration of

 

      benefit for Prozac, but if you take the TADS trial

 

      as an example of benefit, there, you can look at

 

      the benefit difference, and the benefit difference

 

      in the TADS trial, difference between drug and

 

      placebo in percent of responders, using that as the

 

      measure of benefit, it is about 25 percent.

 

                Again, you can interpret that in the same

 

      way, so that if you look at 100 patients who are

 

                                                                22

 

      treated with fluoxetine, you can expect that about

 

      25 out of 100 will have that benefit if you are

 

      looking at response as the benefit.

 

                So, you balance that against the risk,

 

      which again in that trial, the risk actually was

 

      greater than the 2 percent, it was probably more on

 

      the order of 7 percent, but you balance that risk

 

      against the benefit.  That is the kind of calculus

 

      that a clinician has to do.

 

                Finally, as was pointed out, there were no

 

      completed suicides in any of these trials.

 

                Again, we did not see the same signal in

 

      looking at the item data.  One exploration we tried

 

      to do to see if that could be explained by patients

 

      dropping out, and unfortunately, that was not an

 

      explanation.  The analysis of completers did not

 

      show really any difference from the analysis of the

 

      patients who dropped out.

 

                So, how should these findings be

 

      interpreted?  I think that this is an indication

 

      that there may be some increased risk for

 

      suicidality during short-term treatment, and I

 

                                                                23

 

      think this is probably a class effect.  Again, you

 

      are not seeing it in every drug that we looked at,

 

      Serzone and Wellbutrin being the two exceptions,

 

      but I think there is enough here to suggest that

 

      this is probably a class effect.

 

                The signal appears to be most compelling

 

      in major depression.  It may not be limited to that

 

      population, but again we are left with this very

 

      unusual variation in the signal across trials,

 

      within programs and across programs that we have

 

      not been able really to explain.

 

                What I want to do next is to talk about

 

      what some of the regulatory options are, and I

 

      first want to talk about possible labeling changes.

 

                As you recall, we already made a fairly

 

      major change to labeling back in March, and all of

 

      those changes have now been implemented.  There is

 

      a fairly prominent warning statement that directs

 

      the attention of prescribers to this possible

 

      event.

 

                Now, that language as it currently is

 

      written suggests that causality has not been

 

                                                                24

 

      established.  One thing that might be done to

 

      modify that, if there is agreement on this, we

 

      could say that causality has now been established

 

      for this risk in pediatric patients.

 

                In addition to that, we could go beyond

 

      that and provide specific suicidality findings in

 

      the labels for different products.  We could also

 

      provide more specific information about the

 

      efficacy findings for specific products in that

 

      language.

 

                There are other things to talk about in

 

      terms of that warning statement including things

 

      like bolding language or putting black boxes.

 

      These are all options that are on the table.

 

                The other option that you need to think

 

      about, and you heard many yesterday in the open

 

      session ask us to do this, you can think about

 

      contraindications.  The one thing I want to point

 

      out is that in this country, for our label, a

 

      contraindication means never.  It means that that

 

      drug will never be used in treating these patients,

 

      it is not an option.

 

                                                                25

 

                The other thing I want to point out is

 

      that the term "contraindication" has different

 

      meanings in different regulatory settings.  In some

 

      settings, it does not mean never.  If you read the

 

      fine print in the UK, for example, there is a

 

      suggestion that specialists may still use that

 

      drug.  So, you need to keep that in mind that in

 

      this country, a contraindication means that that

 

      drug is never an option.

 

                In addition to labeling changes, there are

 

      some other obvious actions that we can and almost

 

      certainly will take.  Our plan at present is to

 

      write a medication guide. This is basically

 

      labeling which ideally would be attached to the

 

      medication when it is prescribed in unit of use

 

      packaging.

 

                In addition to that, we will undoubtedly

 

      have another public health advisory when we decide

 

      on what needs to be done, and we will try and

 

      communicate these findings to our partners.

 

                Now, what I would like to do again is to

 

      quickly go through the questions and the topics. 

 

                                                                26

 

      The first topic is again we would like to have your

 

      comments on our approach to classifying these cases

 

      and to our analysis of the data.

 

                One of the questions for which we really

 

      need to have you vote on is do you feel that 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 that question is yes, to

 

      which of these nine drugs does this increased risk

 

      apply, in other words, is this a class effect for

 

      all antidepressants, does it apply to certain

 

      subclasses within this broader class, or to

 

      specific drugs?

 

                If this is a class risk or if it applies

 

      to certain drugs, how should this information be

 

      reflected in the labeling for each of these

 

      products, and what, if any, additional regulatory

 

      actions should the agency take?

 

                Finally, there is this question about what

 

      additional research is needed to further delineate

 

      the risks and the benefits of these drugs in

 

                                                                27

 

      pediatric patients with psychiatric illness.

 

                At our last meeting, I suggested one type

 

      of study that you might think about, and I am going

 

      to make that suggestion again, because we think

 

      that this is one study that might get at one of the

 

      deficiencies here, and that is, not only do we not

 

      have enough information about short-term benefit,

 

      we also have little information about longer term

 

      benefit or risk.

 

                One way of getting at longer term benefit

 

      is the randomized withdrawal study.  Basically, the

 

      way the study works is that patients who are

 

      responders or appear to be responding to treating,

 

      at some point in the course of treatment, are

 

      randomized to either continue on drug or randomized

 

      to placebo, and one looks at time to relapse as the

 

      outcome.

 

                Now, I know there are concerns about that

 

      design. You know, one concern is the ethical issue

 

      of taking patients off a medication when they

 

      appear to be responding. I agree that is a concern,

 

      but I think there is a way of dealing with that.

 

                                                                28

 

                The usual randomized withdrawal trial is

 

      done after too short a period of time on treatment.

 

      I mean typically, they are done now after 12 weeks

 

      or so of treatment.  That is too soon.  No

 

      clinician would take a patient off of one of these

 

      medications at that point in time.

 

                On the other hand, at some point in the

 

      course of treatment, whether it is six months or

 

      nine months or a year, it seems to me that it is a

 

      reasonable question.  At some point, you reach

 

      equipoise where the clinician has to ask the

 

      question, well, is this long enough, you know, is

 

      there any benefit in continuing the treatment

 

      beyond this point in time.

 

                Now, that is a much harder study to do, to

 

      keep patients on treatment for nine months or a

 

      year before you randomize them, but that would be a

 

      way of answering that important question of whether

 

      or not there is continuing benefit beyond that

 

      point in time.

 

                The other concern that has been raised

 

      about these trials is the issue of distinguishing

 

                                                                29

 

      between withdrawal symptoms and relapse.  Again, I

 

      agree that this is a reasonable concern, but I

 

      think there is also a way of addressing that.

 

                In clinical practice these days, these

 

      drugs are tapered.  One doesn't stop them cold

 

      turkey.  I think that could also be part of that

 

      design, and that could address that issue.  So,

 

      that is one thing to think about.

 

                Before I end, I want to leave you with two

 

      thoughts.  We clearly have an obligation at FDA to

 

      inform clinicians and patients about the risks that

 

      are associated with these drugs, and we take this

 

      obligation very seriously.

 

                Along those lines, I just want to point

 

      out that our current regulations do not require the

 

      same level of certainty with regard to safety in

 

      terms of causality as is required for efficacy.  In

 

      other words, we can issue warning statements with

 

      somewhat lesser certainty about causality than is

 

      required to support a claim.

 

                Secondly, as I have pointed out several

 

      times, the lack of efficacy data in this setting

 

                                                                30

 

      for most of these drugs needs to be part of this

 

      discussion.  On the other hand, and I am not making

 

      your job easy, please bear in mind that depression,

 

      whether in adults or children, is a very serious

 

      illness that is associated with morbidity and

 

      mortality quite apart from whatever role

 

      antidepressants might have.

 

                As was pointed out yesterday, this is the

 

      major cause of death in this population, the

 

      depression itself, so please bear that in mind.

 

                I have very profound respect and gratitude

 

      for the clinicians who are out there on the front

 

      lines still willing to take care of these patients

 

      despite what has become a very controversial and

 

      difficult environment.

 

                I hope that as we discuss these issues and

 

      make a decision, that we not make it impossible for

 

      them to practice medicine.

 

                Thank you.

 

                DR. GOODMAN:  Thank you, Tom, for a cogent

 

      and clear presentation.

 

                I would like to ask committee members if

 

                                                                31

 

      they have any questions of Tom.

 

                   Committee Questions and Discussion

 

                DR. FOST:  This is for Tom or anyone else

 

      who has a handle on the numbers.  I know there is

 

      no precise answer to it, but it would be helpful to

 

      me to just hear you or someone else, maybe Dr.

 

      Shaffer, if he is still here and is allowed to

 

      talk, this question.

 

                Suppose there were no SSRIs, suppose they

 

      were contraindicated, that is, prohibited,

 

      approximately, let me just ask the question about

 

      suicides, about completed suicides, and I

 

      understand there is no suicides in the FDA data,

 

      but based on everything that we know,

 

      approximately, would there be more suicides, fewer

 

      suicides, or the same amount if there were no SSRIs

 

      in children?

 

                DR. TEMPLE:  There is not going to be any

 

      way to answer that, in part because you can't do

 

      rigorous studies of the kind that would answer

 

      that.  No one is going to let you not treat, not

 

      institutionalize, et cetera, someone who is getting

 

                                                                32

 

      worse and worse, and it would require long-term

 

      studies presumably against no treatment, and it is

 

      not easy to figure out how anybody is going to do

 

      those.

 

                So, you are left with the kind of data

 

      that people have pointed out is always uncertain,

 

      the data on suicide rates and whether they are

 

      going up or down, so it is very hard to answer that

 

      question.

 

                There were no completed suicides in the

 

      pediatric data, so that doesn't give you a clue.

 

      You can form your own judgment about whether

 

      increased suicidal behavior or thinking is going to

 

      lead to suicides in a certain fraction of cases.

 

      It is hard to imagine that it couldn't, but you

 

      don't know what that ratio is.

 

                The success rate of suicidal attempts is

 

      relatively low.  I gather it is higher in males

 

      than females, but I don't think there is going to

 

      be ways to put numbers on that.

 

                You have to form your judgment about

 

      whether you think the overall decline in suicides

 

                                                                33

 

      has got something to do with therapy or has

 

      something to do with other aspects of life in the

 

      United States, and nobody can give you a firm

 

      answer to that, as Dr. Wysowski said and as others

 

      have said.  So, it is very hard to answer that

 

      question.

 

                Certainly, some of the people who spoke

 

      yesterday, some of the treating physicians were

 

      quite sure that they were helping people with the

 

      drugs, and you heard families who said that their

 

      relatives were made much worse by the drugs.

 

      Putting numbers on that, though, isn't feasible

 

      based on the data we have.

 

                DR. FOST:  A related question.  To those,

 

      Dr. Shaffer and others who note a decline in

 

      suicides in the United States, in parallel with the

 

      increased use of SSRIs, and let's just say which

 

      should be an increase in suicidality, suicidal

 

      ideation due to SSRI, what is the hypothesis there,

 

      that there is fewer suicides, but more suicidal

 

      ideation?  That is what the data seemed to suggest,

 

      and I am confused by that.

 

                                                                34

 

                DR. TEMPLE:  Can I make another comment?

 

      The studies you are looking at are all the

 

      short-term studies. As Tom was pointing out, we

 

      have none of the long term sort of relapse

 

      prevention data.  It seems entirely possible that a

 

      drug could be causing early suicidality, but once

 

      you are over that period, it prevents relapse,

 

      which could have an impact.

 

                You know, there is just literally no way

 

      to sort that out with present data.  I mean it has

 

      never been my thought that any benefit these drugs

 

      have consists entirely of their treatment of the

 

      acute episode, because in adults anyway, we have

 

      lots of data showing that the likelihood and timing

 

      of relapse is affected by continued therapy.

 

                As Tom said, most of those studies go

 

      earlier than you would like to do in a pediatric

 

      population, because they consistently show that

 

      quite reliably.  Maybe that is where their

 

      importance is, it is very hard to know.

 

                DR. GOODMAN:  Dr. Pine is next.

 

                DR. PINE:  I have a question about some of

 

                                                                35

 

      the regulatory options.  In thinking both about a

 

      number of the comments that were made yesterday, as

 

      well as your comments at the end about how

 

      difficult the decision that we will have today,

 

      related at least in part to the dearth of data that

 

      we really need.

 

                Are there any options from a

 

      pharmacovigilance standpoint as far as regulatory

 

      actions that might increase the degree to which we

 

      are focusing over the next time period on the

 

      emergence of these events or bring, you know, new

 

      data over the next months to years based on a

 

      regulatory action?

 

                DR. KATZ:  There is the mechanism of Phase

 

      IV requirements that say we can impose requirements

 

      on sponsors to do various studies in Phase IV and

 

      postmarketing environment.  The question would be

 

      what those studies would look like.  I think that

 

      is the question.

 

                There are other obviously entities, the

 

      NIMH and others who were set up obviously to do

 

      large trials, and again the question is what would

 

                                                                36

 

      those trials look like.  You could do I suppose

 

      large long-term, and again, you have heard, I

 

      think, a lot of people say that there is a need for

 

      long-term data.

 

                I suppose you could do long-term

 

      comparative trials, you can't do long-term

 

      placebo-controlled trials, so other than the sort

 

      of randomized withdrawal design I think that Tom

 

      talked about.

 

                So, there is a mechanism to require

 

      studies.

 

                DR. PINE:  I guess I am not so much asking

 

      about studies, and this maybe is a bit of an unfair

 

      analogy, but in New York, for example, as well as

 

      other states, whenever you write a prescription for

 

      a psychostimulant, there are a whole host of

 

      procedures that kind of go with that, that are

 

      designed to allow monitoring of the use of

 

      psychostimulants and the associated effects.

 

                Is there any--again, I realize I am

 

      thinking a little bit out of the box--is there any

 

      form of, I don't know, computer based or monitoring

 

                                                                37

 

      system that might give us a better handle on how

 

      many of these events are actually happening in

 

      regular treatment?

 

                DR. TEMPLE:  ODS should comment on that,

 

      but it is worth just looking at, say, the study Dr.

 

      Jick tried to do. There isn't any no-treatment

 

      group in that.  He is just comparing the risk with

 

      one group of drugs with another, and you can

 

      definitely do studies like that, but if you tried

 

      to compare treated people with untreated people,

 

      there will always be the concern of whether the

 

      groups are fundamentally different, a very

 

      difficult problem because people are treated.

 

                There might be environments in which

 

      treatment is not so common, where there is less

 

      likelihood to treat.  Maybe in those environments,

 

      you could do something like that, but Anne wanted

 

      to talk.

 

                DR. TRONTELL:  Just to expand briefly, you

 

      are talking about using observational data as Dr.

 

      Temple pointed out, where you don't have a control

 

      group, and although you might register patients, we

 

                                                                38

 

      have seen even in clinical trials that we have been

 

      discussing this past day, that the issue of

 

      ascertainment of these events is very complicated

 

      when you actually have a clinical trial mechanism

 

      in place to capture those events.

 

                The other challenge that you face with

 

      observational data, because people don't receive

 

      the drugs randomly, there is a phenomenon called

 

      "confounding by indication," in fact, some of your

 

      sicker patients you might presume are the ones who

 

      are getting the medication.

 

                We try and control for that, but it is

 

      very complex.  I think the better option is to

 

      think of some systematic way, and then you are in

 

      the realm of studies, as Dr. Katz was saying.

 

                DR. MURPHY:  I just wanted to follow up on

 

      one last thing.  Because we already know that using

 

      the system we have now for follow-up

 

      post-exclusivity because it is already mandated

 

      that we do one-year reporting once these products,

 

      whether they are approved or not, so we are looking

 

      at all-use.

 

                                                                39

 

                We do look at that and we report that, and

 

      we know that that is not going to inform us, you

 

      know, to answer the questions we need to answer,

 

      because of all the things that will impact that

 

      reporting.

 

                DR. GOODMAN:  Dr. Temple.

 

                DR. TEMPLE:  I just wanted to mention one

 

      related, but not quite on-point matter.  We talked

 

      yesterday about concern that the studies that had

 

      been done to gain exclusivity might have been not

 

      as good as we would like.

 

                We weren't particularly talking about the

 

      design of the studies, which we think is okay, but

 

      let's say the approach to them.  Maybe there was

 

      too much of a rush, and so on.  If we were to put

 

      out a written request now, it would be one that

 

      required a third arm to the study, namely, a Prozac

 

      arm, because we know that Prozac can be shown to be

 

      effective.

 

                So, the study wouldn't count unless it had

 

      been able to show that it had what we call "assay

 

      sensitivity," the ability to tell effective drugs

 

                                                                40

 

      from ineffective drugs. We couldn't do that before

 

      because there wasn't anything at the time we wrote

 

      those requests that was known to be showable in

 

      children, but now there is.  There is three studies

 

      that all seem to show something.

 

                So, we should have much better information

 

      about what the pediatric population does in future

 

      requests.  That doesn't help the present

 

      discussion.

 

                DR. MURPHY:  I wanted to address that

 

      issue again, too, because I think I want the

 

      committee to be very clear on the fact that the

 

      Agency tells the company very clearly the type of

 

      studies that need to be done.

 

                We do give them, you know, a broader

 

      picture of the number of patients.  We tell them

 

      what we know will be the minimum, and, in general,

 

      I think Tom would agree that most of these studies

 

      have come in with the numbers in each arm that we

 

      have seen in other studies where they have shown

 

      effectiveness.

 

                So, the point here being that we do have

 

                                                                41

 

      control over the types of trials that are done, the

 

      number of patients, and the monitoring.  However,

 

      because there is a template up on your web that

 

      basically tells you what we ask for in depression

 

      trials.

 

                When you look at what the safety is, as

 

      has been pointed out many times, these trials were

 

      not set up to answer that question.  So, I think it

 

      is those kinds of issues that we would like to hear

 

      more about today.  As Dr. Temple said, it is how

 

      better to do these trials in the future.

 

                Thank you.

 

                DR. GOODMAN:  Thanks for that statements,

 

      Dianne. I just want to make sure I understand it

 

      completely.

 

                I think what you are saying, that if the

 

      conditions had been different at the time, that is,

 

      that the drug company was required to show, not

 

      only have a study, but a study that was positive.

 

      Then, the design would not have been any different,

 

      the sample size would not have been any different

 

      under those circumstances than the ones that

 

                                                                42

 

      existed at the time.

 

                DR. MURPHY:  I think what we are saying,

 

      that for the trials that we designed, they were the

 

      same for the one that did show some effect, which

 

      is Prozac, as those that did not, and that what we

 

      don't know is if a company is putting a trial

 

      together, and let's say we said that they had to

 

      have 300 patients to get their exclusivity, but for

 

      other reasons they really wanted this product

 

      approved, and they felt the enrollment was not

 

      going the way that they needed, would there be some

 

      other push within that company to then go out and

 

      get more patients, so that their enrollment would

 

      be better versus an exclusivity where all they had

 

      to do was meet that criteria.

 

                I am making that number up.  I think the

 

      issues that people were trying to get at is that is

 

      there a difference that affects behavior when you

 

      just know you have to do certain things versus you

 

      have another goal, which may be approval.

 

                DR. GOODMAN:  Dr. Temple.

 

                DR. TEMPLE:  The requirement for a third

 

                                                                43

 

      arm in evidence of assay sensitivity leaves it up

 

      to the company to decide how they are going to do a

 

      successful study.  They can look at the available

 

      data on Prozac and say, oh, here is the number I

 

      need, here is the kind of patients I need.  That

 

      succeeded in those three trials.

 

                They would then know that the trial would

 

      have to be one that can show the difference between

 

      Prozac and placebo.  That doesn't mean their drug

 

      has to show a difference between drug and placebo.

 

                That would be determined by the results,

 

      and there is no obligation that the drug be

 

      successful, but we would at least know we had a

 

      study that was capable of detecting effective drugs

 

      and distinguishing effective drugs from ineffective

 

      drugs.

 

                That would then become a requirement for

 

      meeting the terms of the written request because

 

      they would have to show that they had an adequate

 

      study.  Before there was an effective drug, there

 

      was no way to do that.  You couldn't tell whether

 

      the study was a good study or not.

 

                                                                44

 

                DR. GOODMAN:  Dr. Marangell.

 

                DR. MARANGELL:  If I could go back and

 

      address the question of what would the hypothesis

 

      be for long term, certainly, in the absence of

 

      data, there is some degree of speculation.  I do

 

      have a question directly to the FDA.  Is it okay if

 

      I respond?

 

                I think the number one hypothesis would be

 

      in the short run when you have depressed patients

 

      who are not yet stabilized, you may see an

 

      increased risk, and you do see certainly in this

 

      population an increased risk of suicidality.

 

                I imagine that what we would see with

 

      longer term data is a substantial decrease in

 

      suicidality over time, and that is what we are

 

      inferring from the cohort and the epidemiologic

 

      data.  I think that clinically makes sense, as well

 

      as mechanistically makes sense.

 

                The question for the FDA, can you give us

 

      a sense, I mean do we feel confident that we

 

      actually have all the available studies now in both

 

      children, adolescents, as well as in adults, and

 

                                                                45

 

      what is the FDA policy on requiring review of those

 

      studies including negative studies, when do they

 

      come to you and when do they become publicly

 

      available?

 

                DR. TEMPLE:  Well, let me start, others

 

      can comment.  When you submit to us an application

 

      to change the labeling, to add a claim, say, for

 

      pediatric use, you are clearly obliged under the

 

      law to provide every study, successful ones,

 

      unsuccessful ones, things that were interrupted,

 

      and so on.

 

                As far as we know, we are getting all

 

      those studies.  Of course, if there were something

 

      that were done that we didn't know about, well,

 

      then, we wouldn't know about it, but as far as we

 

      know, we are getting them all.

 

                So, most of the pediatric submissions to

 

      us were associated with labeling requests or

 

      something like that, so as far as we know, we have

 

      all those data.

 

                Dianne can tell you what is required under

 

      the best BPCA, and I think there, too, they have to

 

                                                                46

 

      provide them.  We have no rule that affects whether

 

      people have to publish results.  Congress is

 

      considering that, so are the journals and everybody

 

      is talking about that.

 

                Under BPCA, however, when we grant

 

      exclusivity, we provide summarized results, and we

 

      have done that for the drugs where the written

 

      requests were written after the BPCA, and we have

 

      gone back and asked the companies for permission to

 

      summarize our analyses for all of the others where

 

      it wasn't totally clear whether we could do it or

 

      not.

 

                So, the summarized result, that is not the

 

      same as a complete study report, the summarized

 

      results are now available publicly on all of those.

 

      I am sure between PhRMA's commitment to provide a

 

      registry between the journals insistence that they

 

      will get a registry, between congressional

 

      interest, I am quite confident that there will be a

 

      change in the way things get published.

 

                DR. MURPHY:  The only thing that I could

 

      add to that is that for the committee, for the

 

                                                                47

 

      routine practice within FDA, if a company submits

 

      an application, we review it, the studies are

 

      negative, there is no public acknowledgment of that

 

      unless the company for some reason wants to make

 

      that knowledge public.  We are not allowed to

 

      comment on that.

 

                Now, under BPCA, it said, it has a

 

      disclosure section that says you, FDA, will

 

      publish, as Dr. Temple is referring to, the

 

      summaries, the medical and pharmacology summaries

 

      up on the web--make them public, and actually, we

 

      have chosen to do that on the web--and we have done

 

      that.

 

                One of the issues that has happened is

 

      that between the enactment of the new legislation

 

      and the old legislation, legally, things were

 

      considered issues under the old legislation, so

 

      even though the studies came in, we had to reissue

 

      all those written requests to be able to say they

 

      now were subject to this new mandate.

 

                So, what again Dr. Temple was telling you

 

      is that unfortunately, many of the antidepressants

 

                                                                48

 

      came in, in that period when we had not yet issued

 

      that letter, but despite that, we have asked the

 

      sponsors to allow us to put those summaries up, and

 

      they have given permission to do so.

 

                That is why yesterday we said up on the

 

      web now are the summaries.  Again, this is not the

 

      data.  There is variations in, you know, some

 

      medical officers will put in more information than

 

      others in how much data is in these summaries, but

 

      they are up now, publicly available.

 

                DR. MARANGELL:  Is that true for adults,

 

      as well?

 

                DR. MURPHY:  No, adults are still under

 

      the same standard.  In other words, if the study is

 

      negative, we don't talk about it.

 

                DR. MARANGELL:  So, as an example, if an

 

      antidepressant manufacturer did a study in a new

 

      indication for a drug that is currently available,

 

      found increased risks of suicidality, no one would

 

      be under any obligation to make that public?

 

                DR. MURPHY:  That is a different issue.

 

                DR. MARANGELL:  But that is the question.

 

                                                                49

 

                DR. MURPHY:  The issue is safety, and the

 

      Agency always has the ability to make public safety

 

      issues that arise.

 

                Bob, do you want to say anything else

 

      about that?

 

                DR. TEMPLE:  We consider, for example, if

 

      someone with an antidepressant comes in for, I

 

      don't know, obsessive compulsive disease, and we

 

      don't buy it, we do not make those data available,

 

      they are considered confidential commercial

 

      information.  Obviously, a lot of the people, a lot

 

      of the public doesn't like that approach.  We think

 

      that is what we are required to do.  I can't

 

      comment on that, I am not the lawyer here.

 

                However, companies have a separate

 

      obligation for drugs that are marketed to report

 

      serious and unexpected, and any serious adverse

 

      reactions to us, and to do so promptly.  A finding

 

      of increased suicidality where that was not known,

 

      clearly meets that test, and they would be obliged

 

      to report it to us.  If we then thought that was

 

      true, we would add it to the label or do whatever

 

                                                                50

 

      we are supposed to do.

 

                So, safety data meets a different

 

      standard.  A new carcinogenicity study or

 

      something, those do have to be reported to us.

 

                Other studies have to be reported in the

 

      annual report, but they are not necessarily

 

      reported in detail, and not that much is

 

      necessarily made of them, and they do not

 

      necessarily become public.

 

                DR. GOODMAN:  Dr. Pollock.

 

                DR. POLLOCK:  Yes, the serious safety

 

      issue would have to be reported while the trial is

 

      ongoing to you, right?

 

                DR. TEMPLE:  Well, if it arises from a

 

      trial, it has to be.  Actually, the requirements

 

      for reporting serious unexpected events in a trial

 

      are more or less identical to the requirements

 

      before a drug is marketed.  They have to be

 

      reported to us within 7 or 15 days.

 

                A finding from an epidemiologic study,

 

      there is some judgment involved in whether that

 

      represents the kind of thing that has to be

 

                                                                51

 

      reported promptly, but they basically do.

 

                DR. KATZ:  There is also some judgment

 

      involved in whether or not an event is considered

 

      to be unexpected.  So, for example, suicide in a

 

      study of patients who are at risk anyway might not

 

      be reported to us in real-time, because it might be

 

      considered to be expected, the blind is still

 

      intact, you don't know if it's drug or placebo if

 

      it is in the context of a controlled trial.

 

                Afterwards, though, when the trial is done

 

      and analyzed, and it turns out that there is an

 

      increased incidence on drug compared to placebo,

 

      that is something we would find out about.

 

                DR. GOODMAN:  Go ahead, Dr. Pollock.

 

                DR. POLLOCK:  I actually wanted to explore

 

      your thinking a little bit about the recommendation

 

      for a maintenance trial.  I guess there are a

 

      couple of things. One is if there is this acute

 

      toxicity that we are concerned about, clearly, it

 

      doesn't address that because you are dealing with

 

      the children or the adolescents who have actually

 

      responded, and then are withdrawn.

 

                                                                52

 

                But I wondered if there was implicit in

 

      your request for that, a concern that still that

 

      the shorter half-life SSRIs seem to be, maybe not

 

      statistically, but certainly qualitatively more at

 

      risk in causing this phenomenon.

 

                I was taking that as implicit perhaps in

 

      your suggestion, maybe I am over-interpreting it,

 

      but is there a belief that somehow--I mean it just

 

      seems more than coincidence that signals seem a

 

      little bit higher.

 

                I know it has now emerged with Prozac, but

 

      certainly, Effexor, venlafaxine stands out at one

 

      end, then followed by paroxetine, and if there was

 

      kind of an implicit question that you were asking,

 

      assuming that people are still using after we are

 

      finished, you know, those medications, that you can

 

      require that those manufacturers actually conduct a

 

      serious maintenance trial as part of you were

 

      saying your Phase IV regulatory requirement.

 

                DR. LAUGHREN:  We certainly, you know,

 

      until we saw the TADS data, were entertaining the

 

      notion that discontinuation might be one

 

                                                                53

 

      explanation for the bigger signal, the apparent

 

      signal that we are seeing with Paxil and Effexor.

 

                The TADS finding certainly challenges that

 

      notion as a unitary explanation, since that is the

 

      single trial among the 24 that, by itself, has a

 

      statistically significant finding for that signal.

 

      That doesn't mean that the other explanation isn't

 

      possible.  I mean this could be a much more complex

 

      situation than one might seem at first glance.

 

                But a maintenance trial is not going to

 

      answer all those questions.  I mean a maintenance

 

      trial is only going to answer the question of

 

      longer term benefit, but the reality is that many

 

      clinicians, despite these concerns, are probably

 

      going to continue to use these drugs, and we have a

 

      dearth of information about what the longer term

 

      benefits are.  The maintenance trial is one way, I

 

      think, of getting at that.

 

                Now, there is this issue of how to

 

      interpret emerging symptoms in that setting, you

 

      know, when you take patients off the drug.  Of

 

      course, the drugs like Paxil and Effexor, that are

 

                                                                54

 

      known to have a stronger signal for

 

      discontinuation, obviously are a challenge in doing

 

      that kind of trial, but I think that one could, as

 

      one does in clinical practice, taper those patients

 

      to try and address that, and then look for what

 

      would be considered for relapse.

 

                DR. GOODMAN:  Dr. Temple.

 

                DR. TEMPLE:  There is another reason to do

 

      randomized withdrawal studies.  As everybody knows,

 

      in adults, the failure rate for conventional

 

      clinical trials of the acute episode is about 50

 

      percent.  That is, half the trials can't tell drug

 

      from placebo, and that is true even when you

 

      include a third arm of a drug that is known to

 

      work.  That appears to be the nature of the beast.

 

                Nobody really has a good explanation

 

      because if they did, they would fix it, but we at

 

      least think it has something to do with the

 

      environment and the discussions that go on even

 

      informally, even if it is not planned as part of

 

      the treatment.

 

                In the randomized withdrawal setting, the

 

                                                                55

 

      success rate for drugs that are known to work is

 

      nearly 100 percent. Very few of those trials ever

 

      fail.

 

                There are at least two reasons.  One, only

 

      people who seem to be doing well are in the trial,

 

      so they are enriched with a responder population.

 

      You can make of that what you will.

 

                The other possibility, though, is that the

 

      environmental things that help people get better

 

      aren't really there, they are just out living in

 

      the community, there is nothing nurturing about it.

 

      They are just back in their usual environment.

 

                So, one of the attractiveness of these is

 

      to find out whether the drugs actually provide some

 

      benefit, even in people who seem to be doing well

 

      on them, which seems an important question here.  I

 

      mean, as Tom has pointed out repeatedly, the

 

      failure of most of the drugs to show effectiveness

 

      doesn't mean they don't work.  On the other hand,

 

      we don't have evidence that they do work, and that

 

      is not irrelevant either.

 

                A good way to show that, if they do, is

 

                                                                56

 

      the randomized withdrawal study.  At least that has

 

      been the history in adults, so there is a lot of

 

      attractiveness to it.

 

                DR. GOODMAN:  Dr. Chesney.

 

                DR. CHESNEY:  Thank you.  I have two

 

      questions.               The first one is for Dr.

 

      Murphy and Dr. Temple, and the second for Dr.

 

      Laughren.  The first question addresses the

 

      exclusivity issue.  I feel like in this case, we

 

      bypass the Phase I/Phase II stages that we would

 

      normally go through with new drugs, so we never did

 

      do the pharmacokinetic/pharmacodynamic dose finding

 

      in children that we would have done had these been

 

      new drugs.

 

                I wondered, I probably should know this,

 

      but could either of you explain, when we offer

 

      exclusivity with a new drug, if it is a new drug to

 

      children, do we require those studies, or do we

 

      not?  I am sure it is not that straightforward.

 

                DR. MURPHY:  We did required

 

      pharmacokinetic studies.  Actually, on the

 

      template, we outline three types of studies.  They

 

                                                                57

 

      have to do two randomized, double-blind,

 

      placebo-controlled, acute treatment trials with

 

      recommendation at six to eight weeks for safety and

 

      efficacy.  They also are to do a pharmacokinetic

 

      study to provide information pertinent to dosing of

 

      study drug, and they are to do a safety study.

 

                So, all of those were asked for.  Now, if

 

      you are asking do we go back and demand redoing

 

      dose finding again in these, no, they were not

 

      worded that way.  It was said that the PK study

 

      could be a traditional PK or, alternatively, a pop

 

      PK, and actually, I don't think that the study had

 

      any other information that would have, in essence,

 

      told the company that they needed to redo the dose

 

      finding, if that answers your question.

 

                DR. CHESNEY:  So, do we have dose

 

      information on all of these drugs?  Do we know what

 

      the usual ranges are, and what excessive ranges

 

      are, all those things?

 

                DR. GOODMAN:  Go ahead, Dr. Katz.

 

                DR. KATZ:  I think Tom mentioned this in

 

      one of his slides yesterday.  The written requests

 

                                                                58

 

      that we issue now are very different from the

 

      written requests we issued that probably generated

 

      most of the trials that we are talking about here

 

      yesterday and today.

 

                As Dianne pointed out, for example, in

 

      pharmacokinetics, we gave sponsors the opportunity

 

      to generate the kinetics in kids based on so-called

 

      population pharmacokinetic analyses, which is to

 

      say from data generated in the controlled trials.

 

                So, it was sort of after the fact.  It was

 

      just what is the kinetics of the doses you happen

 

      to give in the trials.

 

                In the earlier written requests, it was

 

      sort of the pediatric drug development was sort of

 

      tacked onto the adults, in other words, when the

 

      trials were designed even, the treatment effect

 

      size, for example, was used to calculate sample

 

      size was taken from the treatment effect size seen

 

      in adults.  We had no information, even preliminary

 

      information in kids.

 

                So, we didn't have a lot of preliminary

 

      information in those days that could inform

 

                                                                59

 

      adequate trial design in this population, in this

 

      setting.

 

                Nowadays, we ask for different things.  We

 

      ask for formal PK, so we can learn before the

 

      definitive trial design, what the kinetics are,

 

      what doses give rise to what plasma levels.  We ask

 

      for dose finding studies, so we can determine

 

      before we design the definitive trials what the

 

      tolerated dose range is.

 

                So, the written requests are much

 

      different now than they were at the time that the

 

      requests are generated, these data were written.

 

                DR. MURPHY:  Just to reinforce that is

 

      that these were some of the earliest written

 

      requests that went out, so they really, as has been

 

      stated, and I think we tried to say this earlier

 

      on, we are learning.

 

                I mean because of the lack of prior

 

      research and some fundamental scientific questions

 

      haven't been answered, we are learning from the

 

      trials that we have now about how to do a better

 

      job on designing some of these trials, but these

 

                                                                60

 

      were some of the very earliest ones that were

 

      issued.

 

                DR. CHESNEY:  Dr. Temple, did you want to

 

      comment on that?

 

                DR. TEMPLE:  Well, I just wanted to say

 

      there isn't any pharmacodynamic measure to allow

 

      you to do what is called PK/PD other than

 

      effectiveness itself.  In a lot of cardiovascular

 

      settings, there is at least something you think

 

      relates to the desired effects, so you can do

 

      relatively short-term studies and get a PK/PD

 

      relationship.

 

                Here, your only way to do it is to insist

 

      that every drug, every study be a dose response

 

      study, which is of considerable difficulty.  We

 

      have trouble getting really good data even in

 

      adults actually given the sample sizes involved,

 

      but there isn't any measure yet.  Maybe one of

 

      these days there will be an MRI measurement or

 

      something, but not yet.

 

                DR. CHESNEY:  Well, I don't want to

 

      overstay my welcome, and I do have a question for

 

                                                                61

 

      Dr. Laughren, but one does wonder about some of

 

      these children who didn't even express ideation and

 

      just suddenly, very early on, if they didn't have

 

      excessive levels.  I guess that is one issue I was

 

      getting to.

 

                Dr. Laughren, I wanted to come back to the

 

      point Dr. Pine was making.  I thought Dr.

 

      Reisinger's point in the open session yesterday was

 

      a very interesting one, which is that you would

 

      have to undergo some kind of computer-based

 

      learning program or some kind of program that

 

      authorized you to prescribe psychoactive drugs.

 

                Certainly, we have to do computer-based

 

      CBLs for all kinds of things in our hospitals and

 

      in other areas nowadays.  That had a real

 

      attraction to me, and I guess the question is what

 

      kind of authority does the FDA have in an area like

 

      that, can you say that anybody that prescribes

 

      SSRIs must do a computer-based learning program on

 

      line, or is that something that the professional

 

      societies take on?

 

                You offered several options, black boxes,

 

                                                                62

 

      revised label warning, but is this a potential

 

      option?

 

                DR. TEMPLE:  We can certainly recommend

 

      things like that.  Every labeling for a cancer drug

 

      says that this should only be used by people who

 

      are trained in oncology. That comes with no

 

      enforcement on our part except that people may be

 

      anxious about the consequences if they don't have

 

      that training.

 

                A labeling recommendation is certainly a

 

      possibility.  A step further to limit the drugs to

 

      people who have been given that way, those are very

 

      iffy questions, and it is not clear whether we can,

 

      in fact, do that.  There would have to be a debate

 

      about it.

 

                There are some examples of fairly

 

      interventionist activities.  As you all know, you

 

      can't get clozapine unless you have a white blood

 

      count, so no blood, no drug.

 

                There are not a whole lot of other

 

      examples like that, but there are other cases where

 

      patients must be given a form that lists what some

 

                                                                63

 

      of the adverse effects might be, and things like

 

      that.  You have to weigh the risk you are concerned

 

      about with the burdensomeness to the community and

 

      to the medical profession of those kinds of

 

      interventions.

 

                Putting something in labeling about what

 

      you should know doesn't carry those kinds of

 

      concerns, so if something sensible, suggesting that

 

      people ought to be trained in a certain way seemed

 

      like a reasonable thing, we could certainly

 

      consider that.

 

                DR. TRONTELL:  I would just like to add on

 

      to Dr. Temple's comments, because the FDA regulates

 

      drugs, but doesn't regulate the practice of

 

      medicine, and we walk a fine line in terms of

 

      dealing with some drug products where we may feel,

 

      as with clozapine, that only very tight controls on

 

      prescribing and dispensing and use of the product

 

      are allowed.

 

                There are a very small handful of drugs,

 

      they tend to be the exception rather than the rule,

 

      where training has been required as a condition of

 

                                                                64

 

      approval.  One product in particular is the drug

 

      product dofetilide, where, in fact, training is

 

      required for pharmacists or clinicians.  There is a

 

      highly structured way in which that product can be

 

      used.

 

                Again, those have tended to be reserved

 

      for situations where we feel the drug cannot be

 

      safely used without that very high level of

 

      precaution.  It is extremely difficult to put those

 

      in place for products that have already been

 

      marketed and used by professionals.

 

                DR. CHESNEY:  The public sees your role I

 

      think in a much broader perspective, as we heard

 

      yesterday, and I think that is something that is

 

      useful to clarify as to where your limits are.  You

 

      mentioned there is a fine line, and I think that is

 

      what we are all looking for, is where does your

 

      authority end and that of prescribing physicians

 

      begin, I guess in a sense.

 

                DR. TRONTELL:  I don't think we yet have

 

      an answer.  I think we always have the authority of

 

      our agency and hopefully, our ability to persuade

 

                                                                65

 

      individuals, but I think that the actual legal

 

      authority to do some of these is a matter of debate

 

      within and outside of the agency.

 

                DR. GOODMAN:  Dr. Nelson.

 

                DR. NELSON:  I would like to return to the

 

      topic of the incentives on the part of industry to

 

      perform well-conducted trials.

 

                There has been a lot of discussion about

 

      the evolution of the written request and about the

 

      improvement with three-arm studies and changes in

 

      the ability to request that, but my understanding,

 

      I am interested to know if this is accurate, is

 

      that there is still two potential linkages that

 

      don't exist that might decrease the incentive to do

 

      a well-conducted study, and that is, absent safety

 

      concerns, there is no tie to putting any efficacy

 

      information in labeling, so that they receive

 

      exclusivity if a labeling change occurs.

 

                Second, is that there is no link of

 

      exclusivity to a well-conducted study unless that

 

      has changed with written request, since I read them

 

      on the current web site, there is one asthma study

 

                                                                66

 

      where there was members of the drug group that had

 

      no drug level, members of the placebo group that

 

      had measurable drug levels, and the FDA concluded

 

      that the data was uninterpretable, but

 

      nevertheless, exclusivity was granted.

 

                I am wondering, is that a problem with the

 

      written request that is now fixed, or is there

 

      other solutions that would need to be put into

 

      place, such as legislation, to address those two,

 

      what I perceive as gaps.

 

                DR. MURPHY:  I think there was significant

 

      discussion about how exclusivity should work,

 

      should it be only if the product is approved.  I

 

      was not privy to those discussions, but I know they

 

      occurred.

 

                The reason for why it was put in place the

 

      way it is, I can't give you, Dr. Nelson, but I can

 

      tell you that one of the explanations I have heard

 

      is that there was such little data, and FDA was

 

      given the authority to define the trials, so again,

 

      as you have heard, we would like to improve, and we

 

      know we have to learn from what trials we have,

 

                                                                67

 

      that by providing FDA the authority to define the

 

      trials, that they hope that the trials would be,

 

      you know, of the best that they could be, and that,

 

      therefore, we would learn from the trials even they

 

      were failed, because that is important information,

 

      failing is important.

 

                So, I guess what you would say, you are

 

      asking if, and that is in a number of our labels,

 

      and that is a whole other discussion, but in

 

      situations, you know, we know that is the only

 

      study we are going to get and this is it, failing

 

      is put, that they failed to show effectiveness has

 

      been put in the label in a number of situations,

 

      and certain dosing or safety information.

 

                As I said, about a fourth of the time, we

 

      are describing, even irrespective of whether the

 

      study is positive or negative, we are finding

 

      safety signals, you know, important dosing

 

      information, and we are able to put that

 

      information in a label.

 

                The intent is that the information that is

 

      obtained, whether the product is proven to be

 

                                                                68

 

      effective or not is important, and that safety

 

      information, et cetera, would be obtained.

 

                So, that is the best explanation I can

 

      give you as to why it is set up the way it is right

 

      now.

 

                DR. NELSON:  I understand, but let me

 

      focus my question, I guess.  Right now the efficacy

 

      or lack of efficacy data is not in the existing

 

      labeling that we are discussing, so, for example,

 

      just to pick one, paroxetine, there is five

 

      studies, and the pediatric use just says it has not

 

      been established.

 

                Although that is a true statement, it is a

 

      bit misleading because many people interpret that

 

      to mean the studies hadn't been done.

 

                The other question is you could ask them

 

      to do a three-arm active control study, but if they

 

      do it badly, do they still get the money?  Even if

 

      they have done it, if they do it badly, do they

 

      still get the money?

 

                DR. GOODMAN:  Dr. Temple wants to respond.

 

                DR. TEMPLE:  If the written request says

 

                                                                69

 

      you need to do a three-arm study and need to show

 

      that the trial has assay sensitivity, that is, the

 

      ability to distinguish active drugs from inactive

 

      drugs, and the Prozac arm doesn't beat placebo,

 

      then, they would have failed to meet the

 

      requirement of the written request.

 

                We couldn't do that before, as I said,

 

      because we didn't have a known active control, so

 

      we wouldn't have known what to say.  So, in that

 

      case, the incentive to do a proper study becomes

 

      quite clear.  If they don't do a proper study, and

 

      succeed in showing that, they would not get

 

      exclusivity.

 

                In other cases, we have insisted that the

 

      variance be such that for, say, a blood pressure

 

      drug, an effect size of 3 or 4 millimeters of

 

      mercury could be detected, so if the whole thing is

 

      done sloppily and they could not have detected such

 

      a thing, then, they would not get exclusivity.

 

                Some of the other things, however, that

 

      you mentioned, don't have an obvious remedy.  I

 

      mean I guess following the example you said, we

 

                                                                70

 

      could say, oh, by the way, people should have blood

 

      levels showing that they took the drug.  Well, we

 

      hadn't been smart enough to think of that, and

 

      maybe that is something we should be adding, that

 

      is, some kind of compliance check.

 

                That, I don't think has been part of

 

      written requests to date.  That doesn't mean it

 

      couldn't be.  The test that Congress imposed is

 

      that if you comply with the terms of the written

 

      request, you get exclusivity.  That means if we

 

      weren't smart enough to ask a question, that is not

 

      considered their fault, and they are supposed to

 

      get it.

 

                DR. MURPHY:  And we have denied

 

      exclusivity where we thought the trials were done

 

      sloppily, and actually, sometimes when the sponsor

 

      said, well, we know you asked for this, but we

 

      didn't think it was correct to keep going, so we

 

      didn't do this for some reason, and we said, no,

 

      you should have come in and talked to us about why

 

      you weren't going to do it, you didn't do it, we

 

      told you, you need to do it, sorry, you don't get

 

                                                                71

 

      it.

 

                So, what I guess we are trying to say is

 

      if it's really sloppy, and they don't do what we

 

      tell them, we deny them exclusivity.  The problem I

 

      think we are dealing with here is that we all are

 

      learning how to better do the trials, and your

 

      other question about whether that should go in the

 

      label, the negative information should go in the

 

      label, is a whole other discussion.

 

                DR. GOODMAN:  I have a list of seven other

 

      committee members who wish to speak.  After we give

 

      them that opportunity, I am going to ask Dr.

 

      Wysowski to come up to the podium.  We had asked

 

      her to follow up on something from yesterday.  Is

 

      there somebody else that has a burning--we have one

 

      more and that is it--two more, that's it.

 

                Dr. Irwin.  His question has been

 

      answered.  Thank you.

 

                Dr. Rudorfer.

 

                DR. RUDORFER:  Yes, thank you.

 

                I would just like to revisit a couple of

 

      issues that concern me at the front end of these

 

                                                                72

 

      studies, and I recognize everyone from the FDA is

 

      pointing out that this is a learning process, on

 

      the other hand, we are faced with the dilemma of

 

      having these particular trials to deal with.

 

                The dosing question that was just

 

      discussed brings to mind a concern I have related

 

      to how the suicidal events we have been looking at

 

      were ascertained.

 

                As I understand it, for the most part,

 

      these were from adverse events questionnaires and

 

      surveys.  Is that correct?  I mean there was no

 

      particular suicidal scale?

 

                DR. LAUGHREN:  Well, all of these trials

 

      included standard depression rating instruments

 

      like HAM-D or CDRS, and so forth, and there is a

 

      suicide item in each of those instruments, and that

 

      is part of what we analyzed.

 

                But the problem is we don't really know

 

      how those were applied.  My guess is that most of

 

      the event data we are dealing with were spontaneous

 

      report or general questioning rather than specific

 

      ascertainment.

 

                                                                73

 

                That is really one of the areas that we

 

      are trying to explore with Columbia to try and work

 

      on a more specific instrument for improving

 

      ascertainment for suicidality, but no, in these

 

      trials, I don't think ascertainment was very

 

      specific.

 

                DR. RUDORFER:  My question, as we deal

 

      with these data, would be this.  I appreciate the

 

      very dedicated and elegant work that both the FDA

 

      and Columbia have applied to these findings.  The

 

      question I have relates to the issue of the active

 

      drug versus placebo groups.

 

                Since it sounds as if much of the data

 

      were spontaneous reports or I assume perhaps

 

      discussion between the raters and subjects, or the

 

      investigators and the subjects, I am wondering if

 

      part of this is not dependent on the assumption

 

      that the blind was kept intact throughout the

 

      studies, and I wonder if we have any measure of

 

      that or any sort of quality control on that issue.

 

                DR. LAUGHREN:  No, we have no idea of

 

      that.  That is typically not something that is

 

                                                                74

 

      really ascertained.  It is the assumption, but how

 

      would you check on that?

 

                DR. RUDORFER:  In some studies, patients

 

      and raters are asked at some point.  I mean here, I

 

      am just wondering if, in fact, if a patient

 

      volunteered that, for instance, they were

 

      experiencing some side effects, they come in, the

 

      rater asks how are you doing this week, and their

 

      first comment relates to GI distress or something

 

      that sounds like a side effect, if they simply

 

      don't get more attention, in other words, maybe

 

      there is more discussion, maybe there are more

 

      questions asked as opposed to a patient that comes

 

      in and say, gee, I am feeling pretty good, I don't

 

      seem to have any side effects.

 

                Again, that would not obviate the fact

 

      that if we find signals, then, the signals are

 

      present.  I guess I am just concerned about the

 

      active drug versus placebo difference.

 

                DR. GOODMAN:  Let me interject.  I don't

 

      think I am as concerned about the unblinding, but

 

      your question raises at least in my mind the

 

                                                                75

 

      possibility that in the data, is it possible that

 

      we would see other somatic symptoms, more side

 

      effects reported in those patients, who also

 

      reported suicidality than in the opposing group,

 

      was there any attempt in the data to look at

 

      whether there were any other--was any other

 

      increase of adverse experience outside the target

 

      symptoms of suicidality in those patients who

 

      reported suicidality, the reason being that if

 

      there was, that would suggest it was part of a

 

      larger behavioral syndrome that was being induced

 

      by the medication.

 

                DR. LAUGHREN:  Our analyses had to be

 

      limited by what we had in our database, and we had

 

      to design this database late last summer.  We

 

      didn't anticipate all of these questions.  As it

 

      was, the database we had was a very time-consuming

 

      process to put together.  It took a number of

 

      months to get it.

 

                They are all good questions, but we don't

 

      have all those answers, but I agree that

 

      ascertainment for suicidality was not optimal here.

 

                                                                76

 

                DR. GOODMAN:  But the question is at this

 

      point, could you go back to that same data and look

 

      to see if there is a higher rate of other adverse

 

      experiences reported in those patients who were

 

      also identified as experiencing or exhibiting

 

      suicidality.

 

                DR. LAUGHREN:  Not without designing

 

      another database and going back to the companies

 

      and waiting for a number of months, and I am not

 

      confident enough in the quality of the data we have

 

      here that that would justify that additional

 

      effort.

 

                I mean again, these are all good

 

      questions, but we are faced with making a decision

 

      at this point in time with what we have, and we are

 

      asking the committee's advice on what you think we

 

      can do now based on what we have done.

 

                DR. GOODMAN:  No, I agree with that, I

 

      understand that, but we were also asked what other

 

      advice we would give in terms of future research or

 

      studies or data that we would like to see.

 

                DR. TEMPLE:  Tom, we did look at the

 

                                                                77

 

      association with certain kinds of things, the

 

      activation syndrome, things like that, right?

 

                DR. LAUGHREN:  We included in our database

 

      two other symptoms, hostility and agitation based

 

      on the preferred terms that the companies used, and

 

      again, we haven't looked, I suspect that there is

 

      variability across different companies in what

 

      actually got subsumed under those two things.

 

                There are the only two other events, and

 

      we don't even have the timing for that.  All we

 

      have is an indication of whether or not, at some

 

      point during treatment, a patient experienced

 

      agitation or hostility.  We don't have all the

 

      other somatic kinds of things that you are alluding

 

      to.  That would mean going back and trying to

 

      create another database.

 

                DR. GOODMAN:  Dr. Temple.

 

                DR. TEMPLE:  Let me just mention one other

 

      thing that has come up briefly and that Dianne

 

      touched on, and that is inclusion of negative

 

      results in labeling.

 

                As Tom has explained at the previous

 

                                                                78

 

      meeting and now, as a general policy, we don't

 

      usually put in labeling the fact that a study

 

      hasn't worked, because we don't think that proves

 

      that it doesn't work.  It just means that that

 

      study failed.

 

                But we are actively thinking about that

 

      policy for the pediatric part, because the whole

 

      point of doing the studies was the possibility that

 

      adults and children are different, otherwise, you

 

      wouldn't even think about doing that whole program.

 

      All I can say is we are actively thinking about it.

 

                It is not an easy to thing to do, however,

 

      because what you would want to say could depend on

 

      how good you thought the study was, and then there

 

      is the conundrum of what do you do if there is one

 

      study that says yes and one study that says no.

 

      That is virtually somebody a claim, which we really

 

      wouldn't want to do if it wasn't merited.

 

                So, I am not going to suggest that this is

 

      easy, but we are reconsidering this whole thing,

 

      because the whole point of the Best Pharmaceuticals

 

      for Children Act is to find the data and see

 

                                                                79

 

      whether drugs work in children, and not putting

 

      anything in seems funny, so we are reconsidering

 

      that.

 

                DR. GOODMAN:  Dr. Perrin.

 

                DR. PERRIN:  Part of my question Dr.

 

      Chesney eloquently asked before, but I wonder if we

 

      can get access to the wording that you used for

 

      cancer drugs as perhaps a guide to us for our

 

      considerations.

 

                My other quick question, I think back to

 

      one of the FDA group is am I hearing you right that

 

      if you have a drug that has been shown to be

 

      efficacious in a particular indication, that all

 

      trials requested in the future require an arm that

 

      includes that drug?

 

                DR. TEMPLE:  I am not ready to say that

 

      one would always do that, there are other ways to

 

      try to assure quality, but in this setting, it is

 

      reasonable to assert that we need to know whether

 

      your trial was an adequate test of whether this

 

      drug worked, and the only way we know to be sure

 

      that it is an adequate test is to have an active

 

                                                                80

 

      control, and to have that active control be

 

      distinguishable from placebo.  Then, you know this

 

      is a trial capable of showing things.

 

                We have determined that our future written

 

      requests will include a requirement for a three-arm

 

      trial, because that's the only way we know to be

 

      sure that the trial is a trial that is capable of

 

      showing what the answer is, and we want to be sure

 

      we get the answer.

 

                This comes up in written requests all the

 

      time, how much assurance do you have to have and

 

      how do you gain that assurance that the trial is a

 

      useful trial, and the reason it comes up is the one

 

      that everyone has alluded to, we don't think people

 

      are deliberately trying to mess things up, but the

 

      incentives to do a really good trial are greater

 

      when you have to win.

 

                DR. PERRIN:  I am a little confused.  As a

 

      clinician, you know, typically, if I am looking at

 

      a new medication, I want to know that it is better

 

      than current therapy.  I mean all of us are really

 

      interested in that.

 

                                                                81

 

                There are a number of pediatric drug

 

      trials, not in the area of antidepressants that I

 

      am aware of, where new drugs come on the market,

 

      approved by the FDA, where there are only

 

      drug/placebo trials, and not trials comparing the

 

      new drug with currently approved FDA medications.

 

      That is where I am confused.

 

                DR. TEMPLE:  Good question.  There are two

 

      possible uses for having an active control.  One is

 

      where you want to compare the two therapies.  Now,

 

      to do that, you would need a very, very large

 

      study, because you would be interested in even

 

      modest differences.  That is not what we are

 

      talking about.

 

                We are talking about the use of the third

 

      arm to show something about trial quality.

 

      Actually, a third arm is extremely common in

 

      depression trials now, because if the trial fails

 

      to show that your drug is better than placebo,

 

      there are two possibilities.

 

                One is that your drug is no good, and the

 

      other is that the study was no good, and it is very

 

                                                                82

 

      important to somebody developing a drug to know

 

      which of those two things it is.

 

                If the trial shows that Prozac, say,

 

      works, and your drug doesn't, you get rid of the

 

      drug.  If the trials shows that neither Prozac nor

 

      your drug works, you do another study.  So, it is

 

      extremely important.  But the two purposes of the

 

      trials are quite different.

 

                To actually do a comparison and try to

 

      detect a small difference, you would need very,

 

      very large groups. That is an unusual thing for

 

      people to do, and usually, the drugs can't be

 

      distinguished.  It is very hard to do that.

 

                DR. GOODMAN:  Dr. Temple, I heard you say

 

      before, if I heard correctly, that incentives are

 

      different when you need to win.  Were you referring

 

      to the conditions of the six-month exclusivity

 

      arrangement, and if you were, if the incentives

 

      were different at that time, would you predict any

 

      difference in the design of those trials or the

 

      conduct of those trials?

 

                The reason, let me say, I think that many

 

                                                                83

 

      of us keep harping on this point, is not so much

 

      because we think that the suicidality data would

 

      have turned out differently. I think it is the

 

      absence of a benefit, the absence of efficacy that

 

      at least I am concerned about, because that is

 

      mostly what we have in assessing benefit or those

 

      trials, and we only have 3 out of 15 that are

 

      positive, so if there was something about the

 

      conditions in which those studies were designed or

 

      conducted that might have negatively impacted the

 

      outcome, I would like to know it.

 

                DR. TEMPLE:  Well, Russ and Tom need to

 

      respond, but we haven't seen anything in the design

 

      of those trials as written in protocols that makes

 

      them look any worse than any other trials.  They

 

      seem to have reasonable size, so there is nothing

 

      obvious.

 

                But, you know, this is an issue that comes

 

      up when you do so-called "non-inferiority" trials.

 

      The incentive, you know, the point of such trials

 

      show no difference between treatments, and as I

 

      have written repeatedly, that is not a good

 

                                                                84

 

      incentive to give people.

 

                It doesn't stimulate the kind of optimal

 

      behavior that you want, which is stimulated by the

 

      need to try to show a difference between

 

      treatments, and that is a problem here if you don't

 

      need to win, to gain exclusivity, and I don't

 

      disagree with the idea that you shouldn't need to

 

      win, the point is to get the data.  That is why the

 

      BPCA was done that way.

 

                On the other hand, you do want a good

 

      trial, and one way to guarantee that the trial is a

 

      good trial, however the drug comes out, is to be

 

      sure that it is capable of showing something we

 

      need to be true, namely, that Prozac seems to work.

 

                DR. KATZ:  Can I just add?  One thing you

 

      need to remember about studies done in response to

 

      written requests is that they are very time

 

      sensitive, or at least it's possible that they are

 

      time sensitive.

 

                What I mean by that is you only get

 

      exclusivity if your study reports, your supplements

 

      containing the data come in while you still have

 

                                                                85

 

      some residual patent life left or exclusivity left.

 

      So, they have to be done within a particular time

 

      frame.  In fact, the letters that we send, the

 

      written requests include a date by which the

 

      studies have to be submitted.

 

                So, in some cases, there is at least

 

      potentially motivation to do studies rapidly, so

 

      that they are done and study reports are written,

 

      and the supplement, which includes these data, are

 

      submitted in time, so that they can still get their

 

      exclusivity.

 

                So, one at least potential question that

 

      has been raised is enrollment so rapid or does it

 

      need to be so rapid into these trials that maybe

 

      not all the patients are adequately diagnosed, and

 

      maybe they have something other than depression.

 

                It is very, very difficult for us, if not

 

      impossible for us, to be able to independently

 

      corroborate diagnoses in something, in conditions

 

      like these, so we, of course, take it on faith that

 

      they got the right patients, but maybe, for

 

      example, because of time constraints, they didn't

 

                                                                86

 

      get the right patients, and that might contribute

 

      to a negative finding even if the drugs were

 

      effective in a true population.  So, that is one

 

      possibility.

 

                DR. GOODMAN:  I think that is a fair

 

      answer.  Anybody that wanted to comment

 

      specifically on that?  Dr. Marangell.

 

                DR. MARANGELL:  Are you aware, is there a

 

      greater proportion of non-academic sites in these

 

      trials?

 

                DR. MURPHY:  I don't know that we have

 

      looked at that.  I mean I know that there are

 

      definitely, in some of these studies, very, you

 

      know, academic sites that have been involved in

 

      numerous or actually well-known to us

 

      investigators.

 

                I do want to make one thing again.  One

 

      thing that every division within FDA is told, when

 

      writing their written requests, they are asked a

 

      number of questions - what is the public health

 

      benefit, what are the trials to get to that public

 

      health benefit, and you are not to take into

 

                                                                87

 

      consideration--and most of the time they don't even

 

      know because you would have to go into a lot of

 

      patent law--they don't know or are told to not pay

 

      any attention to when the patents expire or the

 

      exclusivity marking would go out, they must look at

 

      it only from what are the trials that they need to

 

      have done.

 

                Now, what is being told to you, though, is

 

      that--and we have written requests where the

 

      companies come back and say, well, that is not

 

      going to help us, because you put a date on here

 

      that it was due by 2007, and our patent expires in

 

      2005, and we have said, you know, we are sorry, we

 

      need these kind of trials.

 

                Now, would, in that situation, a company

 

      try to compress by getting more sites or, you know,

 

      whatever, would they try to do that trial in a

 

      different way?  Yes, possibly.

 

                I mean that is what we are trying to

 

      explain the balance between the way the process is

 

      set up, it is not to be driven by the time when the

 

      patents are expiring, the marketing exclusivity is

 

                                                                88

 

      expiring, the divisions are to determine what the

 

      studies are that are needed to the best of their

 

      knowledge at that time.  They are to design those

 

      studies to answer those questions.

 

                Do we try to be reasonable and say, gee,

 

      we would like a 10-year follow-up study, but we

 

      don't ask that for other--you know, we have to be

 

      reasonable within the realm of what we would

 

      normally ask for, for an approval product.

 

                Again, though, maybe we can be--we say we

 

      have to get this information because children grow

 

      and will go through a period where that might be

 

      effective.

 

                DR. GOODMAN:  Thank you, Dianne.

 

                DR. MURPHY:  So, you have to ask for

 

      additional information, you might not, for adults.

 

      I am trying to explain the process.

 

                DR. GOODMAN:  I will accept some questions

 

      out of order if they are on this specific topic.

 

                Dr. Rudorfer, I think  you had one.

 

                DR. RUDORFER:  I just wanted to follow up

 

      on Dr. Katz's comment about whether we are looking

 

                                                                89

 

      at the right patients, which was an issue we

 

      discussed some yesterday.

 

                Just one point that I want to follow up

 

      on.  It is clear that in young people who present

 

      with major depression, there is a disproportionate

 

      number who go on to develop bipolar disorder, and I

 

      think one concern that we expressed yesterday was

 

      that the trials are very inconsistent in that

 

      especially in terms of accounting for family

 

      history, it sounded as if in some trials, a subject

 

      could literally be brought to the clinic by a

 

      parent who has bipolar disorder, and yet the child

 

      could be included in the trial.

 

                I realize this question might be, as we

 

      said, a little out of the box.  I would think that

 

      if there is any way to encourage the companies to

 

      actually try to find some of these thousands of

 

      young people and see what has happened to them in

 

      the 5 or 10 years since they were in the study, it

 

      could be tremendously informative simply in seeing

 

      whose longitudinal course has played out as what we

 

      recognized in young adults as major depression, who

 

                                                                90

 

      developed bipolar disorder, who developed some

 

      other disorder, and go back and re-look at, for

 

      instance, those who after the fact are confirmed to

 

      have the diagnosis that we thought they did on

 

      inclusion.

 

                DR. GOODMAN:  Dr. Pfeffer.

 

                DR. PFEFFER:  Yes, I want to I guess

 

      continue on what Dr. Rudorfer is saying, because I

 

      think diagnosis is critical, and I think we can

 

      learn something about this that we have learned a

 

      little bit about depression in other realms, too,

 

      namely, that children are, in fact, different than

 

      adults.

 

                So, what appears to be adult depression

 

      and what appears to be childhood depression may, in

 

      fact, be quite different, so that perhaps a lack of

 

      efficacy in most of the studies tells us something

 

      about the nature of the developmental course, first

 

      of all.

 

                I agree with what you are saying about the

 

      potential for bipolar.  That is one issue that is

 

      crucial, I think, in terms of maybe the adverse

 

                                                                91

 

      response that children are having, but also if we

 

      think of the number who had some suicidal thinking,

 

      that also might be a subgroup of the children who

 

      are in these studies also.

 

                The other part that I want to mention is

 

      that when I gave that talk last meeting, I talked

 

      about the complexities about what looks like

 

      depression in children, and not only course and

 

      family history, but life event circumstances, and

 

      that has not been looked at.

 

                So, for example, children who might have

 

      been having immediate family turmoil and looked

 

      depressed, that is an issue that might have led to

 

      some resistance in response, for example.

 

                The other point I would like to make is

 

      that we hear from some of our childhood

 

      psychiatrist colleagues yesterday who advocate to

 

      not ban use of these drugs, because they do see

 

      efficacy, and it may very well be that in their

 

      practice, with very careful assessment, careful

 

      diagnosis, they are selecting the subgroup of

 

      youngsters who potentially could respond, and

 

                                                                92

 

      respond very, very well.

 

                So, I think the question of diagnosis is

 

      crucial, which means that in terms of the study

 

      design, in a way, who has the most reliability to

 

      make a diagnosis, and what kinds of questions

 

      really are being asked and what data is being

 

      collected that might help us even look at

 

      predictability of response, and I don't think we

 

      have that, such as life events, such as family

 

      history, such as perhaps other issues that we would

 

      need to come up with and understand.

 

                DR. GOODMAN:  Thank you.

 

                Dr. Gorman.

 

                DR. GORMAN:  A lot of us keep saying that

 

      children are different, and I don't think it should

 

      come to us, then, as a surprise that children may

 

      respond differently to medicines than adults do.

 

                I think I would be more concerned about

 

      the efficacy of these trials if they were all

 

      unidirectional in the sense if they had all failed

 

      or they had all succeeded. I have heard nothing

 

      from the FDA to this point that says that the

 

                                                                93

 

      playing field has been tilted in any way since one

 

      of these drugs in this class, which may not

 

      actually be a class, but it seems like it might be

 

      a class, actually works for children in the bar

 

      that the FDA sets up.

 

                So, I am now going to address my single

 

      question to the rushing hypothesis.  After Monday

 

      Night Football last night, I like the rushing

 

      hypothesis.  There is one small question I have to

 

      ask.

 

                Prozac was the first mover in this field,

 

      therefore, I assumed it came to market first, and

 

      probably then had the least time before its patent

 

      extension.  Is that a safe statement?

 

                So, it came to market first.  Did it have

 

      the smallest amount of time?  It was the first to

 

      go off patent, yes or no?

 

                DR. TEMPLE:  I believe it was the first

 

      one to go off patent by a little bit.  It is off

 

      patent now, and only, I don't know, are any of the

 

      others off patent?  So, we know it was the first

 

      off patent, which happened sort of a year ago.

 

                                                                94

 

                DR. GORMAN:  So, that would run

 

      counterintuitive to the rushing hypothesis, because

 

      Prozac had to get there first, and therefore, seems

 

      to have had the least time and would be the most

 

      likely to be rushed to get labeling.

 

                DR. TEMPLE:  Some of the trials were done

 

      before this program even started, I think, and they

 

      were done a long time ago.

 

                DR. LAUGHREN:  One of the trials was done

 

      by Emslie several years before, and the company

 

      obtained the data and submitted those data as part

 

      of that supplement.  It was done in the early '90s,

 

      though.

 

                DR. KATZ:  Right.  The studies that we

 

      asked for in the written requests don't necessarily

 

      have to be done or initiated after the written

 

      request is written.

 

                If they have a study that is very old, but

 

      that meets the criteria that we put into the

 

      written request, they can use that, so they don't

 

      have to be done specifically in response to the

 

      written request, they have to meet the criteria

 

                                                                95

 

      that we lay out, and it can have been submitted to

 

      us either before the written request.

 

                But they could have done a study many,

 

      many years in advance before we even contemplated

 

      written requests.  If they met the criteria, they

 

      can submit it in response.

 

                DR. TEMPLE:  But, also, remember it's a

 

      hypothesis.  We don't know why those trials fail.

 

      It could be that children really don't respond.  I

 

      mean we don't know the actual answer.

 

                DR. GORMAN:  Well, I would love to be in

 

      the position where I can say something nice about

 

      the pharmaceutical industry, because it sometimes

 

      seems to happen so rarely, but if Lilly did the

 

      trials before there was the potential for financial

 

      gain, because all they were doing was looking for

 

      labeling in children without the congressionally

 

      mandated reward for that particular behavior, and

 

      therefore had these studies in place, maybe the

 

      rushing hypothesis fails, but there is another

 

      hypothesis that could be generated from that.

 

                DR. LAUGHREN:  Again, in fairness, the

 

                                                                96

 

      Emslie trial was funded by NIMH.  This was not

 

      sponsored by Lilly.  They went back and obtained

 

      the data, and they did subsequently an independent

 

      trial that also succeeded.

 

                DR. GOODMAN:  Dr. Newman.

 

                DR. NEWMAN:  I think Dr. Temple did a good

 

      job of explaining why, if you have an active

 

      treatment arm, the trial is likely to be of higher

 

      quality when asked to demonstrate that difference.

 

                I wonder if another approach to motivating

 

      high quality studies would be to require that in

 

      order to get the exclusivity, that the trial be

 

      written up in a way that passes some sort of peer

 

      review and be published.

 

                That way, even published on FDA web site,

 

      that way, if the trial is sloppy and finds the drug

 

      doesn't work, those results would not be buried,

 

      they would become public and that I think would

 

      provide some motivation to do a good job.

 

                I am a little troubled.  I wrote down a

 

      quote from Dr. Murphy.  It said, "If a study is

 

      negative, we don't talk about it."  I think if

 

                                                                97

 

      that's the case, then, there is a lot less

 

      motivation to do a really good job on the study.

 

      Why not require the studies be published, be

 

      written in a way that it is of sufficient quality

 

      that they can be interpreted, and then maybe the

 

      quality would improve.

 

                DR. MURPHY:  But for peds now, we do.

 

      That is the difference.  That statement was for

 

      adults.  For pediatric studies, well, I should say

 

      it is for pediatric studies that aren't done under

 

      exclusivity, but for pediatric studies done in

 

      response to these written requests, we now are

 

      mandated to make them public whether they are

 

      approved, they are not approved, or even if they

 

      are withdrawn.

 

                DR. TEMPLE:  But you are also talking

 

      about a level of detail in the presentation

 

      sufficient for people to really get into was it a

 

      high quality study, and things like that.

 

                DR. NEWMAN:  Why not?

 

                DR. TEMPLE: it is a fairly good question.

 

      We don't believe we have authority to insist that

 

                                                                98

 

      things be published.  We get full details, we get

 

      all the data.

 

                DR. NEWMAN:  But you could peer review,

 

      you could peer review them.  You could send them

 

      out and say is this something that is publishable,

 

      and have people at FDA, who I am sure are very good

 

      at that, say no, this gets an F, you know, this is

 

      not good enough, send it back, or you don't get the

 

      exclusivity.

 

                DR. TEMPLE:  Well, our reviews, when we

 

      approve something, you get on our web site the

 

      contents of our reviews, so you get to see what we

 

      thought of all of the studies.  If we do not

 

      approve, however, we don't believe we have

 

      authority to make those data public, so you don't

 

      get to see our reviews.  That is our legal

 

      interpretation of what confidential commercial

 

      information is, and I can't rebut it or comment on

 

      it.  It's a legal determination.

 

                DR. GOODMAN:  Dr. McGough.

 

                DR. McGOUGH:  Just on that point, does the

 

      FDA now have the authority, if you wanted to, to

 

                                                                99

 

      put negative studies in the pediatric label, do you

 

      have the authority or does Congress have to do

 

      something for you to get the authority?

 

                DR. TEMPLE:  We have authority.  What I

 

      was saying before is--and we are, as I said,

 

      considering whether in the pediatric case, we

 

      should do that.  In other cases, we would, too, if

 

      we thought it was important to point out the

 

      negativity, and the negativity was a true bill.

 

                It is just the fact that if one study

 

      fails, doesn't necessarily say that something

 

      doesn't work, so we have been somewhat reluctant to

 

      just do that until it was convincing.

 

                But as Dianne said, we are actively

 

      thinking about amending that policy for the

 

      pediatric setting where the whole point of getting

 

      the studies done was to see how the drugs worked in

 

      children, for the very same things that they have

 

      been studied for in adults.

 

                It is a little different from novel use or

 

      something like that.  The BCPA calls for studies of

 

      the exact same things that have been studied in

 

                                                               100

 

      adults.

 

                DR. MURPHY:  And we are putting negative

 

      information in some of the labels already for other

 

      types of products, but because of the complexities

 

      that you have heard, it has been the policy for

 

      antidepressants for children not to do that at this

 

      point, but I think, as has been mentioned, it is

 

      being reconsidered.

 

                So, we have, and I have got all the labels

 

      here that we have done, we are putting that

 

      information in some of these labels.

 

                DR. POLLOCK:  For the new approvals.

 

                DR. MURPHY:  No.

 

                DR. TEMPLE:  For where we grant

 

      exclusivity.

 

                DR. MURPHY:  Right.  In other words, if a

 

      product comes in and doesn't work, we have put that

 

      information in some labels where we think it is

 

      very clear-cut, you know, eight more studies is not

 

      going to change this for whatever reason, and we

 

      put that in here.

 

                We have also put in information where it

 

                                                               101

 

      hasn't worked where there are safety issues

 

      involved, and we are not clear what those safety

 

      issues are, but we want to tell you about them.

 

      So, those are in the label, too, even when it

 

      wasn't approved for that indication.

 

                DR. GOODMAN:  Dr. Santana.

 

                DR. SANTANA:  I have a comment and then a

 

      question that really relates to a point that Dr.

 

      Chesney made about issues regarding the boundary of

 

      practice and FDA regulation.

 

                My comment is that there was some comment

 

      related to oncology and issues, how we deal with

 

      some prescription and safety issues in oncology,

 

      and I think we have to recognize that pediatric

 

      oncology is unique in this country and that most of

 

      the trials, even the exclusivity trials, of which I

 

      have participated in some in oncology, are really

 

      under the umbrella of research centers and academic

 

      centers. Very little pediatric oncology is done in

 

      the private practice.

 

                So, by force, you are now dealing with a

 

      group of individuals that are more specific and

 

                                                               102

 

      more geared up to looking at issues that

 

      potentially could be relevant, whereas, I think in

 

      the other pediatric arenas that we are talking

 

      about, that doesn't occur.

 

                So, I think it would be a misnomer to use

 

      pediatric oncology, maybe it should be the gold

 

      standard, but I think we need to recognize that it

 

      is kind of unique in the way it is practiced in

 

      this country.

 

                Having participated in some of the

 

      exclusivity oncology trials, I can tell you that

 

      they are at the same caliber and at the same

 

      rigorous structure as any of our other oncology

 

      trials are in the cooperative group setting, et

 

      cetera, et cetera.  So, that was just a comment to

 

      clarify the pediatric oncology issue.

 

                I want to get back to patients and

 

      practicing physicians, because we have been talking

 

      a lot about study design and how to analyze data.

 

      I want to get back to the issue of patients,

 

      parents, and practicing physicians, and this

 

      boundary of what the FDA can regulate and cannot

 

                                                               103

 

      regulate in terms of the practice of medicine.

 

                I was struck yesterday by many of the

 

      testimonies from parents and families, and

 

      actually, there was even a gentleman who showed a

 

      slide, in which his child was given the medication

 

      as a free sample.  I am not sure that all these

 

      whistles and alarms that we put in labels are

 

      really going to work unless somehow that practice

 

      stops for certain medications that we think

 

      potentially have a greater risk.

 

                I wanted the FDA to address the issue

 

      historically.  Is there any ruling that you guys

 

      can impose or potentially think about, about how

 

      these medications are given without prescriptions,

 

      that is, either free samples or in the marketing

 

      world, so you could comment on that.

 

                Secondly, does the FDA have any historical

 

      data on successful programs?  There was a mention

 

      that maybe a med guide to parents and families

 

      would be a way to address some of the safety issues

 

      and bring people to a better level of

 

      understanding.

 

                                                               104

 

                Can the FDA comment on any successful

 

      programs that they can point where this has truly

 

      worked?

 

                DR. TEMPLE:  Just on the free sample

 

      thing, my understanding, but I don't really know,

 

      was that a physician did use a free sample to, you

 

      know, like start the child out.  That is not

 

      without a prescription, it may not have been well

 

      done and may not have had adequate follow up, but I

 

      am not sure that it is the free sample that is

 

      involved, it is the lack of follow up that was

 

      described that seems like the problem.

 

                It is not easy to know how successful our

 

      various endeavors have been, and Anne Trontell may

 

      want to comment on that.  Some of them have effects

 

      that are not entirely what we wanted.  She

 

      mentioned the program on dofetilide.

 

                To start, dofetilide is a drug that is

 

      used to prevent recurrence of atrial fibrillation,

 

      but it is a drug that causes QT prolongation and

 

      Torsade de Pointes, and there is no doubt about it.

 

                The recommendation in labeling, and it is

 

                                                               105

 

      enforced by the need to give out various

 

      information requires that you come into a hospital

 

      or outpatient facility for a couple of days to see

 

      what your creatinine clearance is and to see

 

      whether you are a person who has QT prolongation to

 

      an excessive degree.

 

                Then, after that you can go out and be

 

      treated with it for long-term use in preventing

 

      atrial fibrillation.

 

                What appears to have occurred is that that

 

      is sufficiently difficult, so that people instead

 

      use sotalol, which doesn't have such a program, or

 

      quinidine, neither of which are an improvement of

 

      the situation.

 

                So, people can avoid some of these things

 

      if they are inconsistent across the drug classes,

 

      so you always worry about that.

 

                There is a very rigorous requirement for

 

      periodic measurement of liver tests with a drug

 

      called Bosentan, which is used for pulmonary

 

      hypertension, and although the drug was quite toxic

 

      when it was being developed, my most recent

 

                                                               106

 

      information is that we haven't had any fatal liver

 

      outcomes, perhaps a testimony to the fact that

 

      people are indeed following up these patients.

 

                Of course, this is a class of patients who

 

      are very sick and very closely watched.  You don't

 

      know if that is typical how we are going to do.

 

                Anne, you want to comment on some of the

 

      other programs.

 

                DR. TRONTELL:  Sure.  On the issue of

 

      sampling, first of all, I think in some instances,

 

      at the time of product approval, there have been

 

      informal agreements, but no FDA authority to

 

      restrict sampling exists to my knowledge, but there

 

      may be agreement, you know, certainly, we don't

 

      sample oncology drugs.  There are things that just

 

      don't happen.

 

                On the issue of what is a successful

 

      program, I think we struggle in the agency, because

 

      good evaluations have not been done on a standard

 

      basis.  We have the best information for those

 

      programs that are most restrictive, programs like

 

      clozapine or programs like the one for thalidomide

 

                                                               107

 

      to prevent pregnancy exposures.

 

                So, the available data to us to tell us

 

      what works tends to be only in those extreme cases

 

      where we have put, as Dr. Temple just described,

 

      for Bosentan, you know, very severe restrictions.

 

                If you are asking for specific information

 

      about medication guides, I think we have in the

 

      general literature evidence to suggest that good

 

      education certainly facilitates good behaviors, but

 

      I don't think we have any evidence yet that it

 

      guarantees that they do take place.

 

                So, if you had questions about the

 

      intermediate ones, I think for the most part, we

 

      don't have information about those specific

 

      educational programs or the reminder ones.  Not

 

      uncommonly, education is applied in the context of

 

      these very restrictive programs that I just

 

      described, and again, teasing out what the

 

      education alone does is very difficult.

 

                DR. GOODMAN:  Dr. Katz.

 

                DR. KATZ:  You are hearing the

 

      difficulties that we think we have with regard to

 

                                                               108

 

      imposing various sorts of restrictions although

 

      again, there are ways to do it although they may be

 

      very difficult to implement.

 

                But it occurs to me that it might be

 

      particular difficult in this case because the use

 

      we are contemplating in all but one case is off

 

      label, and I don't even know what the implications

 

      of that are.  Certainly, there are legal questions

 

      about what you can say and what you can restrict

 

      with regard to off-label use, and I don't think

 

      that we have thought through all the implications

 

      of that.

 

                DR. SANTANA:  So, as a follow up to that,

 

      since we last met in February and there was a

 

      recommendation to do something with the label that

 

      occurred and some warnings, has the Agency

 

      monitored the change in practice?

 

                I heard a number yesterday of 10 percent.

 

      That is prescriptions, but has that been rigorously

 

      looked at, that there was an impact of that

 

      modification that translated to something very

 

      tangible?

 

                                                               109

 

                DR. TRONTELL:  I will ask either Michael

 

      Evans or Judy Stafford from the Office of Drug

 

      Safety.  All we have really been able to monitor

 

      since the last advisory committee is volume of use,

 

      but they do have some information on how that has

 

      changed recently.

 

                DR. GOODMAN:  Ms. Griffith.

 

                MS. GRIFFITH:  I would just like to pursue

 

      this for a moment with respect to the patient and

 

      physician relationship.  When Dr. Chesney was

 

      proposing perhaps some sort of a computerized

 

      programming or education, or even with respect to

 

      these med guides, when Dr. Temple suggested that

 

      perhaps there would be, you know, a mechanism much

 

      like you have for other drugs, that the patient and

 

      practitioner would be signing a consent form

 

      outlining the risks and benefits, I want to

 

      understand the reason that you thought that that

 

      might be too great a deterrent to pursue, simply

 

      because from my perspective as patient rep and

 

      parent, it seems to me that in the course of any

 

      treatment process for any severe illness, which as

 

                                                               110

 

      we all understand depression is, you are often

 

      asked to look at the risks and to sign some

 

      statement to the effect that you understand what

 

      these risks are.

 

                You even have to do that if you get a shot

 

      of botox, not that I know, but it just strikes me

 

      you have put the parents now in the position of

 

      actually doing the risk-benefit analysis.  That is

 

      where we all are.

 

                If by providing the families with the

 

      statement that these risks are indeed serious, I

 

      think that what we heard yesterday was how little

 

      awareness there was on the part of the parents that

 

      these drugs could be lethal in certain cases.

 

                I am arguing for more information rather

 

      than less, not more restrictions, and I agree with

 

      the point that Dr. Santana made, that how often

 

      does a parent either open the box and read the

 

      information or understand it.

 

                So, if it is very clearly stated between

 

      the doctor and the patient or the parent, I think

 

      it goes a long way to satisfying the need to know

 

                                                               111

 

      for parents.

 

                DR. TEMPLE:  There are gradations of

 

      information, and we wrestle with how to do that

 

      without being an attempt to be informative, but not

 

      disruptive, so that, for example, a lot of drugs

 

      have what are called med guides.  These are patient

 

      labelings that are actually, under the law,

 

      supposed to be given out by the pharmacist.

 

                My own view is that if you don't make it

 

      part of the unit of use package, you might as well

 

      not bother, but in any case, we know that there are

 

      ways to get that information to patients either

 

      through the proper functioning of the pharmacy or

 

      by making it part of the package.

 

                An enormous additional step, which has

 

      been done in some cases, but, you know, thalidomide

 

      is a level of risk that is sort of in its own

 

      category, where there is a requirement that the

 

      patient and physician discuss all these matters.

 

      That is a very huge step, and what you might think

 

      is reasonable for thalidomide, something that is

 

      used infrequently, you might find more disruptive

 

                                                               112

 

      than you want or more difficult than you want for

 

      drugs that are much more widely used.

 

                As Russ pointed out, it is particularly

 

      tricky when the recommended use isn't even in the

 

      label.  How to write a med guide or something like

 

      that for something you are not really recommending

 

      and don't feel able to recommend yet, that may

 

      sound like a bureaucratic worry, but I think it's a

 

      serious worry.

 

                You don't want to warn people and

 

      simultaneously recommend a use that you don't think

 

      is recommendable, and any discussion like that is

 

      tantamount to recommending the use.  So, we will

 

      need to worry all of those things based on your

 

      conversation.

 

                MS. GRIFFITH:  Could I follow up?  I

 

      understand that and I understand that there are all

 

      sort of issues involved, liability on the part of

 

      the physician, but I am suggesting, from the naive

 

      perspective of the parent, I think of depression as

 

      every bit as serious as the use of thalidomide

 

      posing birth defect risks or, as Dr. Santana said,

 

                                                               113

 

      you know, the cancer example.  Parents need to be

 

      informed about those risks.

 

                I don't think that this is any different,

 

      frankly, and if it is an extraordinary measure to

 

      take, I think that it benefits both the

 

      practitioner and the patient parent.

 

                DR. TEMPLE:  For oncologic drugs, the

 

      label says you should be a properly trained

 

      oncologist.  There isn't anything in there that

 

      says what you need to discuss.  Patient med guides

 

      for oncologic drugs is by far the exception, I

 

      think because it is assumed that there always has

 

      to be such a conversation in the course of therapy.

 

                I guess what is being discussed is whether

 

      there is a common practice of having that kind of

 

      conversation in someone who is depressed, and

 

      obviously, we all think that there should be such a

 

      conversation.  The question is now to induce it and

 

      what to provide people to help them be sure they

 

      ask the right questions.

 

                DR. GOODMAN:  We have a representative

 

      from the Office of Drug Safety at the microphone. 

 

                                                               114

 

      Could you please state your name?

 

                MR. EVANS:  Michael Evans with the Office

 

      of Drug Safety.

 

                With regards to drug use, comparing the

 

      first six months of this year to the first six

 

      months of last year, the market rose with all ages

 

      about 7 percent.  Adolescents and children, in the

 

      first six months of the year, still comprised

 

      between 7 and 8 percent of that total.  So, they

 

      are still widely used in children.

 

                DR. GOODMAN:  How up to date is that data?

 

      There must be some sort of lag time, isn't there,

 

      between when the prescription--

 

                MR. EVANS:  It is according to IMS Health,

 

      and this is January through June is what we looked

 

      at.  This is outpatient prescription data, which

 

      comprises about 45 percent of all pharmacies in the

 

      country.

 

                DR. GOODMAN:  Let me make sure I

 

      understand.  You don't see any significant drop?

 

                MR. EVANS:  No.  I believe a woman

 

      mentioned yesterday that they saw a 10 percent

 

                                                               115

 

      decline.  We did not see that.

 

                DR. GOODMAN:  Dr. Irwin.

 

                DR. IRWIN:  Has the rate of increase

 

      remained the same or has it leveled off, or what is

 

      the direction?

 

                MR. EVANS:  In February, one of our

 

      colleagues, who gave drug use for 2002, that age

 

      group was still 7 to 8 percent of the total.  It is

 

      still the same this year, first six months.

 

                DR. GOODMAN:  So, there has been no great

 

      change.

 

                I will take again other questions out of

 

      order as long as they are directed to a

 

      representative from ODS.

 

                Dr. Marangell.

 

                DR. MARANGELL:  Actually, a comment

 

      directed to this.  I think it is really critical to

 

      this discussion that we keep in mind that our goal

 

      is to protect risk, but also that this is really a

 

      devastating illness, and I am not sure that I

 

      necessarily--I don't want to necessarily see

 

      prescriptions drop.  These people need to be

 

                                                               116

 

      treated.

 

                What we want to do is make sure that

 

      people are educated of what to look for early on in

 

      terms of risk for those people that are at risk,

 

      children or otherwise.  They are not necessarily

 

      the same thing .

 

                DR. GOODMAN:  Other questions for our

 

      speaker?  Dr. Gorman.

 

                DR. GORMAN:  Is the data on the level of

 

      the class or is it on the level of individual

 

      drugs?

 

                MR. EVANS:  We looked at the class as a

 

      whole and then we looked at each individual drug in

 

      the class.  That was according to IMS Health

 

      National Prescription Audit, and we also looked at

 

      the National Disease and Therapeutic Index from IMS

 

      Health, and tried to apply those percentages to

 

      outpatient projected prescriptions.

 

                Only the players changed in that age group

 

      of children 1 through 17.  Paroxetine was knocked

 

      out of the top five, but sertraline still is the

 

      market leader, followed by fluoxetine.

 

                                                               117

 

                DR. GORMAN:  So, the information, there

 

      seems to at this point only be one drug that is

 

      efficacious in this age range, moved it up the

 

      ladder, but didn't make it number one?

 

                MR. EVANS:  Not necessarily.  This is what

 

      we observed when we were just looking at drug use

 

      in prescriptions outpatient, and the National

 

      Disease and Therapeutic Index is an office-based

 

      survey where a drug is mentioned during that survey

 

      and linked to a diagnosis.

 

                DR. GOODMAN:  Can you differentiate

 

      between the prescriber classes, whether it is a

 

      primary care physician versus psychiatrist?

 

                MR. EVANS:  We did look at specialty in

 

      MBA-Plus.  Psychiatry was still about 65 percent of

 

      the specialty, pediatrics, somewhere between 15, 20

 

      percent still.

 

                DR. GOODMAN:  Dr. Fant.

 

                DR. FANT:  Could you comment on the

 

      indications for the prescription, was it all

 

      depression or other off-label--

 

                MR. EVANS:  We looked at mood disorders,

 

                                                               118

 

      anxiety disorders, ADD, and other disorders.  In

 

      age group 12 to 17, it still appears there is not

 

      really any change.  It is still mood disorders,

 

      which includes major depression, is still

 

      two-thirds of the indications.

 

                It looks like in the 1 to 11-year age

 

      group, perhaps more shift to the ADD.

 

                DR. GOODMAN:  Dr. Pollock.

 

                DR. POLLOCK:  I heard rather consistently

 

      yesterday a lot of concern about the

 

      direct-to-consumer advertising and the role that

 

      that has played in this, and it may not be the

 

      purview of this committee, but I am asking if we

 

      can address this aspect and how that plays with the

 

      implications of labeling, that if we do put, as was

 

      suggested, a specific negative label in terms of

 

      the indications and certainly as a warning, let

 

      alone a black box warning, that the amplitude of

 

      these warnings are heard.

 

                I mean it is almost a penalty then for the

 

      intense direct-to-consumer advertising, which does

 

      play, as I understand it, a huge role in driving

 

                                                               119

 

      sales for some of these antidepressants.

 

                I just wondered if you could give us some

 

      indication, I mean is there a direct policy with

 

      D.D. Mack how these various gradations get

 

      translated into the few seconds that go on the tail

 

      end of a commercial.

 

                DR. TEMPLE:  They are certainly supposed

 

      to.  The presence of a strong warning or box

 

      warning should be reflected right in the major

 

      statements that are made.  The direct-to-consumer

 

      comes in two flavors, written and TV.

 

                In TV, you can't give as much information

 

      easily, but it has to be available readily.  You

 

      can argue about whether people make use of that

 

      availability.  But the major statement would have

 

      to reflect the balance between those two things.

 

                You know, I am sure people have views

 

      about whether that is done successfully or not.  If

 

      it is written, then, the written statements have to

 

      show that balance.  Any box warning has to be

 

      reflected in it.

 

                So, yes, it is supposed to reflect the

 

                                                               120

 

      balance of information that is in the labeling, so

 

      if the labeling changes, the direct-to-consumer

 

      advertising should change.

 

                DR. GOODMAN:  Dr. Perrin.

 

                DR. PERRIN:  Yes.  Back to the ODS person.

 

      A number of the anecdotes yesterday suggested that

 

      people were put on antidepressants quite off label

 

      and probably not for major depression, but rather

 

      for minor depression and acute depression.

 

                You said that you have the evidence on

 

      mood disorders that includes major depression.  Can

 

      that be disaggregated at all into other non-MDD

 

      forms of mood disorders?

 

                MR. EVANS:  We could look at that.  We

 

      didn't, we lumped them together just for a top-line

 

      statement at this time, because we wanted the focus

 

      to be more on suicidality than drug use.

 

                DR. GOODMAN:  Ms. Griffith.

 

                MS. GRIFFITH:  I wanted to know, since the

 

      data you got was January to June, and the Advisory

 

      didn't come out until late March, is it possible to

 

      look at the data that you got April to June to see

 

                                                               121

 

      if there is a decline?

 

                MR. EVANS:  We did look at it monthly in

 

      those months, and there was not any decline.  I

 

      mean it wasn't a change.

 

                DR. GOODMAN:  Are these new prescriptions?

 

                MR. EVANS:  These were total

 

      prescriptions, new and refill.

 

                DR. GOODMAN:  Did you separate out by new

 

      prescriptions in terms of the monthly rate?

 

                MR. EVANS:  We can, and we did, and we did

 

      not see much of a decline in those, as well.

 

                DR. GOODMAN:  Dr. Chesney.

 

                DR. CHESNEY:  On the surface, this looks

 

      not bad in the sense that 65 percent are being

 

      written by psychiatrists, but although I am not

 

      here as a patient representative, I do have a

 

      daughter who has been on these medications, and I

 

      know for a fact that most often psychiatrists do

 

      not prescribe these medications.

 

                My image is that at the end of the day,

 

      they take a whole packet of prescriptions--and I

 

      will be interested to have the psychiatrists

 

                                                               122

 

      respond to this--a whole packet of prescriptions

 

      that have been written by social workers,

 

      pharmacists, psychologists, and sign their name.

 

                So, I think when we are talking about

 

      educating primary care providers, looking at this,

 

      I am reassured, but I know that this does not

 

      represent who is actually writing the

 

      prescriptions.

 

                MR. EVANS:  Yes, this is a limitation of

 

      the data, too, the data is only as good as what the

 

      pharmacist inputs at the computer, and, you know,

 

      if that specialty is on there, hopefully, they will

 

      put that on there.

 

                DR. CHESNEY:  I am sure they don't, but I

 

      think this is very important in the educational

 

      issue, because the people who are prescribing this,

 

      on the whole, are not child psychiatrists, and they

 

      are family practitioners, they are ER physicians,

 

      they are nurse practitioners, they are pharmacists.

 

                I mean I was appalled at what happened

 

      when we visited one of these pharmacists, but no

 

      disrespect to pharmacists, but this is very much

 

                                                               123

 

      happening out there.

 

                DR. GOODMAN:  One last question for ODS

 

      representative from Dr. Wang.

 

                DR. WANG:  I was curious, has anyone

 

      studied what happened after the British

 

      contraindicated these in children, just to get a

 

      sense of what the impact of a labeling change, such

 

      as that, might be?

 

                MR. EVANS:  In February, they looked

 

      through 2002, the market between 2002 and 2003

 

      group, 15 percent with no change really in the

 

      adolescent and children population.  It was still

 

      around 78 percent, so I don't think there was a

 

      change much in this country.

 

                DR. WANG:  But you don't know of any data

 

      in the British--

 

                MR. EVANS:  We didn't look at that.

 

                DR. GOODMAN:  Thank you very much.  You

 

      may step down.

 

                We have six more presenters.  I am not

 

      taking any more, that's it.

 

                Dr. Leslie, do you remember your question?

 

                                                               124

 

                DR. LESLIE:  My question goes way back and

 

      is for the FDA.  I think reading through the

 

      materials that we received from the public, two of

 

      the major concerns about the data that was coming

 

      in were suicidality, et cetera, being captured

 

      under other labels, such as emotional ability, and

 

      then also the issue about dropouts were people

 

      dropping out of either the placebo or the drug

 

      groups, that were having the kinds of adverse

 

      events that were of interest to us, and then not

 

      being counted in the data.

 

                So, I had two questions.  One was do you

 

      feel confident that the data you have received has

 

      addressed those two issues for the analyses that we

 

      looked at yesterday, and the second was what steps

 

      could you potentially take to address those

 

      drawbacks that were raised by the public in the

 

      written requests that proceed from here on out.

 

                DR. LAUGHREN:  I can respond to the first

 

      part of that.  In terms of the data that we

 

      received, if you recall, we issued letters to

 

      companies in July of last year, which specified a

 

                                                               125

 

      very clear research strategy for looking for

 

      adverse events that might be related to

 

      suicidality.

 

                It included both preferred terms and

 

      verbatim terms.  All these data are electronic, so

 

      it was a string search to look for events that

 

      might be possibly related to suicidality.  In

 

      addition to that, we asked companies to look at all

 

      their serious adverse event narratives, any event

 

      that had been classified as a serious adverse

 

      event, they would have to look at and make a

 

      decision whether or not that might represent

 

      suicidality.

 

                Then, later in the year, we issued

 

      additional requests to basically ask them to give

 

      us all the serious adverse event narratives, so

 

      that we could have Columbia themselves look at

 

      those data, and also, all accidental injuries and

 

      accidental overdoses to try and broaden the search,

 

      to make sure that we could capture everything that

 

      might be related.

 

                Now, it is true, despite all of that, it

 

                                                               126

 

      is possible that certain events that didn't rise to

 

      the level of being a series adverse event might

 

      have been captured under some other either verbatim

 

      term or preferred term.

 

                The other question is whether or not the

 

      narratives that we received fully reflected the

 

      case report forms.  The narratives are created by

 

      the companies.  To try and address that, we have

 

      sort of a second level of this contract with

 

      Columbia that is ongoing right now.

 

                We have done a 20 percent sampling of the

 

      case report forms for the narratives we have, to

 

      have them check the narratives against the case

 

      report forms basically to see whether or not they

 

      fully reflected, the narratives fully reflected

 

      what was in the case report form.

 

                In addition to that, we have asked for the

 

      dictionaries.  The dictionaries, basically,

 

      companies, when the code data, they subsume them

 

      under preferred terms, and once they do that, that

 

      creates basically, a dictionary.

 

                So, we have asked for the dictionaries

 

                                                               127

 

      from all these sponsors.  Columbia is currently

 

      looking at those dictionaries to see if there are

 

      any other additional adverse event terms that might

 

      be of interest to look at, again to answer that

 

      question whether or not all relevant events have

 

      been captured.

 

                That is a very tedious, time-consuming

 

      process, but it is ongoing right now.

 

                Dropouts, Dr. Hammad addressed that

 

      yesterday.  We did look at dropouts, and as he

 

      suggested, it is true, many patients were dropping

 

      out for these events.  In a sense, it was almost a

 

      surrogate for that endpoint.

 

                DR. GOODMAN:  Dr. Posner, did you have a

 

      comment?

 

                DR. POSNER:  I just wanted to say that, in

 

      addition, because we asked for all of the

 

      accidental injuries, and that would be the most

 

      likely place, that all of these events involved

 

      some type of injury or another, that you would find

 

      events that were missed, so we can feel reasonably

 

      confident that this body of data represents

 

                                                               128

 

      everything we would want to look for, but we are

 

      doing these additional steps, as well.

 

                DR. GOODMAN:  Dr. O'Fallon.

 

                DR. O'FALLON:  Yes, this sort of follows

 

      up.  We are back to what I am concerned about, the

 

      people who came here, they are worried about the

 

      side effects, the toxicity here.  Right from the

 

      beginning, when you told us back in February about

 

      this study, I was worried about what wasn't

 

      recorded in the drug companies' records, for

 

      whatever reason.

 

                I think that is still, no matter what we

 

      do going forward, we have got to address the issues

 

      there.  So, what I am wondering about, I would like

 

      to propose, and you shoot at and tell me that these

 

      things are not feasible, but it seems to me what we

 

      really need are somehow a standardized suicide

 

      monitoring procedure or whatever for future studies

 

      in mental illness, any kind of a drug that is

 

      targeted toward the mind, we should be looking for

 

      this type of thing, the suicidality side effect.

 

                Then, I think we are going to have to have

 

                                                               129

 

      some sort of standardized suicide coding.  They

 

      have done it in adverse events, not great, but it

 

      could be done better for suicide coding because of

 

      the work that has been done here.

 

                I think this has been a wonderful outcome

 

      in terms of the coding issues.

 

                Now, here is one that is going to kill

 

      everybody, but you can make suicidality a goal, a

 

      primary goal in, say, mental illness or maybe

 

      depression more specifically, where you really

 

      think that this side effect or toxicity, this

 

      adverse event is also a symptom of the disease.

 

                In cancer, they have had to struggle with

 

      the issue of distinguishing side effects from

 

      symptoms of the disease for decades, some way of

 

      going after that.

 

                Just one more comment.  This is a comment.

 

      I believe that there was a 40 percent--in the stuff

 

      I saw before I came out here--I think I saw 40

 

      percent placebo effect in TADS, the TADS study.

 

                If that is true, this is a major issue.

 

      That is one of the reasons why we really do need to

 

                                                               130

 

      have placebo arm in these different studies,

 

      because if 40 percent of this population will have

 

      a beneficial effect due to sugar pills, to try to

 

      tease out true effectiveness of these medications

 

      given their severe side effects, it is very

 

      important that we have a placebo arm even going

 

      forward.

 

                I know that you are not thinking of it,

 

      but I think some of the people in the room are

 

      wondering why we have to go with sugar pills.

 

                DR. LAUGHREN:  Let me comment on the last

 

      point first.  We clearly agree with you about

 

      placebo, but it is not just the act of giving a

 

      pill.  In all of these trials, there is a lot that

 

      happens that results in improvement.

 

                DR. O'FALLON:  Yes, I know that.

 

                DR. LAUGHREN:  There is a lot of

 

      attention, the patients have a lot of interaction

 

      with staff.  That is really the placebo effect.

 

                But the other point you are making, I

 

      completely agree that ascertainment is ultimately

 

      the issue.  If you don't collect the information,

 

                                                               131

 

      it doesn't make any difference how carefully you

 

      search the database, if it wasn't collected, it's

 

      not there, so ascertainment is key.

 

                Again, that is one of the things that we

 

      hope to get out of this effort with Columbia is a

 

      better guidance document for future trials to make

 

      sure that suicidality is properly ascertained, but

 

      it is an evolving thing in the field.  I mean there

 

      is not at this point in time an optimal way of

 

      doing that, so we hope to get an instrument that we

 

      can apply for future trials.

 

                Again, I agree with you that coding of

 

      data needs to be standardized, and again that is

 

      one of the things that we expect to come out of

 

      this.

 

                DR. POSNER:  Could I just add to that?  We

 

      are very committed to addressing the question that

 

      you are referring to.

 

                DR. GOODMAN:  Would you bring the

 

      microphone closer.

 

                DR. POSNER:  I said we are very committed

 

      to addressing this issue in terms of suicidality

 

                                                               132

 

      adverse event monitoring, and Dr. Laughren

 

      mentioned guidelines that we are going to write and

 

      measures that we actually have developed that we

 

      can implement in all trials, that will help us

 

      collect the right data and then be able to use

 

      these consistent definitions to classify events, so

 

      we can make sense across all of these trials.

 

                What is important to note is that we are

 

      working on a National Institute of Mental Health

 

      study called TASA, Treatment of Adolescent Suicide

 

      Attempters, which is very focus on this issue of

 

      adverse event monitoring, and it is wonderful

 

      because it is helping us inform the process, so we

 

      have developed very, very rigorous standards of how

 

      we ask these questions, what measures we use, and

 

      how to do it consistently, and that will help

 

      inform the guidelines and the measures that

 

      industry and everybody else can use.

 

                So, we have made a lot of progress in

 

      that, I think.

 

                DR. GOODMAN:  Dr. Temple.

 

                DR. TEMPLE:  I just want to follow up on

 

                                                               133

 

      the last discussion.  It seems to me there are two,

 

      somewhat separate things, and I would be interested

 

      in people's views.

 

                One is to make the periodic routine

 

      question better than it is.  There is a suicide

 

      item on the score, but that didn't show anything.

 

      Maybe that will never show anything because when it

 

      happens, it happens abruptly and you don't happen

 

      to pick it up at the two-week period, but it does

 

      seem as if a better questionnaire on that question,

 

      done routinely, might be useful.

 

                The second part of it is how to

 

      characterize events, what questions to ask about

 

      those, what to write down.  Is that what you are

 

      thinking, they are two somewhat different things?

 

                DR. LAUGHREN:  I agree, they are two

 

      separate things.  There is the suicide item that is

 

      part of every one of these instruments and sort of

 

      standardizing how that routine information is

 

      elicited, but then when an event occurs, you have

 

      to ensure that the appropriate questions are asked

 

      to flesh out that situation, so that someone down

 

                                                               134

 

      the road who is looking at the data is able to make

 

      sense of it.

 

                DR. O'FALLON:  But I would like to point

 

      out that the monitoring procedures, especially for,

 

      say, the first two weeks or something like  this,

 

      should include a real collaboration with the

 

      children and their caregivers, their parents,

 

      whoever they are living with, to be on the watch

 

      for those and to report them immediately, and that

 

      those things would be part of the data.

 

                DR. LAUGHREN:  Let me just respond to that

 

      quickly.  Basically, you are switching gears to a

 

      clinical setting, I think, other than a clinical

 

      trial.

 

                DR. O'FALLON:  You guys can write the

 

      regulations for the clinical trial, right?

 

                DR. LAUGHREN:  Right, but obviously, the

 

      points that you are making apply to clinical

 

      practice, as well.

 

                DR. O'FALLON:  Yes, but they would apply I

 

      would say in the clinical trial, because I think

 

      that you are not possibly getting all your

 

                                                               135

 

      information.  If you don't come in for two more

 

      weeks, people forget that they were scared 10 days

 

      ago.

 

                DR. LAUGHREN:  Absolutely, I agree.

 

                DR. POSNER:  I just wanted to add that we

 

      are also working with the CDC just on this

 

      question, what are the right one or two questions

 

      that need to be asked in any trial or clinical

 

      setting to get this information to be able to

 

      classify it appropriately, which is exactly what we

 

      are talking about, and it is not necessarily the

 

      best questions on the measures that were used in

 

      this trials, but that is exactly the pertinent

 

      point in clinical setting or in research settings

 

      with the increased monitoring that you are

 

      referring to.

 

                DR. GOODMAN:  I am going to need to wrap

 

      up the remaining questions in the next five

 

      minutes.

 

                Dr. Irwin.

 

                DR. IRWIN:  The question I wanted to ask

 

      specifically was related to the one that is on the

 

                                                               136

 

      table right now.  Yesterday, we heard from several

 

      families and individuals about really homicidal

 

      behavior and more violent behavior outwardly

 

      directed, not internally directed.

 

                Of concern to me is that the focus has

 

      been so much on suicide, but what I wanted to know

 

      is what kind of monitoring or what kind of tools

 

      are in place to really measure that phenomenon in

 

      these trials, because it seems to me that we don't

 

      have any data that has been shown to us at least on

 

      adverse experience or events with the clinical

 

      trials.

 

                DR. LAUGHREN:  Our focus here clearly has

 

      been on suicidality, and not on hostility and

 

      violence.  There was a lot less of that in these

 

      trials than we had suicidality, and we have not

 

      come to grips with that yet, but it is a whole

 

      other area that needs to be fleshed out and

 

      developed in the same way that suicidality has been

 

      fleshed out because again we have included in our

 

      database information on whether or not these

 

      individual patients at some time during the course

 

                                                               137

 

      of treatment were coded as having hostility or

 

      agitation as a preferred term.

 

                If you go back and look at what got

 

      subsumed under that, I am sure it is going to be

 

      quite different depending on different sponsors,

 

      and it really requires a parallel development to

 

      try and understand what that means.

 

                Again, all the things we have been talking

 

      about for suicidality apply to that domain, you

 

      know, how do you ascertain for it, what kind of

 

      questions do you ask to flesh it out, it is a real

 

      problem.

 

                DR. GOODMAN:  By the way, the placebo

 

      response rate from the TADS trial is 35 percent.

 

      Looking at the paper again, I see 35 percent.

 

                DR. O'FALLON:  Okay.

 

                DR. NEWMAN:  Just to clarify, that is much

 

      or very much improved in the TADS trial.

 

                DR. GOODMAN:  I don't think that one is

 

      based on the CDRS, right, that is what you are

 

      saying, it is based on the CGI?

 

                DR. NEWMAN:  The dichotomous outcome was

 

                                                               138

 

      were they much or very much improved, so if you

 

      said just improved, reasonably, it would have been

 

      a lot more.

 

                DR. GOODMAN:  But that is the standard, I

 

      mean it has to be much or very much improved to be

 

      a responder.  That is pretty much across all

 

      clinical trials.

 

                Dr. Pine, please.

 

                DR. PINE:  I want to return to a point

 

      that was raised by Dr. Goodman and just call the

 

      committee's attention to a couple things that he

 

      said and then also raised a couple other issue

 

      relevant to the discussion about 10 or 15 minutes

 

      ago with FDA.

 

                That is the issue of both how perplexing,

 

      but also how important it is to think very

 

      carefully about the efficacy data and the

 

      difference between the data for fluoxetine, on the

 

      one hand, and all the other antidepressants, on the

 

      other hand, and how do we understand that.

 

                Number one, just to underline that I agree

 

      that the importance of that point cannot be

 

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      overstated.  I guess there is a couple of issues

 

      that were not discussed 10 or so minutes ago in

 

      sufficient detail, and really two points to raise.

 

                One is that I do appreciate from a

 

      regulatory standpoint that it is very difficult to

 

      specify exactly how one is to do an appropriate

 

      study.  We talked about a lot of the details that

 

      we don't need to go over again except one thing was

 

      not discussed, and that was a discussion of the

 

      level of rigor that goes into both the training of

 

      the investigators who are going to ascertain the

 

      samples and document the diagnosis, on the one

 

      hand, but then also follow the response of the

 

      patients throughout the trial.

 

                Then, I think the last thing to say about

 

      that specific point is that when we look at the

 

      data that have been published, and probably the

 

      most extensive data are from the sertraline trial

 

      as opposed to the TADS trial, with the sertraline

 

      trial being a pharmaceutical-sponsored study that

 

      appeared in JAMA, and the TADS trial being an

 

      NIH-sponsored trial that was also published in JAMA.

 

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                There are some fairly clear signs that the

 

      manner in which investigators were trained, that

 

      the criteria for enrolling patients for the process

 

      of evaluating the response as it was manifest

 

      throughout the trial was quite different in those

 

      two studies.

 

                Again, when we come to the issue of how

 

      important it is to compare the data for fluoxetine

 

      and the data for the other agents, I think we need

 

      to acknowledge that there are already signs in the

 

      data that have been published in the reports that

 

      have appeared in peer review, that the quality of

 

      the studies appears to be different.

 

                I think it is also important to note that

 

      if we were to look at the efficacy data by industry

 

      sponsor versus federally funded, there have been,

 

      to the best that I can recall right off the top of

 

      my head, two federally funded SSRI trials, both are

 

      positive.

 

                So, we are 2 out of 2 on that score,

 

      whereas, if we look at all the others, we are

 

      basically 1 out of 13 or 1 out of 14.

 

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                DR. GOODMAN:  Those two are both in

 

      fluoxetine, isn't that correct?

 

                DR. PINE:  That's true, so, you know, we

 

      have a confound between federally sponsored and the

 

      compound, but those are the data that we do have,

 

      and I think given the issues that I just discussed,

 

      you know, we are going to be very hard pressed to

 

      say this is a funding or design feature issue,

 

      which it might be, or that this is a medication

 

      issue, which again it might be.

 

                DR. GOODMAN:  I want to make sure I am

 

      clear on the source of the fluoxetine data for the