FOOD AND DRUG ADMINISTRATION

	CENTER FOR DRUG EVALUATION AND RESEARCH

	PSYCHOPHARMACOLOGIC DRUGS ADVISORY COMMITTEE

	8:09 a.m.

	Wednesday, November 3, 1999

	Salons A-C
	Hilton Hotel
	620 Perry Parkway
	Gaithersburg, Maryland

	ATTENDEES

COMMITTEE MEMBERS:

CAROLE A. TAMMINGA, M.D.
Professor, Department of Psychiatry
University of Maryland at Baltimore
Maryland Psychiatric Research Center
Spring Grove Hospital, White Building
Baltimore, Maryland  21228

SANDRA TITUS, PH.D.
Executive Secretary
Food and Drug Administration
Center for Drug Evaluation and Research
HFD-021
5630 Fishers Lane
Rockville, Maryland  20857

EDWIN H. COOK, JR., M.D.
Director, Laboratory of Developmental Neuroscience
Department of Psychiatry, MC3077
University of Chicago
5841 South Maryland Avenue
Chicago, Illinois  60637

ROBERTO A. DOMINGUEZ, M.D.
Professor of Psychiatry
Department of Psychiatry
University of Miami, School of Medicine
1611 N.W. 12th Avenue
Miami, Florida  33136

ABBY J. FYER, M.D.
Anxiety Disorders Clinic
New York State Psychiatric Institute
College of Physicians and Surgeons
Columbia University
722 W. 168th Street, Unit 82
New York, New York  10032

BARBARA GELLER, M.D.
Professor of Psychiatry
Washington University School of Medicine
4940 Children's Place
St. Louis, Missouri

	ATTENDEES  (Continued)

COMMITTEE MEMBERS:  (Continued)

ROBERT M. HAMER, PH.D.
Associate Professor
Department of Psychiatry
R.W. Johnson Medical School, D-331 UBHC
University of Medicine & Dentistry of New Jersey
Piscataway, New Jersey  08854

ANDREW WINOKUR, M.D., PH.D.
Director of Psychopharmacology
Department of Psychiatry, MG1410
University of Connecticut Health Center
10 Talcott Notch Road
Farmington, Connecticut  06032

COMMITTEE CONSULTANTS:

MARY ALTEMUS, M.D.
Weill Medical College
Cornell University
1300 York Avenue
New York, New York  10021

BARBARA PARRY, M.D.
Department of Psychiatry
University of California, San Diego
9500 Gilman Drive
LaJolla, California  92093-0804

SUSAN THYS-JACOBS, M.D.
St. Luke's Roosevelt Hospital Center
425 W. 59th, Suite 9C
New York, New York  10019

	ATTENDEES  (Continued)

FOOD AND DRUG ADMINISTRATION STAFF:

RICHARD CHEN, PH.D.
RUSSELL KATZ, M.D.
THOMAS LAUGHREN, M.D.
SUSAN MOLCHAN, M.D.
ROBERT TEMPLE, M.D.

ON BEHALF OF ELI LILLY AND COMPANY:

GREGORY T. BROPHY, PH.D.
EILEEN BROWN, PH.D.
JEAN ENDICOTT, PH.D.
RAJINDER JUDGE, M.D.
CATHY SHULER, M.S.
MEIR STEINER, M.D.
GARY TOLLEFSON, M.D.

ALSO PRESENT:

SHERRY A. MARTS, PH.D.

	C O N T E N T S

	NDA 18-936(S), Prozac (fluoxetine hydrochloride)
	ELI LILLY AND COMPANY
	Indicated for the Treatment of
	Premenstrual Dysphoric Disorder

AGENDA ITEM	PAGE

CONFLICT OF INTEREST STATEMENT
  by Dr. Sandra Titus	7

WELCOME
  by Dr. Russell Katz	9

FDA OVERVIEW OF ISSUES
  by Dr. Thomas Laughren	10

ELI LILLY AND COMPANY PRESENTATION
  Introduction - by Dr. Gregory T. Brophy	15

  Overview of PMDD - by Dr. Jean Endicott	17

  Efficacy and Safety of Fluoxetine in PMDD -
    by Dr. Rajinder Judge	31

QUESTIONS FROM THE COMMITTEE	70

OPEN PUBLIC HEARING PRESENTATION
  by Dr. Sherry A. Marts	129

COMMITTEE DISCUSSION AND VOTE	134

	P R O C E E D I N G S
	(8:09 a.m.)
		DR. TAMMINGA:  I'd like to call this meeting to order.  This is a meeting of the Psychopharmacologic Drugs Advisory Committee, and we've gathered to discuss an application, fluoxetine hydrochloride for the treatment of premenstrual dysphoric disorder.
		First, I'd like to have everybody at the table go around and introduce themselves so that the committee can refresh our memory with each other.  Dr. Dominguez, do you want to start?  I should remind people to talk directly into the microphone.
		DR. DOMINGUEZ:  My name is Roberto Dominguez from the University of Miami.  I'm Professor of Psychiatry.
		DR. ALTEMUS:  I'm Margaret Altemus.  I'm a psychiatrist at Cornell Medical College. 
		DR. HAMER:  I'm Robert Hamer.  I'm a statistician at Robert Wood Johnson Medical School.
		DR. GELLER:  Barbara Geller.  I'm a child psychiatrist, Washington University in St. Louis.
		DR. THYS-JACOBS:  I'm Susan Thys-Jacobs.  I'm the Director of the Metabolic Bone Center, St. Luke's Roosevelt Hospital and Columbia University, New York.
		DR. COOK:  Ed Cook, child psychiatrist, University of Chicago.
		DR. PARRY:  Barbara Parry, Professor of Psychiatry, University of California, San Diego.
		DR. TAMMINGA:  I'm Carole Tamminga.  I'm a professor in the Department of Psychiatry at the University of Maryland. 
		DR. TITUS:  I'm Sandy Titus.  I'm with the FDA, the Advisors and Consultants Staff.
		DR. WINOKUR:  Andy Winokur.  I'm professor in the Department of Psychiatry at the University of Connecticut Health Center.
		DR. FYER:  Abby Fyer, psychiatrist at Columbia University in New York.
		DR. CHEN:  Richard Chen, statistical reviewer, FDA.
		DR. MOLCHAN:  Susan Molchan, medical reviewer, FDA. 
		DR. LAUGHREN:  Tom Laughren, team leader for Psychopharm at FDA.
		DR. KATZ:  Russ Katz, Director of the Division of Neuropharm, FDA.
		DR. TAMMINGA:  We're waiting for our consumer representative, Gaurdia Banister. 
		Sandra?
		DR. TITUS:  I'm going to read the conflict of interest statement regarding this meeting.
		The following announcement addresses the issue of conflict of interest with regard to this meeting and is made a part of the record to preclude even the appearance of such at this meeting.
		Based on the submitted agenda and the information provided by the participants, the agency has determined that all reported interests in firms regulated by the Center for Drug Evaluation and Research present no potential for a conflict of interest at this meeting with the following exceptions.
		A waiver has been granted to Dr. Robert Hamer.  A copy of this waiver statement may be obtained by submitting a written request to FDA's Freedom of Information Office located in room 12-A30 of the Parklawn Building. 
		In addition, we would like to disclose for the record that Drs. Andrew Winokur and Carole Tamminga have unrelated interests in Eli Lilly which do not constitute financial interests within the meaning of the 18 U.S.C. 208(a) rule, but which could create the appearance of a conflict.  The agency has determined, notwithstanding these interests, that the interests of the government in their participation outweighs the concern that the integrity of the agency's programs and operations may be questioned.
		In the event that the discussions involve any other products or firms not already on the agenda for which an FDA participant has a financial interest, the participants are aware of the need to exclude themselves from such involvement, and their exclusion will be noted for the record. 
		With respect to all other participants, we ask in the interest fairness that they address any current or previous financial involvement with any firm whose products they may wish to comment upon.
		DR. TAMMINGA:  Dr. Katz is the Director of the Neuropharmacological Drug Products Division.
		DR. KATZ:  Thank you.  I'll just be very, very brief.  I just really want to extend my personal welcome to the committee and thanks for the work you've done prior to the meeting and for the work you're going to do today. 
		I particularly want to extend a welcome and thanks to our three invited consultant experts, Dr. Altemus, Dr. Thys-Jacobs, and Dr. Parry, who have been gracious enough to come and help us out with their expertise. 
		Once again, you know we have asked you here to advise us on an application for a drug to treat an indication for which there are no approved treatments.  So, the application presents some generic problems about how to study this indication as well as, we think, interesting data-specific and application-specific questions.  
		So, I really just want to say thanks for coming.  We look forward to an interesting discussion.  I'm sure it will be, and with that, I'll turn it back to Dr. Tamminga.
		DR. TAMMINGA:  Thanks, Dr. Katz.
		Dr. Laughren will begin now with the FDA overview of the issues.
		DR. LAUGHREN:  Good morning.  I'd also like to welcome the committee back here. 
		As Dr. Katz mentioned, we're going to be focusing today on this application for fluoxetine in the disorder of premenstrual dysphoric disorder, but as Dr. Katz mentioned, given that there are no regulatory precedents for this indication, we would like to have some general discussion about this entity as an indication.  Following that, we will have some specific questions about this application that we'd like to have discussed, and finally, as always, at the end of the day, we'll want you to vote on specific questions of safety and effectiveness for this application.
		Now, whenever we consider a new indication, we like that indication to have some acceptance in community.  We like it to be reasonably well-defined, and we like there to be some reasonably well-accepted diagnostic criteria. 
		Now, PMDD of course is mentioned in DSM-IV, but one potential issue for discussion is the fact that rather than being in the main body of DSM-IV, it's in an appendix.  So, we probably ought to have some discussion of what the relevance of that is.
		Secondly, as defined, PMDD has a lot of affective features, and so another question that naturally comes up is whether or not this is distinct from other disorders that are characterized by affective symptoms, such as, for example, major depressive disorder.
		A third question that comes up is what is the relationship of PMDD to the broader category of PMS.  Some have suggested that this is a severe subtype of PMS, and I think that merits some discussion.
		Now, one issue which is really not the focus of today's meeting, but it would be useful to have some discussion on, is this question of whether or not this broader category, PMS, is a candidate for a new indication.  The reason I ask that is that, as you are well aware, there are many companies who are interested in looking at this category, and so even if you were to accept PMDD as a reasonable candidate for a new indication, one question is whether or not this broader category of PMS would be a candidate for an indication.
		Next I want to focus on some specific questions that we'd like to have addressed with regard to this application.  One issue has to do with the fact that the focus in these studies supporting this claim was focused primarily on affective symptoms as part of this larger syndrome.  For example, in study 19, the visual analog scale, although it included 7 items, the focus was on the 3 mood items, and similarly for study 22, a 16-item visual analog scale, there was a focus on the mood-4.  So, one question is whether or not it's appropriate to focus on that subset of a larger scale.  In general, the issue is whether or not one should focus on a subscale when one has an instrument that's focused on a broader syndrome.
		Ordinarily in psychopharm, for example, in depression or schizophrenia, in choosing a primary endpoint, one would focus on the total scale, such as the HAMD or the PANSS or the BPARUS.  So, that's another question, whether or not these should be the primary outcomes in these trials.
		Again, if one would accept those as primary endpoints in those trials, what relevance, if any, would that have for the way the claim should be stated?  For example, should the focus be rather on the total syndrome, should it be on the affective symptoms of PMDD?
		Now, another issue that comes up is the manner of dosing.  In this program, of course, with fluoxetine, the dosing was continuous throughout the cycle.  I'm sure you're aware of reports in the literature for other SSRIs where, rather than continuous dosing, dosing was during the luteal phase and, at least from those reports, appeared to show some benefit.  So, the question is, what is the relevance from a regulatory standpoint of these different possible dosing strategies?  Would that have any relevance for us in making a regulatory judgment about this application?
		Another feature of this program was the exclusion of patients who were taking oral contraceptives.  One can certainly understand the rationale for doing that. There is some literature suggesting that oral contraceptives may in themselves have some benefits in the symptoms of PMDD.  However, The impression one gets is that the data are not entirely consistent, and it may be that there's a population of patients who, even though they are taking oral contraceptives, still have PMDD.  So, the question then is whether or not fluoxetine would have any benefits in that population that was excluded from these studies.
		Similarly, one might have a question about whether or not fluoxetine has been shown to be safe in a population of patients taking oral contraceptives.
		Another issue, as was the case last month with PTSD, is that this program is relatively small in terms of the safety exposure.  Of course, there is a substantial body of systematically collected data on patients taking fluoxetine for other disorders, and so again, a question as to whether or not one can extrapolate from that larger database to this population in terms of safety.
		Another issue that also came up at our last meeting on PTSD is the question of the appropriateness of a crossover trial for a chronic psychiatric disorder.  Now, we had that discussion last month, and everyone I think pretty much agreed that for that disorder, a crossover trial would not make much sense.  Now, this is also a chronic disorder, but it has some unusual features that may lend itself to this design.  In particular, there's a very predictable cyclicity with patients returning to baseline during every cycle.  So, again, I'd like to have some discussion of whether or not that design is appropriate for this drug in particular, but also in general for this condition.
		Now, this list of questions was not intended to in any way limit your discussion.  Clearly, if you have any other issues that you think are important to discuss, please bring them up.  This will be helpful to us not only in reaching a judgment about this application, but again, as you know, there's interest more generally in developing drugs in this area.  So, it would be helpful to us in advising sponsors on other development programs and then ultimately in making judgments about applications that we expect in the future.
		As I said, at the end of the day, we'll want you to vote on these two questions.  Number one, has the sponsor provided evidence from more than one adequate and well-controlled investigation that supports the conclusion that fluoxetine is effective for the treatment of premenstrual dysphoric disorder?  And has the sponsor provided evidence that fluoxetine is safe when used in treatment of this disorder?
		And I'll stop there. 
		DR. TAMMINGA:  Thank you very much, Dr. Laughren.  You've done a good job in laying out the pivotal questions for the committee to consider.
		But the next thing that we'll do is actually hear from Lilly in their presentation of the data on fluoxetine in the treatment of premenstrual dysphoric disorder.  I'll turn this over to Dr. Gregory Brophy who will take charge of the Lilly presentation.  Thanks.
		DR. BROPHY:  Good morning.  On behalf of Eli Lilly, I'd also like to welcome you and express our appreciation to the committee for their contributions today, as well as for allowing us the opportunity to present data substantiating the safety and efficacy of fluoxetine in the treatment of premenstrual dysphoric disorder.
		As my colleagues will elaborate, PMDD is a serious disorder, one that can be clearly distinguished from other depressive disorders.  It's also a disorder associated with significant morbidity as its symptoms characteristically can adversely affect the functioning, particularly the social functioning, of its sufferers.
		I'd like to introduce our two primary speakers this morning.  They are Dr. Jean Endicott.  Dr. Endicott is the Professor of Clinical Psychology within the Psychiatry Department at Columbia University.  She also serves as the Director of the Premenstrual Evaluation Unit at Columbia-Presbyterian Hospital.  Jean has a longstanding clinical trial and clinical experience in this area as a PMDD expert.  She'll focus her discussion today primarily on a lot of background information on the disease itself, in particular diagnostic criteria classifying as PMDD.
		Our second presenter will be Dr. Rajinder Judge.  Dr. Judge is the Medical Director within Lilly Neurosciences.  Dr. Judge's presentation will be primarily on the clinical trials themselves, particularly focused on outcome measures, as well as the results of those studies, demonstrating the activity of fluoxetine in this disorder.
		I'd like to ask, if possible, that since both of these presentations build upon each other, that if we could hold most of the questions until the completion of Dr. Judge's presentation, other than clarifying questions, I think some of the questions may well be answered in Dr. Judge's presentation.
		In addition to these two presenters, we're also honored to have another PMDD expert and one of the principal investigators for the largest trial that Dr. Judge will describe, Dr. Meir Steiner.  Dr. Steiner is Professor of Psychiatry and Behavioral Neurosciences at McMaster University and will also help us address questions this morning. 
		With that, let me turn the podium over to Dr. Endicott.
		DR. ENDICOTT:  Today I'm going to be focusing on the menstrual cycle and a condition that is exquisitely entrained with phases of the menstrual cycle, both the onset and the offset of the condition.  The symptomatic phase is during the late luteal phase of the menstrual cycle, the period after ovulation.  In some women, the symptoms start earlier, but the most severe symptoms are seen during this premenstrual or late luteal phase of the cycle.
		After the onset of menses, the women, within a couple of days, often the first day of the onset of menses, become asymptomatic.  The syndrome, the disorder, goes away, and during particularly the mid-follicular phase of the cycle up to the time of ovulation, they're essentially symptom-free.  This is a unique feature of this condition among the mental disorders.
		Now, this is not a new condition.  It is not something that we have discovered in the 20th century.  Even in ancient history, there was literature that described severe changes in mood behavior that occurred just prior to the onset of menses.  It was mentioned in early Greek literature that some women had a delay of menses and that pregnancy would be a cure for it, which is rather interesting. 
		By the 1930s, the term "premenstrual syndrome" was coined and was used to describe problems experienced by 15 women, and it was described very well.  The description clearly fits the current diagnostic criteria by Dr. Frank in the Archives of Neurology and Psychiatry.  Between ancient history and the 1930s, there were other mentions of severe problems with mood and behavior prior to the onset of menses in the medical literature, but he coined the term "premenstrual tension syndrome."
		A great deal of work was done in the 1930s, 1940s, and 1950s, and by the 1950s, the term "premenstrual syndrome" came into more common usage in recognition that it was not just tension, that there were other dysphoric mood states associated with the syndrome.
		In 1983, NIMH convened a workshop on premenstrual syndrome, and this was in recognition that a lot of investigators were beginning to study the condition and were interested in coming up with some guidelines to help in the study of the condition.  A number of different divisions within NIMH sponsored this workshop, and the workshop did yield some suggestions for criteria for premenstrual changes and premenstrual syndrome.  The major criteria was the contrast between the mid-follicular phase and the late luteal phase in terms of severity and the nature of the symptoms.
		In 1987, in response to advice of an advisory group, the DSM-III-R nomenclature group included specific criteria for late luteal phase dysphoric disorder in the appendix of DSM-III-R as a proposed diagnostic category needing further study.  Of great interest and particularly relevant for this group is the content was almost identical to the DSM-IV criteria.  The requirement that there be severe, marked dysphoric mood states was included, and in fact, the DSM-IV criteria adds only one symptom to the possible list, and I'll go into that later. 
		In the early 1990s, as a result of this, of course, there was an explosion of research in the area looking at both treatment of the condition and also efforts to understand the pathophysiology.
		By the early 1990s, the DSM-IV nomenclature committee had a work group called the Premenstrual Dysphoric Disorder Work Group to review literature up to that point in time, and the literature review, which is included in the DSM-IV source book, included literature up to 1993.  The group worked together and with many advisors, and there was agreement among the group in their recommendations to the nomenclature committee on the suggested criteria and name of the condition.  There was also very good agreement on the summary of the evidence and the written materials that were included in the DSM-IV source book. 
		There was some lack of consensus among the members of the work group regarding recommendations of the placement of the condition within the nomenclature.  Some recommended that it be in the body of the nomenclature with the criteria.  Others had some reservations for various reasons, and the nomenclature committee decided to put PMDD in the body of the nomenclature but to include the criteria in the appendix.
		Now, how do we conceptualize PMDD currently?  Currently it is thought to be in the upper range of the broader category of PMS.  That's partially because the work has not yet been done to decide whether or not there is a discontinuity between the conditions.  But this is somewhat similar to the concept of depression.  If you think of depression and general minor depression and major depression, there's no clear-cut pathophysiological cutoff, but most clinicians are very comfortable with thinking major depression as being different from minor depression or depression in general.  So, currently PMDD is conceptualized as being at the upper range of severity of the broader category of PMS, but there are additional differences.  It's not just the upper range of severity.
		In premenstrual dysphoric disorder, the mood symptoms are prominent.  It's the dysphoric mood symptoms that are prominent and are the primary clinical complaints of the women who are seeking treatment.  They're not only prominent, they're severe, and they include particularly irritability, low mood, and anxiety. 
		There is functional impairment associated with these mood symptoms.  The mood symptoms themselves are associated with functional impairment particularly in psychosocial relationships.
		There are physical symptoms, just as there are with the garden variety PMS.  Breast tenderness and bloating are there.  
		The prevalence in many studies have suggested that it's around 3 to 5 percent of regularly menstruating women.  Some recent evidence suggests it may even be higher.  It may be up to 8 percent.  But these are women who are having regular menstrual cycles.
		The symptoms appear regularly every cycle.  During the week before menses, the premenstrual period, or the late luteal phase of the menstrual cycle, and they remit following the onset of menses.
		Now, in contrast with the more general premenstrual syndrome, the physical symptoms tend to be most prominent, particularly again the breast tenderness and the bloating.  Mood symptoms tend to be less severe.  If they're there, they're no big deal.  They don't bother the women that much.  There's little or no functional impairment associated with the syndrome, and the prevalence, of course, is much broader, 20 to 80 percent.
		Now, to go over the DSM-IV criteria, I want to stress a number of features.  
		First of all, this is a chronic condition.  The criteria require that the symptoms occur in the late luteal phase of most menstrual cycles during the past year.  Most women who seek treatment report that they have had it for years and that it has tended to get somewhat worse over time.  The average in several studies has been around 8 years.  Also, that it remit within a few days of the onset of menses, and this is an important differential diagnostic point. 
		There are 11 types of symptoms or groups of symptoms in the criteria.  At least 5 of the 11 symptoms must have been present most of the time during each symptomatic phase, but at least one of those symptoms has to be one of these first 4 dysphoric moods:  depression, anxiety, affective lability, persistent marked anger/irritability.  Now, the reality again is that most women who seek treatment may have one primary symptom, but they tend to have all of these, not just one of them.
		The additional symptoms are decreased interest in usual activities, subjective sense of difficulty in concentrating, lethargy, easy fatigability, marked change in appetite.  The most common is increased, but some women have decreased.  Hypersomnia or insomnia, and the one added criteria was subjective sense of being overwhelmed and out of control.  That's the only criteria different between LLPDD and PMDD.  Therefore, any woman who meets the criteria for LLPDD would have met the criteria for PMDD as well.  And then other physical symptoms.  
		So, you can see that the emphasis in these diagnostic criteria, at least five had to be present, or on the dysphoric mood changes and the associated features, the physical symptoms are there, but they're not a major part of the criteria.
		The criteria continue.  The syndrome must markedly interfere with work, school, or usual social activities and relationships.  It's not sufficient just to have the syndrome.  There should be marked impairment and functioning.  
		It should not be merely an exacerbation of the symptoms of another disorder, such as major depressive disorder, generalized anxiety disorder, dysthymia.  So that part of the criteria is that you rule out another ongoing condition that could account for the symptoms.
		And furthermore, the criteria required that the diagnosis be made provisionally until it is confirmed by prospective daily ratings, and those prospective daily ratings have to confirm the timing of the onset and the offset of the symptoms, as well as the severity of the symptoms, and the impairment during at least two consecutive symptomatic cycles. 
		Now, what about the impact on functioning?  How is this a clinically significant syndrome or disorder?
		First of all, a woman who develops the disorder, by age 26, may experience more than 200 symptomatic cycles between then and menopause, or 1,400 to 2,800 symptomatic days, depending upon the duration of her premenstrual disorder.  As I've mentioned, in the DSM-IV criteria the symptoms are severe enough to have a significant, clinically significant, impact on social, home, and occupational functioning, and I'll be illustrating that with some data in the next slide.
		The social functioning is affected more than vocational functioning.  Many of the women manage to push themselves, spend extra time, energy and effort on their vocational functioning, and it's in their social functioning, particularly interpersonal relationships with mate and children, in which it shows itself more. 
		Women with PMDD may report impairment of family and social activities at a level similar to that of depression.  This is illustrated in this next slide in which women with major depressive disorder are compared with women with PMDD on these social adjustment scale, with the self-report scale developed by Myrna Weisman, in which there are a number of different dimensions measured.  As you can see, the women with PMDD report impairment in functioning that is nearly equivalent to that, and in some cases is equivalent to that, of women with major depressive disorder, particularly social activities, marital activities, extended family, and parenting.
		This is very important because some people say, well, it only lasts a week to 8 or 9 days, so it must not be that impairing.  Frankly, it is quite impairing and it occurs every cycle.
		What do we know about the etiology of PMDD?  Well, just as is the case with most mental disorders, we don't fully understand the etiology.  However, we do know some things about it.  
		The most likely theories are based on observations of cyclic changes in ovarian steroids do cause dramatic changes in brain neurotransmitter systems, a number of them, including serotonin.  What has been clearly established is that in women sensitive or otherwise predisposed to mood instability, the normal events of the ovarian cycle -- in other words, there's nothing wrong with the menstrual cycle -- the normal events of the ovarian cycle may trigger severe mood changes.  And I'll be reporting some other information on that topic.  So, this is one thing that has been clearly established.  The exact mechanism the way the neurotransmitter systems are involved is not as clearly established, but a great deal of work has gone on and is currently going on in this area. 
		How is PMDD distinct from the other depressive disorders, particularly major depression and dysthymia?
		Well, first of all, the mood disturbance is cyclical.  It is very tightly linked to phases of the menstrual cycle.  It has a highly predictable onset and offset, not only by phases of the cycle, but within an individual woman, you will find that her onset and offset, relative to her circulating gonadal hormones, is very tightly linked and very consistent from cycle to cycle.
		The most common chief complaint is irritability.  Although the other symptoms may be there, the women who seek treatment tend to focus on irritability.
		The cyclic occurrence of these symptoms cease during pregnancy and post-menopause.  This is not the case with either major depression or dysthymia or the anxiety disorders.
		Prevention or suppression of cycling gonadal hormones relieves the symptoms.  Again, this is not the case with the other depressive and anxiety disorders.
		Furthermore, hormone replacement therapy can provoke cyclic dysphoric changes in women who have a history of PMDD.  This has been done in double-blind studies and is clearly established.  This does not happen in women who have a history of major depression or dysthymia.
		The HPA axis functions normally in PMDD.  There's no evidence that the HPA axis is abnormal in any way, and this is unlike the documented disturbances in major depression. 
		There is great symptom stability seen across cycles.  Again, this is in some contrast with studies across episodes of major depression in which there is somewhat less symptom stability.  Here the symptom stability is very stable and very predictable for the individual woman.
		And most important, recently in 1998, Ken Kendler published the results of a very large study of twins, comparing monozygotic and dizygotic twins, in which both premenstrual related symptoms, focusing mainly on depression, and lifetime major depression had been evaluated at least at two points in time.  What he found was that both the genetic and environmental risk factors for these two conditions were not closely related.  They were not shared. 
		There was a large genetic contribution for premenstrual mood changes but that was not accounted for by major depression, lifetime major depression, and this was a very important study in this area. 
		There are some other ways in which PMDD is distinct from the other depressive disorders.  It's most likely to respond to the serotonergic antidepressants than to other antidepressants.  As you know, in the comparison studies between the TCAs and the SSRIs, with major depression you don't find that distinction.  It's a clear distinction here.  The serotonergic antidepressants are superior. 
		Furthermore, upon treatment, the symptom improvement in PMDD is very rapid, as shown within the first treatment cycle, even though the women have not been on the medication that long.  This is in contrast with major depression and dysthymia. 
		The physical symptoms shown with women with PMDD are unique to that condition.  Breast tenderness and bloating are the most common.  This is rarely seen in women with simple dysthymia or major depression. 
		Upon treatment cessation, the symptoms return rapidly, and the reemergence is more predictable.  It's quite predictable with PMDD.  There have been a number of studies, two of which are summarized here, about the reemergence of symptoms after stopping treatment. 
		Dr. Pearlstein in 1994 published an article on after 1 year of successful fluoxetine treatment, 31 women, they discontinued treatment, and the PMDD symptoms, meeting criteria for PMDD, returned within two cycles in 30 of the 31 women.
		Kimberly Yonkers did a study published in 1997 in which there was double-blind randomization from sertraline to placebo in women who had been on the medication 3, 6, or 9 cycles.  So, the women did not know when placebo was going to be instituted.  The rates of recurrence were 66, 66, and 60 percent within a couple of cycles after cessation of the active compound. 
		Now, in recognition of the clinical significance of this condition and of the need to find effective treatments for it, a very large number of compounds and interventions have been studied.  This is just a sampling.  This is not exhaustive.  Other compounds have also been studied. 
		The most work has been done with the SSRIs, and this is shown here in which there are 32 studies, published studies, with SSRIs.  The greatest number are with fluoxetine, but there have been published studies -- the double-blind, placebo-controlled studies are in the dark blue and the open-label trials are in the light blue.
		31 of these 32 studies were successful, were effective.  There was a single study with fluvoxamine in which there was no difference.  There are some other issues about that study, but 31 out of 32 studies of SSRIs have shown the SSRIs to be effective in the treatment of PMDD.
		So, in conclusion, PMDD appears to be a distinct clinical entity with exquisite onset and offset of timing and clinical features and other characteristics that occurs in 3 to 5 percent of menstruating women and maybe even more.  It has clinical and biological profiles that differ from those of major depression.  It is a severe form, we think now, of the broader category of PMS that impacts normal functioning to a clinically significant degree.  
		It should be better diagnosed and treated.  There are plenty of women who have not had the diagnosis made.  There is currently no registered treatment in the U.S. for PMDD.  And there is an unmet clinical need for safe and effective treatment for the psychological as well as the physical symptoms of PMDD.  There is evidence that the SSRIs meet this need, and Dr. Judge will be presenting that data now. 
		Thank you.
		DR. TAMMINGA:  I'd just like to remind the committee that all the slides that are shown are in the navy book in front of you.
		DR. JUDGE:  Well, good morning.  It's my pleasure to present to the advisory committee and to the FDA this morning. 
		As you heard from Dr. Endicott, PMDD is a disorder which causes suffering to many, many American women.  The data I will present this morning on fluoxetine will show how highly effective fluoxetine is in treating the symptoms of PMDD. 
		Firstly, I will address the efficacy with respect to the PMDD studies, and I will focus on the key symptoms of premenstrual dysphoric disorder, i.e., the mood symptoms, the physical symptoms, and the social impairment that accompanies these symptoms.
		Secondly, as you know, fluoxetine is a drug which has been marketed for over 10 years, and the safety profile is very well established.  I will, therefore, provide a succinct summary of the safety and importantly compare that to the overall fluoxetine safety database. 
		And finally, I will provide conclusions and dosing recommendations. 
		These slides show the listing of the published studies in PMDD for fluoxetine, firstly, the double-blind studies on the left and the open-label studies on the right.
		The first three studies here comprise the application for fluoxetine in PMDD.  Although these comprise the application, all of the studies in the literature are consistent with respect to the results for fluoxetine in efficacy and safety.  They have all utilized the DSM-III-R criteria for LLPDD.  As you heard from Dr. Endicott, as these patients conform to DSM-III-R, that means that they also conform to DSM-IV criteria. 
		Furthermore, all of these studies in the main utilized a dose of 20 milligrams daily, and that was considered an effective and safe dose for patients with PMDD. 
		Although these studies are open-label, there is some nice information that can be obtained from them, namely, for patients going out to longer than 6 months, as for the shorter-term studies, patients going out to even up to 20 months did show a maintenance of efficacy with fluoxetine.  Furthermore, there was also evidence from these studies to suggest that when fluoxetine was stopped, even after the long term, there was very quickly a reemergence of symptoms following cessation of treatment.
		Three trials, as I've indicated, comprise the application for fluoxetine in PMDD, and these are listed here below in more detail.  These are studies C019, X022, and X037.  For purposes of perhaps ease of communication, I will refer to these studies as studies 1, 2, and 3.  All were double-blind, parallel-controlled.  One was a crossover trial. 
		The efficacy measures utilized in these studies are listed here and spelled out in full here.  For the first study, number 1, the visual analog 7-item scale was utilized as the primary outcome measure.  For study number 2, X022, a 16-item visual analog scale was utilized as the primary outcome measure.  For the third study, X037, an overall measure of improvement, the clinical global impression, was utilized as the primary outcome measure.
		In addition to the ones I've just indicated, there were a number of other scales utilized in these studies, particularly in studies 1 and 2, the premenstrual tension syndrome.  Both patient rated and clinician rated tools were also used in these studies.
		There are a wide variety of scales utilized here.  There is not a gold standard of scales that is currently utilized in PMDD studies, but all of the scales here are appropriate and are reliable in treatment and study of PMDD.
		I'll just go into a little bit more detail.  These slides list the scales that were used in these studies, the main scales across the top, and across here, down here, are the DSM-IV criteria for mood, for physical symptoms, and social impairment.  The numbers listed here list the items of these scales which correspond to each of these symptoms as listed by DSM-IV.  This shows that all of the scales used in these studies did employ items that correspond to the DSM-IV symptoms. 
		So, for example, if we look at the premenstrual tension syndrome scale, both the clinician rated and the patient rated, listed here are items that are part of these scales and that correspond to the mood symptoms of DSM-IV, as listed in DSM-IV, and then over here they also contain items which list physical symptoms and they also contain items which list social impairment.
		For the primary outcome variable in study 1, visual analog scale-7, again the items in this scale do correspond to the mood symptoms of PMDD.  It also contains items corresponding to the physical symptoms of PMDD.  It did not contain items corresponding to social impairment, but for that study, the PMTS scales were utilized.  So, we can glean social impairment information from those scales.
		With respect to the second study, the visual analog scale 16-item was used, and this scale contained items which corresponded to all of the symptoms as listed by DSM-IV, i.e., the mood symptoms, the physical symptoms, and the social impairment symptoms.  
		So, all of these scales utilized are appropriate and reliable to measure treatment change as listed for the core symptoms for PMDD.
		Going on to the studies for PMDD, this slide lists the inclusion and the exclusion criteria for these studies.  First of all, the studies obviously included females 18 years and over, and they had regular menstrual cycles.  
		All the patients did conform to a DSM-III-R diagnosis of late luteal phase dysphoric disorder, and as you heard from Dr. Endicott, as they conform to the DSM-III-R, they therefore conform to DSM-IV criteria. 
		They also had to have an adequate method of birth control other than hormonal.  I'll make another comment on that a little bit later.  
		And they also had to meet criteria for protocol predefined symptom severity.  For example, in study 1, patients had to exhibit during the prospective cycles, during which they were monitored for this baseline state, either at least a 50 percent change in the core items for the mood items for the visual analog scale, a 50 percent increase from follicular to luteal phase, or they could exhibit, for example, a 100 percent increase or more in just one of those items corresponding to the mood scales.
		The exclusion criteria.  Patients were excluded if they had serious health problems, and they were also excluded if they were on the following medications:  any psychotropic, diuretic, or hormonal medication, including oral contraceptives.  As you've heard and just to reiterate the point, it is essential to quite clearly delineate the effects of fluoxetine on PMDD.  As you've heard, oral contraceptives can have some effect on PMDD symptoms.  There's a variety of literature which shows an inconsistent and variable effect on PMDD symptoms, perhaps most often the physical symptoms, and for that reason, rather than introduce another variable into the study, it was felt prudent to exclude oral contraceptives. 
		Also, patients with concurrent Axis I diagnosis of other disorders were excluded as appropriate. 
		Going on to these studies in more depth now, the reference here on the corner of each slide indicates the study to which this refers.  Study 1, C019.  
		This is the first study, study 1, C019.  This is a double-blind, placebo-controlled, dose range-finding study.  After the screening period here with two cycles, patients then entered a placebo single-blind period here, and this provided an adequate basis for prospective monitoring for the patients and adequate baseline measurements of symptoms.
		At this point, patients who still met the DSM-III-R criteria for PMDD and importantly excluded placebo responders, patients were then randomized in a double-blind fashion at this point to receive either fluoxetine 20 milligrams a day, fluoxetine 60 milligrams a day, or placebo.  For those patients who received 60 milligrams a day, they were put on 60 milligrams a day from day 1, straight off the bat.  They did not have the ability to titrate up to this dose; 60 milligrams a day from day 1.
		The study then continued for 6 treatment cycles, making this a long-term study.
		Patients were seen during each cycle twice, once during the follicular phase and once during the luteal phase. 
		The primary objective of this study, as you heard from the first speaker, was to assess the efficacy of fluoxetine in PMDD as measured by the luteal phase Mood-3 average of the visual analog scale -- and I will go into this in a little more depth later for clarity -- average change from mean baseline to mean treatment score. 
		Now, originally in the protocol, it did not specify the VAS Mood-3 specifically.  It was enlisted as just the visual analog scale.  As the study started, Lilly and the primary investigator for this study made an agreement that the most appropriate outcome measure for this protocol should be the VAS Mood-3.  That was decided upon and confirmed in writing before the completion of the study, just after the study had started in fact.
		In addition to the primary, obviously I will show you items, the second objectives of the study, further measurements for the efficacy of fluoxetine in PMDD pertaining to the symptom clusters for the mood items to the physical items and social impairment as measured by the visual analog scale and also as measured by the subtotals of the premenstrual tension syndrome rating scales, patient rated and physician rated, obviously, also an opportunity to assess the safety and tolerability of fluoxetine in PMDD.
		This slide here shows the visual analog scale that was utilized in this study.  Patients were asked to rate themselves on a scale 0 to 100, ranging from no symptomatology to extreme symptomatology here.  The items in yellow comprise the core items for mood and, therefore, the primary efficacy analysis for this study.  So, the primary items for mood here are item 1, calm and unruffled, going to tense, uptight, uneasy; number 2, happy, content, and energetic, going to extremely depressed, sad, apathetic, and lethargic.  Item 7 measured irritability.  There were three physical items score here:  headache, bloating and tenderness, and breast tenderness.  And item 4 looked at emotional lability, even-tempered to extreme mood swings.  So, that's the visual analog scale 7-item.
		So, the primary efficacy variable is the average of the three mood symptoms here highlighted in yellow:  the average scores of dysphoria, irritability, and tension.  And secondary efficacy variables included the VAS Mood-4 average, which incorporated the other emotional lability item here, also the average of the physical symptoms, and then the subtotals for mood, physical, and social impairment for the PMTS scale. 
		This just shows in depth the PMTS scales for purposes of clarity.  The clinician rating scale is listed on the left on both slides, and the corresponding items of the patient rating scale, PMTS-P are listed on the right. So, overall the range for both scales is 0 to 36.  For the clinician rating scale, there were 10 items which were scored from 0 to 4 for most of the items, apart from number 7 and 8 where the items are scored from 0 to 2.  The corresponding patient rating scale simply asked the patient to respond a yes or no to each question.  Again, the items here correspond to those items as per the clinician rating scale. 
		This is looking at the calculation of the efficacy measures in a little bit more depth.  This is a pictorial representation of the follicular and luteal cycles in this study.  The first two cycles are the baseline placebo cycles, and then the six studies are the six treatment cycles.  F is follicular; L is luteal.  As I indicated, patients were seen twice during each cycle, once in the follicular phase, once in the luteal phase, and at those visits patients were assessed in terms of their efficacy.
		So, measurement of the average luteal scores here for these two placebo cycles provided the mean baseline score.  The average of the luteal scores for these six cycles here provided then the mean treatment score, and the calculation of the overall efficacy measure was the mean treatment score minus the mean baseline score. 
		Now, originally Lilly did plan to analyze the percent change in the analysis plan.  However, the percent change would have assumed a normality assumption.  There were extreme outliers, which violated the normality assumption.  And therefore, it was felt appropriate to look at the mean treatment change. 
		Going on to some characteristics of the patients in the study, these are the baseline characteristics, and these are listed in more detail in your briefing document supplied to you.  But essentially the age of entry for these patients in these studies was mid to late 30s.  Importantly for the demographic variables listed here and also in your briefing document, there were no differences in the groups at baseline. 
		The average VAS Mood-3 follicular and luteal scores are represented here more visually.  Importantly all three treatment groups, with respect to their scores, are similar at baseline.  Moreover, as one would expect for PMDD, the luteal scores are higher.  This is the mean score on the visual analog scale, VAS Mood-3.  The luteal scores are higher than the follicular scores, the follicular scores indicating insignificant symptomatology, as one would expect with patients with PMDD.
		This lists the patient disposition for the study with respect to the percentage of patients.  Overall, fluoxetine 20 milligram patients were the highest number of patients who completed the study.  The highest percentage of patients completed the study were on fluoxetine 20 milligrams. 
		In terms of patients who dropped out for any reason, these are shown here.  For the patients who dropped out due to an adverse event, more patients on fluoxetine 60 milligrams who dropped out due to an adverse events.  There were a low level and similar level for dropouts with respect to placebo group and fluoxetine 20 milligrams.  For lack of efficacy, as one would expect, a higher proportion of placebo patients dropped out due to lack of efficacy.
		I'm going on to now show the efficacy measures by means of a series of bar graphs.  In all of these graphs, fluoxetine 20 milligrams will be shown as orange, fluoxetine 60 milligrams will be shown as yellow, and placebo in green.
		Moving on to the primary efficacy measures -- and, again, I will concentrate on the mood symptoms, then the physical symptoms, then the social impairment symptoms from each study.
		First of all, the mood symptoms in the luteal phase.  This looks at the mean reduction from baseline to mean treatment here, so the greater the reduction, the greater improvement in overall outcome.
		This is the primary objective here, the VAS Mood-3.  We see here there's a greater reduction with statistical significance for both fluoxetine 20 milligrams and 60 milligrams versus placebo here.  If one looks at the individual items that comprised the primary outcome, VAS Mood-3, which is dysphoria, irritability, and tension, then one sees that indeed in each case fluoxetine 20 and 60 milligrams are statistically significantly superior in their reduction of symptomatology versus placebo in each case.  
		There does appear to be some numerical superiority for fluoxetine 60 milligrams versus 20, but the difference between the two groups was not statistically significant with respect to the two fluoxetine groups.
		The results here are mirrored by the consideration of the results seen on the PMTS scales, both the PMTS-P, the patient rated scale, and the PMTS-C, the clinician rating scale.  Again, showing the reduction from mean baseline, patients on fluoxetine on any dose, either 20 or 60, achieved superior clinical improvement versus placebo, and the difference between the active treatment groups and placebo did attain statistical significance.  Again, some numerical superiority observed with fluoxetine 60 milligrams versus fluoxetine 20 milligrams, but the difference between the two fluoxetine arms was not statistically significant in this case.
		Moving on to the physical symptoms, again this looking at the visual analog scale, the overall physical average is shown here, again mirroring the mood symptoms, a statistical difference for superiority for the fluoxetine arms versus placebo.  Then if one looks at the individual physical items which comprise the physical average, bloating, breast tenderness, and headache, one sees that it is the effects of breast tenderness and bloating which lead to the overall significance.  There does not seem to be any difference between the groups with respect to headache.  But as you heard earlier, bloating and breast tenderness are two of the most common symptoms in patients with PMDD.
		Again, the effective results for fluoxetine in the mood symptoms and the physical symptoms here are also mirrored by consideration of the PMTS subtotals, for the PMTS-P and the PMTS-C.  Again, a significant reduction for physical symptoms for both fluoxetine arms versus placebo, and again some evidence of numerical superiority with fluoxetine 60 milligrams versus 20, but the differences were not statistically significant.
		Moving on to the social impairment.  As I noted earlier, the visual analog scale from this study did not measure social impairment, and so we view the items from the PMTS-P with respect to social impairment.  Again, reduction from mean baseline for the PMTS-P and the PMTS scores showing a very nice improvement in social impairment for patients on fluoxetine 20 and 60 milligrams versus placebo, the difference between the active treatment arms versus placebo attaining statistical significance.
		So, I've shown you the subtotal scores for the mood and physical symptoms and the social impairment.  I just want to point out now that analysis of the overall scores for each of these measures, the overall visual analog scale 7-item, the overall PMTS-P, the overall PMTS‑C.  Also I showed that fluoxetine was statistically superior with respect to its effects on those scores versus placebo.
		So, efficacy was seen for both fluoxetine 20 milligrams and 60 milligrams for all of the symptom clusters of PMDD. 
		Two pertinent questions at this point.  How quickly was the efficacy apparent and what was the course of the treatment effect? 
		With respect to how quickly was the efficacy apparent, we viewed here the efficacy seen with respect to the mood symptoms and the physical symptoms at the first treatment cycle.  So, remember, patients were asked to take medication from the first day of their menses.  So, this is just after a couple of weeks of treatment.  We see that even at the first cycle, there is superiority for fluoxetine versus placebo in the mood symptoms and in the physical symptoms as shown here by the primary analysis of Mood-3 average and also the physical average on the visual analog scale.  So, a very quick response to fluoxetine was evident.
		With respect to the course of the treatment effect, this is shown here for the last observation carried forward for the primary analysis, the VAS Mood-3, placebo here, this line; fluoxetine 20 milligrams, the orange line here; and fluoxetine 60 milligrams, the yellow line here.  So, this is looking at the mean reduction from baseline, and what we see is that up to 6 months, at each cycle, there is a statistical difference maintained between placebo and both of the fluoxetine groups, both the 20 and the 60 milligram groups, showing that the efficacy of fluoxetine is maintained for out to 6 months.
		So, with respect to the conclusions in the study, both fluoxetine 20 and 60 milligrams a day were effective in the treatment of PMDD.  Statistical differences were shown with respect to placebo, with respect to the primary objective, the VAS Mood-3, and the secondary objectives, and I also indicate there's also the consideration of the total scores as well.  Efficacy was seen in all of the symptom clusters of PMDD.  So, although mood was defined as the primary outcome measure, it's also interesting to note that the mood symptoms, the physical symptoms, and the social impairment associated with PMDD all improved very quickly.  Efficacy was demonstrated in the first treatment cycle and maintained for up to 6 months.  There was some evidence that fluoxetine 60 milligrams was in general numerically greater than 20 milligrams, but the differences were not usually statistically significant. 
		Moving on to the next study, this is study number 2, X022, and this is a double-blind crossover study.  As was alluded to earlier, the disorder of PMDD comprises symptoms which are very closely entrained to the menstrual cycle.  So, the predictable nature of these symptoms emerging cycle after cycle after cycle makes it a very predictable disorder with discrete episodes of disorder.  Furthermore, studies would suggest that there is symptom stability across cycles.  So, symptom stability being the rule rather than exception.  So, these two characteristics of PMDD do make it an ideal disorder to study in a crossover design.  This is also evidenced by the literature where a number of studies with various treatments have used the crossover design in order to study PMDD.
		So, in this study after 3 cycles of screening and evaluation, patients were entered into this study.  Patients were either randomized to the fluoxetine arm or the placebo arm for 3 cycles.  After this there was a 1-cycle crossover, 1-month crossover, and then patients were crossed over to the other treatment, again for another 3 cycles here.  For the fluoxetine arm, patients were started on 20 milligrams, and investigators, at their discretion, could titrate up in increments of either 10 or 20 milligrams, according to safety and efficacy, to a maximum of 60 milligrams.  
		Patients who entered here are listed here:  9 for the fluoxetine group, and placebo, 10 patients.  Obviously, each patient acted as their own control.  This enhanced sensitivity allows for relatively fewer patients. 
		Originally this protocol was intended to recruit 30 patients, but in an earlier analysis done for purposes of a scientific abstract, the investigator noted significant differences between the treatment groups and elected to stop the study at that point.  It's important to realize that all of the patients who were recruited at that time were allowed to finish.  That numbered a total of 19 patients.  And moreover, the raters who were assessing the patients and the patients themselves, who obviously were assessing themselves on scales remained blind to treatment assignment, first, to minimize any kind of bias in this study.
		The prime objective here was to assess the efficacy in the treatment of PMDD as measured by the average within-cycle change from follicular to luteal phase in the VAS Mood-4.  So, there are differences here with respect to the outcome measures from the first study.  Just to point out that patients did score themselves every day in this, they did do some measurements every day during this study, and they did some measurements again for every visit.  Again, they were seen for two visits each cycle, follicular and luteal phase.
		So, I'm going to talk about this in a little bit more depth, but just to emphasize that the outcome measure here was the average within-cycle change from follicular to luteal phase, in the VAS Mood-4 subtotal.  So, this is a 16-item VAS and the VAS Mood-4 subtotal comprised the primary efficacy outcome, and that comprised the mood swings, depression, irritability, and anxiety.
		Again, the secondary objectives were obviously to look at the other items of the visual analog scale and the PMTS scales with respect to the other subtotals, the mood subtotal, the physical symptom subtotal, and the social impairment.
		This slide shows the visual analog scale used in this study.  So, this is a 16-item visual analog scale.  Patients were asked to rate themselves from no symptoms to severe symptoms, and the symptoms listed in yellow again comprise the primary mood items, rapidly changing mood to mood very stable; item number 8, most sad ever to most happy ever; the irritability item, and the most anxious ever to most calm ever.
		The other items that comprise physical symptom items are shown here:  number 5, extreme breast pain; extreme bloating; and extreme physical discomfort.  You see all the other items that were also in the scale. 
		This shows the daily rating form which also comprised one of the secondary scales in the study.  This form, obviously as the name implies, was rated daily by the patient and the patient rated the severity of each item on a scale of 1, none, to 6, extreme, the total score ranging up to 108.  Listed here are those items which pertain to mood, the physical symptoms, social impairment, and there are a variety of other symptoms which were also scored on this daily rating form.
		Now, just to go into the depth of how the efficacy analysis was calculated, again just to reiterate the primary outcome variable was the VAS Mood-4 subtotal.  This is how this was collected. 
		The luteal score was the average of the patient's score for 7 days prior to the menses.  The follicular score was the average of the patient's score over the 7 days post-menses.  Subtracting one from the other provided the within-cycle change, and this was averaged over 3 months of treatment to provide the primary patient treatment outcome measure. 
		Baseline characteristics, very similar to the first study.  Most of the patients were caucasian and the age of these patients were similar to the first study, mid to late 30s.  Importantly, consideration of the follicular scores here for the PMTS patient total for the PMTS clinician total, and for example, in the Beck's Depression Inventory, if you look here, the scores are very, very low in the follicular phase, indicating an absence of any significant premenstrual symptomatology, as one would expect with respect to the cyclicity of PMDD.
		With respect to patient disposition, the majority of patients completed this study.  Very few patients dropped out for any reason at all. 
		Again, I will go through the efficacy outcomes with respect to the mood symptoms, the physical symptoms, and then the social impairment.
		Firstly, with respect to the mood symptoms.  Now, here the scale is looking at average within-cycle increase.  So, within-cycle increase from follicular to luteal, so indicating an increase in symptomatology.  So, an increase in scores here would indicate an increase in  symptomatology and therefore deterioration in the patient's outcome.
		For the primary outcome measure, the VAS Mood‑4, the 4 items on the visual analog scale, you will note there's a greater increase with respect to the symptomatology seen in the placebo patients shown here in green, and this increase was statistically superior than the increase evident for fluoxetine patients.  So, the fluoxetine patients improved with statistical superiority versus the placebo patients.
		When one sees the individual items which comprise the VAS Mood-4 items, again fluoxetine is superior with respect to placebo in each of these items, the mood swings, depression, irritability, and anxiety.  And fluoxetine patients exhibited far less increase in symptomatology versus the placebo patients.
		This was mirrored by consideration of the secondary outcome variables, the daily rating form, and the PMTS-P and PMTS-C.  For both the DRF and PMTS-C -- that's the clinician rating and patient rating -- again, evidence of fluoxetine superiority with statistical significance versus placebo.  For the PMTS-P, quite clearly there is fluoxetine superiority, but the differences did not attain statistical significance.
		Going on to the physical symptoms with respect to this study, again shown here are the physical average for the symptoms comprising from the visual analog scale.  This shows the individual items which made up this physical average, and fluoxetine is highly effective with respect to placebo for breast pain, bloating, and physical discomfort, giving an overall highly statistically significant effect versus placebo on the visual analog scale.
		Again, consideration of the secondary measures employed in this study further mirrored the evidence seen for the primary outcome measure in that for the physical symptoms, for the daily rating form completed by the patient, the PMTS-P completed by the patient, the PMTS-C completed by the clinician, statistical superiority for fluoxetine versus placebo in each case.
		The similar results are evidence for social impairment with highly statistical significance for fluoxetine versus placebo with respect to the visual analog scale here, the overall social impairment.  This comprised two items, work efficiency and social activity.  So, this is important.  It shows that the patients rates themselves as improving with fluoxetine with respect to their efficiency at work and their social activities.
		Again, this is mirrored by the consideration of the secondary outcome variable.  Patients rated themselves as improving with statistical significance over placebo for the daily rating form, and for PMTS-P and PMTS-C, again quite clearly there is numerical superiority for fluoxetine, but the differences did not attain statistical significance here. 
		Going on to the same questions as we asked in the first study, when was the efficacy apparent and what was the course of the treatment effect, these two slides go to show some evidence for those questions.  
		First of all, again, entirely consistent with the first study, a consideration of the first treatment cycle, within-cycle increase, showed that for the primary VAS Mood-4 for the physical symptoms and for the social symptoms, all from the visual analog scale, at the first treatment cycle was exhibited a superiority for fluoxetine versus placebo, again entirely consistent with the first study.
		The course of treatment effect is shown here just for one measure, the VAS Mood-4, which is obviously the primary outcome measure.  For patients here for the purple, here we see here for the patients who started off the treatment with placebo.  Now, scores higher on this graph indicate increase in symptomatology.  Scores in the lower half of this graph indicate lower symptomatology.  So, higher scores are considered bad for the patient. 
		So, for the patients who started off on placebo, as indicated for the first 3 cycles, their scores are in the upper half of the graph, indicating significant symptomatology for these patients.  After the crossover -- you see then the patients who then were crossed over to fluoxetine -- then their scores for the next 3 cycles were in the lower half of this graph, indicating improvement for the patients.
		Exactly the opposite is evidenced for the opposing group.  We see here for fluoxetine, the patients who started off on fluoxetine, their scores for each of these 3 cycles are in the lower half of the graph, indicating very little symptomatology for these patients, and after the crossover, when they were switched over to placebo, we see that their scores shoot up to the higher portion of the graph, indicating an increase in symptomatology.  So, a nice visual representation of the comparative effects of fluoxetine versus placebo.
		Now, the crossover washout phase here was a 1-cycle duration, 1 month.  As we appreciate, for fluoxetine, the half-life is relatively long and also contains an active metabolite, norfluoxetine.  So, therefore, a reasonable question at this point is, were there any carryover effects, and if there were any carryover effects, what was the implication of that carryover effect with respect to the overall efficacy seen in this study?  I'd like to elaborate on those results.
		First of all, with respect to the mood symptoms across the treatment cycles for this study.  This is just looking at the VAS Mood-4 and another example of mood, the DRF mood subtotal.  This shows that for the overall treatment effect for all cycles shown here, the overall value for fluoxetine versus placebo, was highly statistically significant, p, 0.002.  This column here shows the possibility of the carryover effect.  As you see over here with the p values of 0.9 and .26, there is no carryover effect evident.
		When one then moves on to the first treatment cycle, the results from the first treatment cycle only, we see here again for the same items the VAS Mood-4 and the DRF Mood subtotal.  We see, if we look over into the carryover effect column here, .09, .12, then there is a suggestion of a carryover effect.  But it's worth bearing in mind, again just to emphasize, we're looking at the within-change from follicular to luteal.  So, in actual fact, a carryover effect present here would actually bias against fluoxetine.  
		So, in spite of that bias, when we look at the overall p value for the treatment effect at cycle 1, we see, in spite of the carryover effect, which is biased negatively versus fluoxetine, the differences between fluoxetine and placebo still attain statistical significance.
		Just to show the robustness of the scores in another manner, I'm now going to focus on looking at the first 3 cycles here.  I'm going to show you results from just the first 3 cycles which really approximate to a parallel group study.
		This is looking at the so-called first period analysis.  That's the analysis from the first 3 cycles of that study.  This is looking at a variety of measures with respect to the moods on the left side and respect to the physical symptoms on the right side. 
		For VAS Mood-4 subtotal, for DRF Mood subtotal, for PMTS-P subtotal, for PMTS-C subtotal, overall, whichever way you look at it, even in the first period analysis only, statistical significance is for fluoxetine versus placebo.  And the same is evident for the physical symptoms.  Again, just looking at the first period only, statistical significance is for fluoxetine versus placebo.
		So, in conclusion for efficacy in the study, a flexible dosing for fluoxetine in the range of 20 to 60 milligrams a day -- and the patients attained a mean dose of 27 milligrams in this study -- was effective in the treatment of PMDD.  Again, we saw statistical differences superior to placebo with respect to the primary objective, the VAS Mood-4, and importantly also the secondary objectives.  Efficacy was seen in the symptom clusters of PMDD for most variables with respect to mood, physical symptoms, and social impairment.  Just an overall analysis of the total scores for the visual analog scale 16-item, again, statistical differences for fluoxetine versus placebo.
		Improvement, as demonstrated in the first study, was demonstrated in the first cycle and maintained for up to 3 months. 
		So, thus far, I've presented two well-designed, randomized, placebo-controlled studies that have shown fluoxetine is statistically significantly superior to placebo in the treatment of PMDD.
		Moving on to the third study, this is X037, study number 3.  This is a placebo-controlled, parallel study.  Initially after the screening period here, patients, first of all, entered a single-blind placebo period here, after which they were randomized to receive either fluoxetine, bupropion, and placebo.  Bupropion is a predominantly dopaminergic agent, and patients were randomized to 300 milligrams a day, as 100 milligrams three times a day, and fluoxetine 20 milligrams a day.
		For this study, the CGI score was listed as the primary outcome measure.  That was specifically the CGI in terms of those patients who achieved a score of 1 or 2 was listed as the primary outcome measure.  So, this is the percentage of responders, the percentage of patients who achieved a score on the CGI of 1 or 2, the primary outcome measure here. 
		As we see here, for fluoxetine patients in orange, there was quite clearly a trend toward significance; p, 0.07 for fluoxetine patients versus placebo.  The differences did not attain statistical differences between fluoxetine and placebo, but you see that the percentage of responders between the bupropion and the placebo groups is very similar, so indicating perhaps, as Dr. Endicott had alluded to, some evidence of the serotonergic specificity for patients with PMDD.
		When one considered any improvement on the CGI, a secondary outcome measures, scores of 1, 2, or 3 -- so, patients who listed any improvement when they scored 1, 2, or 3 on the CGI, and then the differences between the groups are statistically significant in that fluoxetine patients attained the greatest number of patients who were responders, with statistical superiority versus placebo.  Again, essentially no differences between the bupropion and the placebo groups. 
		Consideration of the secondary outcome measures for this study in terms of the daily assessment of functioning, the GAS scores, all showed similar results to the first outcome measures shown here in that the differences indicated some superiority for fluoxetine but not attaining statistical significance.  So, I'm not going to show all of those here. 
		So, two studies have confirmed the efficacy of fluoxetine in PMDD, and a third study has provided supportive evidence with respect to the efficacy of fluoxetine in PMDD.  Importantly, the efficacy shown in these studies is entirely consistent with the other double-blind studies reported in the literature. 
		I'd like to move on to show you the effect size.  As was evidenced in these studies, there were a variety of scales used because there is no one gold standard scale for PMDD.  But it's also interesting to note that even when one makes a comparison of the effect size across the studies, you see a moderate to large effect size consistently for these patients.  This is shown in the next slide. 
		So, effect size can be regarded as a unitless measure that can compare across different studies and different scales.  Generally, the traditional thing is that patients with an effect size of 0.5 to 0.8 have demonstrated a medium to large effect of treatment.
		Now, the circled shapes here are the primary outcome measures.  This lists basically the outcome effect size for study 1 and study 2.  Study 1, the circles are the study 1 outcome measures for the mood items, the physical items here, and the social impairment.  The primary outcome measure is this one, VAS Mood-3.  For study 1, with respect to the 60 milligram arm, the black circle, that is the VAS Mood-3 here.  For study 2, the primary outcome measure, the VAS Mood-4, is shown here.  So, for the primary outcome measures for the first two studies, we see an effect size which is medium to very large, consistently for these studies for the fluoxetine groups.  If you look at broadly the picture of effect for the other effect sizes listed here with respect to the other mood subtotals, the other physical subtotals, and the social impairment subtotals, one sees very broadly an effect size which is ranging from medium to large in the main.
		So, overall in terms of efficacy, I'm going to conclude on the efficacy here.  The PMDD studies were randomized, double-blind, and placebo-controlled.  The study populations were appropriate and consistent, and the outcome measures were appropriate to measure changes in PMDD symptoms.
		PMDD studies demonstrated the efficacy of fluoxetine in the range of 20 to 60 milligrams a day.  Again, just to reiterate, 20 and 60 milligrams appeared to be similarly effective, although there was some numerical superiority for 60 milligrams.  And importantly, fluoxetine was effective in treating the symptoms of PMDD for up to 6 months.  The efficacy of fluoxetine was also evident during the first treatment cycle in all of these studies. 
		Moving on to the safety, as I have indicated, the safety profile of fluoxetine is well-known.  Hence, I will provide a rather succinct summary.
		First of all, with respect to the safety population in the PMDD patients -- and I will compare that to the overall fluoxetine safety database for the indications for which it has been approved in the U.S., that is depression, OCD, and bulimia, numbering almost 4,000 patients.  I will also compare the safety profile of the patients with PMDD to a subgroup of this larger fluoxetine database, and that is the female patients aged 18 to 45 years which most closely approximates PMDD patients.  That database is numbering almost 1,700 patients.
		I will focus on study 1 in terms of the PMDD studies.  Study 1, study 2, and 3.  The adverse events collected here were spontaneously collected for study 1 as treatment emergent adverse events.  For studies 2 and 3, the adverse events were collected in a different manner, and so it was difficult to merge the database with respect to the adverse events.  So, I'm going to concentrate on study 1 when I show you the adverse event profile for PMDD patients.
		First of all, in looking at the overall study drug exposure for the PMDD safety population in total, the total days of exposure was over 27,000 for fluoxetine at any dose.  Importantly, about 50 percent of this exposure was in the range of 151 to 220 days.
		This is looking at study 1 and looking at the percentage of patients who reported one or more adverse events, as one would expect overall, a high level of reporting for the three groups and with more patients reporting adverse events in the fluoxetine arms versus the placebo arms.  With respect to the patients who dropped out for any adverse events for this study, more patients dropped out in the fluoxetine 60 milligram arm as compared to fluoxetine 20 and placebo.  No statistical differences in the patient dropouts in the fluoxetine 20 or placebo arm. 
		I just want to reiterate that the patients who were on 60 milligrams in this study did start on 60 milligrams at day 1.  They did not have the ability to titrate up to that dose.  So, from what we know about fluoxetine, it may be that if they had started on 20 and titrated up to 60 milligrams, this higher rate of dropout would not be evident for patients as shown here.
		This is also evidenced by the fact that when the dropouts did occur in the 60 milligrams, most of the dropouts were, in fact, in the first portion of the study, so fairly early on with fluoxetine treatment.
		There were very few serious adverse events in this study at all. 
		This lists the most common treatment emergent adverse events in study 1 reported by at least 10 percent of patients taking fluoxetine.  This is fluoxetine 20 milligrams, fluoxetine 60, on both slides.  Overall, the pattern of reporting of adverse events for fluoxetine are what we would expect for what we know about fluoxetine.  Importantly, fluoxetine 20 milligrams appeared to be very well tolerated with very similar differences, not statistically significant to placebo, for any adverse events of any clinical significance.
		For patients on fluoxetine 60 milligrams, there were high numbers of adverse events reported and in some cases the differences between fluoxetine 60 and both placebo and 20 milligrams were statistically significant.  As I stated earlier, the fact that these patients did start out on 60 milligrams from day 1 may have been a factor in this.
		Now, these slides compare the most common treatment emergent adverse events in the three databases that I alluded to.  Firstly, for study 1, this is the incidence of adverse events for the fluoxetine groups. There is a combination of the 20 and 60 milligrams groups, and this is compared, first of all, to the approved indications database.  These are patients with bulimia, depression, OCD, and then this is again compared to the approved indications females subgroup of that database, females aged 18 to 45.  If you view overall the adverse events, the pattern of adverse events is as expected for fluoxetine, and importantly no unique adverse events were emergent which showed any uniqueness for PMDD patients.
		In order to assess tolerability, it's perhaps pertinent to look at patients who had dropped out due to any adverse events.  This shows patients who dropped out in study 1, study 19.  We view that overall, first of all, for fluoxetine 20 milligrams the incidence of dropouts was low, and no one particular adverse event contributed in particular to a high level of reporting of dropout due to adverse event.  Very few patients dropped out in studies 2 or 3 due to adverse events.  So, again, the dropout here would be as one expected for fluoxetine.
		So, in conclusion for safety, fluoxetine has been used in over 35 million patients worldwide and a very, very large safety database does exist for fluoxetine.  I've provided evidence to show its safety in PMDD patients and compared that with respect to the approved indications database.  Also extensive post-marketing surveillance for this pharmacological agent has shown it to be a very safe product. 
		Fluoxetine patients with PMDD is therefore safe and well-tolerated and, importantly, clinically comparable to the known profile of fluoxetine with no unique events seemingly for the PMDD patients.
		Fluoxetine 20 milligrams appeared to be better tolerated than fluoxetine 60.  Overall fluoxetine 20 milligrams was as expected, well-tolerated and safe for PMDD patients.
		I'll now provide dosing recommendations based on the efficacy and safety data that I have just reviewed.  Again, just to reiterate, fluoxetine 20 and 60 were similarly effective in patients with PMDD.  While fluoxetine 20 to 60 is safe for patients with PMDD, 20 milligrams did appear to be better tolerated than 60 milligrams.  So, therefore, the optimal dose should be 20 milligrams for patients with PMDD, and some patients may, indeed, benefit by increasing their dose to 60 milligrams. 
		Before providing the concluding the comments, I'd like to address one of the questions that the FDA have raised with respect to the use of oral contraceptives.  I've indicated in these studies patients with oral contraceptives were excluded for the reasons previously alluded to in that they do have variable effects on premenstrual symptoms.  Where they do have an effect, it seems to be on the physical symptoms, and that is inconsistent so.  So, in order to clearly delineate the effects of fluoxetine in these studies, oral contraceptives were excluded.  Nevertheless, for menstruating females, reports anything up to 30 percent of patients may be taking oral contraceptives.  So, the question arises, does the combination of the use of oral contraceptives in combination with fluoxetine have any implications for efficacy or safety for that combination?
		First of all, what are the potential for possible interactions from the pharmacokinetic point of view?  Fluoxetine is metabolized primarily by the P450 2D6 enzyme system.  The oral contraceptives are primarily metabolized by the P450 3A4 enzyme system.  Now, the effect of fluoxetine on the 3A4 system has been investigated by virtue of in vitro and in vivo studies.  The in vivo studies, using the 3A4 substrates of midazolam and terfenadine, did not indicate any clinically significant interactions between the combination.  So, this suggests that there is unlikely to be any potential for interaction between fluoxetine and oral contraceptives. 
		I'd now like to provide evidence from clinical data which further supports this.  As I've indicated, there is a very large efficacy and safety database for fluoxetine with respect to other indications.  So, although the PMDD patients did not have any oral contraceptives concomitantly, in the other indications, for example, depression, OCD, and bulimia, there were patients who did take oral contraceptives.  So, by subgrouping those existing safety database with respect to efficacy and safety, it was possible to try and tease out any possibility of interactions between oral contraceptives and fluoxetine.
		First of all, with respect to efficacy, just to reiterate, many of the women in the approved indications database were taking oral contraceptives.  So, in viewing the efficacy of patients with depression, OCD, bulimia, and comparing it for those patients who did take oral contraceptives versus those that did not, there was no clinical evidence that concomitant use of oral contraceptives either augmented or lessened the efficacy of fluoxetine.
		The same analysis with respect to the safety during clinical trials of fluoxetine, no drug interactions were noted for patients who were taking oral contraceptives.
		Importantly, extensive post-marketing surveillance has not shown any evidence for interactions between fluoxetine and oral contraceptives.  It's important to note that fluoxetine has been on the market for over 10 years.  Also, a search of the literature yielded no case reports of such an interaction.  
		So, it would seem from the data presented, that oral contraceptives and fluoxetine can be used safely with respect to efficacy and no safety implications.
		So, my concluding remarks.  PMDD is a distinct clinical entity which can be differentiated from depression and other anxiety disorders.  It can be considered a severe form of premenstrual syndrome that causes impairment of functioning.  It's quite clearly inadequately recognized and treated at the present time.  For fluoxetine in PMDD, three randomized, double-blind, controlled studies presented support for the efficacy of fluoxetine in PMDD.  The results presented are entirely consistent with the numerous other published studies for fluoxetine in PMDD.  Safe and well-tolerated at the recommended dose, and the dosing recommendation is appropriately supported by the data presented.
		Thank you very much for your attention.
		DR. TAMMINGA:  On behalf of the committee, I'd like to thank Dr. Judge, Dr. Endicott, and Dr. Brophy for their very well done presentation of the data set.
		I'd like to suggest that we take a break and formulate questions, and following the break, the committee will come back and address questions both to Lilly and to the FDA.  We'll take a break and be back by 10:15 please.
		(Recess.)
		DR. TAMMINGA:  I'd like people to take their seats so we can restart the meeting please.
		The committee has now heard a presentation from Lilly about their indication.  We've heard the issues laid out and many probing questions laid out by Dr. Laughren.  Now, the committee will have a chance to ask questions to Lilly about the presentation of their data.
		I would like to encourage not only the committee members, but also the advisors to satisfy every question, so to speak, to Lilly because after we come back from lunch, the committee will then talk about all the issues that came up about the presentation.
		One more thing I need to remind the committee of.  Unlike our last meeting, all the microphones are active all the time.
		(Laughter.)
		DR. TAMMINGA:  So, if people would just keep that in mind. 
		There are a number of committee members who have questions for Lilly about the presentation.  I would suggest that Dr. Judge actually come up to the podium, if you do not mind, rather than getting up and going down all the time, and you can actually address questions from the committee.  I did not mean to say that Dr. Judge had to answer these questions all by herself.
		(Laughter.)
		DR. TAMMINGA:  But I suspect all of your Lilly will help out anytime.  Also, we might have questions for the rest of the Lilly people, but you can really moderate the response.
		I might just take the chair's prerogative and ask the first question.  Would you remind us, Dr. Judge, what is actually the half-life of fluoxetine and its major metabolite?
		DR. JUDGE:  The half-life of fluoxetine, 4 to 6 days.  The active metabolite, norfluoxetine, up to 16 days.
		DR. PARRY:  I'd appreciate it if you could review on each of the studies you presented, the authors, the site of the study, and where it was published.
		DR. TAMMINGA:  If the person who's asking the question could just identify themselves for a minute.
		DR. PARRY:  I'm Barbara Parry, Professor of Psychiatry, University of California, San Diego.
		DR. JUDGE:  Study 1 was conducted in Canada in 7 centers and was published by the principal investigators, Dr. Steiner, et al. in the New England Journal of Medicine.
		Dr. Schmidt was the primary investigator for the second study, X022, and that was conducted in that one center.  That was published in which year, my colleagues can remind me.  We'll get that information. 
		And the third study was conducted by -- the principal investigators were Terry Pearlstein, et al., and were conducted in two centers, the other investigator being Dr. Stone.  That was published also a number of years ago.
		DR. THYS-JACOBS:  I'm Susan Thys-Jacobs, and I want to just ask a couple questions about study 19, which was the multi-center trial. 
		All the studies that you had presented are double-blinded and I'm assuming that the tablets looked alike.  But in 19 there was placebo, 20 milligram dose, and there was a 60 milligram dose.  When they went from single-blind into double-blind phase, how did you carry that out?
		DR. JUDGE:  It was one capsule.  There was always one capsule for 60 milligrams, 20 milligrams, and placebo.
		DR. THYS-JACOBS:  It was one capsule for the 60.
		DR. JUDGE:  Yes. 
		DR. THYS-JACOBS:  Okay.
		Another question for 19 was that you defined baseline scores as visit 3 and 5.  Were the true baseline scores before entering the single-blind washout different or similar?  Luteal mean scores.
		DR. JUDGE:  Dr. Steiner can perhaps elaborate on this as well.  But for the patients, as they entered the screening phase, and then prior to that, the scores were similar, but I don't have the scores for that on hand. 
		Dr. Steiner, can you comment?
		DR. STEINER:  There's no difference in the baselines for the two or three cycles that actually screened the patients before they went into the single-blind assessment phase.  The data that are used are for placebo nonresponders that entered into the randomization.
		DR. THYS-JACOBS:  I have another question for 19.  You showed the data at the first treatment through treatment cycle 6.  At treatment cycle 6, however, at the 20 milligram dose, there seemed to be a diminution effect, not major, but there did, indeed, seem to be some decreased effect.  Was that effect significantly different from treatment cycle 1?  
		And how do you explain the fact that there was a decrease of rapid decline in symptoms in treatment cycle 1 and then there seemed to be a gradual increase in symptoms by treatment cycle 6?  Do you think that women over time become more tolerant to this drug?
		DR. JUDGE:  I'll make an attempt at answering that, and perhaps Dr. Steiner can also comment. 
		What's interesting at cycle 1 of that study, as you correctly noted, is a very, very robust and fast response, and it may be evidenced by the fact for the extreme relief experienced by these patients.  Remember, they've had several cycles at that time of prospective monitoring, and it may be reflected in their extreme relief.  
		Now, that was a 6-month study and so, therefore, a long-term study.  Also, it may be reasonable to assume that patients towards the end of the study are less able to reflect or relate to their baseline levels of functioning as they would earlier on in the study.
		The important thing is that throughout the study 20 milligrams was statistically significant from placebo in the LOCF population.
		DR. THYS-JACOBS:  Well, that was the mean and at all cycles.
		DR. JUDGE:  At all cycles.
		DR. THYS-JACOBS:  No.  My question was, was there a difference --
		DR. JUDGE:  Was there a difference between the last --
		DR. TAMMINGA:  One at a time please.
		DR. JUDGE:  My statistician, Dr. Brown, will attempt to answer that. 
		DR. BROWN:  This analysis looks at the comparison of the treatment effect at the first treatment cycle to the last treatment cycle, cycle 1 versus cycle 6.  These are, of course, just those patients that completed all the way through.  So, it's just those patients that completed that 6-treatment cycle.  We show the means and the standard deviations, of course, for the first and the last.  It's just a basic paired t-test looking from the first to the last, and you can see for the within-group comparisons for the placebo and the 20 and the 60 milligram groups, there were no statistically significant differences between the first and the last.  For fluoxetine 60 milligrams, it's a trend for a difference.
		Now, looking at the physical, there was a difference between the first and the last for the fluoxetine 60 milligram group, but not the fluoxetine 20 milligram group.
		DR. TAMMINGA:  So, this is a completers only analysis.
		DR. BROWN:  Yes.  This is only completers.  That's correct. 
		DR. TAMMINGA:  So that if you look at a completers only analysis, it looks considerably different than the last observation carried forth, which is a slide that Dr. Judge showed.
		Dr. Hamer.
		DR. HAMER:  I actually have lots of questions, but just one that's -- 
		DR. TAMMINGA:  Do you want the statistician to sit down or stand up?
		DR. HAMER:  I'm not sure who's appropriate to answer this one. 
		Remind me again about what direction the scoring is; that is, let's look, for example, at fluoxetine 60, first cycle, 23.7; last cycle, 31.6.  Does that mean they got better or they got worse?
		DR. JUDGE:  From baseline, the average follicular scores for fluoxetine 60, as in all of them, for VAS 3, was actually around 50.  So, the mean here is -- this is 23, which -- and so the mean here is 31, which is slightly worse than 23.  The lower the score, the better the patient.
		DR. HAMER:  So, here for the fluoxetine 60 group, they got non-significantly worse between the first treatment cycle and the last treatment cycle.  Right?
		DR. JUDGE:  This is a difference of 7 points on this score.
		DR. HAMER:  In many of the analyses that you presented earlier, you presented a lot of data in which one group had a number that was bigger than another group and non-significant, but nonetheless, you pointed out to us that one was numerically different than another.  Here you're choosing not to pay attention to that numerical difference.
		DR. JUDGE:  I don't understand what you mean.  We are paying attention in showing that to you.  There is a numerical difference.  Here the difference is from the baseline to the mean, to the mean, there is, for example, for the 20 milligrams, maybe there's a difference from here to here.  The last treatment cycle is about 5 points and only about 7 points for fluoxetine 60 milligrams.  So, it's not that great.
		DR. TAMMINGA:  Dr. Dominguez.
		DR. DOMINGUEZ:  Yes.  This is an unusual application in that not only the total number of patients that were entered into the application, which was similar to the OCD application, but also from the fact that, as far as I'm concerned, at least 80 percent of the strength of the treatment effect is carried by one study.  And perhaps you could argue 90 percent of it is carried by the 019 study, the other two studies being relatively small. 
		Was there an extension phase to the 019 study?
		DR. JUDGE:  There was not a formal extension phase to that study.  Dr. Steiner can perhaps comment anecdotally on what happened to patients after that study, but there were no formal extensions to that study.
		Dr. Steiner, would you like to comment?
		DR. STEINER:  In all sites, most of the subjects who were completers on fluoxetine requested to stay on the drug and did so.  We have informal or anecdotal evidence up to 1 year that women still were on the drug.  I'm talking 20 milligrams. 
		DR. DOMINGUEZ:  Was fluoxetine available in the market at the time that the study was initiated in May of 1990?  And could this have influenced your retention rate?  I am not surprised with regards to the lower retention rate with the placebo group and the 60 milligram group, but I am somewhat surprised at the low retention rate in the 20 milligram group since they seem to be doing so well.  So, could the fact that the medication was already available in Canada at that time have influenced your retention rate?  What are your thoughts?
		DR. STEINER:  I can only speculate.  But the drug was available.
		DR. DOMINGUEZ:  It was available.
		DR. STEINER:  Yes.  At the end of the study, the drug was available.
		DR. DOMINGUEZ:  At the beginning of the study, it was also available.  Correct?
		DR. STEINER:  Yes.
		DR. TAMMINGA:  Dr. Judge, in this study number 19, could you review for us again the retention rate in the placebo and the 20 and the 60 milligrams?
		DR. JUDGE:  If we could go back to the primary analysis that shows the patient disposition for study 19 please.
		Green, placebo; in orange, fluoxetine 20; and in yellow, fluoxetine 60.  For fluoxetine 20 milligrams, about 65 percent of those patients completed the study.  Remember, this is actually a 6-month study, which is a long-term study.  As you would appreciate in doing studies with obsessive-compulsive disorder, depression, other studies, it's actually very difficult to keep patients in a long-term study.  But nevertheless, 65 percent of them completed, and the completer rate in terms of placebo and 60 milligram arm ranged from 40 to 50 percent.
		With respect to the dropouts due to adverse events, as you pointed out, it's higher in the 60 milligram group than the other groups.  The dropouts due to adverse events between fluoxetine 20 and placebo was not statistically significant, and to be honest, with respect to other studies that we know for depression, OCD, or whatever, it's not remarkably different.  Again, remember, this is over a 6-month study. 
		As I pointed out, for fluoxetine 60 milligrams, patients were started on that drug at day 1, 60 milligrams at day 1.  It would be more appropriate to start them on 20 and titrate them up, giving them a chance to tolerate the side effects.  If that had taken place, the titration, one would in fact expected a perhaps lower dropout rate due to adverse events. 
		In terms of lack of efficacy, as we predicted, about 25 percent of placebo patients dropped out due to lack of efficacy.
		DR. DOMINGUEZ:  Yes.  I appreciate the fact that this was a 24-week study and the OCD studies were 13 weeks.  On the other hand, one could view it as a 6-cycle study versus a 13-week OCD study, and that the percentage of response in these trials was very similar to the percentage of response in OCD trials with regards to the active treatment and in comparison also with the placebo group.  Basically you had no placebo effect here.  You got no placebo effect in your OCD application. 
		So, since 80 percent of the patients in the 20 milligram OCD study completed the study, I'm a little bit surprised at 65 completing after 24 weeks.  Just an observation.
		And I wanted to relate that to the availability of the drug in Canada that some patients may have opted out of the study, either seeing insufficient response, and also based on the population that you treated, which was principally a college graduate population or higher education.
		DR. TAMMINGA:  Yes, Dr. Geller.
		DR. GELLER:  I just want to comment on comparing OCD to this disorder, that OCD bothers you every day of the month.  This bothers you just part of the month and that might account some for the difference in dropouts.
		DR. TAMMINGA:  Additional questions for Lilly?  Dr. Fyer.
		DR. FYER:  I just want to follow up somewhat more informally this observation because this is the main study that the efficacy depends on.  The fact is that they start our randomizing 320 patients out of over 400, and then we end up with 172 patients at the end.  I agree that it doesn't seem immediately obvious why that should be true despite the length of the study.  If you look at the table about attrition, it doesn't look like there's such a much higher initial rate of attrition in the 60 milligram group.
		So, what I'd like to just ask is just informally do the people from Lilly have any idea about why so many people dropped out in that study?  Because in the other studies, Dr. Judge made the point that very few people did drop out.  Is it just because you have a more representative sample, you're going to have a higher dropout rate?  Or is there something about that study?  What were people's informal observations about that situation?
		DR. TAMMINGA:  Can you comment on this, Dr. Judge?
		DR. JUDGE:  Just on that point when you said there wasn't evidence of attrition early on in the study, there was in fact, and I think we have a slide to show in terms of patient dropouts due to adverse events for the 60 milligram arm versus the 20.  You'll see that most of them did, in fact, drop out in the first two cycles.  I'll just show you that, and the slide will show you that.
		Thereafter, the attrition rate for fluoxetine 20, placebo -- placebo patients dropped out more towards the end.  We show this here.  So, this is the patient discontinuations due to adverse events by time.  This is a number of patients dropping out.  So, for fluoxetine 60, you see that in the first couple of cycles, the patients dropped out.  Thereafter, it's a steady dropout, not particularly different from cycle to cycle, and it's fairly constant for the other two arms.
		Do you also have the slide due to lack of efficacy, the same slide?  This is true for the lack of efficacy.  As one would expect, for placebo patients, more patients drop out as the study continues over the course of time due to lack of efficacy.
		In reviewing this data, I think overall the highest number of patients stayed in the study for 20 milligrams.  When one looks at the attrition rate for some of the long-term studies for depression and OCD, there is quite a high attrition rate when you refer to OCD studies.  The short-term attrition rates are obviously better than -- short-term attrition rates would be not as high as this study.  This is a long-term study, and generally when one looks at long-term studies for all drugs, there seems to be a high attrition rate in general.  But even so, 65 percent of patients on 20 milligrams were still remaining at the end of the study.
		DR. TAMMINGA:  Dr. Fyer?
		DR. FYER:  Yes.  I don't want to get into a picky thing about 10 patients, but I think the important thing is that there's a continued steady drop-off.  You have a very slight increase in the number of people on 60 milligrams in the first week, but then at every time another 10 percent of the patients are leaving the study.  It's not just in the 60 milligram group.  Again, I'd just like to ask you if you have some idea as to what was going on in that study.
		DR. JUDGE:  Can I refer also Dr. Steiner here?
		DR. STEINER:  This is not unusual in PMS/PMDD that you lose at the end up to a third of your population, A.
		B, this was a very labor-intense study.  These women were with us for a year.  They had to come twice a month, and some of them just gave up after a while.  And the steady decline is really not unusual in these studies.
		DR. TAMMINGA:  There was some part of Dr. Fyer's question that would contrast the dropout rate in this study with the dropout rate in the next two.  While you're up there, maybe you could just more specifically --
		DR. STEINER:  This was the longest and more labor-intense than the others.  The requirements were different.  We were bringing them in.  They had to be, twice a month, in the clinic for up to 90 minutes, 2 hours sometimes.  Canada is a big country.  There are all not in the big cities.  They're coming from far away.  We had winters.  All the stuff that you see under "other" is transportation, distance, and cold weather.  And then you had to sort of drop them out because if they missed two or three visits, they were out.
		DR. TAMMINGA:  Dr. Winokur.
		DR. WINOKUR:  Related to this study, you mentioned early on in introducing it that a decision was made to focus on the VAS Mood-3 as the primary outcome measure.  I wasn't clear about the rationale for that choice.  I wonder if you could elaborate on that a little bit.
		DR. STEINER:  If you recall -- we're talking the late '80s, early '90s -- the visual analog scale was a homegrown thing that we developed.  At the time when we started working with Lilly, we did not anticipate, nor did we know that fluoxetine is going to be helpful for the physical symptoms.  We thought that if we lumped together the 7 symptoms and if it doesn't work for the physical symptoms, we will actually wash out some effect on the other 3 major components.  So, we picked irritability, dysphoria, and tension as the primary outcome.  We left the lability out because some people questioned whether this is a unipolar or bipolar dimension, and we then separated them out. 
		But as you have seen, we have the same statistical significance for the 3 VAS.  We have it for the 7 VAS, and we have it for the physical separately.
		DR. WINOKUR:  My other question.  This now switches to safety, adverse events.  Can you comment either from your specific studies that you talked about or other information in the literature about the occurrence of hypomanic or manic symptoms in this specific population on fluoxetine?
		DR. JUDGE:  With respect to the occurrence and switch into mania for fluoxetine in general, there's a very low switch rate.  That's evidenced by the clinical trial database.  In fact, one of the few double-blind studies of bipolar depression with fluoxetine versus imipramine, evidenced again a nice treatment effect, without any increase in switch-over to mania versus placebo.  So, that's for general fluoxetine.
		For switch-over to mania in this study, there were no patients in the PMDD population that ascribed to or switched to mania.
		DR. WINOKUR:  If you scale it down from full-blown mania to more just --
		DR. JUDGE:  To hypomania?
		DR. WINOKUR:  -- manifestations suggestive of hypomania, I'm just wondering whether there's -- I'm focusing on this population because this is going to be a population that's going to be extending the use of this drug.
		DR. JUDGE:  Right.
		DR. WINOKUR:  And if there's any even clue of the potential for activation of --
		DR. JUDGE:  Yes.  From the studies in this population, there wasn't any event that we'd say, oh, my gosh, this is happening.  
		Anecdotally perhaps Dr. Steiner can comment about his other experience or even Dr. Endicott.
		DR. STEINER:  The exclusion criteria were that they should not have an Axis I diagnosis.  Therefore, we did not include bipolars.  But we did not have hidden bipolar II's and we did not have a single switch in this study.
		DR. WINOKUR:  That's really what I'm trying to focus on is excluding the known bipolars.  Is there any even hint?  Because what we're really talking about now is extending this drug to a totally separate population not known to have bipolar, and that's why I think that's a crucial issue.
		DR. STEINER:  We did not witness one single case.
		DR. JUDGE:  And that was also evident for the other two studies.
		DR. THYS-JACOBS:  There was no placebo effect noted during the double-blinded study period 2 in this trial.  Was there a placebo effect going from the screening period to study period 1?  Was anything noted?
		DR. JUDGE:  Are you talking about study 1?
		DR. THYS-JACOBS:  19, yes.
		DR. JUDGE:  Can you repeat your question?
		DR. THYS-JACOBS:  There was no placebo effect noted during the double-blinded phase at all, and apparently that was being screened for during the single-blinded study.  I'm asking was there a placebo effect noted during the screening period into the single-blinded phase?
		DR. JUDGE:  Yes, indeed.  And Dr. Steiner will elaborate.  But there were some patients who did drop out during the screening phase because they were placebo responders.  So, a placebo effect was evident.
		Dr. Steiner?
		DR. STEINER:  There were 12 placebo responders during those first two cycles and they were not randomized.
		DR. TAMMINGA:  12 out of 320 or 12 out of 450?
		DR. STEINER:  Out of 450.
		DR. JUDGE:  Remember, by this time in terms of the placebo effect, patients had really undergone several cycles of screening with respect to their diagnosis and prospective daily ratings.  So, really --
		DR. THYS-JACOBS:  There were two cycles.  We're talking about two cycles.  There were two screening cycles.  Is that correct?
		DR. JUDGE:  There were screening cycles, but even before then, patients in terms of their screening, that they brought patients into the study -- we're talking about one would expect a fairly low level of placebo responders in this study because, for example, in depression or other studies, we don't prospectively diagnose patients by prospective measurements.  This is unusual and I think serves to lower the placebo response in PMDD studies in general anyway.
		In fact, the placebo effect noted here is not appreciably different from placebo effects noted in other SSRI studies in the literature.
		DR. THYS-JACOBS:  Most of the studies that I know of have a 25 or 20 percent to 30 percent effect.  You're saying that in these studies, in the PMDD trials, there is no placebo effect?
		DR. JUDGE:  You saw that there was a placebo effect, and in fact for this study, as Dr. Steiner will comment as well, there is a placebo effect.  The placebo effect is low which can be sometimes attributed to the screening allowed for these patients.  But also remember, in general -- this study was conducted quite a while ago, and maybe as with other studies, maybe there may be a creep up of placebo effect due to other phenomena, as we see with OCD, as we see with depression.  That may be evident, and maybe that's what you're ascribing to PMDD studies.
		DR. THYS-JACOBS:  No.  Most of the published trials on PMDD and PMS have shown effects of anywhere from 20 to 70 percent.  So, how are you talking about 12 out of 300 patients going from the screening period into the study phase?  That's a very small number.
		DR. JUDGE:  But there is no study that shows a 70 percent response rate for PMDD.  When we talk about those high levels of placebo responses, we're talking about studies which really are not specifically PMDD but more often listed as severe PMS or PMS in general.
		Dr. Steiner, would you care to comment on that?
		DR. STEINER:  Two things.  I agree with Susan that -- we were very surprised.  It was a low placebo response.  Two things to say about it. 
		The literature is really not about PMDD.  It's mostly about PMS, and there the placebo response was obviously much higher.
		The other thing is that between the initial screening and the randomization, we have lost not only 12 placebo responders, we have also lost approximately 80 other patients which we were not able to document whether they were placebo responders and that's why they left us.  They just disappeared for other reasons.  So, maybe it was a little bit higher.  But we have documented to date on 12 placebo responders who stayed with us and had to be told that they cannot be randomized because they're placebo responders.  That's what I can report on.  The others are speculations.
		I think that overall we had a very low placebo response because of the extremely rigorous inclusion criteria.  This was the first time that that kind of rigor was actually applied.  So, we excluded them before they even were coming into the placebo phase.
		DR. TAMMINGA:  Dr. Temple.
		DR. TEMPLE:  Just a point of terminology.  The placebo response is not measured in clinical trials.  What you measure is the response in the placebo treated group, which is a mixture of true placebo response, that is, response to drug taking, and the natural history of the disease.  This comes up a lot.  
		The idea that in depression the placebo response is 60, 70 percent I think is totally unreasonable and is a quirk of study design.  You take people who are in the process of being at the worst part of a cyclical disease and then you put them in a trial, it's not surprising they regress toward the mean and do other things like that.  But if they got a good history of regular monthly symptoms over many years, it doesn't surprise me at all that when you put them in a trial, nothing much happens because they're not regressing toward a mean.  This is something they have.
		So, these are very study-determined.  I have a sort of personal quest to not call these responses in the placebo group placebo response until somebody actually includes a no-treatment group, that is, someone who doesn't get any drug at all, and that is almost never done.  So, we don't really know what the placebo response is here.  We just know how the placebo group responds, which is not necessarily the same thing at all.
		DR. TAMMINGA:  Dr. Hamer.
		DR. HAMER:  After a number of years of doing this, I think I have a reasonably good idea of how to interpret these sorts of studies when the studies have been designed with rigorous protocols by pharmaceutical companies involving an end of phase II/pre-phase III meeting in which the design, the outcome measures, and the statistical analyses are planned and consultation takes place.  It's less clear to me how to interpret studies whose purpose is registration when apparently that kind of process didn't take place here.  
		So, to help me understand this, could somebody from the pharmaceutical company please, in some sense, take me through the history of these studies, tell me whose idea they were, if indeed rigorous documentation, such as protocols that specify design, outcome measures, statistical analyses, in as much specificity as might take place in sort of the usual situation and to what extent things like the switch apparently from a measure that consisted of a total of a full-blown set of visual analog scales to a measure that consisted of only a subset of them, of an analysis that switched from an analysis of percent change to an analysis that consisted of absolute change, even though, if you analyzed the data both ways, you get consistent results. 
		But there's in some sense at least the potential for kind of a hidden multiple comparison issue here which, thankfully for Lilly, is probably obviated by the fact that there was such a strong effect that we probably don't need to worry about it much. 
		But I would like to know sort of how these studies got designed and what role Lilly played, if any, in the design, funding, and execution of them. 
		DR. TAMMINGA:  And your question pertains to all three studies.
		DR. HAMER:  It pertains to all three studies.
		DR. TAMMINGA:  Dr. Judge.
		DR. JUDGE:  Well, study 1 was a protocol designed collaboratively by Lilly and Dr. Steiner.  The protocol was put into place and agreed by Lilly and by Dr. Steiner.  It was Lilly monitored.
		DR. HAMER:  So, this is what we would call an investigator initiated study?
		DR. JUDGE:  Yes, and Lilly funded and Lilly monitored.
		For the other two studies, they were conducted more independently.  For study number 2, this was conducted under an independent IND, and number 3 was exempt from IND.
		For all three studies, protocols and analysis plans were put in place by the investigators before the study obviously started.  Lilly, when comprising their analysis plans -- it's important to note that all analysis plans were put into place and very strict audit and quality controls were done for each of the sites to ensure that the studies had been conducted to GCP standards, had been conducted according to protocol, and with the exceptions that I've stated with the reasons for those exceptions.  In all studies, we're confident that the quality of the studies is as one would expect, good quality, GCP conducted studies.  Importantly, with respect to the analysis plans, which were prospectively put in place, before any of those Lilly personnel had information or unblinded to the individual patient information.
		DR. HAMER:  Well, then to move to the blinding issue, I got confused by the statement that apparently the crossover study terminated early because the blind was broken somewhere in the middle and then the investigators did an analysis, presented an abstract, and then decided not to continue the study.  Is that the case that the blind was broken part way through it?
		DR. JUDGE:  As you indicated, yes, but the blind was not broken to individual patient assignment to the raters who were rating the patients and, moreover, to the patients.  As you remember, the primary outcome measure was patient-rated visual analog scale.
		Now, when the analysis was done for that study, it involved very few numbers of patients.  In fact, the investigator found a treatment effect and stopped the study.  In fact, there were a number of other patients enrolled in the study at that time, and they were allowed to complete.  That numbered a total of 19, as you saw.
		DR. HAMER:  I'll save other questions until later.
		DR. TAMMINGA:  Dr. Chen.
		DR. CHEN:  Let me add some questions for this topic here.  Could you briefly describe the early termination for the second study?  How many times you have unblinded the data, when you decided?  Did the investigator decide, how they decided to terminate the study?  Do you have that knowledge here for this?
		DR. JUDGE:  In addition to what I've just alluded to, it was an independent decision by the investigator to terminate the study at that time.  But as I said, if someone from my group can elaborate on how many patients exactly that analysis involved.  But I said there were a number of other patients ongoing in the study.  It wasn't that 19 had completed and then the analysis involved 19 patients.  Only a fewer patient number had completed, and in fact when he found that statistical difference, he decided to terminate the study independently.  Then the other patients who were already enrolled in that study were allowed to complete.  As I said, the clinicians who rated the patients, the patients themselves remained blinded in order to minimize any bias in that study.
		DR. TAMMINGA:  Dr. Fyer.
		DR. FYER:  I just want to ask a clarification.  So, that was an independent investigator study.  Who were the clinicians versus the investigator that all this was kept --
		DR. JUDGE:  Well, as with any site, there is a principal investigator, and there are people who work with the investigator who are the study coordinators that are more involved in the actual screening of the patients, the rating of the patients week by week, and assessing them per protocol.
		DR. FYER:  I'm aware of how clinical trials are done generally.  But what I'm interested in is, are you aware on a person-by-person basis of exactly who knew and who didn't know?  Because very often, especially in smaller organizations, there's a lot of functional overlap.
		DR. JUDGE:  Yes.  In fact, for that study -- and my team can correct me if I'm wrong -- it was mainly the other co-investigator for that study, Dr. Su, who was actually seeing more of the patients.
		DR. FYER:  And so, there was no communication about the overall outcome or any issues about patterns of side effects or anything of that nature.
		DR. JUDGE:  Not that I'm aware of.  As I said, the audit on that study has been very meticulous in terms of quality assurance and quality control.
		DR. TAMMINGA:  Dr. Hamer.
		DR. HAMER:  Well, to continue Dr. Chen's question, I think maybe one of the things that might be related is, in the protocol, was this interim analysis that led to the early termination of the study planned?
		DR. JUDGE:  This was an unplanned interim analysis.
		DR. HAMER:  Do you know if there were other unplanned interim analyses?
		DR. JUDGE:  No, there were not.
		DR. HAMER:  So, if you think about spending your alpha in terms of sequential analyses, there was no adjustment for that here.
		DR. JUDGE:  If I can ask my statistician to comment on this.
		DR. BROWN:  No, there wasn't an adjustment.  But like we said, the investigator initiated this unplanned interim analysis at 10 patients, found a significant effect, and decided to stop the study, and continued the patients that were currently enrolled, so we ended up with 19 patients.
		If we go ahead and use a penalty for an early look, say, an O'Brien-Fleming type of a spending rule, and adjust for those looks at the data at the 10 and the 19, we would still show a significance all the way through.  That would be about a .01 nominal significance level we would be looking at at the 19 patient level.
		DR. HAMER:  Although since this is a post hoc use of an O'Brien-Fleming sequential rule, we really don't know how many interim analyses we should be adjusting for since they might have chosen to have done other interim analyses than the ones that they did.
		DR. BROWN:  Right.  They might have chosen to do something else, but they did just do the one look at 10.  So, you're right.  It is a post hoc.
		DR. TAMMINGA:  Should we understand that Lilly looked into whether they did any other unplanned analyses and the answer is no?
		DR. BROWN:  That's right.  No, they did not.
		DR. HAMER:  Although perhaps the blind to the raters was not broken, did the raters know that an interim analysis had been done and that the interim analysis apparently showed that fluoxetine was superior to placebo?
		DR. JUDGE:  There was, as I said, an abstract generated from that interim analysis.  So, anyone who viewed that abstract would, in fact, know that that was the case.  But remember, that was on a fewer number of patients.  So, the abstract actually reported a fewer number of patients, but the actual end of the study involved almost a double number of those patients.
		DR. HAMER:  As long as I have gotten us onto the crossover study --
		DR. COOK:  Can I follow up on this one?
		DR. HAMER:  Yes.
		DR. TAMMINGA:  Dr. Cook.
		DR. COOK:  I really feel the need to know very specifically how this study was blinded because it just raises many questions if it wasn't blind to the investigative team.  So, I really feel the need to have detailed knowledge of how this was blinded to where it could be relatively arbitrarily unblinded.  Were the capsules identical?  We have to get the details since it's at variance with usual practice.
		DR. JUDGE:  In terms of the blinding for this study -- and perhaps, Cathy, if you could comment on the actual capsules.  Unlike the first study where there was one capsule for like 20 milligrams, 60 milligrams, and placebo, for this study there were, for example, tablets corresponding to 20 milligrams, 30, 40, 50, 60.  And in each case, if there was a titration, there was a titration.  So, for example, the number of placebo capsules would also increase as well.  So, the blinding in terms of the numbers of capsules was exactly identical so physicians could titrate up according to safety and efficacy, and the titration would therefore involve, if it was placebo, a greater number of placebo capsules; if it was fluoxetine, a greater number of fluoxetine capsules.  
		Even the principal investigator was blinded to individual treatment assignment. 
		And that interim analysis, the only one planned for that study, was undertaken on 10 patients.  There were 9 other patients in the study at that time, and they were continued on.  So, the final analysis involved 19 patients.
		Cathy?
		MS. SHULER:  That's accurate with the exception of the fact that the capsules were in 10 milligram increments.
		DR. JUDGE:  Dr. Tollefson?
		DR. TOLLEFSON:  My name is Gary Tollefson, President of Neuroscience at Lilly.  I want to just say a few words so that we don't make this more complicated than it perhaps is.
		This was an independent investigator initiated trial.  However, it was done under conventional double-blind methodology, as you would expect with any clinical trial.
		Now, it happened at mid-course with the patient numbers that you have seen that the primary investigator opted to look at a group level for whether or not there was a treatment effect.  The primary investigator, as you heard, saw a very robust treatment effect between the two groups, and for ethical reasons elected to terminate the study at that point.  So, the patients that were represented as study 2 patients were patients randomized prior to an unscheduled interim analysis, and given the robustness of the treatment effect -- you might recall the slide showing overall treatment effects -- the investigator felt that it would not be prudent or ethical to continue prospectively in light of the drug/placebo difference that he saw.
		DR. TAMMINGA:  Dr. Hamer.
		DR. HAMER:  I'm now puzzled, as usual.  You're saying that they did an interim analysis after 10 patients.  For ethical reasons, they decided to terminate the study.  There were patients in that study then at that time currently assigned for placebo, but ethically it didn't bother them then to continue those patients on placebo double-blinded to the end of the study.
		DR. TOLLEFSON:  The patients that had been initially randomized to the trial were followed throughout the entirety of the trial.  Thus they provided the basis for the interim analysis.  Once that analysis was done, no additional prospective patients were enrolled to go up to the initially targeted patient sample of 30.  So, in other words, no additional randomizations occurred after the interim.  The interim was based on those patients previously randomized which was the study cohort you saw.
		DR. HAMER:  Right, but the ethical concerns were not sufficient to terminate patients on placebo in the trial rather than continue to give them placebo for the rest of the trial.
		DR. TOLLEFSON:  Yes.  You remember the crossover design, and it was felt that the value of the additional scientific information that would be generated via the crossover was justifiable in order to continue patients through the rest of the trial.  However, based on the phase I data, separation between drug and placebo, it didn't make a lot of sense to repeat that by enrolling additional patients in the eyes of the investigator.
		DR. TAMMINGA:  But the decision was made on an efficacy basis, not on a side effect basis.
		DR. TOLLEFSON:  That's correct by the PI.
		DR. TAMMINGA:  Dr. Temple.
		DR. TEMPLE:  No one obviously approached us to see whether we thought it was ethical to continue to randomize people to this non-lifesaving treatment.  I'm appalled at the idea that someone thought it was ethically imperative to stop the study because of this.  That would imply you couldn't do more studies in this disease, which is really a garbled view of what's ethically necessary.  But nonetheless, it seems to have happened.
		DR. TAMMINGA:  Dr. Katz.
		DR. KATZ:  I just had a question about the interim analysis.  It was done on 10 people.  Are those the 10 people who at the time had completed both arms of the trial, or did it include data from all the 19 that were enrolled in their various periods and states?
		DR. JUDGE:  It included data from 10 patients.
		DR. KATZ:  Who had completed?
		DR. JUDGE:  Yes.
		DR. COOK:  I still haven't had my question answered in terms of how this blind could be broken in terms of the security of the blinding codes, et cetera.  This seems to have been relatively arbitrary.  It obviously wasn't being kept separate from the investigator for the investigator to be able to do this analysis.  I just need assurances that we know the blinding was secure.
		DR. JUDGE:  Investigators and all the raters in this study were blind to the individual patient assignment to drug.  It is not uncommon to do interim analyses, as you know, for studies to delineate a group effect.
		DR. COOK:  But if they're blind, they can't do the analysis.
		DR. TAMMINGA:  Are you asking the question, Dr. Cook, who was allowed to be unblinded?
		DR. COOK:  Yes.
		DR. TAMMINGA:  Who was allowed to be unblinded in this study?  Do we know that?  Was that prospectively determined?
		DR. JUDGE:  I don't know specifically the names of those people, but the people who did the analysis were not involved in the conduct of the study in terms of rating the patients or ascribing treatment and seeing them from cycle to cycle and providing them with treatment, monitoring the adverse events, and rating their scales.  So, those raters, which are specifically those who saw the patients, were not the ones who completed the statistical analysis.  The statistical analysis was done by statisticians who were not part of the rating cohort of that study, and in fact patients themselves who rated themselves on the primary outcome measure were also kept blind to their individual patient assignment as well.
		DR. TAMMINGA:  Are you worried, Dr. Cook, that people might have taken other peaks at the data?
		DR. COOK:  It just seems non-standard.  It is true that the patients are rating themselves, but it is certainly possible if anyone working with them or involved in the study knows who is on which, then you violate the basic principles of blinding.  That's my real concern.
		DR. JUDGE:  And that was obviously a concern for Lilly.  It's a necessary requirement that a study is blinded and kept blinded to the raters of that study, and in comprehensive audit, absolutely comprehensive, a very meticulous audit, assurances were made and received with respect to the blinding of this study.
		DR. TAMMINGA:  Dr. Katz.
		DR. KATZ:  You probably believe that you've already answered this.  Maybe you have.  But we've heard that the PI took a look at the data.  Now, did the PI have anything to do with evaluating patients?  Was that person involved in the conduct of the trial?
		DR. JUDGE:  No.  The principal rater of that study was Dr. Su.  In fact, the authors of that study were Su and Schmidt, and Dr. Schmidt was the person whose name is on the abstract.  Dr. Su actually was more involved with the patients from a day-to-day basis, and he was at that time not privy to the individual patient assignment, as I've already alluded to.
		DR. TAMMINGA:  Dr. Fyer.
		DR. FYER:  I guess what makes me a little uncomfortable about this is the smallness of the operation.  What we're talking about is a 19-patient trial with two physicians involved in a relatively small sort of organization.  
		I think I would feel a lot more comfortable if the sponsor had just presented the data saying, look, this is what happened.  We had two doctors.  One was the PI.  They decided to take a look at the data.  We don't really know to what extent these individuals communicated or the ethos or sort of cultural environment in a small clinic, which all of us at this table have worked in this kind of environment, might have contaminated this data.  But the fact is that the effect at 10 patients was very robust, and we looked into it.  We're inclined to think that this didn't occur.  That kind of straightforward thing I think would be a lot more reassuring than what's sort of going on here.
		The other thing that I would just raise as a point is if there was a robust treatment effect at 10 patients, did the sponsor consider just presenting that straightforward data about which there could really be no questions at all?  Even though it's a smaller n, in fact we're dealing with a very small n overall.
		DR. JUDGE:  Firstly, I do apologize if you felt that it wasn't straightforward.  I was trying to give straightforward answers to these questions in that this study was conducted by one center.  And, yes, it's relatively small compared to the other study.  Patients acted as their own control, so providing enhanced sensitivity.  So, in crossover studies in general one would expect smaller patient numbers. 
		The individuals involved in this study are very well established in terms of their research field. 
		But in terms of our assurances, we also wanted to assure ourselves before coming to you guys that, indeed, the data was collected in a manner that is conducive to GCP standards and to assure ourselves of the highest quality for the data.  So, regardless of anything else, we did assure ourselves with very meticulous comprehensive audit that went on at both sites, including the other sites in the other studies as well.  All three studies involved comprehensive audit from Lilly personnel, which was also ascribed by also independently conducted audit as well.  So, regardless of that, we actually did a lot to assure ourselves of the study in terms of the quality and the integrity of the data.
		DR. TAMMINGA:  Dr. Hamer.
		DR. HAMER:  But good clinical practices don't usually include an unplanned interim analysis, do they, by the investigator?
		DR. JUDGE:  Good clinical practice assures the safety and benefit for those patients done in a double-blind way per protocol.  And, yes, there was an unplanned analysis in this study, as you heard, and that was unfortunate, but we've tried to explain to you the reasons why.
		DR. TAMMINGA:  Dr. Parry.
		DR. PARRY:  First a comment.  It would just be helpful for purposes of references to have copies of the published papers.  
		But I was interested in whether there was a difference in primary outcome measure as a function of site.  As I recall, Meir Steiner's Canadian study, there weren't differences as a function of site, but were there in the Stone-Pearlstein study?
		DR. JUDGE:  In the Stone-Pearlstein study, the publication did cite the CGI as an outcome measure, and it involved the CGI 1 or 2 as the primary outcome measure.
		For Dr. Su-Schmidt, for the second study, X022, the publication -- it was difficult to ascertain from the publication, if you just viewed the publication in the cold light of day, it talks about the DRF and the VAS Mood-4 as relevant outcome measures.  We will have copies of that.  We could provide them to you perhaps during lunch, and the FDA have been provided with copies of the publications.
		DR. PARRY:  But I mean, not the measures but the change scores.  Were there differences as a function of where the study was conducted in the primary outcome measures, whichever primary outcome measure was used?  Whether it was western Canada or eastern Canada or New Jersey or New York.
		DR. TAMMINGA:  Is your question about the number 1 Steiner study?  Was there a site effect?
		DR. PARRY:  As I remember, there wasn't.
		DR. JUDGE:  If we're talking about the individual site effect for seven centers in Canada, we've got some information on that and my statistician will take you through that.  Dr. Brown.
		DR. BROWN:  For the primary efficacy variable, the VAS Mood-3, there was, in fact, a site by treatment interaction.  This graph here shows the results by site for the VAS Mood-3.  Again, green is placebo, and orange is 20 milligrams.  Yellow is the 60 milligrams.  We can see for sites 3 through 7, the dose response is quite similar.  Remember that the placebo going above the 0 mark means that the placebo group, in fact, got worse.  So, the dose response is quite similar.
		And it appears that the interaction was being driven perhaps by sites 1 and 2 where you can see in site 1 the 20 milligram dose group responded better, in fact, than the 60, which is not consistent across the other sites.  In investigator site number 2, the 20 milligram group did not respond as well, in fact, as the placebo group.
		DR. HAMER:  Were there particularly small numbers of subjects at sites 1 and 2?
		DR. BROWN:  Here are the site-by-site patients entered and randomized.  So, sites 1 and 2 are a little smaller, but about the same size as sites 6 and 7.  Sites 3, 4, and 5 were the biggest sites, but the spread was pretty good among them. 
		DR. TAMMINGA:  Dr. Dominguez.
		DR. DOMINGUEZ:  Do you have a similar breakdown as far as discontinuations between sites?
		DR. BROWN:  No.  I'm sorry we don't have that.  Well, there are completers there, but I don't have discontinuations for a particular reason by site.
		DR. DOMINGUEZ:  For specific reasons per site.
		DR. BROWN:  No.  Sorry.
		DR. THYS-JACOBS:  (Inaudible) or entered treatment.  You have 400 -- 
		DR. BROWN:  Pardon me.  What was the question?
		DR. THYS-JACOBS:  405 patients entered.  I thought the definition of entering was the treatment phase.  So, this is screening.
		DR. BROWN:  That's screening, and then the numbers there, the 108, 104, and 108, those sum to the 320 randomized.
		DR. THYS-JACOBS:  What was the difference when patients actually entered treatment phase in terms of numbers?  Do you have that data?
		DR. JUDGE:  Patients who entered the placebo, fluoxetine at randomization numbered 108, just over 300, 320.  So, that's the difference between 405 as the patients went to screening.
		DR. TAMMINGA:  Do you have additional questions on this issue?  Any additional questions for Dr. Judge?  Dr. Chen.
		DR. CHEN:  I have one more question about the study number 2.  So, could you tell me about the resource?  It seems to me today you are real clear about the randomization scheme and the interim analysis, but it seems to me when I reviewed the study, the application, the document said it depends on the investigator's decision.  It was not very clear in the submission. 
		But two weeks ago, we asked the same question about the early termination of study 2.  At that moment, we didn't get it answered.  But it seemed to me our question what's the resource -- within two weeks everything becomes clear to you.
		DR. JUDGE:  No, indeed.  You're referring to the telephone conference that we had with the FDA, that Lilly had, to understand our presentation, whether you felt that our presentation was suitable.  We asked you to comment on our slides.  You said to us that it would be important for us to provide additional information on various questions, and one of them was the use of oral contraceptives.  One of them was with respect to this question, and one of them was with respect to study 19 in terms of the primary outcome measure.  
		We didn't really go through, at that time, all of the answers, but we did undertake to provide to you in a few days some of how we would elaborate on it today, which we did just a few days after that telephone conference.  So, today you find we understood and then we provided all these answers to you today in terms of your request to us for all of those questions at that time. 
		DR. CHEN:  So, are all of those, what you mentioned today, documented.
		DR. JUDGE:  Yes, indeed, they are.
		DR. TAMMINGA:  Dr. Laughren.
		DR. LAUGHREN:  One of the concerns about SSRIs as a group is an effect on sexual dysfunction.  That wasn't something that was looked at specifically in these trials, but I did notice, as you were going through the various rating instruments, that the PMTS did have one item that looked at sexual drive and interest I believe.  Do you have any data on that specific item?
		DR. JUDGE:  If we could bring up those.  Dr. Steiner would like to comment before we bring up those slides as well.
		DR. STEINER:  We actually started to look at the data just a few weeks ago not because of this, because we were interested in looking at it.  If you look at our baseline data for that particular question on the PMTS, you see that women rate sexual dysfunction premenstrually as part of the symptoms of PMDD.  They're not interested in sex.  It's not a very specific question.  It just asks are you interested more or less or not at all.  So, you see that their baseline, their normal, is during the follicular phase and then they score high during the late luteal phase because they're not interested in sex.
		What we have done is we have then looked across the six cycles of treatment, and there was no change in this course during the follicular phase.  This was continuous treatment with fluoxetine 20 and 60.  It was no worse than during the follicular phase in terms of what they score on sexual functioning, and there is an improvement, an overall improvement, in that question during the late luteal phase.  So, overall we have not seen that in this particular population Prozac caused sexual dysfunction.
		I have to say that we're now looking at how many actually we lost or how many were dropped out of the study because of sexual dysfunction, and I believe that there is a total of 5 subjects. 
		DR. TAMMINGA:  Dr. Steiner, could you be more specific about when the improvement occurred in the luteal phase, what percentage of that of the follicular phase -- how high did it --
		DR. STEINER:  It's not back to the same normal baseline, but it's halfway there. 
		DR. TAMMINGA:  Dr. Parry.
		DR. PARRY:  I want to address the issue of suicide.  Many of these patients may actually present with suicidal ideation.  So, it is a potentially lethal illness.  There has been some, though maybe erroneously, association with fluoxetine and suicide.  I was wondering were patients with suicidal ideation excluded from studies, and if not, was that targeted?  What was the effect of treatment?
		DR. JUDGE:  In general, patients with significant coexisting other illnesses, generally medical, were excluded and, as you heard, also patients with other Axis I diagnoses were excluded.  
		Now, specifically in terms of patients presenting symptoms, I'm not aware from the data that we have in these studies, that anyone presented with a suicide attempt as a presenting symptom.  I can tell you that from these studies, all of the studies, there was no one who attempted suicide, and I think it's pertinent at this point to perhaps ask Dr. Tollefson to comment in the overall Prozac and the suicide question because, obviously, it's very important.
		DR. PARRY:  But it's also suicidal ideation --
		DR. JUDGE:  Well, remember, the scales that were used -- in this study, for the big study, Dr. Steiner's study, for the Su study, there was a Beck's Depression Inventory scale that looked at, in the follicular phases of that study -- the Beck's is the Beck's, and we saw nothing significant in the follicular phase indicating that in the follicular phase the patients had very, very low levels of symptomatology.  You're looking at a score of around 4 on the Beck's, which is really, really very low.
		In terms of Dr. Steiner's study, study number 1, there was no instrument that captured the suicidal ideation per se, as one would expect, for example, in the HAMD.
		Dr. Tollefson, if you could comment on the --
		DR. TOLLEFSON:  Well, I think that when we look at spontaneous events in these clinical trials, a suicide attempt or a completed suicide would register as a spontaneous event.  None of those were observed in the clinical trial, to answer your question.  I think that is consistent with our overall meta-analysis across not only depression but OCD and bulimia where see certainly a higher emergent rate in patients randomized to placebo than we do on active therapy.  In fact, active therapy in other indications at least is associated with a reduction in suicidal ideation, as measured by HAMD item 3.  Those were gender indicated.  
		We did not have specific suicide indices built into these prospective studies, so one would have to just really rely on the adverse event data, of which there was no evidence of a suicide attempt.  There was one drug overdose with cocaine.  That is the only event that would map to "overdose" in the entire cohort.
		DR. PARRY:  I think it argues for using the Hamilton or some other scale.  I think it argues for using the Hamilton or some item that assesses that in future studies.
		DR. TAMMINGA:  Dr. Judge, would you -- Dr. Steiner, do you want to say something?
		(Laughter.)
		DR. STEINER:  They were screened for major depression, and if they had major depression, including suicidality or not, they were excluded.  So, they were not included.  But that is not to say that we have not screened them for that.
		DR. TAMMINGA:  Thank you.
		Dr. Judge, the committee would note that the dosing throughout these three studies is continuous.  Certainly there is some question about whether dosing needs to be continuous or whether it can be intermittent.  I would wonder whether you would like to comment on that, and also if you could give us some indication of whether Lilly is continuing to pursue, in Lilly-sponsored studies, additional questions in this area, if would be helpful to the committee.
		DR. JUDGE:  Thank you.
		If you could bring up my slide with respect to intermittent dosing.  I've tried to attempt to note the considerations with respect to intermittent dosing on one slide.
		Intermittent dosing.  Certainly there have been anecdotal reports that would indicate intermittent dosing may be effective.  I think in order to explore this fully, there are various considerations that one has to think about. 
		First of all, in respect to safety, when we talk about intermittent dosing, as I would understand you, something like 10 to 14 days perhaps of drug before the onset of menses.  Firstly, does the intermittent administration of fluoxetine, or indeed any other agent, subject that patient to repeated typical adverse events month after month after month.  As you appreciate with fluoxetine, there is a diminution in the adverse event profile with time.  If you administer intermittently month after month, does that subject the patient to a continuous high level of adverse event reporting?
		Furthermore, we know that fluoxetine with its longer half-life -- patients don't really report discontinuation symptoms, but perhaps patients on the maybe more shorter half-life agents may, in fact, report discontinuation symptoms.  So, that's important to establish that.
		With respect to efficacy, also there's a question of compliance.  Will patients comply to treatment that they perhaps have to -- will they find it easy to take treatment for a few days in the month rather than every day?  
		Importantly, this question of kindling.  Is the possibility of kindling phenomenon -- is that going to take place in these patients?  I think that's also important. 
		With respect to fluoxetine, there is one pilot trial with intermittent dosing with fluoxetine.  Again, Dr. Steiner did this trial.  This is an open label, single-blind trial in which patients were administered 14 days of fluoxetine treatment prior to menses, and this was compared to continuous dosing 20 milligrams throughout the cycle.  There was some evidence of a similar response for both groups of patients.  
		However, it's worth noting that that was not randomized appropriately.  In terms of the patients who had a past history of depression, they were given the continuous trial of 20 milligrams of fluoxetine, and patients who did not have a past history of affective disorder were administered intermittent fluoxetine.  So, that is an open trial, but nevertheless to your other question, yes, Lilly is pursuing other intermittent studies.
		In the literature, all of the SSRIs, it's fair to say, have the largest body of data for continuous dosing, roughly at around the same dose that is also applicable to the depression population.
		DR. TAMMINGA:  Could you be specific about what Lilly is doing to address these considerations?
		DR. JUDGE:  There are studies underway with intermittent dosing for fluoxetine.
		DR. TAMMINGA:  Lilly-sponsored studies.
		DR. JUDGE:  Indeed.
		DR. TAMMINGA:  Dr. Temple.
		DR. TEMPLE:  It's not easy to have a discontinuous study of Prozac because 14 days after you stop, with a 14-day half-life, you still have half the same amount of long-acting metabolite on board, which raises the larger question which I know will come up later, but you need to address it too.
		Is this a sensible approach to an intermittent disease?  You basically are on Prozac.  You didn't find any abnormalities with sexual function.  It's not quite clear to me how hard you looked.  But there are consequences to being on an SSRI all the time.  So, the committee is going to address that later, but you may want to comment on it in advance.
		DR. JUDGE:  With respect to fluoxetine, continuous dosing of fluoxetine, as one attributes to PMDD, as well as other disorders, we know that fluoxetine at a dose of 20 milligrams, which seems to be the optimal dose in this population, is very safe and very well tolerated.  There is very long-term experience and a large body of evidence which relates to fluoxetine with respect to that.
		I think the question is more around intermittent dosing.  Yes, indeed, fluoxetine does have a longer half-life, but nevertheless, if patients are given intermittent dosing from day 1, do they have enough time then to reach that steady state in order to have high levels when patients are off dose? 
		Furthermore, these other safety questions would also be still relevant, and that is ongoing in terms of clinical trials.  And there are also pertinent questions to other treatments that are being studied for intermittent dosing.  So, the questions are more around intermittent dosing I think than relate to continuous dosing.  I think we're fairly comfortable with particularly the safety profile for fluoxetine in continuous dosing.  Even though the disorder is just intermittent, as you say, many disorders are intermittent with respect to intensity of symptoms, but nevertheless, a longer-term approach prevents their reemergence and relapse of those symptoms.
		DR. TAMMINGA:  Dr. Temple.
		DR. TEMPLE:  Usually you don't know when a disease is going to relapse.  So, you have no choice except to treat continuously.  This is a little different.  You know exactly when it's going to happen.
		DR. TAMMINGA:  That's what Dr. Endicott emphasized in her presentation.
		Dr. Fyer.
		DR. FYER:  Sort of two comments.  First, on your response, Dr. Judge, I think that there's a big difference between a drug being overall safely tolerated the way these kinds of databases are put together and the question of individual people taking a drug for a very long period of time and it having effects that impact their life.  It may not be medically dangerous.  I would like to feel that the sponsor, in undertaking to get this kind of indication, would really take that seriously in terms of labeling and how they advertise and promote the drug because we're talking about women who might conceivably take this for a very long time.
		The second comment I have is actually a question to Dr. Steiner.  I was glad to hear that the reason for your dropouts -- it seemed to me that it was just a very hard study to do and that there wasn't something odd going on with the drug. 
		But the question I have is that in most of the studies we have mean scores as opposed to responder outcome.  In the one study where we had the CGI used, in fact the 1's and 2's -- it was a small study and there weren't significant differences.  I wondered if you could give us from your clinical experience some idea as to whether we're dealing with a situation like OCD where even the people that get better don't get completely better or very few of them do, or if we're dealing with a situation like major depression or panic disorder where a large proportion of the responders are really better, you know, just in terms of risk-benefit ratios, things like that. 
		DR. STEINER:  As old as I am and have been in this field, this is the first time that something works.  This is the first time that the clinic got flowers from husbands --
		(Laughter.)
		DR. STEINER: -- because we treated something that sort of restored life in some of these households.  This is not something to sneeze at.  I don't care about statistics.  I'm telling you that clinically this was so impressive that it was almost unbelievable.  
		You were asked who was driving this study.  We had 10 or 12 patients that we piloted before we went to Lilly and we said, this is the first time.  I have worked with a lot of other compounds.  They were all as good or as bad as placebo, and really nothing works after works after three or four cycles.  This was the first time that something worked.  We went to Lilly and we said we must do that properly.
		DR. TAMMINGA:  Dr. Steiner, did all the patients get a little bit better or did all the patients get totally better?
		DR. STEINER:  Most of the patients got totally better.  I'm talking about the completers.
		DR. FYER:  How would you comment on the third study where they did do CGIs and they didn't find for the 1' and 2's?  Remember, 1 is completely and 2 is slightly.
		DR. STEINER:  I wasn't involved in that study and I don't think that I should be commenting on it. 
		DR. FYER:  Somebody else?
		DR. JUDGE:  Again, for that study, there was clearly a trend towards significance, .07.  When one looked at the overall CGI any improvement, then there was a statistical separation.  Again, there were small numbers of patients in that study which might have accounted for some of the lack of significance.  But generally the results are entirely consistent with the efficacy noted in the other studies.
		DR. FYER:  Respectfully, I just submit that if in fact all the patients got all better, you couldn't have seen that kind of CGI outcome.  I don't know what happened, but that's not consistent.
		DR. TOLLEFSON:  I think it might be useful if we put the CGI response slide up for you to take a look at.  Again, remembering it's a very small sample size, which increases the hurdle for showing a p value less than .05.  If you look just at treatment effect size, you look at the 20 to 60 milligram fluoxetine arm, you're seeing a response rate on CGI 1 or 2 that is in excess of 50 percent.  I would argue that's as good as any response data, schizophrenia, depression, OCD, that we see in the literature. 
		If you then expand it a little bit more to include 3, you see now that we're approaching 90 percent plus who had CGI improvement with fluoxetine, and despite the small sample size, there's a very robust statistical separation between fluoxetine and placebo.  You can see that there is a very strong differentiation from that of bupropion. 
		So, I would argue that that's a fairly impressive response rate with CGI, statistics aside for a moment, at either of the score of 1 or 2, which a priori was the primary outcome, or scores 1, 2, and 3 as a secondary analysis.
		To Dr. Laughren's earlier question, which I'm not sure was fully answered, we do have the sexual functioning item from the PMS scale that we could up for you.  I think that might provide some light on the issue of either improvements or, alternatively, deterioration in function between drug and placebo.
		Go ahead, Rajinder.
		DR. JUDGE:  This is looking from study 1 for those patients during the study who scored on the PMTS patient rated scale.  So, this is looking at those patients who had sexual drive increased or sexual drive decreased.  For the placebo group, these numbers are 58 and 51 percent, respectively.  For the fluoxetine group, roughly around 50 percent each group, and for the fluoxetine 60 milligram arm, again roughly around 50 percent each group. 
		So, it seems from the data here that, overall, sexual drive could increase or decrease with respect to any treatment, and also that the differences between fluoxetine and placebo were not statistically significant as noted here. 
		DR. TAMMINGA:  Dr. Laughren.
		DR. LAUGHREN:  Is this follicular phase or luteal phase data?
		DR. JUDGE:  This is luteal -- at any time, at any time during any visit.  And patients were scored in follicular and luteal visits, so this is at any point in that study they could have sexual drive increased or decreased.  
		In fact, this is consistent with other studies with fluoxetine where we note that patients -- if you just flick on to the second carry-on in this file, with the overall depression database patients improving or not improving.  It's the last slide in this file.  
		So, this is looking at a meta-analysis of several studies with fluoxetine.  It looks at another parameter, the SCL-58, and looking obviously at females only.  We see that for overall fluoxetine database, indeed, some patients do worse with the use of fluoxetine on fluoxetine or placebo.  Nevertheless, some patients' sexual dysfunction remains the same, but some patients actually do improve and a greater number of patients do improve on fluoxetine versus placebo. 
		So, I think the sexual dysfunction question in terms of what we know less about the PMDD population, we know less about how these patients are at baseline, how is their sexual function at baseline.  That's really information that is not very clear at the moment.
		DR. TAMMINGA:  Yes, Dr. Altemus.
		DR. ALTEMUS:  Do you have any data about anorgasmia?  Because that's really the main side effect.  Would that have been picked up in any of the measures?
		DR. JUDGE:  If we could go back to the first slide of this file, the overall treatment adverse events for all three studies.  Specifically they're items relating to sexual dysfunction in each of the three studies.  For study number 1, anorgasmia was reported in 0 placebo patients, in 1 fluoxetine patient in 20, and again a similar number for fluoxetine 60 milligrams.  
		For decreased libido, again small numbers of patients reported decreased libido in this trial, as you can see here.  Highest numbers for fluoxetine 60, but then again we're talking about 8 patients, which is 7 percent.  The p value was not statistically different for the placebo versus fluoxetine in these groups.  
		In these studies you see perhaps a higher level of reporting, but it's more important to note that the way that these adverse events were not just spontaneously -- they were not just treatment emergent.  They were any adverse events collected at any point.  So, one would expect a higher level of reporting. 
		Again, most importantly to note, the differences between fluoxetine and placebo were not statistically significant for any measure.  That's the data that was evident from these studies, the PMDD studies.
		DR. TAMMINGA:  Dr. Laughren.
		DR. LAUGHREN:  One comment on these data.  In all cases you're relying basically, I think, on spontaneous reporting of those events, and you may see a different picture if you have sensitive scales designed to look at sexual function.
		DR. JUDGE:  Yes, indeed.  The interesting point would be also again to exploit such scales at baseline as well to see what the baseline level of functioning was.
		DR. TAMMINGA:  Any additional questions from the committee for Dr. Judge or for Lilly?
		(No response.)
		DR. TAMMINGA:  Thank you, Dr. Judge. 
		Before we break for lunch, we have one person who has requested a time in open hearing to speak on this particular topic.  I'd like to ask Dr. Sherry Marts from the Society for Women's Health Research to come forward and give her remarks.
		Also, I would ask, if you would, in the spirit of disclosure, to indicated whether or not you actually get money, your organization gets money, from Lilly, and give us an idea of what percent of your finance of that might be.
		DR. MARTS:  My name is Sherry Marts.  I'm Scientific Director for the Society for Women's Health Research, which is a Washington-based advocacy group dedicated to improving the health of women through research.  We were founded in 1990 when we brought national attention to the need for research on conditions that affect women not only solely because they're women but also differently from men or more often than men.
		I would like to say that we do get support from Eli Lilly.  They have been a longtime supporter of our efforts, and they provided a grant for the consensus roundtable on PMDD, which I'm going to talk about today.  This was convened by the society in 1998, and a peer-reviewed summary of that conference was published in the Journal of Women's Health this past June.  I have a few copies of it.  Unfortunately, I didn't get the speaker's guidelines in time, and I only brought four copies.  But if you're willing to share, I'd be happy to hand those out.
		The group that assembled for that conference included experts in psychiatry, psychology, gynecology, and epidemiology.  This conference report was published as a peer-reviewed paper, as I mentioned.  Among the conclusions of that conference are that PMDD is a distinct clinical entity with a clinical picture that is not a typical picture for depression, mood, or anxiety disorders, and in particular, internal tension, anger, and irritability are characteristics of PMDD.
		The key differences between PMDD and other disorders is the clear onset and disappearance of symptoms, both linked to the menstrual cycle.  There's considerable stability in the course of PMDD from cycle to cycle and over time in the absence of treatment.
		The conference noted that PMDD is a chronic condition that in some women can worsen over time.  Age of onset varies and it can be any time after regular menstrual cycles are established. 
		PMDD differs from other disorders in that there may or may not be comorbidity with other mood disorders, and unlike in depression, in PMDD the hypothalamic-pituitary-adrenal axis often functions normally.  Blocking the menstrual cycle, as happens in pregnancy, can eliminate PMDD, but has no effect on other mood disorders, and after pregnancy, symptoms return once the menstrual cycle is reestablished.
		Finally, the consensus conference concluded that there is biological evidence for the involvement of the serotonin system in PMDD.
		Now, I want to say that the society does not have expertise in the evaluation of therapeutics.  I'm not here to encourage or discourage the approval of any particular pharmaceutical agent for treatment.  We gladly leave those decisions to the experts.  
		But we want to emphasize that PMDD is a severe, often debilitating disorder that is distinct from premenstrual syndrome.  PMDD's symptoms significantly interfere with a woman's life, preventing a sufferer from functioning effectively at work and at home. 
		We're concerned that this disorder may go unrecognized, undiagnosed, and untreated in many women.  Among the barriers to diagnosis and treatment are the stigma that may be attached to a condition associated with the menstrual cycle.  There's still a negative connotation against seeking treatment for something that's just in your head or just PMS.  The admission that treatment is needed is seen as a weakness.  Because this condition is not well understood, physicians may not recognize the signs and symptoms or know how best to diagnose PMDD by distinguishing it from mood disorders.  
		The possibility of a medical treatment for this disorder is heartening and it's evidence that women have succeeded in bringing attention to this condition to their health care providers. 
		We as the Society for Women's Health Research are committed to reducing the stigma of diagnosis with PMDD and committed to educating women that PMDD can be diagnosed and treated and that symptoms are, as I said, not just part of being a woman or all in your head.  We encourage women to consider all treatment options and to insist on treatment that is effective and appropriate to the severity of their symptoms.  We encourage the members of the advisory panel to consider the significance of this disorder for the approximately 5 percent of menstruating women who suffer from it. 
		Thank you.
		DR. TAMMINGA:  Thank you very much, Dr. Marts.
		Although Dr. Marts was the only person who requested a spot for remarks, this is the open public hearing part of the meeting, and I'd like to ask if anybody else has any statement to make. 
		(No response.)
		DR. TAMMINGA:  In that case, I think we ought to break for lunch.  I would like people to come back promptly at 1 o'clock, and at that time the committee will have a discussion both about the diagnosis and about the efficacy and safety questions.
		DR. TITUS:  There is a table reserved for you in the restaurant, and I would like to caution you that the conversation needs to be about weather and neutral topics.  The topic we're discussing -- you need to come back here and do it publicly.
		(Whereupon, at 11:55 p.m., the committee was recessed, to reconvene at 1:00 p.m., this same day.)

	AFTERNOON SESSION
	(1:03 p.m.)
		DR. TAMMINGA:  I'd like to reconvene the meeting.
		The committee is now in the committee discussion and deliberation portion of our meeting.  I'd like to focus our discussion on the items that Dr. Laughren raised for us this morning about the questions that the FDA has of this indication, both of the indication and of the drug, and remind the committee that the question that Dr. Laughren would like some discussion of, first of all, is the general question regarding PMDD as a new indication.  With some more specific questions, Dr. Laughren asked about the relevance of the DSM-IV appendix status for PMDD, PMDD as a distinct disorder, distinguished from MDD, the relationship of PMDD to PMS, and as a follow-up question, the possibility, although we're not considering a drug for this today, the related question of PMS as a candidate for an approved indication. 
		So, I'd like us to start this afternoon meeting's deliberating about these kind of things.  I would actually invite our consultants, who are experts in this area, to perhaps take a lead-off in the conversation.  Dr. Parry.
		DR. PARRY:  Well, I think that the studies that were presented this morning and most other studies that are accepted for publication use the criteria for premenstrual dysphoric disorder.  There was a lot of deliberation going into making those criteria.  The term "premenstrual syndrome, PMS" is amorphous and ill-defined.  There's no definition of it.  So, to say that one is a subset of the other or how it's differentiated I think is really a moot point.
		I would strongly advise against fluoxetine being considered for use in this amorphous term PMS because the studies that the decision will be based on do not use ‑‑ specifically and go to a lot of trouble to define criteria for PMDD.  So, we really don't have information on this amorphous, ill-defined PMS.  So, I think we should confine our focus of attention on the studies and even treatments to the very carefully and very rigorously defined premenstrual dysphoric disorder.  It's more rigorous than most other psychiatric disorders.  The terminology that's used in the DSM-IV was based on pooling studies from across the country.  So, I think given that background, the focus should be on premenstrual dysphoric disorder.
		DR. TAMMINGA:  Dr. Thys?
		DR. THYS-JACOBS:  I think PMS is a definitive and distinct disorder.  Women who have had it -- and I would say across the board, there are about 70 to 80 percent of premenopausal women who are suffering with premenstrual syndrome.  So, I think it's a very distinct disorder.
		DR. PARRY:  What's the definition?
		DR. THYS-JACOBS:  I think it's been defined as an occurrence of physical and affective mood symptoms that occur during the luteal phase of the cycle, as distinct from the follicular phase.  Now, exactly what that ratio is in terms of symptomatology -- is it a 30 percent increase?  Is it a 50 percent increase?  Is it 100 percent?  We all know that premenstrual syndrome exists, it's a luteal phase disorder, and we know that these symptoms indeed occur.
		Is PMS distinct from PMDD?  Now, there is a definition in the DSM-III and the DSM-IV that cites specifically that five out of a lot of these symptoms define PMDD.  I think it's fine.  I think for a woman who has the very severe end of the spectrum -- and I don't see any difference between PMDD and PMS, not at all.  In my practice and in my research, I don't see any distinction between the two.  What I do see is that the women who come in who have PMDD indeed have a prominence of affective symptoms.  Are they more symptoms than physical symptoms?  I don't find that, not at all.
		But I do agree that it is a distinct disorder.  It's distinct in terms of defining it from other depressive or other mental or mood disorders.
		DR. TAMMINGA:  You're talking about PMDD.
		DR. THYS-JACOBS:  PMDD and severe PMS.  I do not consider them as different.  Not at all.
		DR. TAMMINGA:  Dr. Altemus?
		DR. ALTEMUS:  I imagine that if this is approved, in the general public and in primary care, people aren't really going to know how to diagnose PMDD, and it will probably be used very widely for anyone with any premenstrual symptoms at all.
		DR. THYS-JACOBS:  I think the criteria are pretty well spelled out in terms of the DSM-III and DSM-IV.  I think women know what PMS is.  I don't think there's any question about it.  The people that I speak to who are seeing these women, the gynecologists, the primary care internists, they all know what PMS is.  They all know that it's a group of these symptoms, whichever symptoms you want to define, that occur specifically during this phase of the menstrual cycle, the luteal phase of the cycle, and remits with menses or the follicular phase.  That is PMS.
		Is PMS distinct from PMDD?  No, it is not.  It is not different.
		DR. ALTEMUS:  Well, I don't think we can make the leap that the drug is effective for PMS.  I mean, there have been two studies in PMDD.  Even though you intuitively think that it will be effective for PMS.
		DR. THYS-JACOBS:  I'm not saying that.  I'm not saying that this particular drug --
		DR. TAMMINGA:  We're really just talking about the diagnoses now just as a starter.
		DR. THYS-JACOBS:  -- should be indicated for premenstrual syndrome.  When I think of premenstrual syndrome, I think of the global syndrome and I think of the physical and the affective, the water retention symptoms and the pain symptoms.  I think of the whole global syndrome.  I think what we've seen is that we have defined PMDD mostly as an affective syndrome with these particular group of symptoms, and this drug is or is not effective for this particular group of symptoms in this disorder.  Is it effective across the board for the entire syndrome?  We haven't seen that.
		DR. PARRY:  What's your operational definition in terms of severity of symptoms?  They do make a distinction between major depressive disorder and depressive symptomatology.  So, I think not only in terms of the nature of the symptoms -- and you specified timing, but what about severity?
		DR. THYS-JACOBS:  I think the timing makes the syndrome.  There's no question about it.  It's the timing during the luteal phase.  That's why it was late luteal phase dysphoria and premenstrual dysphoria.  It's the timing of the syndrome that makes this different from major depression and all the other mood disorders.  There's absolutely no question this disorder remits, subsides, ends with the beginning of menses, period.  So, it's the timing.  Whatever symptom you want -- it could be cravings, it could be pain, it could be depression -- any symptom you want that occurs during this luteal phase of the cycle and recurs, you have PMS.
		DR. PARRY:  Well, but again it's severity.  Would you use fluoxetine to treat a little bit of breast swelling?
		DR. THYS-JACOBS:  I'm talking about PMS not versus PMDD.
		DR. PARRY:  Yes, but what are your severity criteria for PMS is what I'm asking.
		DR. THYS-JACOBS:  There's no severity.  It's the timing of those symptoms that occur during the luteal phase of the cycle.
		DR. ALTEMUS:  But you're saying it's a disorder.
		DR. THYS-JACOBS:  It's a disorder.  It's not a disease.  It's an occurrence of symptoms, whatever group of symptoms the woman has for that particular phase of the cycle.
		DR. ALTEMUS:  Would you say 80 percent of people have this disorder?
		DR. THYS-JACOBS:  Yes, absolutely.  I think 70 to 80 percent of women who are walking around have suffered at some point in their life with PMS.  There's absolutely no question.  If you're out there and you're seeing women on a daily basis, yes, there are women out there who are suffering with this syndrome.
		DR. TAMMINGA:  Let me focus this discussion, if you would, for a minute on PMDD since the question on the plate -- we have sort of a minor question about PMS, but the major question on our plate is the PMDD question, the suitability, if you will, of the PMDD as a diagnosis and as an indication for drug treatment.
		Good, Dr. Dominguez.
		DR. DOMINGUEZ:  I would like to ask the consultants, taking a step back from the discussion that just happened, why was LLPDD not elevated in DSM-IV to a distinct disorder?  We learned from Dr. Endicott that there was a lack of consensus in that area.  What were the major issues that drove this lack of consensus?  Can the consultants or perhaps even Dr. Endicott enlighten the committee as to why?
		DR. PARRY:  Well, from my view, as Dr. Endicott indicated, there was consensus on the nature of the symptoms.  I view it that was a political decision, not a scientific one.  But the concern was that if it was put in the main body of the text, it would implicate all women as having a disorder, even though it specified that based on the estimates we had from studies, only 5 percent of women met criteria, but the concern was that it would stigmatize women.  So, I'm happy to hear other comments, but I think it was primarily a political decision, not a clinical or scientific one.
		DR. TAMMINGA:  Why was the diagnosis changed from LLP -- whatever that was -- to the PMDD?
		DR. PARRY:  Well, it was first listed in the DSM-III-R as late luteal phase dysphoric disorder because the attempt was to define it as carefully as we could into the luteal phase of the menstrual cycle.  But I think it was changed to premenstrual dysphoric disorder because late luteal phase dysphoric disorder was a bit cumbersome.  It got referred to as L squared PD squared, and the premenstrual terminology was more user friendly.
		DR. DOMINGUEZ:  So, if the issue was political, as you say, then this disorder is going to remain in the appendices of future DSMs forever and ever?  I think it is worded as studies that need further research and further verification.  What else has to happen in order for this to rise to a clear Axis I category?
		DR. PARRY:  I think the majority of the people who were on the board wanted it to go in not under the appendices, but the board, because of a few dissenting opinions and because of the public controversy, overrode that.  So, my view would be we made a little bit of progress just getting it in, and I would hope that the next step would be to put it in.   
		Would you share that, Jean?
		DR. TAMMINGA:  Dr. Endicott.
		DR. ENDICOTT:  Dr. Parry and I were both on the work group that were advisory to the nomenclature committee, and it was fairly apparent from day 1 of that work group or advisory group that there were going to be issues around this political issue and that there was going to be some disagreement on the ultimate recommendation.  But the group was able to work together very well on the subset of criteria and on the evidence to support those criteria.
		There was a desire on the part of the nomenclature committee to have some kind of consensus recommendation, and they finally accepted that there was not going to be a consensus from our group.  So, they were presented with the evidence. 
		As Barbara said, both in the advisory committee and in the overall nomenclature committee, most of the people were in favor of moving it up from the appendix.  But there were other issues going on, and this is always a committee kind of decision in a general setting in which political issues do get considered. 
		DR. TAMMINGA:  Dr. Laughren.
		DR. LAUGHREN:  Let me try and clarify the question that I'm interested in having answered.  Actually there are two questions.
		One has to do with this entity PMDD and whether or not that's a reasonable clinical entity to focus on as a claim, an indication in labeling.  In terms of this application, that's the only entity that we're focusing on because that's what they studied.
		The second question really relates more to our advising other companies who are interested in this area and what to tell them about broader claims that they might be approaching.  There is some interest in looking at this broader entity of PMS.  My question is, separate from your answer to whether or not you think PMDD is a reasonable entity, is this broader entity something that, in a sense, is ready for prime time in terms of an indication?  Is it well enough defined?  Is there a consensual agreement about what the diagnostic criteria are so that a company could reasonably run a development program and submit an application for this more diffuse claim?  That's really the question.
		DR. TAMMINGA:  So, I'd like to hear from both the consultants and the committee members in response to each of those questions, addressing the first question about PMDD first and then the broader question about PMS.
		Abby, do you want to go first?
		DR. FYER:  Sure.  Actually I guess I would take it from the other point of view.  What is it about this disorder that makes you feel that it might not be something viable to address as an indication for a drug treatment?  Usually we look at epidemiologic data, we look at distress and impairment, et cetera, we look at distinctness from other disorders.  It may be slightly different in some aspects from others, but I guess I'm missing the point.  Maybe it's a little new in the history of the explicit definition of the disorder, but not really much different than panic which had a similar long history unofficially and then came into --
		DR. LAUGHREN:  Actually my own bias is in favor of what you said, that this entity is reasonably well defined.  Really more my question has to do with this broader entity of PMS and whether or not that's a candidate for drug development.  The questions I have listed here.  Whether or not this entity is distinct from depressions, say, major depression, I think that has largely been addressed, but other committee members may want to weigh in on that.  But really, my main question has to do with future development programs for possibly this broader entity of PMS and whether or not that's a reasonable course for companies to be taking.
		DR. FYER:  You mean whether or not it's reasonable to advise people to develop indications for PMS.
		DR. LAUGHREN:  Right.  Is PMS at this point well enough defined, well enough accepted in the community, and does it have enough agreement about diagnostic criteria that companies could reasonably go down that path and submit applications for that entity?
		DR. TAMMINGA:  Well, we've had two answers from our committee.  One is yes and one is no.  So, why don't the two of you restate your opinions, and then the rest of the committee can comment?
		DR. THYS-JACOBS:  I think PMS, premenstrual syndrome, is a distinct, defined disorder.  There is absolutely no question that what makes this group of symptoms with this disorder or this phenomenon different from any other affective or any other disorder is the occurrence of these particular group of symptoms during the luteal phase of the cycle.  I can't stress more to you that I really believe it.  We have all recognized this for centuries.  It has been spoken about, written about by historians.  We've defined it.  
		I think there was, indeed, a National Institute of Mental Health consensus that defined a 30 percent increase from luteal to follicular phase, that you had to know that there was a difference in scores, in visual analog scales, that there was, indeed, this difference of symptoms during the luteal phase to the follicular phase of the cycle.  
		So, we know what it is.  We've defined it basically as a group of symptoms that occur.  It's phase-related.  It's temporally related to the menstrual cycle.
		DR. LAUGHREN:  Are you talking about PMS or are you talking about something called severe PMS?
		DR. THYS-JACOBS:  I'm talking about premenstrual syndrome, PMS.
		DR. LAUGHREN:  So, you're not making -- earlier you were talking about --
		DR. THYS-JACOBS:  No.  I am not making any distinction in terms of severity, no, because I believe and my research has shown that, that the occurrence of premenstrual symptoms is abnormal.  It's like being pregnant.  If you're pregnant, you're pregnant.  If you're a little pregnant, you're 1 month pregnant, versus 9 months pregnant.  It's the pregnancy that makes the difference in terms of the reproductive cycle. 
		What I'm saying to you is that the occurrence, the presence of symptomatology during the luteal phase of the cycle is not normal.
		DR. TAMMINGA:  Dr. Temple.
		DR. TEMPLE:  Couldn't the relationship between these two terms be described as PMS is the larger term, and when the dysphoric symptoms are particularly prominent and are also premenstrual and have the appropriate timing, you call it premenstrual dysphoric disorder?
		DR. THYS-JACOBS:  Yes.  I look at it that way.
		DR. TEMPLE:  So, one is perhaps a subset of the other.
		DR. THYS-JACOBS:  Yes.  Yes.
		DR. TEMPLE:  And the way you get into a trial of premenstrual dysphoric disorder is you meet the criteria for those. 
		DR. THYS-JACOBS:  You focus more on the affective --
		DR. TEMPLE:  If someone wanted to do PMS more generally, then they would be focusing on whatever the symptoms that happen to accompany this person's premenstrual syndrome, but they might even not have a dysphoric disorder.  They might just be bloating or something.  But you'd say that's still PMS, but no one would say that's premenstrual dysphoric disorder because they're not dysphoric.
		DR. THYS-JACOBS:  Right.  I definitely agree with that. 
		I should actually qualify this.  What I look for is a difference between follicular and luteal phase.  When I treat a woman who has premenstrual syndrome, what I look for after treatment is the equalization between luteal and follicular mean scores.  That's what I look for.  It doesn't have to be absent.  I like to see absent symptoms.  So, when I even tell you the presence, that's not really right.  It's not the presence.  It's the increase in symptoms during the luteal phase compared to the follicular phase.  That's what I look for.  I look for the decrease in luteal phase symptomatology, those mean scores -- or you could use a visual analog scale -- between one phase of the cycle and the other, and I look for the equalization between these phases.  Then I say, yes, this woman is adequately treated.
		DR. TAMMINGA:  Dr. Hamer has a comment.
		DR. HAMER:  No.  Actually, as usual, I'm just confused.  Did I hear you say at one time that 80 percent of women had this and then at another time that it was abnormal?
		DR. THYS-JACOBS:  Yes.
		DR. HAMER:  I just wanted to make sure I heard that. 
		DR. THYS-JACOBS:  Yes.  I think 70 to 80 percent of women are suffering with premenstrual symptomatology.
		DR. HAMER:  Then why isn't that normal?
		DR. THYS-JACOBS:  Well, it depends on what normal is.  If somebody comes in and says, I feel wonderful and their vitamin D level is 0 and then you start treating them, and they say, wow, I've never felt better, what's baseline, what's normal?  I don't have the answer to that question.
		DR. TEMPLE:  It's like asking whether presbyopia is normal or not.  It's a matter of definition.  Everybody gets it, but the lens isn't working anymore. 
		DR. TAMMINGA:  The committee would like to hear from both Dr. Parry and Dr. Altemus about the broader question of PMS and the suitability, if you will, of PMS as a diagnosis.
		DR. ALTEMUS:  Well, I think PMDD is definitely well defined, and that's definitely an indication.
		I have a more conceptual question I guess.  For a drug to be approved, does there have to be a disorder with diagnostic criteria?  I'm just thinking of, say, pain medication.  Do we approve pain medications for arthritis?  Does there have to be a severity criteria for the drug to be accepted?
		DR. TAMMINGA:  Maybe Dr. Laughren can answer or Dr. Katz can answer this question.
		DR. ALTEMUS:  I think the problem with PMS is there's no severity criteria, like 80 percent of women have some symptom.  I'm wondering for a drug to be approved, do we have to have a defined disorder with diagnostic criteria, or is it possible to have, say, a pain medication approved that works for all different severity of pain?  Do you know what I'm saying? 
		DR. KATZ:  Well, you could have a pain medication approved I suppose for all different severities, and they are.  But pain is something that everybody understands.  I mean, it's commonly accepted that pain is a syndrome, if you will, that's commonly understood.  Everybody knows what you mean when you say I have pain, although there are different types of pain, of course.
		The question here that Tom is asking, that we'd like to hear what everybody has to say about, is, is PMS so well-defined, so clearly understood by the community and accepted as a bona fide diagnosis in the community so that we could reliably identify people who have PMS, know what their symptoms are, and that there would be a common understanding so that we could write a label that says, this drug is approved for patients with PMS?
		DR. ALTEMUS:  Well, if you wanted to do that, you'd have to have severity criteria, and the way you're describing it right now is there are no severity criteria.  It's just symptoms.
		DR. THYS-JACOBS:  No.  I'm not --
		DR. KATZ:  I don't know exactly what you mean by severity criteria, other than everything is on a continuum.  First you're normal with anything and then eventually you're abnormal.  So, I guess in some sense any disease state is defined almost by a severity criteria. 
		DR. TEMPLE:  You could use presence or absence, that kind of thing.
		DR. ALTEMUS:  I guess what I'm saying is I think right now PMS is in the same sort of realm as pain, that it's a subjective report, and there really aren't diagnostic criteria for what's the severity of bloating or discomfort that's defined as PMS.
		DR. TEMPLE:  You could develop one, and in fact you have to develop one or you won't be able to detect improvement.  So, make a visual analog bloating scale and check it out and see if people -- it's subjective anyway.  Actually nobody gave weight change measurements with this drug, which I meant to ask about and forgot to.  But they're subjective symptoms.  There are always ways to develop a scale for those things.  People do it when they're forced to because they want to study a drug usually.
		DR. ALTEMUS:  No.  I agree there are scales.  But right now, I'd say for PMS, as it's generally understood, there's no diagnostic criteria.
		DR. KATZ:  Well, then how do you know somebody has it?
		DR. ALTEMUS:  It's like pain.
		DR. TEMPLE:  But I think we heard this.  They have cyclical symptoms of one kind or another and they vary, that come at that time -- 
		DR. KATZ:  Right.
		DR. TEMPLE:  -- and are not there otherwise.
		DR. KATZ:  Right, but the question is if you're developing a treatment for it, do you study people who only have bloating, only have breast tenderness, who are dysphoric?  That's what we're asking. 
		Ordinarily when we consider an application for an indication, the indication is something that is generally recognized as being a bona fide, reliably identifiable entity by the community so that people know what Parkinson's disease is, people know what major depression is.  It's well understood what those things consist of.  
		Here the question is, how do we define PMS?  Does the field in general believe that one definition as opposed to another is acceptable?  That sort of thing. 
		DR. TAMMINGA:  Do you have another comment, Tom?
		DR. LAUGHREN:  Well, I guess another question that I have, and this is really a more subjective thing.  It's true that we approve drugs for something like pain or for nausea which are conditions which people understand.  You don't have to have, in a sense, diagnostic criteria. 
		I guess my question is here what we're talking about is committing patients with this entity to possibly decades of treatment, of continuous treatment, with a drug which has some risk associated with it.  The question is, if this entity is so vaguely defined that it exists in 80 percent of menstruating women --
		DR. THYS-JACOBS:  I can't imagine that you're saying that this is vague.  I think it's very clear-cut.  I think it's cyclical.  It's recurrent.  There's a group of symptoms that are increased during the luteal phase of the cycle.  I cannot see that as vague.  If this group of symptoms is increased by 30 percent, 50 percent, 100 percent compared to the follicular phase of the cycle, for me that is a definition of what this syndrome is all about.  I don't think you really have to say does this person who is suffering with premenstrual syndrome have this particular symptom.  No, we don't look at that.  
		You have to go back in history and realize that there have been clearly over 150 symptoms that have been associated with this syndrome.  We've come down to maybe we've agreed to maybe 15, 17, or 20 symptoms.  Do you want to look at the whole syndrome?  That's fine.  What I look for is this group of symptoms that occur and it's the change from the follicular phase, and that's the definition.  I think that's clear.  That is not vague.
		DR. TAMMINGA:  Dr. Parry, do you want to weigh in on this question?  This is the PMS question.
		DR. PARRY:  Well, to try to go back to the original question, I do think that the disorder, premenstrual dysphoric disorder, as defined in the DSM-IV, has substantial evidence for clinical viability, the nature of the symptoms being primarily affective in nature, the severity of the symptoms.  
		When the DSM was initially developed, the definition of psychiatric disorder was that condition which causes symptoms of distress as well as a certain amount of impairment in social or occupational functioning.  Now, for research criteria, we may use a cutoff score, but as with any other psychiatric disorder, it has to impair some aspect of social, occupational, or even school functioning, as Dr. Endicott reviewed this morning. 
		Then the other nature of the diagnostic criteria is the distinct timing of the symptoms in relationship to the menstrual cycle.  Many women may have cyclic mood symptoms, but they may bear no relationship to the timing of the menstrual cycle.  And retrospective reports on that are notoriously unreliable.  So, a prospective documentation of symptoms I think is critical in making the diagnosis.
		So, not only the nature, the severity and the timing of the symptoms have been, I think, very carefully described in the premenstrual dysphoric disorder, but the associated features of the course of the illness, its inheritance patterns have also been described, and also its relationship to other psychiatric conditions and differential diagnoses.  So, I do think that premenstrual dysphoric disorder is a well-defined, viable clinical entity.
		I do not think that premenstrual syndrome is a defined clinical entity, and I think that there would be a great risk in trying to develop a drug treatment for a very, what I consider, ill-defined syndrome.  It would be comparable, in my view, to taking someone with -- let's say, developing a drug treatment -- all the work that has gone into defining depression.  Granted, major depression may be a spectrum illness and needs to be differentiated from grief or just feeling cranky or having some irritable symptoms.  But I don't think it's advisable to develop drug treatment for something that's not a disorder that you could get recurrent pain syndrome, you could get very minor symptoms, and to use a drug treatment to mitigate those symptoms I have to say I think would be very inadvisable.
		DR. TAMMINGA:  Dr. Geller.
		DR. GELLER:  I think it will help if we make a distinction between what men accept and what women accept as commonly accepted entities.  I don't want to be disrespectful to the meeting, but if this were a Perry Mason show, I'd ask all women who think PMS doesn't exist to raise their hand.  
		I think there is such wide clinical acceptance that I think that really is not so much the issue as the definitional issues in terms of being scientists.  We don't have good measures that distinguish what the impairments are with PMS from non-impairments.  The challenge to the companies who want to use this as an indication would be to do what Dr. Temple just said, develop instruments that are validated and reliable that can measure PMS symptoms, and then you can define an entity.  From that, you can go on to drug treatment.
		DR. TAMMINGA:  Barbara, the difference between like an entity or a diagnosis, that PMS is in your point of view a diagnosis, as well as commonly accepted entity.
		DR. GELLER:  I think what we generally do is we make things a diagnosis if they produce impairment, and I think until we have validated, reliable scales that show what the impairment is, we ordinarily don't call it a diagnosis.  The experts are telling us that at this point in time, those scales don't exist for PMS.
		DR. THYS-JACOBS:  No, that's not correct.  There are scales for premenstrual syndrome.
		DR. GELLER:  Well, if there are scales and you can show --
		DR. THYS-JACOBS:  That's absolutely not correct.
		DR. GELLER:  -- the severity, then I'm misunderstanding Dr. Parry and I need correction.  I thought you were saying at this point in time you didn't feel that severity of PMS symptoms could be measured in a way that would be appropriate for drug studies.
		DR. PARRY:  Oh, no, I did not mean to imply that.  I think that the scales that were reviewed this morning -- the visual analog scale has been found to be one of the most sensitive markers, and it is a requirement to meet criteria for premenstrual dysphoric disorder that ratings be done on a daily basis over 2 months. 
		DR. GELLER:  Right.  No, for PMS, not the PMDD.
		DR. PARRY:  No.  I'm talking about premenstrual dysphoric disorder.  The symptoms that were listed this morning that are in the DSM-IV are listed by frequency of occurrence based on reports made at least five different centers across the U.S.
		DR. GELLER:  Dr. Parry, I think maybe we're having definitional problems.  I don't think anybody listening to Dr. Endicott and the other presentations this morning has doubts about PMDD being a distinct entity where you can show severity in symptoms.  My understanding is the FDA wants to know about the broader question of PMS, and here it sounds like there's a difference of opinion about how distinct an entity that may be in terms of what we can measure with rating scales.
		DR. TAMMINGA:  I'm hoping that Dr. Endicott might be willing to weigh in on this question.  Even though you're not on the committee, we'd love to hear from you.
		DR. ENDICOTT:  I think I find myself falling kind of in the middle in the sense that I do think that most women know what PMS is and that they could give us a description.  We could just tap any woman in the room and most of the men also could give us a clinical description of PMS that we would all nods our heads and say yes.  However, when it gets to the issue of whether all PMS is a disorder or not, that's where I do part company with Dr. Jacobs. 
		I think of it along the lines of a continuum ranging from just perceptible changes usually in physical symptoms that maybe get worse and worse and involve more and more symptoms, and at some point along that continuum, it becomes bothersome enough for the woman herself and for her mate or her children or her coworkers that treatment is warranted.  Certainly all of us who do studies of PMDD do have women that we don't put into our formal protocols because they don't meet our most stringent criteria for PMDD, but they do have moderate to severe PMS that is causing them problems.  We tend to sedge them over into another protocol or treat them openly because they have sought treatment for a condition that they have identified and that our prospective ratings show exist.  
		So, where is that cut-point along this continuum between what is just a phenomenon that is somewhat bothersome but not necessarily worthy of treatment and at what point is it severe enough that a woman wants treatment, needs treatment, and is willing to put up with the side effects that go with most treatment?  
		I think that there's always this issue.  It comes up with everything else.  How much pain do you have to have before you take an analgesic?  How bad does your headache have to be?  How bad does your cold, sore throat, or flu have to be before you decide I got to do something about this?  
		So, I do think of PMS as ranging from something that nobody would seek treatment for or think is worthy of much attention, all the way up into PMDD.
		DR. TAMMINGA:  And that cut-point in your opinion does not occur at the point of diagnosis of PMDD?
		DR. ENDICOTT:  PMDD is a stringent diagnosis.  There are certainly women who want to do something about their PMS that is just below the threshold of PMDD.  But the idea that every woman might want to pop a pill or something -- even women with PMDD, a lot of them say, well, isn't there anything else I can do, lifestyle, vitamins, diet, exercise?  Are there other things I can do so that maybe I won't need to take medication?  So, for any woman there is always this issue of the balance between whether or not they want to take a medication or not and how severe it is, how much pain it's causing in their lives, and how much impairment it's causing. 
		So, we do see women who don't quite meet our criteria for the studies, but certainly are severe enough to warrant treatment.
		DR. TAMMINGA:  Thanks.
		Other comments from the committee or its advisors?  Dr. Fyer.
		DR. FYER:  Following up on something Dr. Endicott said, years ago when Dr. Endicott started her studies, I remember having a conversation with her about starting the prospective follow-up.  The thing that really struck me was the number of people who self-reported for PMS who did not turn out to have menstrual related symptoms. 
		I guess in terms of Dr. Laughren's question about drug companies using PMS as an indication, I think that it would be particularly important to make sure people get the right kind of care, that the prospective assessment be built into anything anybody does, and also the issue of, if people don't have that particular menstrual related thing, to begin to characterize the other things people have and what other kinds of treatment may be useful for them, and sort of see it as an opportunity to identify other treatment responsive syndromes that are troublesome to women.
		DR. PARRY:  In that line, I think there was a study done a while ago, the De Jong study at the NIH, that looked at women who came in complaining of premenstrual symptoms.  They looked at the group in whom the diagnosis was confirmed versus those in whom the diagnosis wasn't confirmed by these daily prospective ratings.  In the group that was not confirmed, a majority of those, like 80 percent, had other psychiatric diagnoses, the most frequent of which was major depressive disorder.  It was, I think, maybe less stigmatizing to think that they had premenstrual symptoms when they really had major depressive disorder.
		DR. TAMMINGA:  Additional comments, thoughts?  Some of the committee hasn't spoken up.
		DR. THYS-JACOBS:  I just want to mention that most of the clinical trials on PMS have criteria of 2 months of prospective documentation of symptoms, and their criteria varies from trial to trial.  Some people have used a 30 percent, some people have used a 50 percent.  The majority of the studies have ruled out depressive disorders.  So, the trials are there, and I think PMS, as it stands, in research is a distinct entity.  
		There are, indeed, a number of women who come in and say that they have symptoms, and when you prospectively document their symptoms, it's not what it turns out to actually be.  But when you document for two menstrual cycles and you show that there's a luteal phase increase in their symptoms, that's what they have.
		DR. TAMMINGA:  Dr. Cook?
		DR. COOK:  I was just going to say I can't speak because I only have one X chromosome.
		(Laughter.)
		DR. COOK:  No. 
		But I did want to raise the issue, however, that although people are saying women would know what PMS is, most of the objections that have not been represented, other than to describe them as political, particularly have to do with PMS and are raised by women, not men. 
		 So, I think the discussion has covered that there would be some risk in developing an indication for PMS, but if someone wants to go for the broader indication, I think the FDA should seek some input from those who had enough impact to keep what to me sounds like a very clear disorder, PMDD, out of the body of DSM-IV.  I think that those are people that should be heard from.  I don't necessarily agree with them.  I just would suggest that that be included.
		DR. PARRY:  One risk factor I just thought of.  For example, given the cyclicity of the symptoms, one very important differential diagnosis is women with rapid cycling mood disorders, and giving something like fluoxetine or other antidepressants can potentially exacerbate the rapid cycling.  I think that would be one very strong indication.  And 90 percent of patients with rapid cycling mood disorders are women, and it would be one of the very adverse consequences of not having a careful diagnosis.
		DR. TAMMINGA:  Dr. Hamer.
		DR. HAMER:  I'd also like then in my role as an advocate to do the same thing I did last time, which is strongly urge the FDA to, as it usually does, be very careful in writing the labeling for exactly that reason.  As this will probably largely be prescribed by primary care physicians, gynecologists, they really do need to be sure to eliminate rapid cycling disorders so that they don't inadvertently give an SSRI to them.
		DR. TAMMINGA:  Dr. Winokur.
		DR. WINOKUR:  I'll jump in and make a comment.  That was the direction of some of my questions earlier.  I think I want to also distinguish just missing women who may have rapid cycling from the need to really focus down on the potential effects of the SSRIs or other antidepressants for the treatment of PMDD or other menstrual cycle related entities because we are talking about a cyclic mood disorder.  And now we're talking about potentially applying these drugs that we know in other populations have a potential to induce mania or hypomania, as is the case for other symptoms or problems that have been talked about, such as sexual dysfunction.  We know that sometimes symptoms have to be explicitly looked for rather than just kind of observed as adverse events.  So, I think that future research studies might build in specifically assessment of hypomanic type symptoms.
		DR. TAMMINGA:  Additional comments about PMDD as a diagnosis or about PMS as a disorder? 
		(No response.)
		DR. TAMMINGA:  If not, I think we should move on and talk about the appropriateness of the mood scales, of the VAS Mood-3 and the VAS Mood-4, in the data that we heard presented today by Lilly.
		Dr. Parry, you already mentioned something about this, that the visual analog scale was the single most appropriate scale.  Maybe you could launch a discussion of this.
		DR. PARRY:  I was just referring first, in general, that the visual analog scale has demonstrated reliability and validity not just in terms of premenstrual dysphoric disorder but in depression and other disorders. 
		I think that the thing that you want to check is that these women are turning in their scales every week so that they're not retrospectively filled out. 
		I think in evaluating studies, it's important to see sometimes -- some of the earlier studies done just might have only a scale of 1 to 3, no symptoms, some symptoms, severe symptoms.  I think the advantage of at least like 100 millimeter line visual analog scale is it gives the subject a whole range of symptoms and allows for individual variability in completing these scales.
		I think that the ones that were used in these studies were very adequate.  There was one case where they linked I think happiness or mood and energy which may or may not be associated.  But for the most part, they tapped into the main symptoms of depression, anxiety, rapid mood shifts, and irritability.  Thanks to much of the work of -- Jean Endicott has developed the other scales -- it's quite adequate.  They have been used extensively, and I think it's important to have both a clinician monitored -- as well as a subjective and an objective assessment built into the scales.
		But I'd again like to point out compared to other psychiatric disorders, the daily ratings, at least for 2 months to get into the study, is more rigorous than we have for most other disorders.  So, overall it doesn't mean there's not room for improvement.
		DR. TAMMINGA:  Dr. Thys?
		DR. THYS-JACOBS:  I would definitely agree.  The VAS scale has been used extensively for not only PMS but for PMDD, and the fact that it was Mood-3 versus Mood-4 I don't think is really of any major consequence.
		DR. TAMMINGA:  What about using a subscale of the VAS rather than the total VAS score?  We heard from Dr. Steiner this morning about the rationale for doing that.
		DR. THYS-JACOBS:  I don't think it makes that much of a difference because those symptoms that were chosen really are very much reflective of the total PMDD scale.
		DR. PARRY:  Yes, I do think they're much more like same amoeba, different pseudopods.  So, they do correlate but I think it is of interest to go back, at least from a research point of view, and look at the subtypes of symptoms.  Now, that's an area for development which specific subtypes of symptoms to do an item analysis to respond to specific interventions, physical versus emotional symptoms, for example. 
		DR. TAMMINGA:  Dr. Laughren?
		DR. LAUGHREN:  Can I try and clarify again the specific question that I had?  I thought I heard Dr. Steiner say earlier, expressed perhaps some surprise that fluoxetine had as robust effects as it had on physical symptoms, as well as, of course, the affective symptoms.  I'm wondering if in retrospect -- and again, this has to do with our advising other companies in their development programs -- if you would have focused on that affective subset or if you would have focused on the total scale as your primary outcome in that trial.  Again, the question is for future companies, should we advise them -- given the findings that we're seeing here, should the primary outcome be the total scale or should it still be the affective subscale?
		DR. TAMMINGA:  We could ask Dr. Steiner to give us his opinion on that.
		DR. STEINER:  Each line on a visual analog scale is its own scale.  You can look at it that way.  There are studies were you use one line of a visual analog scale and that is your rating scale.  The fact that we picked seven lends itself to the fact that we were able to analyze it in total, which we did, which was statistically significant, lends itself to take the three major emotional behavioral symptoms that we wanted to analyze, and then separately the physical symptoms.  
		If you look at what's available in the literature for other SSRIs, it looks as if all of them work for both the emotional and the physical symptoms.  So, if I were to advise to you guys, I would say take a combined visual analog scale.
		DR. TAMMINGA:  Dr. Katz.
		DR. KATZ:  Yes.  We'd be very interested in the committee's view of this whole question of the effect on the physical symptoms.  Certainly it wasn't expected, and I suppose one possibility is that it's entirely an artifact, if you will, of the primary affective effect of the drug.  I gather there were no objective, quote/unquote, measures of bloating or weight gain or this sort of thing that were examined.  I gather that's true.  Maybe that's not true.  If there are objective --
		DR. JUDGE:  We have information on weight.
		DR. KATZ:  Okay, well, that might be useful to look at because this will have impact if the drug were approved or might have an impact on the label and what this should be indicated for, just the affective symptoms of PMDD or the entire syndrome.
		DR. TAMMINGA:  Because presumably there are some people who have just physical symptoms of PMDD --
		DR. KATZ:  Right.
		DR. TAMMINGA:  -- while emotional symptoms --
		DR. KATZ:  Well, not of PMDD I gather by the diagnostic criteria, but of PMS.
		In fact, it will be interesting, of course, to look and see if there were any work done on the effects of the drug in women who just had physical symptoms.
		So, the whole question of the effect of the drug on the physical symptoms I think is very important for us to hear what the committee has to say.
		DR. PARRY:  I would just like to point out there was a study.  I believe it was in the archives.  Now, this is not PMDD but depressive symptoms in the general population.  When you looked at somatic symptoms of depression, a good portion of those were reported by women.  So, now, it may not be the case in this disorder certainly, but some of the somatics being a depressive equivalent I think is a distinct possibility.
		DR. TAMMINGA:  Dr. Temple.
		DR. TEMPLE:  But my understanding is -- someone tell me if this is wrong -- that you can see cyclical weight changes and actual edema, at least in a fraction of the population.  So, those presumably wouldn't be the result of your improved mood if you could show a difference in those things.
		DR. PARRY:  I think there is documented evidence of fluid and electrolyte changes with the menstrual cycle.  I guess I was being more broad about symptoms other than just weight gain and fluid retention.
		DR. TEMPLE:  It would be extremely interesting to see if a drug that's known primarily at least as an SSRI had an effect on those things which certainly would have been a surprise to us.
		DR. TAMMINGA:  Perhaps, Dr. Judge, you could give us whatever data you have on the objective measures of physical symptoms.
		DR. JUDGE:  I'll take your points about weight with respect to two discrete questions.  Firstly, overall weight changes in the groups per se.  And the information here is -- this is a summary of changes in weight from two of the studies.  We were able to glean information on weight changes from baseline to end point.  What we see is for the placebo group, overall there's a mean change of a gain of .2 kilograms.  For the fluoxetine patients, overall there was a mean loss of 0.4 kilograms.  
		So, individually within the groups, if you looked at the next slide please, in terms of patient numbers who had potentially clinically significant changes in weight -- and that is, patients who had neither a 7 percent increase or decrease in weight -- we see overall for placebo very few patients exhibited any such parameters, and for fluoxetine a few patients again, but more than placebo, did exhibit either a weight gain or a weight loss.  But overall the percentages were very low, 7 and 9.5 percent, respectively.  Those differences were statistically different from placebo.  So, that's the summary of changes in weight with respect to fluoxetine.
		Now, overall in terms of your question with --
		DR. TEMPLE:  What you're really interested in is the difference between the follicular and luteal phase.
		DR. JUDGE:  Yes.  That's what I was going to say in terms of the discrete question with respect to the ‑‑
		DR. TEMPLE:  We already know fluoxetine can affect maybe weight.
		DR. JUDGE:  Yes.  I was going to say with respect to your other question, especially for those patients who had bloating as a reported symptom, we don't have that information.
		DR. TAMMINGA:  Dr. Altemus?
		DR. ALTEMUS:  I'd just add that at first I was really surprised by that information that bloating went down, that those symptoms improved.  But when you think about it, we don't really know what's mechanistically wrong, like what's going wrong in these women, but they have normal shifts in hormones but they have a very exaggerated response mentally to those shifts in hormones.  Certainly there are mild changes in appetite and metabolism and fluid electrolytes with the cycle.  So, when you think about it that way, it's not that surprising if they overreact to the hormone changes in terms of mood, that they'd overreact in terms of appetite or metabolism too.
		DR. KATZ:  The question is whether or not the drug is having an effect on those independent of its effect on -- you may not be able to tease this out, but since they are subjectively reported, if a person is feeling better from an affective point of view, there might be less attention paid to these other physical symptoms or they might feel as if they're lessened when in fact objective measures may show that they're not lessened.  That's the question.
		DR. ALTEMUS:  Yes.  We were talking about this at lunch.  I'm not even aware of a study in normal menstrual cycle that shows weight changes.  I'm not sure that's ever been documented.  It's a really common complaint, but I don't think it has been shown.
		DR. TAMMINGA:  Dr. Endicott.
		DR. ENDICOTT:  There are two issues here. 
		In terms of weight gain, a couple of studies that have tried to actually document the subjective feeling of weight gain have generally not done so.  What they have found is a redistribution of water, not an actual increase, the idea that the bloating is not necessarily from water retention, but from a redistribution of water so that the subjective weight gain may well be response to that.
		Now, on the other issue about whether if you improve the dysphoric mood changes you automatically get a reflected improvement in the physical symptoms, at least in one of our published studies of a drug, unnamed, we got very good changes in irritability, depression, and anxiety with no changes in the physical symptoms.  So, it is possible to demonstrate changes in the dysphoric mood symptoms without changes in the physical symptoms.  In fact, the women often said, well, I still have my physical symptoms, but that's no big deal.
		DR. TAMMINGA:  Dr. Steiner.
		DR. STEINER:  I think that bloating and the sense of bloating is more subjective than the breast tenderness.  My surprise was that the breast tenderness -- and maybe it should not be a surprise -- is a pain and you're giving an SSRI.  The bloatedness is also something like Jean said.  When we tried to measure whether there was a change in weight, there isn't, although there is this complaint in the sense of bloatedness.  But the breast tenderness is really an eye-opener.  These women say I don't have that pain anymore, and I think that that is a drug effect.
		DR. PARRY:  SSRIs and other antidepressants do increase the pain threshold.
		DR. TAMMINGA:  We've been kind of discussing around the issue of whether the indication should be for the affective symptoms of PMDD or for the whole syndrome, however one might define that, of PMDD.
		Dr. Fyer.
		DR. FYER:  Well, this is not at all my area of expertise, but it sounds to me, from what people have been saying, is that we really don't know about the actual effect on the physical symptoms, and that it would be premature to put in labeling something we don't know.  Rather, it seems to me that it would be very nice if the sponsor would undertake the responsibility of doing some well designed studies to address that question.  It would be, I think, a help to everybody.
		DR. TAMMINGA:  Other comments?  Dr. Temple.
		DR. TEMPLE:  What should they do?
		DR. FYER:  What should --
		DR. TEMPLE:  Well, they had physical symptom scores of the usual kind.  Do you have a thought about how they could tease that out further?
		DR. FYER:  Well, like I said, I do anxiety disorders, so I'm not a measurement expert in this area.
		But I think Dr. Katz' comment was well taken.  We don't know to what effect what we're seeing is the result of mood changes, and it seems from what Dr. Endicott just said that, in fact, there's not all that much known about what actually physiologically goes on.  I think it would be very helpful to everybody to do studies in which they actually looked at weight changes, luteal versus follicular phase of the cycle, during the drug treatment, as well as before, and to try to characterize that. 
		DR. TEMPLE:  I suspect that's true.  I guess my nervousness about it is that we don't usually expect that someone will solve a dilemma that's existed for 20 years before they can get a practical claim that they improve it.
		DR. FYER:  Well, no.  Wait a second.
		DR. TEMPLE:  So, one has to balance what's reasonable.
		DR. TAMMINGA:  Dr. Cook.
		DR. COOK:  My concern is that it's new for them to really raise this.  They had almost wanted to take it out in the design of these studies.  So, even if they don't need to do more, they certainly need to test the hypothesis a priori.
		DR. TAMMINGA:  Dr. Fyer.
		DR. FYER:  I'm a little surprised to hear Dr. Temple take that position because I think when we talk about the real world, where drugs are prescribed, I think somebody raised the point before that much of the prescription for this indication is going to be in non-psychiatric settings by GP's where there is a predominance of managed care and limited time.  I really think you want to be careful about somebody saying they have breast tenderness premenstrually and then being put on long-term fluoxetine.  Before we get into that kind of situation, I think some experimental data would be useful.
		DR. TEMPLE:  That seems to me an important but different question.  What level of symptomatology should make you want to go on an antidepressant for many years is a very important question.
		But, for example, the things that occur to me is they could find a population that doesn't have any obvious psychiatric component and see if they improve.
		DR. FYER:  Yes.  That would be an excellent --
		DR. TEMPLE:  So, that's one thing.
		You could also look within the trial to see whether people who have better response on mood also have a better response -- this is after the fact and it wouldn't be as convincing, but that's another thing they might do.  They could look to see if there's a correlation between improvement on one and improvement on the other.  That wouldn't be definitive, obviously.
		I'm just trying to think of what they could do.  But I would say nothing in this database would suggest a claim for treating those conditions alone in the absence of the dysphoric disorder.  So, I don't think anybody has been thinking about that. 
		DR. FYER:  But I think the other issue is to what extent the labeling reflects the idea that a whole syndrome -- where there's the implication that people who don't have predominant dysphoric symptoms will respond to this drug.  I think that's where the sort of gray area issue for labeling comes in.
		DR. TAMMINGA:  Of course, that wasn't tested here at all.  The only thing that was tested here was whether -- it only looked at the population of people with dysphoric disorder, and then we're kind of wondering about the status of the physical symptoms, and that's really less clear.  But for sure, we're not looking at any data of people who had no dysphoric disorder but PMS and had only physical symptoms.
		Would Lilly like to suggest what studies they're doing?  There has been some question in the committee about what studies Lilly might be currently doing that would address these kinds of questions.
		DR. JUDGE:  I just want to make clear that the application is for fluoxetine in PMDD, premenstrual dysphoric disorder.  The question was raised as to what other studies Lilly are doing with respect to PMDD and specifically intermittent dosing.  These are currently the two multi-center, multi-national studies that are ongoing, taking place in Europe and in the United States. 
		Firstly, a randomized, parallel, placebo-controlled study comparing two doses of fluoxetine intermittently and that is defined as 14 days prior to the onset of menses in approximately 250 randomized patients, and this will involve many, many more patients screened, but randomized will be approximately 250 patients.
		Secondly, there is another study ongoing, randomized, parallel, placebo-controlled study comparing infrequent monthly dosing of fluoxetine with an alternative formulation in approximately the same number of patients. 
		These are also again in PMDD patients, not specifically with one or two physical symptoms or PMS, specifically PMDD.
		DR. TAMMINGA:  Dr. Judge, in either of these studies, do you have objective measures of physical symptoms?
		DR. JUDGE:  Again, as we considered with a group of leading researchers in PMDD/PMS, it was felt that the scales currently used in the trials, namely the visual analog scales, namely PMTS, and perhaps one or two other scales, were indeed good scales in order to measure the appropriate outcomes with respect to physical symptoms and mood symptoms. 
		As you saw from the studies presented this morning, the secondary objectives of measuring physical symptoms was, indeed, stated as a secondary objective measure.  Indeed, consistently the effect was found for physical symptoms, and we hope to find consistent effects in the ongoing studies as well.
		DR. TAMMINGA:  Dr. Fyer.
		DR. FYER:  It's really interesting that Dr. Endicott just got up and said that when the objective studies have been done about weight gain, what they found is redistribution.  Yet, you're doing these new studies, and the design of the study is not really addressing what's apparently known in the field.  It might be nice to take these things into account.
		DR. JUDGE:  The studies that I've talked about are Lilly's commitment to further the work in PMDD with respect to intermittent dosing.  The question was raised earlier, is it appropriate to pursue intermittent dosing?  
		With respect to weight change, I think that's a very important question.  Is weight an appropriate symptom to study?  We won't know that from these studies.  That's a different question for which we have not put a study in place.  Perhaps it's more appropriate for that study.  I don't know that someone would have a special interest in that and do that.  I'm not sure.  But the studies ongoing are the ones that I've listed here.  I think that's a very important and nice question, but it's not particularly going to be addressed by these questions.
		DR. FYER:  Yes, that's exactly my point, that it isn't going to be addressed.  I think it would be nice if it were. 
		DR. TAMMINGA:  Dr. Hamer.
		DR. HAMER:  In the existing 019 study that was Dr. Steiner's study, you saw the subjects once during the luteal phase and once during the follicular phase.  Did they get weighed each time?
		DR. JUDGE:  No, they did not get weighed each time.  They got weighed infrequently, and definitely at baseline and endpoint, but not during every visit.
		DR. HAMER:  In the new studies, are they being seen both during the follicular and luteal phases, and are they being weighed?
		DR. JUDGE:  Again, there would be infrequent measurements of weight.
		DR. PARRY:  The inherent problem, though, of course, is that other things can affect weight, particularly diet and carbohydrate craving, which you'd have to control, and that's one of your outcome criteria for PMDD symptoms that you're trying to monitor.
		DR. HAMER:  Sure.  Just asking about weight is asking about, in some sense, result not mechanism.  But it would be nice to design in weight measurements at those places, as well as perhaps some physical measurements, various sorts of circumferences and things like that, so you could look for this redistribution of water. 
		DR. TAMMINGA:  Dr. Altemus?
		DR. ALTEMUS:  If women on their rating forms are feeling significantly less bloated with the treatment, I don't think we would deny them the treatment because they don't actually have a physical change in weight.  It's an interesting mechanistic question, but it really is not relevant to whether this should be an indication for the drug.
		DR. ENDICOTT:  I'd like to comment.  Weight gain is not part of the criteria for PMDD for the very reasons that have been mentioned, that the studies suggest that it is feelings of bloatedness that are part of the criteria but not weight gain, which is one of the reasons that I don't think any of the studies are focusing on weight gain per se because the really careful studies that have been done looking at that issue have found evidence of redistribution, not of actual gain.
		DR. TAMMINGA:  So, the physical symptoms that we're talking about could more precisely be called perception of physical symptoms rather than what we might really document with weight gain.
		DR. ALTEMUS:  Right.  Like somatic symptoms in depression.  People would complain of more aches and pains that improve.
		DR. PARRY:  You can always look at the item analysis on the Hamilton of either subjective or objective measures of weight change.
		DR. TAMMINGA:  This may be a good time to transition into the discussion of continuous versus intermittent dosage, especially since we've seen that Lilly has two current studies now, one in intermittent and the other one in infrequent dosing.  Any comments from the committee or from its advisors on that?
		DR. PARRY:  Well, I think the jury is still out with the luteal phase dosing.  There are some preliminary reports.  I think to me probably one of the primary determinants may be the half-life of the drug.  I think that was mentioned earlier.  So, I think to put this forward, it would be best -- I think to put it on luteal phase dosing at this point I think would be premature. 
		DR. TAMMINGA:  Dr. Thys?
		DR. THYS-JACOBS:  I agree.
		DR. TAMMINGA:  It would be --
		DR. THYS-JACOBS:  Premature.
		DR. TAMMINGA:  Premature to suggest luteal phase dosing. 
		DR. THYS-JACOBS:  Right.  There's not enough evidence at this point in time to advise luteal phase dosing.
		DR. ALTEMUS:  I think it's also not just the half-life of the drug but how long-lasting the changes are in the brain, that it may take several weeks to reverse once you've been on a drug for 2 weeks.  That intermittent dosing might work for regular depression.
		DR. PARRY:  That's why we have patients off fluoxetine for at least a month before they enter studies.
		DR. TAMMINGA:  Dr. Katz?
		DR. KATZ:  I don't think we're asking whether or not we should write labeling that says you should give it just during the luteal phase or however often.  The question is given that it is an intermittent condition and that the presumption that you might be able to just treat this with intermittent dosing maybe even a couple of doses -- who knows -- whether it's appropriate to approve it with chronic dosing, in other words, whether this is something that is -- it's a benefit-risk question, whether it's worth having women on this drug chronically for a condition that occurs just intermittently for a relatively brief period of time.  That's the question.
		DR. TAMMINGA:  The data that's in front of the committee is only continuous data.
		DR. KATZ:  Right and the question is whether or not you think that is appropriate to approve the drug on the basis of that.  Is it worth it?  Or should they do more studies that further define?  Now, it is invariably true that we almost never know, when we approve a drug, the perfect dosing regimen.  We only know what people studied.  The question here is, should they study more before we approve it, or can you live with this?
		DR. TAMMINGA:  Dr. Altemus.
		DR. ALTEMUS:  I don't think so just because I don't think we put that burden on other disorders.  You could say, well, can you give medication half as often for major depression?  I think just because it appears during 2 weeks or a week of the month, I think it's pretty unlikely that -- well.
		DR. PARRY:  Yes, I would kind of echo that, that this is a recurrent, periodic illness and that the medication may work as a mood stabilizer.  To recommend anything less than that, we just don't know if that's going to have the same efficacy until that's demonstrated.
		DR. TEMPLE:  That's not the question.
		DR. COOK:  No, but I would add something, that until you have evidence that the intermittent dosing is both efficacious and safe, I don't think one should presume that it's safer to give it in an intermittent manner.  These drugs have been tested for safety largely in a chronic manner, and as alluded to, I wouldn't use the word "kindling," but sensitization changes from this sort of dosing pattern wouldn't have the safety behind them.
		Now, with fluoxetine, of course, you have the problem is anything truly intermittent, but as you're asking a more general question about SSRIs, hitting it just a few times a month may not be the best paradigm for long-term safety.  We don't know.  It's intuitive that it's worth trying, but the data has to be there. 
		DR. TAMMINGA:  Dr. Temple.
		DR. TEMPLE:  No one thinks we could approve an intermittent regimen that hadn't been studied.  This goes to the fundamental question of the approvability of a chronic treatment for an intermittent disease where, in this unusual case, you actually know when the disease is going to occur.
		DR. THYS-JACOBS:  This is not a disease.  It's a disorder.
		DR. TEMPLE:  Whichever.  But you know when what you're treating, however you will care to define it, is going to occur.  
		It really goes to the fundamental question of whether a drug with a half-life of 14 days if the best way to treat this or an appropriate way to treat this.  In asking that question, I want to be very clear I'm not offering an opinion.  It's just something that ought to be discussed.  That's all.  I'm not saying that we are horrified by that idea.  It might be the best thing in the world for everybody.
		DR. TAMMINGA:  Dr. Winokur?
		DR. WINOKUR:  Well, this is a disorder that we've heard, I think, convincing evidence is associated with a good deal of morbidity and distress, and I think we can evaluate data from studies that have been done to form opinions about efficacy and safety, tolerability, acceptability in this context and then consider alternative approaches to treating when such data come along.  But I don't see anything that is a barrier to our rendering an opinion about continuous treatment for a disorder that is discontinuous, but has significant implications.  We've heard a lot of testaments to that effect.
		DR. TAMMINGA:  Dr. Geller.
		DR. GELLER:  There was mention in the material we got of a sertraline trial that was discontinuous.  Is there more information on that?  Did people get withdrawal when it was taken away and stuff?
		DR. TEMPLE:  I don't think we know yet.
		It's also possible new information will emerge later that will cause people to reconsider what the best approach is. 
		DR. GELLER:  I was wondering if specifically there was more information about the sertraline study at this point in time. 
		DR. TEMPLE:  I don't think we do.
		DR. TAMMINGA:  We don't have it on our table.
		DR. PARRY:  The analogy that just comes to mind is lithium, recurrent mood disorder, and I think that there's substantial evidence at this point that for a recurrent mood disorder that lithium works better the longer you leave it on them, and there are actually risks of taking them off.  I might see that as the closest analogy to address that.
		DR. TAMMINGA:  If you don't mind my interrupting you, I'd like to ask you the question in the case that Dr. Temple proposes that in PMDD this is a predictable cyclic -- I mean, mania is not predictably cyclic, but this is clearly predictably cyclic -- would you still hold the same opinion?
		DR. PARRY:  Yes.  Well, first, mania may be a rapid mood cycling.  In most cases it is, but in not all cases is PMDD predictable.  Of course, as soon as you enter them in the study, they don't get their symptoms.
		DR. ALTEMUS:  Also, I think it's premature to think that because it's cyclic you should give the drug when the symptoms appear.  To really prove that, I bet you could give the drug during the follicular phase every 2 weeks and they may respond just as well.  What I'm saying is it's premature to think that it should be given during the luteal phase just because that's when the symptoms appear.
		DR. TAMMINGA:  Additional comments?  Dr. Fyer?
		DR. FYER:  I think that's an excellent point.  We don't know the pathophysiology.  I think Dr. Parry referred to the possibility that it's acting as a mood stabilizer, and we don't know the important point of entry really is when people are clinically ill.  It might be the week before.
		DR. TAMMINGA:  The data we have on the table are continuous data, and we've seen Lilly present that it's, in fact, doing a couple of different intermittent designs.  So, we'll have some confidence that additional data will be coming.
		I guess the question would be whether Lilly wants it to be continuous dosing because it uses more drug.  That's not the right way to think about it.
		DR. KATZ:  No.  I think Dr. Temple put it well.  It's simply a question of is it appropriate to approve a drug for chronic use when the symptoms occur predictably intermittently.  That's the question.  We're not bringing an opinion to the table.  We're simply asking the question is that an appropriate type of treatment for this sort of disorder.
		DR. PARRY:  Well, yes.  I think the other consideration is if it's not treated in its initial stages, which may be a follicular phase or early on -- and I think there's data to support this, at least in PMDD -- it can get worse over time, I think the point that Dr. Cook was making, that it can exacerbate symptoms.
		DR. TEMPLE:  Part of the problem is it's hard to know how to even talk about this.  With a drug with a half-life of 24 hours, you could ask the question, when do we have to treat, because then you could treat for the week before, the week before and during, you could modify your regimens and actually ask the question.  With a drug with an active metabolite whose half-life is 14 days, you can't even ask the question.  You're treating chronically whether you like it or not, and the only question is how much to give.
		But just from my point of view, I thought what Dr. Winokur said was, look, you can look at the benefit, you can look at the consequences, and you can make a judgment about whether the consequence of being on Prozac a lot for a long time, which is obviously something that happens to a lot of people in this country, is worth it in view of the benefit of preventing these symptoms.  I think that's what we're trying to --
		DR. PARRY:  The risk of no drug treatment and drug treatment.
		DR. TAMMINGA:  Dr. Laughren.
		DR. LAUGHREN:  Let me just give an example.  There are drugs for chronic conditions that are given intermittently.  Methotrexate is given once a week for treating rheumatoid arthritis.  So, there are examples.  That's clearly a drug where you would want to limit the overall exposure.  So, you would want to find a regimen that involved the least exposure to that drug to get a benefit.  So, that's really the question.  Is there a more optimal dosing strategy that works that gives a benefit and limits the risk?
		DR. TAMMINGA:  Dr. Fyer.
		DR. FYER:  Yes.  I think this is a very interesting question, but I think it comes down to sort of pragmatic issues.  I think what you're seeing on the committee is a reflection of that.  The sponsor and other people in the literature have demonstrated efficacy using a certain -- or made a strong case for that using a certain approach, and that certainly seems better than leaving people in distress.  Anything else is going to be more of a question.  
		I think this almost becomes political in that would I personally think that it would be best that all sponsors be required to invest time and effort to find the optimum approach that has the least risk, et cetera.  Yes, I definitely would. 
		Has that and is that going to happen in the current climate in this country?  I doubt it. 
		So, I think if you want to know is it best to do it that way, of course, it's best to do it that way, but what's actually going to happen?
		DR. LAUGHREN:  We simply wanted to raise the question here for two reasons really.  Again, this is a condition where the symptoms are cyclical.  They're not present continuously.  And secondly, there is a suggestion, I don't know how well established, that the possibility of intermittent dosing may be of benefit.  That's not established yet.  I totally agree with that.  So, the question is whether or not there should be encouragement to look at more optimal dosing strategies for this condition.
		DR. FYER:  I personally think there should be encouragement in all kinds of disorders.  What you're saying, Dr. Laughren, is that because of the particular pattern of appearance of the symptoms, this particular question gets raised.  But in fact, since we don't know pathophysiology of most psychiatric disorders, one could legitimately raise that question about most of them.
		DR. TAMMINGA:  Dr. Laughren, is the data that the sponsor presented about the studies that are ongoing encouragement to the FDA or --
		DR. LAUGHREN:  We've not seen any data from any other studies.
		DR. ALTEMUS:  I think just one final point about that.  From what we know about how antidepressants work, it's not an immediate relief of symptoms when you take it.  So, I think it's almost counterintuitive that you would expect it to work within those 2 weeks.
		DR. LAUGHREN:  Except that in this condition, it appears to have a fairly rapid response compared to its rate of onset in depression.
		DR. ALTEMUS:  Do we know, though?  Is it within 2 weeks?  It was a month.
		DR. TEMPLE:  It works 3 weeks later.
		DR. ALTEMUS:  But the question is does it work in the first week.  Is there any evidence of that?
		DR. TAMMINGA:  Your question is, does fluoxetine work in the first luteal cycle?
		DR. ALTEMUS:  No.  It has to start if you start on day 14, would that -- 
		DR. TAMMINGA:  Oh, we don't have those data in front of us.  The only data that was presented to us this morning was when the treatment was started in the follicular stage, yes, there seemed to be a clear response that first cycle.  The major response really occurred.
		DR. ALTEMUS:  So, by then they've been on it for 3 weeks by the time they get to their symptomatic period.
		DR. TEMPLE:  And that's not from the antidepressant.
		DR. ALTEMUS:  Right.
		DR. PARRY:  On the visual analog scale data, how soon do the ratings start going down?
		DR. JUDGE:  All patients starting dosing on the first day of their cycle, first day of menses, and what we saw for all those studies was that at the first cycle, which is usually roughly around 2 weeks after beginning of dosing, 2 to 3 weeks, that they did have a significant effect.  Remember, the visits were done from cycle to cycle and the patients were seen follicular, so I can't answer that question whether at the first week, if we looked at the first week, whether there would be significance at that point.
		DR. PARRY:  But the VASs were done daily.
		DR. JUDGE:  That was not analyzed for purposes of today.
		DR. TAMMINGA:  I think we'll just have to wait till your luteal dosing studies are finished and look at those data.
		If there aren't any more comments on the intermittency of dosing, I'd like to direct our attention to the use of oral contraceptives along with fluoxetine in this condition.  The oral contraceptives were excluded from this study.  They're certainly commonly used in the age range of people who would be treated for this disorder.
		Do oral contraceptives do something promising in this disorder and would we say that fluoxetine is both effective and safe in PMDD people who are using oral contraceptives?
		DR. PARRY:  I think one of the reasons obviously that oral contraceptives are excluded is because oral contraceptives in and of themselves can induce an atypical depression.  They also have physical side effects.  So, they have to be excluded.  I just don't think we have the data to answer whether they can be used concomitantly.
		If you look at what predicts onset of premenstrual dysphoric disorder, if you look at clinical demographic features, many women have previously been on oral contraceptives and some had dysphoric mood symptoms in relationship to that.  Is that data different?
		DR. TAMMINGA:  So, PMDD does occur in women who use oral contraceptives.
		DR. THYS-JACOBS:  Yes, it can definitely occur.  In fact, the evidence is either way.  Some of the studies show that the OCPs can actually increase affective symptoms and diminish physical symptoms.  What the data is on the SSRIs in combination with the OCPs I'm not sure.
		DR. TAMMINGA:  We saw some data this morning, not in PMDD, but in other treated populations, of oral contraceptive use along with fluoxetine, and the safety data looked with and without oral contraceptives looked straightforward.
		DR. ALTEMUS:  And the response data too.
		DR. TAMMINGA:  Right, response data.
		Dr. Winokur.
		DR. WINOKUR:  Yes.  I would just reiterate I think thought Dr. Judge's review of these issues this morning was very on target.  First of all, I think it would have been significantly complicating and confounding to have the presence of OCs in these studies, and then the second issue is potential risks of combining fluoxetine with OC use.  I both agree that there's a pretty substantial database outside of PMDD for us to extrapolate to.  I can't think offhand of any reason why we'd expect there would be different safety risk issues.  I agree that the potential drug interactions, which are nontrivial with some drugs, are not, to my knowledge, a significant concern.  I felt that that was quite thoroughly addressed in the presentation.
		DR. TAMMINGA:  Dr. Hamer.
		DR. HAMER:  It seems there are two aspects of these questions.  One is to help the FDA write appropriate labeling, if this drug is approved, based on the studies that have been done.  There have been no studies done, at least among the three we've been shown, in women on oral contraceptives.  You might consider that you should then write labeling saying that this shouldn't be used in women taking oral contraceptives because we have no evidence. 
		On the other hand, virtually every depression trial that I've ever run, or for that matter, almost any other trial, has excluded people who are suicidal, and we give antidepressants to people who are suicidal all the time.  Most of the antipsychotic trials have excluded people abusing drugs, and we give antipsychotics to drug abusing psychotics all the time. 
		DR. TAMMINGA:  Bob, we saw data this morning of fluoxetine given to women taking oral contraceptives.
		DR. HAMER:  But not for PMDD.
		DR. TAMMINGA:  Right, we didn't see PMDD plus oral contraceptives.
		DR. HAMER:  Right.  But the point I'm trying to make with the discussion of suicidality and depression and so on is that that does not stop the FDA.  The FDA does not then write labeling saying we haven't done clinical trials in suicidal people, so don't give the drug to suicidal people.  They should sort of use the same kinds of judgments in this context too.
		The other issue is whether to encourage or discourage, in further clinical trials or in other clinical trials, the use of oral contraception as an exclusion criterion.  And I don't have any thoughts on that.
		DR. TAMMINGA:  A more naturalistic design.
		Do you want to say anything about that, Dr. Laughren?
		DR. LAUGHREN:  Many parts of the population are left out of typical development programs.  Now, hopefully what we see in a development program is that as you move from phase II into phase III, more heterogeneous populations are enrolled and you are including patients who have other disorders or taking other medications and so forth.  
		Really what we want a sense from the committee about on this issue is how important is this exclusion for this drug for this indication for labeling.  It's likely if you think it's not a critical issue, that the extent of our modification of labeling -- we might say, in describing the clinical trials, simply that patients taking oral contraceptives were excluded.  There wouldn't be any restriction on its use, simply a simple statement that that part of the population was excluded.
		DR. TAMMINGA:  I would feel comfortable with that, especially since we already have data in women with oral contraceptives, even though they don't have PMDD.
		Any other opinions on this?  Dr. Temple.
		DR. TEMPLE:  Just to launch an advertisement, I would say as a general matter, we agree with what was said, that in phase III, as drug development progresses, exclusions should drop off, if possible, to nothing, and you should look at the consequence of the interaction, not avoid it.  One of these days I'm sure we're going to write something to that effect, but I think there's a growing appreciation of that.  In some areas, like exclusion of the elderly and things like that, there is considerable progress, but we all believe that should be much more general and that, in general, trials should include everybody who might get the drug.
		DR. TAMMINGA:  It's a good point to always make.  I think I agree with you that it is becoming more widespread.
		What I would like us to do is to proceed into a discussion of the specific studies that were presented.  We addressed a lot of questions this morning to Dr. Judge and to the rest of the people in the sponsor's group about these studies, the size of the studies, the dropout rate, the single study that had a crossover design, the investigator initiated nature of the studies.  I'd just like to open this phase up for some discussion of the committee and hear people's comments on any aspect of this that they think is important.
		I bet Dr. Hamer could launch this part of the discussion.
		DR. HAMER:  Yes, and I'm going to launch it by saying that I'm really bewildered.  I know how to behave when I look at a set of clinical trials submitted as part of an NDA whose purpose is registration, that the sponsor designed, managed, supervised with prespecified endpoints negotiated with the FDA.  I know how to trust the results of those trials.
		In a set of trials that was much more loosely, in some sense, organized and evolved, I'm not sure I know how to behave with these results.  This is the intersection of science and regulation, and so it's not just a scientific interpretation.  
		For example, it's unclear to me how many other trials there are out in the literature involving fluoxetine and PMDD.  I have actually been looking through the material and if it's in there, which it probably is, I just can't find it.  But why these three trials that we're told about?  
		Again, in the usual NDA, there's half a dozen, a dozen, or whatever phase II trials that I don't pay any attention to because they were small and they were dose-ranging and all that sort of stuff.  What I pay attention to is the negotiated-out phase III trials.  Here I don't know what to pay attention to, and I don't know if there's stuff that I don't know about that I should be paying attention to.  So, I'm very bewildered.
		DR. TAMMINGA:  We're asked to pay attention to the three studies that were presented, 1, 2, and 3.
		DR. HAMER:  What we're actually asked is, is there evidence from adequate and well-controlled trials that the drug is safe and effective?  I don't know that we're asked simply to attend to these three trials.
		DR. TAMMINGA:  Dr. Katz.
		DR. KATZ:  Well, the point about there being perhaps many other trials that are negative is a good one, and I'm sure the sponsor has been through the literature and we can probably hear about that. 
		The question of relying on trials that were not supervised or conducted by a commercial sponsor, when those are submitted under NDAs, is not an infrequent one.  There certainly is plenty of precedent for our approving a drug on the basis of a trial that wasn't conducted or supervised by a commercial sponsor who submits the application.  We do require in those case, almost invariably, that we get the complete information, the protocol, and that the study be as well conducted and designed, prospective protocol, as if it were run by the company.  So, there's certainly precedent for our relying on such trials if they're well done, if they're appropriately designed, and we have the data.
		DR. TAMMINGA:  Dr. Fyer?
		DR. FYER:  Yes.  Could we address the other question?  Because I'm just not familiar enough with the literature.  Are there in fact other negative trials?  And has the FDA conducted a literature search?
		DR. TAMMINGA:  We did actually see a slide this morning from Dr. Judge.  Maybe you'd like to catch us up again.
		DR. JUDGE:  These are the other double-blind studies that have been conducted in PMDD for fluoxetine.  Besides this, there are also a number of open studies which I won't show here. 
		For all of the other studies not part of the submission, there is no negative study for fluoxetine in PMDD.  We've also attempted to try and find unpublished studies, obviously because there tends to be publication bias with respect to negative studies.  We've also tried to look for negative studies with respect to fluoxetine in PMDD, and we could not find any as part of our attempts.
		So, for example, Menkes was a study in New Zealand.  Ozeren's study was a study in Turkey, and Wood and Stone were also studies in the United States of America.  They all comprised patients with a diagnostic category of DSM-III-R and therefore of DSM-IV, as you heard earlier.  The duration of the treatment cycles ranged from 2 to 3 cycles, and all utilized 20 milligrams daily.  All were positive with respect to the efficacy of fluoxetine in PMDD.
		What the open studies showed was further evidence for that for out longest, showing that perhaps fluoxetine is effective much, much longer out, and also the fact that when patients stopped treatment, even after several months, that there can be very quickly a reemergence of symptoms after stopping treatment.  That's the summary of the open-label studies.
		DR. TAMMINGA:  Do you want to speak to why you chose the first three as part of your NDA?
		DR. JUDGE:  Yes, indeed.  We attempted to find the data for all of the studies, but for these studies here, we were limited in terms of, first of all, access to that data, sometimes lack of cooperation from the site for whatever reason, and also sometimes for missing data, for example, substantial missing data that was available.  So, we did attempt to go back to all of this data in order to provide a comprehensive listing.  But this is the three that we felt were of adequate quality, controlled, and we had access to that data.  We had investigator cooperation and we could show to you.
		DR. TAMMINGA:  Questions, comments for Dr. Judge?  Yes, Dr. Temple.
		DR. TEMPLE:  When you say they were all positive, what do you mean, that they were in the right direction or that they attained nominal significance or what?
		DR. JUDGE:  All of these studies, the other ones listed here, for example, the two crossover and parallel design, with respect to the publication, the primary objective listed in that publication, there was significant evidence for fluoxetine with statistical superiority versus placebo.
		DR. TAMMINGA:  One of the things that we're used to seeing from data sets that don't have otherwise large safety databases is large n's.  In this particular study, the n's are not as large as what characteristically we're used to seeing.  We saw this morning the presentation of effect sizes, and the effect sizes were impressive.  But still, the overall number of patients is not great. 
		Dr. Dominguez.
		DR. DOMINGUEZ:  Yes, not only the small n sizes in the other two studies, but the variability of the inclusion and exclusion criteria.  For example, the use of a structured clinical interviews in some of the trials versus just the clinical interview to exclude Axis I diagnosis.  
		The failure to obtain a urine drug screen at the beginning of the trial, knowing that benzodiazepines can be helpful for these individuals, and knowing that at least at some time during the trial, a number of patients did report using benzodiazepines at times, but that was just a listed report.  One cocaine overdose.  
		Again, not knowing the race and ethnic background of the individuals in the larger trial.  Not knowing what previous treatment they had had for PMDD and what had worked and what had not worked. 
		So, it's the variability in inclusion and exclusion criteria which makes this set of studies much harder to interpret.
		DR. TAMMINGA:  To some extent, you're really agreeing with Dr. Hamer, that these are studies that are more investigator initiated than drug company initiated.
		DR. DOMINGUEZ:  And they're valuable, but again that variability one has to always adjust for.
		DR. TAMMINGA:  One of the things that I'm wondering how to measure is the effect sizes that were reported in studies.  I wouldn't mind hearing from some of our consultants about that.  It would make me think that there is some consistency to drug response despite all the variability that you're bringing up, that there's a consistency and a rather sizeable drug response in order to get effect sizes like that.
		DR. PARRY:  Well, I know when the DSM-IV was putting together the database, we looked at different calculations of effect size, and no matter which way you looked at the data, you pretty much got the same phenomena.  So, I think that it has been a pretty robust response no matter which technique has been used.
		DR. THYS-JACOBS:  Effect sizes actually varied from study to study.  Most people use a 50 percent response as a real response rate.  Some studies in PMDD and PMS actually looked at the visual analog scale scores and looked at the difference.  Not all studies actually looked at effect size.
		DR. TAMMINGA:  Any more discussion about the designs of the studies that we had presented?  Dr. Temple?
		DR. TEMPLE:  Well, I'm a little curious about some of the conversation.  Obviously, I think Dr. Hamer shows great wisdom in thinking that the only really credible trials are the ones we help design.
		(Laughter.)
		DR. TEMPLE:  And it's hard to disagree with that.
		(Laughter.)
		DR. TEMPLE:  At least sometimes we've had the view that studies that use somewhat variable entry criteria and yet still get the same result add to the database, and that replicating the identical finding over and over again is perhaps somewhat less interesting than replicating it in a variety of settings.  I guess I think I at least partly believe that, but I'd be interested in the discussion.
		Of course, in general, the more medicines that people might be taking that you don't know about, the more they interfere with showing anything.  So, in a sense, even that lack of knowledge is a sign of robustness, although also simultaneously makes you nervous.
		But I'd be interested in a little more of that.  The fact that they were different environments I wouldn't say discourages me too much.
		DR. TAMMINGA:  Slightly more naturalistic one might think.
		DR. TEMPLE:  Well, and there was a certain trend in that direction.
		DR. TAMMINGA:  Crossover design, Dr. Hamer?
		DR. HAMER:  It's another reason to be skeptical.  Crossover designs really are a can of worms because they're complicated by carryover effects, sequence effects, a variety of things like that.  In this particular design, the fact that with a drug whose principal active metabolite has a half-life that's probably at least 2 weeks and then to have only one menstrual cycle in the middle as your recovery, when, in fact, at least in depression we know that fluoxetine requires a number of weeks to even start working and furthermore, a number of weeks to wash out, is troublesome.  
		On the other hand, the statisticians and Dr. Judge were absolutely right.  In this particular trial, whatever carryover effect there was would have tended to inhibit the ability to show a difference between fluoxetine and placebo rather than exaggerate it, and thus the fact that they did, indeed, show a difference is reassuring.  But I still don't like them.
		DR. TAMMINGA:  I would agree really with Dr. Temple about the what I would call more naturalistic design of this group of trials and still seeing a robust drug response is impressive from my point of view.
		I was troubled, if you will, to use your word, Bob, about the low n.  But then I sort of looked back at the data when I was studying it before the meeting.  Although the n is 19, there's really 2 or 3 cycles per person in order to add up, if you will.  So, if I were doing, for instance, rat studies, we might count that as an n of 28 or something like that.  We have multiple repetitions in the same person of this phenomenon we're observing.
		DR. HAMER:  They're not independent of one another.
		DR. TAMMINGA:  Excuse me?
		DR. HAMER:  They're not independent of one another, the multiple observations from the same rat or the same person.  So, they're not each another degree of --
		DR. TAMMINGA:  Oh, for sure.  But they're a within-subject replication which is impressive.
		Dr. Winokur.
		DR. WINOKUR:  I just wanted to ask Dr. Hamer a follow-up question on his comment to help me understand better.  I understand the general reasons for caution about interpretation of crossover studies, but it struck me in initially looking at the data that in this case with the unique feature of this disorder with the repetitive pattern with what struck me as being a fairly solid design of starting with placebo and fluoxetine and then going the other direction and the results tending to support an impact of active drug treatment in whichever sequence, with all of that sorting out, that actually seems to be a persuasive argument.  So, I'm wondering in this case whether that's a particularly appropriate use of this design, or am I statistically not tuning into something?
		DR. HAMER:  No.  In this case, in some sense, the things that could have gone wrong with this crossover design would have tended to obscure the drug-placebo difference.  So, the fact that there still was one was nice. 
		But on the other hand, there are plenty of other reasons not to like crossover trials in general and including prospectively before you did this, this one.  One is the difficulty of having a long enough washout period in the middle to know that you really are washing out not just the drug but the effect of the drug because, for all we know about things like receptor proliferation and those sorts of things, there may be a whole lot of things that need undoing over a long period of time. 
		The other is that if anything goes wrong in a crossover design, like you have dropouts partially through, so you don't wind up with people doing the entire, full design, you may wind up with only the first period analyzable, in which case you now have simply a parallel group design with a tiny n. 
		Again, in this case, it's reassuring that they analyzed just the first period data and found a significant difference because, if you want to, you can sort of disregard the entire crossover part of the design, and you still have a supportive study.
		DR. TAMMINGA:  Any other comments or concerns or extended discussions people would like to have about the design of the protocol of the data sets that were presented to us?
		(No response.)
		DR. TAMMINGA:  Any other issues that people would like to bring up about the data that were presented to us that speak to the question about efficacy or safety?
		DR. COOK:  I have one comment, and that is this disorder would presumably start at menarche and they limited the beginning to age 18.  Now, it would be one thing to suggest this will never be given to someone under 18, but Dr. Parry has said that this is a sometimes progressive disorder in which it's not clear why one would withhold treatment until age 18.  Obviously, these are challenging risk-benefit issues, but I don't see justification for not having studied adolescents, recognizing that they have reasonable expectation that there will be off-label use in adolescents.
		DR. PARRY:  Well, except that generally physical symptoms predominate during adolescence and you don't see the mood symptoms until -- in most studies, the average age is 30s.  Between like 30 and 38 is the mean age of symptoms, and they may have been there for 5 years.  But you usually don't see severe mood symptoms during adolescence.
		DR. HAMER:  Speaking as the father of three people who used to be adolescents, I would say that it would be pretty hard to tease out mood swings due to premenstrual dysphoric disorder from the normal mood swings that are part of adolescence.
		DR. PARRY:  That's why you need to 2-month prospective documentation.
		DR. COOK:  I have to object to that one because the same thing was said about major depression in adolescence and even pre-adolescence.  So, particularly because you have the timing with the menstrual cycle here, you could make that distinction.
		But I'm impressed by the age of onset except weren't there a lot of 18-year-olds?  In other words, it seemed to me there were some young adults being treated, and the 18-year-old cutoff was arbitrary.
		DR. GELLER:  I just wanted to say, as the other child psychiatrist here, that we are beginning to tease out mood disorders from normal adolescents.  I think this goes back to the comments that Dr. Winokur was making that the labeling here has to really stress differentiating this from rapid cycling mood disorders.  I think without separate study of the adolescent population in this regard, that's going to be hard to do because a common presentation of bipolar disorder in this age group is to rapidly cycle.  A lot of those people come in clinically and the parents tell you their child has a menstrual disorder.  I think this is just an age range that is ripe for study and for separate study.
		DR. TAMMINGA:  So, the committee would certainly like the sponsor to understand that we see studies of this disorder and this drug in adolescents as important.
		DR. GELLER:  Yes.
		DR. TAMMINGA:  Do you want to say that more strongly, Dr. Cook?
		DR. COOK:  I wanted to raise the issue.  I hear now age of onset is different.  My concern is exactly what Dr. Geller says.  In largely primary practice, will this be used off label for this.  So, on the one hand, it should be studied.  Until it's studied, I think there should be strong cautions about its use off label.
		DR. TAMMINGA:  Dr. Katz.
		DR. KATZ:  Yes.  I'll just let you know.  We now have regulations that require sponsors to study drugs in a pediatric population, and they can try and make the case that for any of the particular subpopulations, the condition doesn't exist.  But to the extent that it does exist, they're required to do it, and they have to make a commitment.  If those data don't come in with the specific application, they may have to make a commitment that they will do it and time lines are imposed and all that. 
		DR. TAMMINGA:  So, we can be confident that you'll receive those data.
		DR. KATZ:  At some point.
		DR. TAMMINGA:  Yes, Dr. Geller.
		DR. GELLER:  I think this has to be built in in some way either to post-marketing surveillance or people applying for other kinds of funding to look at the off-label use in the younger population because from what we're seeing as child psychiatrists, it's going to be used when other diagnoses are more likely.
		DR. TAMMINGA:  Yes, Dr. Dominguez.
		DR. DOMINGUEZ:  Another area for further investigation that we have heard very little from this application is issues of predictors of response.  For example, I think the agency may want to look at certain associated features of PMDD that, although may occur rarely as part of the disorder, may serve as predictors of response, for example, psychotic-like features during the worst time in the luteal phase, suicidality, and concomitant substance abuse. 
		The issue of adding the feeling of being overwhelmed and out of control to some of the rating instruments I think would be important as well because it has been my experience, at least clinically, that you do find a set of patients with this disorder where that is the prominent feature, along with the effect of instability that they present with, that is the most disturbing to them.  Yet, I don't think that was probed at all in the data that was presented.
		DR. TAMMINGA:  Dr. Fyer.
		DR. FYER:  I just want to make two sort of comments that concern me, given the small sample size.  That has to do with what's going to happen if and when this whole thing takes place.  It seems to me there are two issues.  
		One is that the sponsor has gone over this whole issue about safety.  I think that generalizing to the Prozac or fluoxetine database, it's sort of clear that we aren't going to have serious, unexpected things given the age and sex distribution of many people on Prozac is the same as for this requested indication.
		On the other hand, the idea this is a chronic disorder, there's a high relapse rate, people are going to take this for a long period of time, I would really feel a lot more comfortable if there were a serious commitment from the sponsor to look carefully at quality of life issues.  For example, in the FDA's review, it was pointed out that a certain subset of women gain weight continuously on this.  That can be a serious health issue as well as a quality of life issue.  It would be nice if systematic studies addressed exactly how can people deal with this and are there alternative strategies that might help that kind of thing, as well as issues of sexual desire.
		The other thing is that it would be in the sponsor's power, if the drug were to be granted an indication and marketed, to do post-marketing studies that would actually look at how the drug was being used and to see if there were consequences that might not be in the best interests of women in this country.  I would think that if an indication were to be granted, that a request or a requirement from FDA that such work be done, given the widespread nature of syndromes related to this requested indication, would really be very helpful.
		DR. TAMMINGA:  Dr. Geller.
		DR. GELLER:  This is another child psychiatrist type comment.  Can the labeling include something to the effect that if underlying conditions are found, they should be treated before treatment is initiated just for PMDD?
		DR. TAMMINGA:  This is a question to the people who design the labels.
		DR. GELLER:  Well, it's not looking for a specific answer, but that kind of thinking, that at least it would encourage people to think if they're going to give it off label.  Dr. Hamer was just asking me, who's going to give it to the adolescents?  Is it going to be the gynecologist or the pediatrician?  Pediatricians are now giving lithium.  They won't think anything of giving Prozac for a menstrual disorder.  Perhaps if there were something in the labeling pointing out that underlying conditions should be treated first, we might head off some of the --
		DR. TAMMINGA:  Well, certainly in the studies that were presented, only people who lacked other conditions actually got into the study.  So, you're really suggesting that something be included in labeling that's consistent with the study data that were presented.
		DR. GELLER:  Right.
		DR. KATZ:  Certainly there's precedent for putting statements in labeling about it's off-label use, but usually when there's an affirmative finding that there is a safety problem in whoever those people are or there's evidence that it doesn't work in those people, those are the two circumstances I can think of where we put statements in labeling about off-label use.
		DR. GELLER:  I wasn't suggesting this is off-label use.  I just meant for all age groups that there be some statement that emphasizes that we really don't have data on what happens if you treat an underlying condition first.  As usual, the sample that was studied was relatively pristine in terms of comorbid disorders that occur commonly when you have PMDD.  I'm going back again to Dr. Winokur's emphasis on people who may be having a bipolar depression, getting the drug for that and then having an exacerbation of their bipolar phase.
		DR. WINOKUR:  Actually, since you mentioned that again, let me make sure.  That was only part of what I said, not to have the other part left out.  I'm also concerned about inadvertently discovering a new phenomenon, which is people who don't have formally bipolar disorder that is just not detected, but have a different form of cyclic mood disorder, namely PMDD, in whom a small subset but not yet detected or appreciated might be stimulated in the hypomanic or manic direction by a drug like fluoxetine.  Again, we don't have any data yet to suspect that to be the case, but I think that from other clinical experiences, that's a lesson that we've learned to be very cautious about.  I think if it is going to get out there more widely in a broader population, that's one area that we don't really have adequate data to judge in my opinion.
		DR. TAMMINGA:  Dr. Parry.
		DR. PARRY:  There's just one safety issue, and this is not what was brought up this morning.  But in reviewing the materials I was sent, I just thought the description of the use in pregnancy could have been more specifically delineated.  For example, there's the Pastuszak study and the Chambers study.  Though there's no major teratogenic effects, the fact that mothers who are taking fluoxetine, their children are in the intensive care unit and they had more respiratory distress and lower birth weight and that kind of thing, I thought for safety reasons should be given attention.
		DR. TAMMINGA:  Except that PMDD is not a disorder that occurs in pregnancy, so there would be no reason to treat it during pregnancy.
		DR. PARRY:  Yes, but you have to address that in a labeling issue, and if a woman becomes pregnant and she's on it, that's part of the presentation.
		DR. TAMMINGA:  Any more comments of any kind about the issue in front of us?  Dr. Katz?
		DR. KATZ:  Yes, I have another question before you vote.  It's sort of under the heading of maybe a theoretical labeling question again.  You know we're obviously very interested in labeling, and you may just advise us to do the usual good job that we do.  And I appreciate that in advance.
		(Laughter.)
		DR. KATZ:  But I'd just be interested in some of your thoughts on the following.
		Suppose that you have concluded or do conclude that there is evidence of effectiveness.  It's possible I suppose to see that effectiveness as just really fluoxetine's antidepressant effect, and that in some sense it could be considered a global antidepressant in that it has been studied up till now in major depressive disorder.  Now it's being studied in a considerably different disorder but that has primarily an affective component.  And right now the drug is approved as an antidepressant and then the labeling describes in whom it has been studied, major depressive. 
		One theoretical option, I suppose, for labeling would be to leave the indication as an antidepressant and then list after what's currently listed, which is it's been studied in major depressive disorder, and now say, well, it's also been studied in another sort of depression-like syndrome, as opposed to giving it its own PMDD claim.  I just wonder what people think about that. 
		DR. PARRY:  Well, I think it's important to recognize that premenstrual dysphoric disorder is categorized as a major depressive disorder, N.O.S.
		DR. KATZ:  Well, that's sort of what I'm asking.  In other words, again if you find it's safe and effective, we could choose to label this as a specific treatment for PMDD in addition to its current indication, or we could subsume under its currently existing indication.  That's the question I'm asking.  I'm interested in your views on that.
		DR. TAMMINGA:  Dr. Geller.
		DR. GELLER:  Just educate us.  What would be the down side of doing that?
		DR. KATZ:  Well, it would imply a couple of things.  Number one, that PMDD is a type of depression, a type of depressive disorder, and it would imply that the drug is sort of a global antidepressant and it works in any setting in which a patient happens to be depressed, whether it's major depressive, whether it's a cyclical entity, perhaps even others which haven't been studied.
		So, I don't know that there's a down side or an up side.  We are going to have to deal with this question, and I'm just interested to know what people think.
		DR. PARRY:  I can just see, women who have premenstrual dysphoric disorder often don't like to acknowledge that this is a major depression.  I'm just trying to think ahead about the potential consequences.
		On the other hand, if you just propose it specifically for premenstrual dysphoric disorder, I guess my concern would be that any woman with any kind of minor, cyclic physical symptom that may or may not be related to the menstrual cycle might see this as a panacea.
		DR. TAMMINGA:  Dr. Laughren.
		DR. LAUGHREN:  Except that in writing labeling, we would rely very heavily on the diagnostic criteria for PMDD to describe the type of patient who would be a candidate, including functional impairment as part of that.  So, we would work very hard to avoid that possibility.
		DR. PARRY:  Yes.  I'm just thinking of the potential abuses that may occur irrespective of that.
		DR. TAMMINGA:  Dr. Cook?
		DR. COOK:  Yes.  I would be much more comfortable with a PMDD labeling.  I think that's what we were here to discuss, and I think that actually there's probably confusion out there in terms of PMDD being just depression.  I thought there was data presented -- and certainly the epidemiology that isn't all that was presented today -- to suggest that this is a distinct disorder.  This would not be like saying it works for melancholic depression as well as other depression.  So, I think this would be reasonable with the caveats that this is not PMS treatment, but PMDD, to have it distinct.
		DR. TAMMINGA:  Dr. Winokur.
		DR. WINOKUR:  I think we've heard a lot of comments from the experts and from the general committee that recognize PMDD to be a discrete and recognizable, diagnosable entity.  I think increasingly in our field and in communication to more family practitioner types, we've been trying to emphasize precision or care in diagnosis prior to treatment.  So, I think that going from data and having discrete, delineated syndromes as a guide to treatment rather than encouraging the older pattern of very broad spectrum triggers for treatment is really something we're trying to encourage.  I would much more see the specific indication as being in that dimension.
		DR. TAMMINGA:  Dr. Fyer.
		DR. FYER:  I agree with what has been said about the diagnosis.
		I think that there's an additional educational issue which I think is positive, but I am concerned about what Dr. Parry raised.  I have a question for the FDA people, and that is, to what extent is it within your power, in addition to just labeling about PMDD, to actually structure interactions between pharmaceutical representatives, et cetera so that there is real education about this sort of limitation, as opposed to something that's on a package label someplace that a lot of people don't read?
		DR. LAUGHREN:  The promotion has to be very closely linked to what's in the label.  So, to a great extent, that does control the level of promotion that can go on outside of labeling.
		DR. FYER:  Somehow, though, we all know that in the long run there seems to be an enormous amount of what's called off-label usage, and maybe again something that could be considered is some post-marketing survey aspects to see because I think there is a widespread potential here for something that I don't think anybody is particularly interested -- at least people in medicine probably not interested in having unnecessary expense and side effects and maybe missing things that would be treatable by other perhaps psychotherapeutic interventions.
		DR. LAUGHREN:  Again, I share that concern.  As I said earlier, we'll go to great lengths to try and define the population that we think are candidates for this treatment.  Beyond that, it's hard to know what FDA can do.  We don't, of course, regulate the practice of medicine, so we can't control off-label use in that sense.  But we will try and write labeling that directs clinicians to what we think is the target population.
		DR. FYER:  You could possibly also ask the sponsors to participate in some post-marketing assessment of exactly what's going on.
		DR. KATZ:  I don't know if we could, and even if we could -- let's assume we learned that there was a lot of off-label use going on.  It's hard to know what we would be able to do about it.
		DR. FYER:  Publish it so that people are aware that that's going on --
		DR. KATZ:  Well, a lot of off-label use is published.  People think it's a good idea.
		DR. FYER:  Some of it is.
		DR. KATZ:  Well, right, right.
		DR. FYER:  Yes, and some of it isn't.
		DR. KATZ:  We could even in labeling put, just as another thing that's possible to do, a patient package insert in there which also tells the patient that this is for PMDD.  It's not for mild symptoms of PMS.  Now, whether or not that's actually going to affect people's behavior is another patient, but you can attempt to inform the patient as well as the prescriber.
		DR. FYER:  I mean, there is a trend, especially with the Internet, for increasing amounts of consumer sort of self-awareness and stuff.  So, something like that might in fact be useful.
		DR. TAMMINGA:  Dr. Temple, did you want to log in?
		DR. TEMPLE:  Well, do I recall correctly that this will have special packaging, a different name, et cetera?
		That really does open the possibility of a patient insert that is targeted to the population.  It reminds them that they should think about whether they want to be on a chronic drug and that their symptoms are severe enough to warrant it.  That very situation is one of the conditions in which we believe patient labeling is important, where there's a decision that the patient really needs to participate in actively.  In this case, you don't have to label all of the uses of Prozac.  You can just label this one perhaps.
		So, we'll think about that.  Special packaging and labeling is a point of some controversy internally I should tell you.
		DR. TAMMINGA:  Unless there's further discussion, I would suggest we move ahead to a vote.  Although we've certainly appreciated all the comments of the consultants, the consultants won't vote on the final efficacy and safety questions.
		So, the first question that the committee will want to vote on is, has the sponsor provided evidence from more than one adequate and well-controlled clinical investigation that supports the conclusion that fluoxetine is effective for the treatment of premenstrual dysphoric disorder?
		I think we just ought to go around the room.  Maybe we'll start with you, Dr. Dominguez.
		DR. DOMINGUEZ:  I believe that there are some limits to the generalizability of the data that was presented with respect to race, with respect to ethnic groups.  Essentially the patient samples that we have been presented today are in non-minority whites, and it appears from the sample that clearly the drug is effective for the indication that is proposed.  I think that this is a clearly distinct disorder.  So, it should be labeled as such for this disorder.
		DR. TAMMINGA:  Dr. Hamer.
		DR. HAMER:  As uncomfortable as I am with the set of studies that wasn't generated in the usual way, yes.
		DR. TAMMINGA:  Dr. Geller.
		DR. GELLER:  Yes, with the proviso that the FDA do its usual outstanding job of writing the labels to take into account the discussion.
		DR. TAMMINGA:  Dr. Cook.
		DR. COOK:  Yes.
		DR. TAMMINGA:  Dr. Winokur.
		DR. WINOKUR:  I vote yes. 
		If I can editorialize for a minute, I'm incredibly distressed about the circumstances of the second positive study that we had to consider with the investigator unilaterally interrupting the study.  I realize that that was not at all Lilly's doing.  I think the data that we are left to consider are overall convincing enough.  But I think it's an extremely dismaying circumstance, and I think it's the kind of thing that really can interrupt the progress of the kind of science that we need to make these kinds of decisions.
		DR. TAMMINGA:  Dr. Fyer?
		DR. FYER:  I would vote yes with two provisos.
		One, Dr. Geller's and that be taken seriously. 
		I'd like to say that I also found this circumstance distressing and I found the sponsor's presentation of the data from that trial distressing.  I would hope that in the future such things will be dealt with in a much more straightforward fashion in sort of due respect to the members of the committee and the public.
		DR. TAMMINGA:  And I vote yes as well with many of the same caveats as people have talked about before, but having some interest in the more naturalistic kind of data that we saw today.
		The second question.  Has the sponsor provided evidence that fluoxetine is safe when used in the treatment of PMDD?
		Dr. Dominguez?
		DR. DOMINGUEZ:  Yes.
		DR. TAMMINGA:  Dr. Hamer.
		DR. HAMER:  Yes, attending in particular to the sorts of things Dr. Winokur has talked about. 
		DR. TAMMINGA:  Dr. Geller.
		DR. GELLER:  Yes.
		DR. TAMMINGA:  Dr. Cook.
		DR. COOK:  Yes.
		DR. TAMMINGA:  Dr. Winokur.
		DR. WINOKUR:  Yes.
		DR. TAMMINGA:  Dr. Fyer.
		DR. FYER:  Yes.
		DR. TAMMINGA:  Dr. Tamminga, yes.
		I think we've had a day and an afternoon where we've discussed an important issue, both an indication and a drug.  We've discussed perhaps, at least for our group, a new style of data, if not necessarily for groups in general.  And we've taken a vote and concluded the meeting.
		Thank you all very much.
		(Whereupon, at 3:15 p.m., the committee was adjourned.)