AHDEPARTMENT OF HEALTH AND HUMAN SERVICES

PUBLIC HEALTH SERVICE

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATOIN AND RESEARCH

PERIPHERAL AND CENTRAL NERVOUS SYSTEM DRUGS

ADVISORY COMMITTEE

Friday, January 28, 2000

8:07 a.m.

Gaithersburg Hilton
Gaithersburg, Maryland

Committee Members Present:
3588t1
	Sid Gilman, M.D., Chairman
	Claudia H. Kawas, M.D.
	Richard D. Penn, M.D.
	Gerald Van Belle, Ph.D.
	James C. Grotta, M.D.
	Ella P. Lacey, Ph.D., Consumer Representative
	LaRoy P. Penix, M.D.

	Sandra Titus, Ph.D., Executive Secretary

Oncology Consultants:

	Sandra Swain, M.D.
	Bill Dahut, M.D.

MS Consultants:

	Jerry Wolinsky, M.D.
	Howard Weiner, M.D.

Neurology Consultants:

	Richard Lipton, M.D.
	Michael Grundman, M.D., M.P.H.

FDA Staff:

	Russell Katz, M.D.
	Gerald Boehm, M.D., M.P.H.
	Robert Temple, M.D.

C O N T E N T S

AGENDA ITEM	PAGE

Call to Order, Introductions
     Sid Gilman, M.D., Chair, PCNS	4

Conflict of Interest Statement
     Sandra Titus, Ph.D., Executive Secretary, PCNS	5

FDA Overview of Issues
     Russell Katz, M.D.
     Director, Neuropharmacological Drug Products	8

Immunex Presentations:	30

   Introduction
     Ann Hayes, M.D.
     Senior Vice President, Medical Development	30

   Efficacy and Safety
     Richard Ghalie, M.D.
     Senior Director, Clinical Development	40,167

   Conclusion
     Fred Lublin, M.D.
     Professor of Neurology,
     MCP Hahnamann University	227

Open Public Hearing	157

     Statement of Frank Vanik	157
     Statement of Mary Elizabeth McNary	160
     Statement of Patricia Redondo	163

Committee Discussion and Deliberation	253

Adjournment	323

P R O C E E D I N G S
	DR. GILMAN:  Good morning.  My name is Sid Gilman, and I am the chair of this committee.
	I would like to go around the table and have people introduce themselves, and would the FDA also introduce any other members of the Department who are here that you would like to recognize.
	Let's start with Dr. Katz.
	DR. KATZ:  Russ Katz, Division of Neuropharmacological Drug Products.
	DR. BOEHM:  Gerry Boehm, Medical Safety Reviewer, Division of Neuropharmacological Drug Products.
	DR. GROTTA:  Jim Grotta.  I am a neurologist at the University of Texas in Houston.
	DR. LIPTON:  Richard Lipton.  I am a neurologist/epidemiologist at Albert Einstein and Innovative Medical Research.
	DR. PENIX:  LaRoy Penix.  I am a neurologist at Moorehouse School of Medicine.
	DR. TITUS:  Sandy Titus.  I am the Executive Secretary for this committee.
	DR. GILMAN:  And I am a neurologist at the University of Michigan Medical Center.
	DR. KAWAS:  Claudia Kawas.  I am a neurologist at Johns Hopkins School of Medicine.
	DR. WOLINSKY:  Jerry Wolinsky.  I am a neurologist at University of Texas‑Houston.
	DR. VAN BELLE:  Gerald Van Belle.  I am biostatistician at the University of Washington in Seattle.
	DR. PENN:  Richard Penn.  I am a neurosurgeon at Mount Sinai Hospital in New York.
	DR. LACEY:  I am Ella Lacey, Professor Emeritus, Souther Illinois University at Carbondale.  I am a consumer representative.
	DR. SWAIN:  Sandra Swain, medical oncologist from the National Cancer Institute
	DR. GRUNDMAN:  Michael Grundman, neurologist, University of California, San Diego.
	DR. DAHUT:  Bill Dahut, a medical oncologist from the Medicine Branch of the National Cancer Institute.
	DR. GILMAN:  Would the sponsor like to introduce any of your team?
	DR. HAYES:  I am going to do that in my introductory talk.
	DR. GILMAN:  That's just fine.  You are perfectly free to do that.
	Let me just make a few opening remarks.  It is a pleasure to see you all here and to welcome the new members of the panel and the consultants to the panel.
	We will be discussing NDA 21‑120, Novantrone, Immunex proposal for the treatment of multiple sclerosis.
	In the course of your presentations, I ask both the FDA and the sponsor to present your material in any way you would like, but please, let us ask you questions along the way.  As you have seen in Dr. Katz' narrative, a number of issues have been raised, and we will want to have you address some of those issues, so please answer immediately if you possibly can‑‑respond to the question' don't put it off.  It is much more helpful if you will do that.
	And for the panel, please signal to me that you wish to ask a question or make a comment so that we can have an orderly meeting.
	With that, I will introduce Sandra Titus, who will read the Conflict of Interest Statement.
	DR. TITUS:  The following announcement address 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 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.
	We would, however, like to note that one of our consultants has had an interest related to Novantrone that we believe should be disclosed.  FDA believes that it is important to acknowledge the participant's involvement so that her participation can be objectively evaluated.
	Dr. Sandra Swain previously participated as a principal investigator on a study of Novantrone for use in the treatment of breast cancer.
	With respect to FDA's invited guests, Dr. Howard Weiner and Dr. Jerry Wolinsky have reported interests which we believe should be made public to allow the participants to objectively evaluate their comments.
	Dr. Weiner would like to disclose that he is a consultant to Teva/Marion on Copaxone.  Further, Dr. Weiner's employer, Brigham and Women's Hospital's Center for Neurological Diseases, will be participating in a trial of Copaxone.
	Dr. Wolinsky would like to disclose that he served as a consultant to Immunex for two years.  In addition, he is the principal investigator on a trial sponsored by Teva/Marion.
	In the event 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 of fairness that they address any current or previous financial involvement with any firm whose products they may wish to comment upon.
	That ends the formal announcement.  Dr. Gilman is going to informally respond to a statement that has been made to him.
	DR. GILMAN:  I'd like to inform the sponsor that I consulted with Biogen Company when they were preparing their presentation for the Food and Drug Administration approximately 8 years ago.  My consultation was after the trials had been completed, and they wanted some help in determining how they would present their material to the Food and Drug Administration.  I have had no contact with them since that time.
	All right.  Are there any other comments about this?
	[No response.]
	DR. GILMAN:  If not, we'll ask Dr. Katz to make his presentation.
	DR. KATZ:  Thank you, Dr. Gilman.
	I'd like to welcome the committee back again.  Thank you very much for braving the cold and coming here.  I would particularly like to thank a few of our invited guests for coming‑‑Dr. Lipton, Dr. Wolinsky and Dr. Grundman, and particularly, Dr. Swain and Dr. Dahut, who are oncologists, as you have heard, and have experience with the product under discussion today.
	[Slide.]
	What I thought I would do in my presentation is really to just give you an overview of the issues that we would like you to think about before you vote on the formal questions that I'll pose at the end of my talk.
	These are issues that have occurred to us in the course of our review of the NDA, and of course, if there are any other issues that you feel need discussion, obviously, we would love to hear those as well.
	As you know, we are here to discuss NDA 21‑120, which was submitted by Immunex Corporation last June for Mitoxantrone, known as Novantrone and anthracene dion [ph.].
	The proposed indication from the sponsor is:  "to slow progression of neurologic disability and reduce the relapse rate in patients with progressive multiple sclerosis."  It is important to keep that in mind throughout your deliberations.
	[Slide.]
	The drug was approved in the United States in 1987 first for the treatment of acute non‑lymphocytic leukemia, and then again in 1996 had additional indication for treatment of pain related to hormone‑refractory prostate cancer.  And it is approved, I believe, worldwide in over 50 or so countries for various other types of cancers.
	[Slide.]
	The application contains the results of two randomized controlled trials which I will very briefly go over, and you will hear much more about it in detail from the sponsor, and safety data in about 600 patients.  There were 145 patients in the two controlled trials, and there are about 450 patients in a retrospective German cohort.  We'll talk a little bit about what methodological problems there were with that cohort, but nonetheless, that was the database submitted, as well as reference to the fact that the drug has been marketed for quite some time.
	[Slide.]
	Study 01 was a randomized controlled trial comparing 5 mg per meter squared, 12 mg per meter squared, and placebo, given every 3 months for 2 years.
	The primary outcome was a complicated multivariate measure which combined results on several scales, including functional measures, the EDSS, a commonly used scale in drug trials of MS, the Ambulation Index, a scale called the SNS, which as far as I know was not used prior to this study, and two measures related to relapse‑‑I think it was time to first relapse necessitating steroid treatment and the number of relapses necessitating steroid treatment.
	[Slide.]
	Study 02‑‑this slide is just wrong in its description of the trial, so I will correct it‑‑was a randomized controlled trial which compared 25 mg of drug plus methylprednisolone versus methylprednisolone alone, and these patients were treated monthly for 6 months, a very different dosing regimen and duration of trial than the first one.
	Here, the primary measure was an MRI measure which is the proportion of patients with no new gadolinium‑enhancing lesions.  So the primary outcome here was an MRI measure, not a clinical measure.
	[Slide.]
	In Study 01, the patients enrolled had either secondary progressive MS or relapsing progressive MS, and they were about split evenly between those two diagnoses.  There were about 190 patients or so in this trial.
	The functional measures were assessed by a blinded neurologist, but the relapse diagnoses were not.  Now, in my memo in the booklet that you have, I say in there that at the time I wrote that, I believed that the relapse‑related diagnoses and treatments were made by a blinded assessor; that we have learned from the sponsor that that is not true, that the diagnosis of relapse and decision to treat the relapse with steroids were made by an unblinded treating physician.
	There were presumably criteria laid out prospectively against which the relapse diagnosis was to be made, but the diagnosis itself was made by an unblinded rater.
	[Slide.]
	Study 02, patients were enrolled who had what the protocol called "severe" MS, which was ill‑defined, and "active" MS, which was defined as at least two relapses in the year prior to enrollment, or an increase in the Kurtzke score of two points after a relapse, I believe.  This is also slightly incorrect.
	Actually, though, this was the inclusion criteria.  Actually, 75 percent of patients were diagnosed with relapsing remitting MS.  And here, the MRI was reviewed blind.
	I should also say that in Study 01, MRI was done in a subset of patients, and those MRIs were read by a blinded panel.  Here, the MRI was reviewed by a blinded reviewer, but again, the clinical events which were measured, EDSS and relapses as well in this study, were made by an unblinded clinician who knew treatment assignment.
	[Slide.]
	Before I go into the issues that we would like you to discuss and that I have outlined in the briefing package, I want to briefly go over the standard in law for a finding of effectiveness.  It will hopefully be a review for some of you, but for some of you, it may be new, and I think it is important to understand what the rules are while you are deliberating and trying to address some of the issues I have raised.
	The sine qua non for approval is a finding of substantial evidence of effectiveness, as described in the law.  This ordinarily comes from at least two adequate and well‑controlled clinical trials.  The law says "adequate and well‑controlled investigations, including clinical investigations, and that has routinely been interpreted as meaning more than one investigation.  So this really just incorporates the bedrock scientific standard of independent replication of a finding or corroboration or what‑have‑you.  So that's the traditional definition of substantial evidence.
	[Slide.]
	But in November 1997, the law was amended to permit the Agency to make a finding of substantial evidence on the basis of a single adequate and well‑controlled trial with what was called "confirmatory evidence."
	[Slide.]
	Neither the law itself nor the legislative history gave any guidance as to when the agency should rely on a single trial or what "confirmatory evidence" is.
	[Slide.]
	Nonetheless, the Agency has written a document which provides guidance to some extent on the matter of when would one study be adequate and what might "confirmatory evidence" be.  And ordinarily, a single adequate and well‑controlled trial with confirmatory evidence would be relied upon in a setting where there was an effect on mortality or irreversible morbidity or some serious outcome and in which the finding could not be replicated for ethical reasons more often than not‑‑in other words, the trial really could not be repeated, and we would be left with just one trial.
	And it talks a little bit about the sorts of things that might constitute what you would call confirmatory evidence.  In a multi‑center trial, for example, all the centers going in the same direction, with some of the centers yielding statistically significant results by themselves, very low p values, constant findings across various subgroups enrolled in the trial‑‑in other words, people with advanced disease, people with mild disease, and the same sorts of findings‑‑findings on disparate outcomes‑‑a clinical outcome plus perhaps some radiographic outcome, which are somewhat independent, might be the sorts of things that could serve as confirmatory evidence in this setting of only one trial having been performed.
	I think it is important for you to know and remember these definitions of substantial evidence, because I think the issues I have raised relate to the nature of substantial evidence in this application.
	[Slide.]
	Let me outline briefly what the issues are that we would like you to think about.  First, again, is the question of replication and has the sponsor provided the replication of the findings in the proposed population.  Now, remember, the population for which the drug is being proposed is patients with progressive MS.
	In Study 01, as we talked about, all the patients had progressive MS‑‑half had secondary progressive, half had relapsing progress, but they all seemed to have progressive by diagnosis.  But in Study 02, the vast majority of patients had relapsing remitting disease.
	[Slide.]
	So we have to ask whether or not there is sufficient information or substantial evidence of the finding in the population for which the drug is being proposed to be used.  Now, there certainly are precedents for a lack of replication for a particular population which have been approved, and I will call these potentially relevant, because they are slightly different from the situation that we have here, but they give an idea of the ways we have thought about similar problems in the past.
	For example, most anti‑convulsants are initially approved as a treatment for partial seizures, and they are usually approved on the basis of at least two adequate and well‑controlled trials showing an effect on partial seizures.  But then sponsors may want to get a claim for primary generalized seizures.  In that case, they would ordinarily only need to do a single trial in that setting.
	Similarly, some Parkinson's drugs have been approved on the basis of two trials, one done as adjunctive therapy in late Parkinson's disease and one done in early Parkinson's where the investigational drug is used as monotherapy.  But if they do one trial in each setting, they can get a claim‑‑a global claim‑‑as an anti‑Parkinson's treatment.
	These approvals are based on our view that the diseases being treated are very similar to each other, and the conditions or symptoms being treated are similar enough to each other so we can gain strength from what we know about one indication and let it support the second indication, even though in the second indication, there may be only be one trial.
	[Slide.]
	So we have to ask the question here, are the two types of MS that patients had in these individual trials sufficiently close to each other so that we can say that there is a replicated finding in patients with progressive MS.  There are experts in MS who feel that these may just be on a continuum of disease, and there are other experts who feel that these may be disparate, pathologically different entities.  So we would like very much to hear what the committee thinks about that.
	[Slide.]
	That's the population that the drug is being proposed for, but there is a specific claim being proposed as well, and that is to slow progression of disability and prevent relapses.  So we have to see if there are replicated findings for each of these claims.
	Ordinarily, the use of the word "progression" in a proposed indication implies to us an effect on the underlying pathophysiology or pathology of the disease as opposed to a symptomatic treatment.  The studies that were done were not directly designed to examine the question of whether or not the drug has an effect on progression.  Such a design would usually involve some variant of withdrawing the drug or a randomized withdrawal and seeing if the patients who had been on drug but now are on placebo in a withdrawal phase, whether or not their condition approaches that of patients who were on placebo from the beginning.  And if they do tend to approach each other, we would generally tend to think that the drug has not had an effect on the underlying structure of the disease, but just simply a symptomatic effect, and when the drug is removed, the patients get back to where they would have been had they never been on the drug in the first place.
	These trials, of course, were not designed to look at things in that way.  It should be noted that one of the approved treatments for MS, Avanex [ph.], I believe, has a claim for progression of disability‑‑I believe that's the claim, or something very close to it‑‑and I believe that was granted on the basis of a finding on the EDSS, I believe‑‑which again, there is here in at least one of these studies.
	So we have to think about whether or not it is appropriate nonetheless, even given that precedent, to use language like "progression" in the face of the particular trials that we have done here.
	[Slide.]
	Now we come to the question of relapse.  As I have mentioned, in both trials, relapses were counted, and they were assessed, but in both trials, we now know that the diagnosis of relapse, the decision to treat with steroids and all relapse‑related phenomena, were made by unblinded clinicians, the physician who knew the treatment assignment.  So we have to ask the question whether or not we think there is a bona fide finding on relapse in either of these studies and certainly whether or not there is a replicated finding on the relapse rate.
	[Slide.]
	Then we come to the issue of the reliance on MRI as a primary measure of effectiveness.  It was the protocol stated primary outcome in the second study, as you know, and in its strictest reading, one can at least make the case that it is the only reliable evidence in that second study because the clinical was unblinded in that study; and one could make the case that all clinical data coming out of that second trial may be unreliable because of the unblinding.  Again, as I say, there were criteria specified, presumably prospectively, about what would constitute a relapse, so the physician would theoretically make the diagnosis consistent with those criteria.  But nonetheless they were made in an unblinded way.  So in the second study, you could say that MRI is really all we have that is reliable.
	The Division has never, as far as I know, relied on a nonclinical measure to approve a drug, but certainly the agency has in many cases‑‑in a number of cases, anyway.  Certainly cancer drugs are approved, as I understand it, on the basis of effects of tumor burden which are assessed by radiographic techniques and the like, and that is done routinely.
	And in betaseron, while the approval wasn't based on an effect primarily on MRI, I believe it is fair to say that the committee‑‑this committee, actually‑‑took the MRI findings very much into account when they were deciding about whether or not they would recommend the drug be approved.  There were clinical findings as well in the one trial in which that approval was based, but nonetheless MRI was the basis.  Technically, that approval was granted by the Center for Biologics‑‑we are the Center for Drugs‑‑and we in the Neuro Division in Drugs have never done so.
	[Slide.]
	Certainly the reliance on surrogate markers, which are nonclinical measures that are not directly measures of clinical effect‑‑certainly, the Agency permits it, as I said.  There is certainly precedent.  It has been in the regulations under what is called the "accelerated approval" provisions or a number of years, and recently the statute was amended to include the provision that the Agency could determine that substantial evidence has been shown when there are effects shown on surrogate markers.  A surrogate marker, though, in that case if it is not completely validated would have to be shown to be reasonably likely to predict a future clinical benefits.  Of course, "reasonably likely" isn't well‑defined, but it talks about reasonably likely based on epidemiologic or pathophysiologic data or some sort of evidence that would to an expert suggest that it would be reasonably likely to predict a clinical outcome of interest.
	[Slide.]
	There are issues, though, that one has to think about when deciding whether or not it is reasonably likely that a finding on a surrogate marker like the MRI would predict clinical benefit.  One would be, for example‑‑this is not an exhaustive list‑‑but one would be, for example, whether or not the treatment applied has any interaction with the measurement itself so that it is really not affecting anything that you would care about pathophysiologically, but it just interacts with the measurement system and shows an effect‑‑which would, of course, not really be particularly useful.
	Certainly there are many examples where effects on surrogates have been misleading.  A treatment may have an effect on a surrogate but have no effect on the underlying condition of interest, or in fact could have a deleterious effect and still have an apparently beneficial effect on the surrogate itself.  So there can be a disconnect there, and it is very difficult to know if that's going to be the case in any given case, and then you have to think about, for example, whether or not an effect that you see on a surrogate in a relatively short study will actually persist in time and therefore predict the clinical benefit out in time.
	So there are certainly problems and pitfalls in the use of surrogates in general.
	[Slide.]
	The use of the MRI in this case, however, can be seen as a different type of surrogate as well.  As opposed to one that predicts clinical benefit in the future, it could be seen as one that reflects the underlying pathology at the time the scan is done.  I would say that there is probably general agreement in the MS community as far as I know that MRI is probably an accurate reflection of the underlying pathology.  I would be interested to hear today what those data are for the particular MRI measure that we are talking about here, which is for the most part gadolinium‑enhanced lesions.  But nonetheless I think there is a general view that it is a reflection of the underlying pathology and therefore that any effect on the MRI will accurately reflect on the underlying brain disease and therefore must be good, because less pathology is presumed to always be better than more pathology.
	Of course, it would be interesting to know what the specific pathology of the particular MRI parameter that we're looking at reflects, if it does, and here, as I say, we are talking mainly about gadolinium‑enhanced lesions, and we would be interested to hear the discussion of what people think that that represents in terms of the underlying brain event.
	And then, of course, we have to think about what the relationship of any effect on that surrogate, on gadolinium enhancement, means for clinical purposes.  Again, any effect on a surrogate in order for it to be useful presupposes that it, either at the time contemporaneously or in the future, will have a clinical benefit.  If a drug doesn't have any clinical benefit, there is really no point in approving it.
	So when we talk about this sort of use of the MRI as a contemporaneous surrogate, we also have to think a little bit about the size of the treatment effect.  Ordinarily, in a typical trial where we have a clinical outcome that we use, seizure counts or whatever it is, we take a face‑valid clinical outcome, and any change from placebo, if it is statistically significant, we make the assumption that that is clinically meaningful, and that would be the basis for a typical approval.
	But when we are talking about a sensitive radiographic technique, we have to ask whether any change we see on it in facta reflects something that could possibly be useful to the patient either now or later.  For example‑‑and I think I mentioned in the briefing book‑‑if the test were so sensitive that it picked up damage to 10 neurons, it is hard to believe that that could ever be clinically meaningful to a patient, so we have to ask questions about treat effects, size‑‑the questions we ordinarily don't ask in a typical clinical setting.
	[Slide.]
	Another issue has to do with the appropriate dosing regimen.  The sponsor is proposing a particular dosing regimen that comes from one of the trials, but the two trials use widely disparate dosing regimens, and we have to ask under the heading of replication or corroboration is there sufficient information, given the findings in the study with the dosing regimen that they are not proposing, whether there is substantial evidence that this particular dosing regimen will have the effect claimed by the sponsor.
	There is one other issue which I don't have a slide for, before I get to safety, and that has to do with the fact that the two studies were entirely foreign.  The first study was done in Germany,  Belgium, Hungary and Poland, and the second study was done in five centers in France.  There is no requirement that a sponsor submit studies performed in the United States in order to gain approval‑‑certainly, approval could be granted on the basis of entirely foreign data.
	We are entitled, though, to ask for a trial in the United States if we think it is important to do so, and the committee should think about this, I believe, in its deliberations.  Were the patients diagnosed in these places the way patients are diagnosed in this country?  Did those patients receive the sorts of typical care that patients would receive in this country?  And are the results from those particular foreign sites relevant for the United States population?
	[Slide.]
	There are the safety considerations which you will need to think about, of course.  As we mention in the documents, we didn't see anything in the population studied that would in our view preclude approval if you found that effectiveness had been established.  But we know that there are risks associated with increasing cumulative dose of Novantrone.  I believe that somewhere, the literature suggests that there is a risk of about 2 percent of hear failure up to a cumulative dose of about 120 mg per meter squared, and that risk rises when the dose goes to about 160 mg per meter squared or thereabouts, although there aren't many patients described well in the literature at those higher doses.
	This drug if approved would be to treat a chronic disease that goes on for years and years and years, and one has to ask the question as to whether or not these sorts of cumulative risks for these sorts of events are acceptable for a disease to be treated chronically.  We have few, if any, precedents for this sort of thing in the neurological world.  So I'd like the committee to think about that in its deliberations as well.
	[Slide.]
	Those are the issues that occur to us.  The Agency is not going to present the specific safety and effectiveness data‑‑the company will do that‑‑because there is largely agreement between the Division review team and the company about the results of the trial.  We believe that they have met the particular specified primary endpoints, and again, you will hear the details.  But it is the interpretation of those results that we bring to you today.
	[Slide.]
	So the first question we have is:  Has the sponsor submitted substantial evidence of effectiveness to support their proposed indication?  Here again, I would ask you to think about whether there is substantial evidence of effectiveness for the particular dosing regimen that is being proposed as well.  That's the first question; it's the usual first question.
	[Slide.]
	But if you find that they haven't submitted substantial evidence of effectiveness for the particular indication that they are proposing, we would ask you if you think there is any reasonable indication in any well‑defined MS population that the data do support effectiveness for.  And if the answer to this question is yes, we would very much appreciate your letting us know what specific indication you think that is.
	[Slide.]
	And the third question:  Do you believe that the safety data presented and available from its previous approvals support the safety of the drug and appropriate labeling?
	There is another safety‑related question that I'd like to ask which is not up here, which you don't necessarily have to vote on, but we would like you to discuss, and that has to do with whether you think any restrictions need to be imposed on this use.  It is a toxic drug; it is more toxic, I would say, than the drugs that we are used to dealing with in neurology.  And right now, the drug does have a boxed warning which says that only physicians who are experienced in the use of these sorts of agents should use it.  We would like to know whether you think the use should be restricted to oncologists or neurologists in conjunction with oncologists or particular centers, or those sorts of things, or what sorts of monitoring you think might be appropriate either in the short‑term or in the long‑term if the drug were approved.
	Those, as I say, are probably just a subset of the issues that will be discussed today, but those are the ones that occur to us, and I think I'll turn it over to the company, or back to Dr. Gilman, if there are no questions.
	DR. GILMAN:  Thank you very much.
	That was a very nice overview of the material that I know the sponsor has had access to and the committee has had access to.
	There are a couple of other issues, a couple of which Dr. Katz did have in his narrative, that you didn't mention here.  One is that the software that was used for the analysis was not a software well‑known to the FDA‑‑in fact, it was unknown to the FDA; it was produced in Germany, and apparently, not a lot is known about that software.  I gather that is not a particular issue for you, though, Dr. Katz.  Is that right?
	DR. KATZ:  Yes.  The company will talk a little more about the details of that, but yes, it was unknown to us, and we had no experience with it.  But again, as I alluded to, the initial assessment was done in this complicated‑‑I'll call it complicated; it was to me‑‑multivariate sort of an outcome measure consisting of these five other individual measures.  But when you look at the five individual measures by themselves, they are quite statistically significant on their own, so that certainly provided us with a great deal of comfort about what that meant and about the findings.
	DR. GILMAN:  The other issue that you touched on here, but let me just make it explicit, is the question of what total dose in the life of a patient should be permitted.  Should there be some sort of limit set on that total dose?  And also, I am wondering what is the total duration of a single infusion of this agent.  In other words, can the patient look forward to an effect that will last 3 months, 6 months, a year, a lifetime?  Is there evidence bearing on that question?  That has to do with the total dose that you might want to restrict a patient to over the patient's lifetime, incidentally.
	The other question that occurred to me is has the SNS been validated in some time?  That is not a scale that I had previously been familiar with, and I hope you can address that question along the way‑‑reliability, validity between individual examiners.
	I am curious to know also why you used five measures as your primary endpoint.  That's rather an unusual approach, and it is interesting, but I am wondering how you arrived at that decision to do that.
	After we had our introductions around the table, Dr. Temple came in, so I'd ask you, Bob, to introduce yourself.
	DR. TEMPLE:  I am Bob Temple.  I direct the Office of Drug Evaluation I.
	DR. GILMAN:  Thank you.
	Are there any issues that committee members would like to let us know about before the sponsor begins?
	[No response.]
	DR. GILMAN:  All right.  The sponsor has read Dr. Katz' narrative and is familiar with the questions, and of course, we are all familiar with the questions, so I hope that in your presentations you will address those questions specifically.
	Let me introduce Dr. Ann Hayes, Senior Vice President for Medical Development, who will introduce the sponsor's team.
	DR. HAYES:  Thank you, Dr. Gilman.
	Good morning.  This morning I will provide you with a brief overview of Mitoxantrone, and then we will introduce the principal investigators of the studies and the consultants we have with us today.
	[Slide.]
	As has been indicated, Mitoxantrone has been marketed in the United States and in Europe since 1987, and we are pleased to be here today to present data in support of an additional indication which we believe demonstrates that Mitoxantrone can produce significant clinical benefit for a population of patients within the area of multiple sclerosis.
	[Slide.]
	Mitoxantrone is currently approved for two indications.  It was approved in 1987 for the induction of remission for acute myelogenous leukemia and was approved for the treatment of hormone refractory prostate cancer in 1996 based on its ability to provide palliation of pain with a manageable and acceptable side effect profile.
	[Slide.]
	Since its initial approval, well over 180,000 patients in the United States have been treated with Mitoxantrone, with more than 400,000 patients treated worldwide.
	Mitoxantrone is administered in different doses and schedules depending on what the clinical indication is.  For acute myelogenous leukemia, the dose is 12 mg per meter squared, but it is delivered daily times 3 every 4 to 6 weeks for the induction of remission.  In solid tumors, the dose of 12 mg per meter squared, or between 8 and 14, depending on the studies, is delivered every 3 to 4 weeks either for induction of remission or actually for a fairly long period of time to maintain remission.
	Mitoxantrone is also delivered in high‑dose chemotherapy for both AML and in proliferative regimens for bone marrow transplant at doses up to 80 mg per meter squared as a single dose.
	In oncology, obviously, the drug is most frequently delivered in combination, and in actual fact, its other approvals in AML are in combination with cytosine arabinoside and in prostate cancer in combination with steroids.
	Twelve years of postmarketing experience with this product have shown that the acute side effects of the drug are quite manageable and of short duration.  The long‑term cumulative effects such as the potential for cardiotoxicity, although dose‑limiting over time‑‑and we will discuss this in fair detail today‑‑can also be managed quite safely with proper precautions and monitoring.
	[Slide.]
	Mitoxantrone is a synthetic anthracene dion [ph.] for intravenous use only.  It affects both dividing and nondividing cells by inhibiting DNA synthesis and the repair mechanisms for DNA.  The two major mechanisms are intercalation within DNA and the inhibition of DNA topoisomerase II [ph.].
	[Slide.]
	The proposed mechanism of action for Mitoxantrone in MS involves forth its antiproliferative effects and its immunomodulatory effects.  This agent is antiproliferative, and it does lead to decreases in B‑cells, to a less extent T‑cells and also macrophages.
	Its immunomodulatory acclivities, other than its effect on the cells involved, can also act indirectly by decreasing antigen presentation and by decreasing the production of the cytokines such as TNF‑alpha, IL‑2, and Interferon‑Gamma.
	Mitoxantrone has been shown to be active in the in vivo EAE model, a model, as you know, frequently used to screen drugs for multiple sclerosis.  And conclusions from those studies and also the proposed mechanism of action in studies done both in vivo and in vitro led to the human clinical trials in multiple sclerosis that Dr. Ghalie will discuss with you today.
	[Slide.]
	As you are all aware, multiple sclerosis certainly can be a debilitating disease and afflicts about 350,000 Americans, of which about 140,000 have a progressive form of the disease for which there is no currently approved treatment.
	[Slide.]
	Just a brief history of our interactions with the FDA in terms of this product for MS.  The data from the registration trials was first presented to the FDA at the end of a Phase III meeting in November.  The application was further discussed with the Division in April of 1999, and based on these discussions, the NDA was filed in June of 1999.  The application was then reviewed and received priority review status due to the lack of approved other therapies in progressive forms of MS, and orphan drug designation was granted in August of 1999 for both secondary progressive and progressive relapsing forms of the disease.
	[Slide.]
	The data that Dr. Ghalie will present to you today and which you have in your briefing documents, we feel supports the expanded indication for Mitoxantrone.  We are requesting approval for the use of Mitoxantrone to slow the progression of neurologic disability and to reduce the relapse rate for patients with progressive forms of MS excluding primary progressive disease.
	[Slide.]
	We will have two further presentations this morning.  Dr. Richard Ghalie will present the efficacy and safety data supporting the indication and also will specifically address each of the concerns that Dr. Katz has brought up with data that we feel supports our filing.
	Dr. Fred Lublin from Hahnemann University will then conclude with a summary of the patient populations which he feels may benefit from Mitoxantrone and also a summary of current treatment opportunities for these patients.
	[Slide.]
	We also have with us today the principal investigators from Europe of these studies who are here to answer questions that you may have concerning the studies.
	Professor Hartung was the principal investigator of the Phase III trial.  Professor Edan was the principal investigator of the MRI supporting trial, and Professor Erich Mauch is the medical director of the clinic in Germany which has provided us with over 500 patients for safety from his clinic.
	[Slide.]
	Dr. Hill Panitch and Dr. Craig Smith are also with us as physicians here in the United States who have used this product in their patients, and also for their expertise in MS, and Dr. David Alberts from the University of Arizona Cancer Center, who is a recognized expert in the use of Mitoxantrone in oncology is also present with us today to help address your questions concerning this drug.
	I would like now to introduce Dr. Richard Ghalie, who will do the presentation on efficacy and safety of Mitoxantrone.
	DR. GILMAN:  Dr. Hayes, before you leave, I wonder if you could answer one question.  In cancer patients, has there been any total dose limitation over time with this drug?
	DR. HAYES:  Yes.  The recommendation for the delivery of Novantrone in cancer patients is that patients have a baseline cardiac evaluation, and then, either based on any clinical evidence there may be cardiac problems or when they get to a total dose of approximately 140 mg per meter squared, that the patients be evaluated prior to each course for left ventricular ejection fraction function.
	It is really a physician decision of whether they go to a higher dose because as Dr. Katz indicated, once you get beyond about 140 or 160, you do get an increase in rate of cardiac involvement.
	The thing is that in oncology, this drug is delivered on a much more frequent basis, and if we have questions later about this, Dr. Alberts can address it, but there certainly is a dose intensity both in dose and frequency of delivery that does bear upon the incidence of cardiac problems with this drug.
	DR. GILMAN:  I didn't see this in your proposal for the package insert, but would you have some sort of guideline for the physician about the total dose that you would recommend?
	DR. HAYES:  Yes.  I can address it right now.  Our recommendations would be that the patient do have a baseline left ventricular evaluation before they start; that when they get to around 100 mg per meter squared that they then start having it prior to each course.  And our recommendation will be in  multiple sclerosis‑‑because we don't know if you give it every 3 months what the long‑term effects will be, and with time, we will be evaluating that‑‑that MS patients not receive more than 140 mg per meter squared.
	DR. GILMAN:  Thank you.
	Dr. Penix?
	DR. PENIX:  In regard to the oncologic indication, are there specific recommendations about the monitoring frequency, the frequency of monitoring the hematology parameters and also the echo?
	DR. HAYES:  Yes.  For hematology, in oncology, the normal practice would be that CBCs with white blood count differentials are done prior to each course.  Now, it is being given every 3 weeks, so they want to make sure the counts are high enough to give the next course.
	Our recommendations for the delivery of this drug at any time would be that a blood count be done prior to the delivery of the course to make sure that their counts are within normal range, and between courses, the most likely time that you are going to have a hematologic dip in your counts with Mitoxantrone is between 7 and 14 days, maybe up to 21.  So if in that period of time a patient has fever or feels ill or develops an infection or a cold, they should have their blood counts checked to make sure they don't have a low count.
	DR. PENIX:  Are there guidelines in the package insert that indicate when‑‑
	DR. HAYES:  We are proposing that there will be guidelines, yes.  Right now, I believe the package insert just reads that frequent blood counts should be obtained prior to dosing.  But we would propose definite guidelines before each course, and if a patient develops a fever between courses, especially in the window of time where one would suspect the blood counts‑‑yes.
	DR. GILMAN:  Dr. Temple?
	DR. TEMPLE:  Is there any information about the possible impact of dexrazoxene [ph.] on cardiac toxicity with this drug?
	DR. HAYES:  I believe there is.  Dr. Alberts‑‑may I defer to Dr. Alberts to answer that question, please?
	DR. GILMAN:  Yes.  Dr. Alberts?
	DR. ALBERTS:  Yes.  There actually have been some in vivo and in vitro studies.  Our group at Arizona showed actually showed that Xenocar [ph.] really did not affect Novantrone cardiotoxicity, but the same experiments published in the European Journal of Cancer clearly showed that‑‑of all things‑‑a thiol [ph.] prevents cardiotoxicity from Novantrone.  I think that what that points out is that the mechanism of cardiotoxicity is quite different between those two drugs.  We all know that doxorubicin's toxicity is considerably greater and has a much more destructive cumulative long‑term effect.
	DR. HAYES:  Does that answer your question?
	DR. SWAIN:  I have another question for Dr. Alberts.
	What is the proposed mechanism of cardiotoxicity of Mitoxantrone?  I know it looks like there is no free radical formation with the drug.  Do you have any idea?
	DR. ALBERTS:  Well, it seems to affect the sarcoplasmic reticular endothelial [ph.] system and affects energy metabolism in the mitochondria.  There is evidence that this drug is actually an antioxidant as opposed to doxorubicin, which is a known pro‑oxidant.  So it is very, very different from what has been shown.  It has also been shown that it affects calcium transport.
	So it still is in somewhat of a black box exactly how it does this.
	DR. GILMAN:  There was some mention of leukemia as a consequence in a small percentage of patients.  Is that dose‑related at all?
	DR. HAYES:  The probability of a second malignancy following treatment with Novantrone is clouded by the fact that it is rarely given as a single agent.  It is usually always given in conjunction with other agents which are known to also have an incidence of second malignancy.
	So that's a very hard question to answer.  And as far as we know, this is not dose‑related, but it is a very low incidence with Novantrone, and as I say, it is clouded by the fact that it is always given with cyclophosphamide [ph.] or cytosine erabinocide [ph.] or VP‑16, which is notorious for causing second malignancies.
	DR. GILMAN:  Are there any other questions?
	[No response.]
	DR. GILMAN:  Thank you very much, Dr. Hayes.  We'll move on, then.
	DR. GHALIE:  Good morning.  My presentation today will be divided into two parts.  First, I will present efficacy data from two randomized trials in multiple sclerosis and then safety data from these two trials and a single‑center retrospective study.  I will also provide information on Mitoxantrone safety from the 12 years' worth of experience with this agent in cancer patients.
	The second part of my presentation will consist of a benefit‑and‑risk assessment of the use of Mitoxantrone in patients with multiple sclerosis.  I will conclude by providing answers, or at least Immunex' perspective, to the issue that Dr. Katz raised in his introduction.
	I trust that this presentation will demonstrate that Mitoxantrone fulfills an unmet medical need in patients with progressive forms of multiple sclerosis.  We exclude in our minds here primary progressive MS, for which we have no data in the clinical trials.  These are disease forms that currently have limited therapeutic options.
	[Slide.]
	The efficacy of Mitoxantrone in animal EAE models which Dr. Ann Hayes alluded to earlier led to the conduct of a number of open‑label studies and randomized studies that are shown on this slide.
	[Slide.]
	Data from five dose‑finding studies and one randomized placebo‑controlled trial have been published in English language journals.  These studies involved a total of 100 patients who received Mitoxantrone at doses ranging from 8 to 14 mg per meter squared with intervals between courses that went from every 3 weeks to every 3 months.
	The aggregate of these studies led to the conclusion that Mitoxantrone when used at the same dose that is used in cancer patients‑‑that is, 12 mg per meter squared‑‑was also well‑tolerated by patients with multiple sclerosis and therefore that further controlled trials in patients with multiple sclerosis were indicated.
	[Slide.]
	As a result, two randomized studies were conducted‑‑study designated 901, which was a Phase III randomized placebo‑controlled study, and Study 902, a Phase II randomized corticosteroid controlled trial.  These two studies serve as the basis for the Immunex filing.
	In addition, in our filing, we have added Study 903, which is a single‑center respective analysis of the experience of a single center experience with Mitoxantrone and multiple sclerosis.
	Taken together, these represent data on 689 patients, of whom 603 had received Mitoxantrone.  Collectively, in our opinion, these data provide evidence of Mitoxantrone's effectiveness and safety in patients with multiple sclerosis.
	So I will first present the design and efficacy results from the two randomized trials, and I will begin with Study 901.
	[Slide.]
	Study 901 was a Phase III randomized placebo‑controlled trial.  It was conducted in 17 centers in four European countries.  It enrolled 194 patients.  IT was co‑chaired by Professor Hartung, who is here, and Professor Gonsette from Belgium.  The German regulatory agency, BfArM, approved the design and the conduct of that study.  The first patients were enrolled in June 1993, and the study concluded in July 1997.  These data were presented at some meetings with Dr. Hartung in the last 2 years.
	[Slide.]
	The main inclusion for that study are listed here, and they include patients age 18 to 55; diagnosis of multiple sclerosis according to Poser's criteria; and a diagnosis of secondary progressive or remitting progressive multiple sclerosis.  Again, this study was designed before the 1996 classification, so I would like to explain what is meant by "remitting progressive" multiple sclerosis.  Those are patients who have relapsing remitting disease with a residual deficit after an attack.  When Dr. Lublin comes up at the end, he will also have some slides to describe how this fits in the continuum of patients with multiple sclerosis.
	Additional inclusion criteria consisted of active disease as defined by an EDSS progression by at least one point in the 18 months that preceded enrollment in the study; and finally, EDSS ranging from 3 to 6.
	[Slide.]
	To illustrate to you what is an EDSS between 3 and 6, this is a graphic description.  The EDSS scale is a 10‑point scale that describes disability in patients with multiple sclerosis.  An EDSS of 3 represents moderate disability in one functional system or a mild disability in three or four functional systems.  An EDSS of 5 or greater indicates an ambulation of impairment.  An EDSS of 6‑‑the upper limit for enrollment in this study‑‑indicates a patient who requires intermittent or constant unilateral assistance to walk‑‑cane, crutch, and so on.  An EDSS of 7 represents a patient who requires a wheelchair.
	[Slide.]
	The main exclusion criteria are listed here, and I would like to point to the fact that patients with benign MS or primary progressive MS were excluded from this study.
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	Patients were randomized in this trial to one of three groups‑‑placebo group; Mitoxantrone 5 mg per meter squared; and Mitoxantrone 12 mg per meter squared.  Treatments were given intravenously by 5‑minute short infusions, and they were repeated every 3 months for a total of 8 courses or 24 months.  In addition, patients were examined at month 36, which is one year after receiving the last dose of study drug, to evaluate disease activity and any delayed toxicity.  I will present the data also on month 36.
	The interval of 3 months between courses was decided based on the promising data that were published in pilot studies by Professor Mauch in the early nineties.  The dose of 5 mg per meter squared that was tested in this trial was added as an exploratory dose to see whether a lower dose may also have an effect on patients with multiple sclerosis.
	[Slide.]
	A number of precautions were taken to reduce the risk of bias in the interpretation of the disability assessment in the study as well as the MRI results, and these are listed here.  
	Methylene blue was used to mimic the color of Mitoxantrone which, as you imagine, is blue, and it served as a placebo to mask patients.  The evaluators of neurologic disability‑‑and these are the scales that I will describe to you in a moment‑‑were masked to study drug, and they were not involved in patient management.
	The physicians who evaluated the MRI scans‑‑and I will explain that a little bit later‑‑were also masked to study drug and also to clinical outcomes.  They did not know the patients' response to treatments.
	The treating physicians who were responsible for study drug administration were not masked to study drug; they knew what they were giving their patients.  They were also responsible for patient management, for assessment of adverse events and the safety profile and also for assessment of relapses and deciding when to treat relapses.
	[Slide.]
	The protocol defined one primary efficacy criterion and multiple secondary efficacy criteria.  So I will guide you now through this primary efficacy criterion that Dr. Katz had difficulty understanding.
	It was a single multivariate test in one hypothesis of five variables.  Three variables assessed treatment effect on disability using three complementary scales‑‑the EDSS scale, the Ambulation Index scale, and the standard neurologic disability status score.  Two other variables assessed treatment effect on relapses, which is time to treated relapse and the number of treated relapses.
	The primary analysis in this protocol was defined as a comparison between placebo and the test dose of 12 mg per meter squared with an alpha equal to 0.05.
	Now, if this multivariate test was significant with p less than 0.05, then each of these variables were to be tested sequentially in a predetermined order that was defined in the protocol and that is listed here, that is, beginning with EDSS and going down to the SNS score.
	There were very strict rules on when to stop doing these comparisons.  For example, just to give you an example.  If, for example, Variable 3 was not significant with p greater than 0.05, then Variable 4 and Variable 5 were automatically declared not significant, and that is how they were sequentially tested.
	The number of patients needed for that study was estimated to be 60 patients per group.  That provided a 90 percent power with alpha equal to 0.05, as I mentioned.
	So as you had requested before, I will review for you now the three disability scales that were used in this study‑‑and copies of these scales were attached to the back of the briefing document that we submitted to you.
	[Slide.]
	This is the Kurtzke Expanded Disability Status Scale, the EDSS scale.  It is a 10‑point scale with 0.5 point increments‑‑so 0.5, 1.0, et cetera, until 10.  It is based on the evaluation of seven functional systems listed here and something called "Other."  EDSS scores of 4.5 and lower are based on these functional scores with specific criteria how to determine scoring.  EDSS scores of 5.0 or higher are really based on ambulation impairment.
	[Slide.]
	The second disability scale used in this study was the Ambulation Index scale, which is again a commonly evaluated scale that is used in the U.S. and other countries, and it is a 10‑point scale with one‑point increments.  It is really focused on ambulation impairment.  An Ambulation Index greater than 3 indicates ambulation impairment.
	The third and last scale used in this study is the Standardized Neurologic Status score scale, or SNS.  To make it easier, I will say "SNS" from now on.  It was developed in Germany by Professor Mauch, in fact, who is here, and it has been used there for over 10 years to assess neurologic disability.  It is a 99‑point scale with one‑point increments, so it is more refined in its increment points than the other two scales.
	It evaluates five functional systems which are listed here, but 50 of these 100 points are weighted by supraspinal evaluations.  I must say that this scale has not been used in the U.S. but is commonly used in Germany, where it was defined, and it was included in the study design.
	[Slide.]
	I will now present to you patient disposition and demographics.  One hundred ninety‑four patients were enrolled in the three groups.  Three patients were found to be ineligible after randomization and before they had received any study drug.  These three patients were withdrawn from the study and never received study drug, and they are not included in any of the safety or efficacy analyses I will present today.
	Three other patients received a single dose of study drug and then decided to leave the study before undergoing the Month 3 evaluation.  Therefore, we have no efficacy data on these patients, and we did not include these patients in the efficacy analysis; we did include them in the safety analysis.
	As a result, there were 188 patients total who were evaluable for efficacy‑‑64 in placebo, 64 in Mitoxantrone 5 mg per meter squared, and 60 in Mitoxantrone 12 mg per meter squared.  Thirty‑nine patients shown here discontinued study drug before completing the 2 years of treatment and all associated procedures that were required for that study.  Overall, if you follow the patient disposition, 73 percent of the patients randomized to placebo, 84 percent of patients randomized to Mitoxantrone 5 mg per meter squared, and 80 percent of patients randomized to Mitoxantrone 12 mg per meter squared compared the 2 years of treatment and all the tests that were required for these 2 years of treatment.
	[Slide.]
	This slide and the next one present patient demographics and show that really, there were no differences between the three groups in patient demographics‑‑female, age, and type of MS.
	A typical patient was a 40‑year‑old patient with a disease history of 10 years.  This population had an average of 1.3 relapses in the year preceding enrollment, and EDSS increased by 1.6 points in the 18 months preceding enrollment.
	Mean baseline EDSS at enrollment was roughly 4.7 in the three groups, and an EDSS of 4.7 represents a patient who had imposed full limitation to full activity or where minimal assistance to walk was required.
	[Slide.]
	I will now turn to the efficacy results of the study.  Again, as the protocol defined, the primary comparison between placebo and Mitoxantrone 12 mg per meter squared, for all the efficacy results I will present now, the p values on these slides correspond to this comparison‑‑12 mg per meter squared versus placebo.  We did put on the slides the data from 5 mg per meter squared to really demonstrate a dose response effect in the study.
	[Slide.]
	Let me begin first with the primary efficacy criteria.  And again, this was mentioned earlier in the study.  As you see here, it was met with p less than 0.0001.  As a result, each of the five primary efficacy variables was tested sequentially as described in the protocol, and as can be seen here, each of these variables was significant with p less than 0.05.
	I will now show you each of these variables on a different slide so you can look at them individually.
	[Slide.]
	This slide shows the  mean EDSS change between month 24, the end of study, and baseline in the three groups.  To help you read the slides, since the EDSS scale as it increases means worsening in the EDSS scale, a positive number indicates worsening in the EDSS scale whereas a negative number indicates improvement.
	There was a significant difference in favor of Mitoxantrone 12 mg per meter squared with p listed here at 0.0194.
	[Slide.]
	Let's look now at the second disability scale, the Ambulation Index.  It follows the same rule‑‑a positive number means worsening.  Again, we are comparing month 24 to baseline.  Here again, there was a significant difference in favor of Mitoxantrone 12 mg per meter squared, with the p listed here of 0.0306.
	[Slide.]
	I will now turn to the third disability scale, the SNS score.  Again, this follows the same rule‑‑a positive number indicates worsening, a negative number indicates improvement, comparing month 24 to baseline.
	Here again, there was a significant difference in favor of Mitoxantrone 12 mg per meter squared, p equals 0.0269.
	[Slide.]
	I will now present the two primary efficacy variables that assessed treatment effect on corticosteroid‑treated relapses.
	There was a 69 percent reduction in the total number of treated relapses with Mitoxantrone 12 mg per meter squared compared to placebo; 24.1 total number of treated relapses versus 76.8, with p listed here at 0.0002.
	[Slide.]
	And if we look now to the time to first treated relapse on the study, here again, there was a significant difference in favor of Mitoxantrone 12 mg per meter squared, shown in yellow, compared to placebo in gray, with p shown here at 0.0004.
	[Slide.]
	This busy slide, which is also reproduced in the briefing document, presents the results of secondary efficacy variables defined in the protocol.  As can be seen, Mitoxantrone 12 mg per meter squared was consistently better than placebo for all of these variables.
	There are two places where you see "Not significant," but again, when you look at the results, they were better than placebo, albeit not significant.
	Of all these results, I will present to you first EDSS data, and then I will present data on relapses.
	[Slide.]
	This graph shows the mean EDSS change from baseline at each evaluation from month 3 through month 24.  Mean EDSS improved in the Mitoxantrone groups in yellow and blue; mean EDSS increased in the placebo group.
	[Slide.]
	Now I present to you another way to look at EDSS, and this is the number of patients who have a one‑point EDSS increase that was sustained for 6 months.  Neurologists consider a one‑point EDSS that was confirmed 6 months later as a clear indication of progression of disability.
	Here again, there was a 64 percent reduction with Mitoxantrone 12 mg per meter squared in the proportion of patients who had EDSS progression by one point confirmed at 6 months compared to placebo, with p equal 0.045.
	[Slide.]
	Another measure of EDSS that is also commonly looked at by neurologists is categorized EDSS change by one point‑‑that is, patients whose EDSS increased by one point or greater, who remained stable within the more or less one point, or improved by one point.
	Here again, one can see the benefit achieved with Mitoxantrone 12 mg per meter squared.  There was a significant difference in the proportion of patients who had deteriorated by one point‑‑8 percent in Mitoxantrone versus 25 percent with placebo, p equals 0.013.
	[Slide.]
	I will now move from disability scales to talk about treatment effect on relapses.  Fifty‑seven percent of the patients who are randomized to Mitoxantrone 12 mg per meter squared did not have any relapse‑‑they were free of relapse during the 2 years of treatment‑‑compared to 36 percent of patients who were randomized to placebo, and the p value here is 0.021.
	If one looks at the calculated annual relapse rate for Year 1, for Year 2, and for both years combined, and if we look at them compared to the baseline, again, there was a significant effect in favor of Mitoxantrone 12 mg per meter squared, and I will not go through the point values here because they are shown on the slide.
	[Slide.]
	As I mentioned earlier, patients were evaluated one year after completing study treatment, at Month 36.  I will present to you now the data of the third‑year evaluation.  I must say right now that the protocol permitted unmasking patients on a per‑site basis when they had completed the 24 months of treatment and all associated procedures.
	[Slide.]
	Let's look first at the disability scales, the EDSS, Ambulation Index, and SNS scores.
	All three scales used to measure disability showed that patients who had been randomized to Mitoxantrone 12 mg per meter squared had less disability progression than patients who were randomized to placebo.  I will take a moment with this slide because it is a little bit complex.
	For EDSS‑‑this is Mitoxantrone 12 versus placebo‑‑that's a 36‑month period of follow‑up‑‑this is the Ambulation Index, and this is the SNS score.  Again, keep in mind the Ambulation Index and the EDSS are 10‑point scales; the SNS a 100‑point scale.  That may also explain some of the differences in the bar graphs.
	[Slide.]
	Now let's look at relapse at month 36.  The rate of relapse and the rate of the treated relapse during the third year of follow‑up‑‑so this is Month 24 to Month 36‑‑was also lower in Mitoxantrone groups compared to placebo.
	[Slide.]
	Then, the last slide I will show about efficacy shows the time to first treated relapse, and looking at time to first relapse from baseline, because it is a Kaplan‑Meyer [ph.] curve.  Here again, it showed that patients randomized to Mitoxantrone had a longer time to first treated relapse than patients randomized to placebo.
	The median time to first treated relapse was still not reached at Month 36 in the Mitoxantrone 12 mg per meter squared, as you can see.  This is 50 percent; it still wasn't reached there.  So one can tell that there is at least 21 months longer time to first relapse in the Mitoxantrone 12 mg per meter squared group compared to placebo‑‑that's a minimum of 21 months.
	[Slide.]
	So in conclusion, for Study 901, we showed that Mitoxantrone significantly slows the progression of neurologic disability; it decreases the relapse rate, and this is in patients with progressive forms of multiple sclerosis.
	We can also tell from the data at Month 36 that there is no disease rebound one year after discontinuing treatment.
	Mitoxantrone 12 mg per meter squared was significantly better than placebo for all five primary variables.  Mitoxantrone 5 mg per meter squared‑‑I do not show this data‑‑was significant in placebo for two of these primary endpoints.  
	Therefore, in our opinion, this shows a dose response effect which supports the biologic activity of Mitoxantrone in this disease.
	[Slide.]
	The next series of slides I will present to you today are the MRI results of the study.  Let me describe to you the MRI protocol.
	T1‑weighted scan with gadolinium enhancement‑‑or, for brevity, I will say "Gd enhancement," since most of you are familiar with the phrase "Gd enhancement"‑‑and T2‑weighted scans were performed following the guidelines published by Miller in the early nineties.  Scans were obtained at baseline, the end of Year 1 and the end of Year 2, and they were obtained in a predetermined subset of 110 patients who were enrolled in the study.  These patients were enrolled in sites that had expertise in doing MRI scans.
	The review of the MRI scan was done at the end of the study concurrently for all the scans, by two investigators who were experienced in reviewing MRI scans and who were blinded, as I mentioned, to the treatment the patients were randomized to as well as the clinical outcomes.  And to make it consistent with the clinical results, I will now present to you the results of Mitoxantrone 12 mg per meter squared and placebo.
	[Slide.]
	This is a slide that shows patients who have Gd‑enhancing lesions on their scans, comparing baseline, end of Year 1 and end of Year 2.  At the end of Year 2, there were fewer patients with Gd‑enhancing lesions with Mitoxantrone 12 mg per meter squared compared to placebo‑‑3 percent versus 16 percent.
	Also at the end of Year 2, no patients had new Gd‑enhancing lesions in the Mitoxantrone 12 mg per meter squared compared to 16 percent of patients who were randomized placebo.
	[Slide.]
	The trend observed in the two sets of data I presented to you today suggest that Mitoxantrone reduces inflammatory lesions of multiple sclerosis in the central nervous system.
	This graph shows the mean change in total lesion load for T2‑weighted scans, so now we are moving to T2‑weighted scans.  T2‑weighted lesions were scored from 1 to 5 using a scale that we had in the briefing document.  As one can see on the slide, lesion load was relatively unchanged in Mitoxantrone 12 mg per meter squared for the 2‑year period.  T2‑weighted lesion load increased in the placebo group.
	[Slide.]
	In conclusion, the MRI results in this study confirmed Mitoxantrone's ability to inhibit the inflammatory process associated with multiple sclerosis, and it can possibly be said that it inhibits the degenerative process associated with multiple sclerosis.
	These MRI results in our opinion support the clinical findings of the study.
	[Slide.]
	Let me turn now to the Phase II Study 902.
	DR. GILMAN:  Can I interrupt here for a question?
	In the narrative that Dr. Katz provided concerning MR scanning, on page 4 of his narrative, he gave a base number of gadolinium‑enhancing lesions of 0.44 in the placebo group, and in the 5 mg per meter squared group, 3.23, and in the 12 mg per meter squared group, 1.88.  So baseline mean number of gadolinium‑enhancing lesions was very much smaller in the placebo group than in the others.
	I just wondered about that finding.  It struck me in looking at these data.  I wonder if you could address that issue or one of the other members, if not now, maybe later‑‑I know I'm asking a very detailed question here.
	DR. GHALIE:  I would like to have Slide B‑89, which will allow everybody to see what Dr. Gilman is alluding to.  It is the number of lesions at baseline.  It is shown here for the placebo at 12 mg per meter squared, where it was somewhat consistent between the two groups for the number of lesions.  It is true that the 5 mg per meter squared group, just by randomization, has had much more lesions at baseline.  Therefore, we felt that they were different from the other two groups we put in the comparison, and that's why we did not include them in the comparison.
	DR. GILMAN:  Well, it's that the placebo group had 0.44.  I don't know if that's significantly different from the 1.88 in the 12 mg per meter group, but you are quite right, the 5 mg per meter group did have a much higher number at base.
	DR. GHALIE:  Right.  These patients, as you remember, were randomized not taking into account the MRI scans.  There were no stratifications based on MRI.  And as you may know, taking this into consideration, it is not surprising that there were some differences among the three groups with baseline value.  This is why you may have noticed that we are talking about subset analysis, and we did not put p values on this slide, because we recognized this as being a subset analysis.
	DR. GILMAN:  Yes, Dr. Grundman?
	DR. GRUNDMAN:  Just a quick comment and then a quick question.  As an oncologist, one thing that is interesting is that you could have patients on for 2 years, where 73 percent of the placebo group remains on study, while with an indication of prostate cancer, the median survival rate is only 10 months.  So it shows you a dramatic difference between the two diseases.
	Secondly, I was wondering what the criteria were for treating relapse.  Was there a standardization or strict criteria as to what happened in oncology based on progression?
	DR. GHALIE:  In this study‑‑and the same will be true for Study 902, so I will address these two at the same time‑‑the protocol specifically defines what is a severe relapse, what are the criteria for severe relapse, and also when a patient can be treated.  This is when a patient has a severe MS relapse.  Those are using standard definition of severe relapses.  And the treatment for severe relapse is, again, a very standardized regimen which is high‑dose methylprednisolone‑‑corticosteroid‑‑500 mg to 1 g daily for 3 to 5 days.  So the protocol had a very strict and specific definition of what is a severe relapse and when it can be treated, and that was true for both studies.
	DR. GRUNDMAN:  Just a clarification.  Which of the outcome measures were performed by a blinded rater and which were performed by the clinician who know the treatment and was treating the patients?
	DR. GHALIE:  The three disability scales which assessed neurologic impairment‑‑that is, the EDSS, the Ambulation Index and the SNS scores‑‑were done by the masked neurologic evaluators.  These physicians were trained at the onset of the study about how to do the EDSS assessment, the AI assessment and the SNS assessment, and those physicians had no contact with the patients as far as management; they had no access to the patients' records, and they were not to talk to the treating physician about the patient's condition.  They just came and did the visibility assessment, and that was it.
	The physicians who were treating the patients, deciding when to treat relapse were unblinded to study drug.
	DR. GILMAN:  Dr. Kawas?
	DR. KAWAS:  In that regard, there is a lot of unblinding in this study as well as Study 902, and in many cases, some of the measures, including time to treating first relapse, obviously were being determined by people who knew whether or not the patients were on drug.  The patients in some of these studies apparently knew.  And all of your 36‑month measures were also unblinded for the most part with regard to patients as well as physicians.
	Why was that decision made, and what were the advantages of having so much unblinding done in these studies?
	DR. GHALIE:  Let's summarize briefly what is blind and what is unblinded.  What was masked for study drug was the neurologic disability for Months 0 to 24.  What was unmasked or unblinded was assessment and treatment of relapses.  Treatment of relapses and assessment, although unblinded, were very well‑defined and gone through in the protocol.  The primary measure was Month 24, so let's focus now first on the first 24 months.
	The decision to have the treating physician treating relapses was made from the outset for practical reasons.  As you may know, relapse in multiple sclerosis can occur at any time; it doesn't come at specifically predetermined periods.  So it was logical to have the treating physician who knew the patients, who had access to the patients, to be the one who made the decision about treating relapse.  This is very commonly used int rials in multiple sclerosis.
	The question now is why the treating physician was unblinded to begin with, and that again is a decision that was made early on based on the fact that this is a chemotherapy, and it was felt‑‑and I would like to have Dr. Hartung address this issue in a moment when I am finished‑‑that it was for the patients' safety to have the treating physician, who was delivering the new investigational chemotherapy, be aware of what treatment the patient was on.
	The patients were masked‑‑they were receiving a placebo that was blue‑‑so technically, they didn't know whether they were receiving Mitoxantrone or placebo; it is a 5‑minute infusion, it is a blue infusion, the urine turns blue in both cases, so it was hard for them to tell what they were on.  If they were to know what they were on‑‑that was strictly said in the protocol‑‑they were asked not to tell the physician during the neurologic assessment what arm they thought they were on‑‑they never knew what they were on, but if they were to know or thought they knew what they were on, they were to keep this information to themselves and not tell it to the blinded neurologic disability assessor.
	For Month 36, it is slightly different, but before we get to that, I would like to have Professor Hartung comment on the fact of why they decided to unmask the treating physician in this study.
	DR. HARTUNG:  I can just reiterate that our foremost motivation to do so was to put the safety of the patient first, considering that we were dealing with a drug which had previously been used in a cancer population with potentially serious side effects and that the treating physician obviously had to have knowledge of lab count, et cetera.
	Nevertheless, as mentioned, there were clearly laid down regulations, stipulations, as to what was considered a relapse, standard definition, a severe relapse, and a relapse necessitating steroid treatment.  And adherence to these guidelines was verified by the audit procedure.
	I think that looking at the magnitude of the effects on relapse, the consistent effects seen in looking at all relapses, those that were considered to require treatment, make us confident that we were in actual fact looking at true effects of the drug.
	DR. GHALIE:  Thank you, Dr. Hartung.
	DR. GILMAN:  Dr. Penix?
	DR. PENIX:  I am still not exactly clear what the specific assessment criteria for the treating physicians were, but were you able to take that data and correlate it with the assessments of the blinded examiners?
	DR. GHALIE:  The blinded examiners looked only at disability; they did not look at relapse.  So comparing disability and relapse are really two different outcomes, and therefore, trying to correlate the two was not necessarily something we could do.
	What I would like to show you now is a slide that shows all the evaluations we did on relapse and how they are all consistent throughout the evaluations that were done.  That will be Slide B‑77, please.
	[Slide.]
	DR. GHALIE:  If one looks at any type of relapses that were treated, relapses that were determined as being severe, relapses that were seen by the treating physician or relapses seen by physicians at home, and the treated relapse that was the primary endpoint, if one looks at all of them, there were really consistency of results with Mitoxantrone that were highly significant compared to placebo.
	So this magnitude of effect gives us some level of confidence of the robustness of the relapse assessment‑‑again, comparing relapse to EDSS may become extremely difficult, because these are really two different endpoints in MS progression.
	DR. PENIX:  Since there were two different relapse assessments that were made by the blinded‑‑the time to relapse and the number of relapses‑‑and also the treating physicians determined whether there was relapse or not‑‑was there any correlation between those two groups or those two situations?
	Dr. GHALIE:  It is the same individual who determined the type of relapse and therefore when the first relapse had occurred, which gave us the time to first relapse.  That was the treating physician who was unmasked to study drug.
	Again, the treating physician was the one who was in charge of patient management and who decided when relapse occurred.   And when we talk about time to first relapse, that was when did this first occur in each patient.
	DR. GILMAN:  Dr. Lipton, then Dr. Temple, then Dr. Wolinsky.
	Dr.  Lipton?
	DR. LIPTON:  Given that you have several endpoints that were assessed by a blinded rater than two endpoints that were assessed unblinded, why did you choose to combine ratings that would be relatively easy to have a lot of confidence in and ratings where knowledge and treatment effects might influence the assessment of the endpoint?
	DR. GHALIE:  This study, as you recall, was started in the early nineties, and at that time, it was unclear whether Mitoxantrone affected disability progression, relapse, or both.  And as you know, when patients with multiple sclerosis have medical problems, they can have either disability progression or relapse.  So it was unclear whether one needed to focus on one, the other, or both.  Therefore, this is why it was decided to look at all these variables early on as the primary endpoint.
	Now, it is true that there was a combination of endpoints that were masked and some that were unmasked, and this is where the primary multivariate test took into account the combination of the five variables.  But if you look at them sequentially, the first two variables were the ones that were done by the masked neurologic disability assessor.  So the two first ones are the primary ones.  If those were not significant, the comparison could not have continued.  The comparison would have stopped at one or two.
	So the two primary variables of efficacy were the ones that were done by the masked evaluators, and they were significant.
	DR. GILMAN:  Dr. Temple?
	DR. TEMPLE:  A comment and a question.  You obviously could have protected the patients by having someone like the local oncologist or someone take care of the drug administration and the monitoring of white counts and things like that, and have the neurologist be actually blind.  I am sure in retrospect you might wish to have done that.
	I have another question about the relapses.  Did this involve just taking the neurologist's word for it, or did you actually review the description and make your own judgment about whether it looked obvious, borderline, or whatever?  Have you rated the relapses in any way other than just yes, there was one, and we treated it?
	DR. GHALIE:  It seems like this is a question that a number of panel members are interested in, so I would like to have the slide that shows the definition of relapse‑‑I believe that is Slide A‑12‑‑in which it spells out in the protocol for that study what is a severe relapse and therefore, the one that needs to be treated.
	So it spells out it is a patient who‑‑I can read it, or you may want to read it‑‑they have to have new symptoms lasting more than 48 hours, two or more functional scores, or‑‑I am not going to read it.  So these patients really had to have something that was clearly obvious as being a relapse.
	There have been audits of that study since it was conducted, first by the auditors in Germany who did the study, then by Immunex, who had sent auditors to review the study, and then, finally, by the Agency's auditors, who were sent there also, at least, to some sites to audit the data.  And there was no evidence from this audit that the definition of relapse was not followed, and whether the patients were treated erratically or not.
	So we are confident that the definition of relapse was followed and that treatment for this relapse was done accordingly based on these three series of audits that we have mentioned.
	DR. GILMAN:  Could we have the slide back again, please?
	So there had been a deterioration of  functional status score, I presume, from what you have said there.  Does that indicate that the patient had a new neurological abnormality on examination or just a change in functional status?
	DR. GHALIE:  I would like to ask Dr. Hartung, who was one of the investigators on that study and who had to make this determination, to answer this question.
	DR. HARTUNG:  Could I just ask you to repeat the question, please?
	DR. GILMAN:  Yes.  The change in functional status score of two points, did that require that the patient have a new neurological abnormality‑‑in other words, an up‑growing toe where there previously was not one; a change in spasticity that was obvious‑‑what did you need to see?
	DR. HARTUNG:  A new abnormality, with an increment by two.
	DR. GILMAN:  You used just the scale; you did not require a new neurological abnormality.
	DR. HARTUNG:  Yes.
	DR. GILMAN:  That was my question. And could you tell us, then, what you mean by "severe"?  It's not clear from that slide what "severe" means.
	DR. HARTUNG:  "Severe" was defined as an increase in the score of at least or greater than two points, or a deterioration of previously existing symptoms of more than one point.
	DR. GILMAN:  Then, would you define "relapse"‑‑not severe, just relapse‑‑please.
	DR. HARTUNG:  Yes.  The occurrence of a new episode of neurologic symptoms or deficits last at least 24 hours in the absence of fever or other precipitants of a pseudo attack.
	DR. GILMAN:  Then, it was just the history that gave the definition of a relapse?
	DR. HARTUNG:  History in the case when a patient who was not close to the MS clinic that participated in the trial was seen by a local neurologist, examination in these centers where we did see the patient.
	DR. GILMAN:  Dr. Wolinsky?
	DR. WOLINSKY:  The question I had intended before, I'll try to come back around to, but this turns out to be an interesting area to further explore.
	So one of the first questions I have is that when we speak about EDSS, it turns out that there are various flavors.  There is the one that Kurtzke described, where patients might or might not have been required to walk; there is the one that Ludwig Kapos [ph.] has a variation of; there are ones which were used in the Lindamide [ph.] trial, and they all have slightly different variations.  One of the most important variations in terms of the total EDSS score is whether the patients are observed to walk a certain distance, and that becomes very critical as the patients get into this lower‑mid portion of the EDSS score.
	What EDSS definitions did you use?
	DR. GHALIE:  Dr. Hartung, please.
	DR. HARTUNG:  We did use Kurtzke's definitions as laid down in the neurology paper.  And we did require the evaluating physicians to observe the patient walking and to also time the walking.
	DR. WOLINSKY:  The next question‑‑and this comes back to the issue of relapses‑‑is was the evaluating neurologist required to examine the patient when a relapse was felt to possibly be occurring, and did the treating neurologist then look at the evaluating neurologist's scores to determine the relapse, or did the treating neurologist have his own scoring set and use those to determine whether the relapse was confirmed?
	DR. HARTUNG:  The latter is true.
	DR. WOLINSKY:  And if the relapse occurred distant from one of the sites and possibly was treated distant from one of the sites, how did you know whether or not the relapse was actually consistent with this definition using the EDSS and the functional scores to help you define it?
	DR. HARTUNG:  In those few instances where the patients were unable to visit the center, we did contact the local neurologist who thought that the relapse was severe [inaudible] and we checked whether these criteria were fulfilled.
	DR. WOLINSKY:  So did the neurologists distant from the sites undergo some kind of a training session to allow you to be sure that they were actually assessing patients in the same way that you would have at the study sites?
	DR. HARTUNG:  They had not undergone training sessions, but they were experienced in the treatment and assessment of multiple sclerosis patients.
	DR. WOLINSKY:  And when you say that this was a low number of attacks that were actually not confirmed at the study sites, could we actually see those numbers?
	DR. GHALIE:  Certainly.  I would like to go back to the slide which shows all the relapses, B‑77.  
	[Slide.]
	DR. GHALIE:  So these are the relapses that were treated by the treating physician.
	DR. WOLINSKY:  But these means that almost an equal number of relapses were not actually observed by the treating physician?
	DR. GHALIE:  No, not here.  These are the total treated relapses, and these are the relapses seen by the treating physicians‑‑treated relapses, in fact.
	DR. WOLINSKY:  But the number of relapses, which is the first level‑‑
	DR. GHALIE:  Yes.
	DR. WOLINSKY:  ‑‑is higher than any of the other levels.
	DR. GHALIE:  Yes, for the total relapses.  So there were some relapses that were seen by the physician near home, let's call it.
	DR. WOLINSKY:  So for example, for the placebo patients‑‑that was almost 50 relapses‑‑were not seen and confirmed in the centers?
	DR. GHALIE:  For general relapses.  But for those who were treated‑‑and unfortunately, I don't have it on that slide‑‑most of the relapses that were treated were treated on the participating site.  And I agree, it is not on that slide.  This is all relapses.
	DR. GILMAN:  So we don't have the number of patients with relapses seen by their local physicians; you don't have that information for us, I gather.  Is that the case?
	DR. GHALIE:  Well, actually, this slide shows the number of patients who had a relapse diagnosis at the instigation site, and total number of relapses.  So the balance, indeed the difference, is what is seen by the local doctor.  What I don't have here indeed is the number of treated relapses by the local doctor.  I don't have it on this slide.  But again, Dr. Hartung says‑‑I don't have the data here, but our statistician may comment on that as well‑‑that these number was a minority of those treated relapses.
	DR. GILMAN:  Please keep the slide on.
	So‑‑Jerry, you can figure it out‑‑it is, what, 50 placebo cases, for example?
	DR. WOLINSKY:  It looks like‑‑and my math was never very good‑‑
	DR. GILMAN:  It looks like about half.
	DR. WOLINSKY:  ‑‑about 50 of the placebo attacks and about 30 of the 5 mg per meter squared and roughly 18 of the Mitoxantrone attacks that contribute to the database were never confirmed at the site, as best I can deduce from this data.
	DR. GHALIE:  This is relapse in general.  What we have looked at primarily was the treated relapses, and those are not seen here, that were seen by the doctor near home, and this is what Dr. Hartung is going to comment on right now.
	DR. HARTUNG:  May I just add that I think the crucial and critical point is those relapses considered to be severe and those that, according to the protocol, necessitated treatment, and you can see in Columns 2, 3, and 4 that there were marginal differences between those that were treated and seen by the treating physician at the center and the total number‑‑66 versus 63.
	Relapses, as you know, in many protocols, or the occurrence of relapse, can be by historical information alone.
	DR. WOLINSKY:  I'm not going to disagree with that at all; I am just trying to understand the data.  So that when we talk about the time to the first treated relapse, we are talking about the time to all of those relapses which are below the first line; is that correct?
	DR. GHALIE:  Yes, correct.
	DR. WOLINSKY:  So the Kaplan‑Meyer curve, for what it's worth, is not contaminated by these locally reported relapses‑‑in general.
	DR. GHALIE:  Correct.
	DR. GILMAN:  Dr. Hartung?
	DR. HARTUNG:  Well, you know, the treating physician‑‑and that may be the complication or misunderstanding generated by this slide‑‑the treating physician saw most of the relapses but decided not to treat them because they were not considered severe.  So that is the larger difference that you see here in the slide.
	DR. WOLINSKY:  If I could change the questions a little bit because I'd like to understand what kind of patients we are treating and what the treatment effect looks like for different kinds of patients.  So do you have a subgroup analysis that would let me see what happened to the change in the disability scores, the EDSS, et cetera, in those patients who never had attacks in trial by treatment?
	DR. GHALIE:  Certainly.  We have, as you would imagine, looked at all of these subset analyses, and they are subset analyses based on whether they were defined as secondary progressive or remitting progressive, whether they were defined as having had or not relapsed prior to enrollment and other variables.  We have looked at that for the five primary endpoints in the three groups as well as for the two primary groups, and I have a number of slides that can look at that.
	I would like to have Slide B‑28.
	[Slide.]
	DR. GHALIE:  This slide shows the five primary endpoints taking into account patients who had a relapse in the year prior to enrollment and patients how did not have a relapse in the year prior to enrollment in the three groups.  That is the primary variable that I show here. We didn't put p values here, obviously, since those are subset analyses, but one can see that for each of these primary variables, it was always in the right direction.  Again, negative values mean it is getting better, positive values mean it is getting worse.  Mitoxantrone 12 and Mitoxantrone 5‑‑that is placebo‑‑is for EDSS in patients who had prior relapse.  And if we look at no prior relapse in the preceding year, 0.13 as the mean change, 0.67 for EDSS.  And if we go down the list for the other three disability scales, we have the same direction.
	DR. TEMPLE:  I don't think that's what the question was.  The question was if you look at people who had no relapses during treatment, what was their disability outcome.  That is even a worse subset analysis.  That is not even based on baseline characteristics.  So‑‑
	DR. GHALIE:  Therefore, we did not look at subset analysis.
	DR. TEMPLE:  Well, that's very prudent, but it still would be interesting.
	DR. GHALIE:  I am sure that we can do that, and Dr. Hartung would probably be interested in looking at that in his manuscript.  We'll check it on our things to do.
	DR. WOLINSKY:  I think I can pass the microphone for a while.
	DR. GILMAN:  Dr. Swain?
	DR. SWAIN:  Well, Dr. Wolinsky asked a couple of my questions, but I had another question.  In the FDA safety review, it was mentioned that I think 52 percent of the placebo patients were on other drugs for symptomatic relief, whereas only in the 30 percent range, the patients on Mitoxantrone were on other medications, suggesting to me that the placebo group was much more symptomatic at baseline and that it was very biased and that the randomization did not work.
	Can you comment on that?
	DR. GHALIE:  Well, these patients were randomized, so if there was any different at baseline, again, these were not stratified based on symptomatic treatment.
	What we have looked at in our analysis is what are the concomitant medications given while on treatment, and there was really no major difference among the three groups.  Most of these symptomatic treatments that were used in patients with MS are antispasmodic or treatment for bladder or vitamins, minerals, herbs, things like that. So really, they did not think this would in any way affect the assessment of disability and relapse as we have seen in the study.
	Maybe Dr. Hartung would also like to comment on what kinds of concomitant medication patients tended to use in this study and if he has an opinion as to whether this would in any affect assessment of treatment.
	DR. HARTUNG:  Well, again, I can only reiterate what you have already listed‑‑the usual antispasmodics, the drugs to treat bladder problems, and alternative medicine/vitamins or whatever.
	I am not aware that there was a significant difference in the usage of these symptomatic therapies in the various treatment arms.
	DR. SWAIN:  Well, that's not what the FDA review has.  I think it has 51.6 percent placebo and 36.7 in the 12 mg, so there was quite a bit of difference in that.
	DR. GHALIE:  Slide C‑42 in fact gives data per patient, so we can make the percentage and give the same information.  It is already here.  So really, the patient on placebo had more myorelaxant and vitamins and antispasmodic‑‑but again, you can see the difference is minor.
	I would like to see if any of our consultants can make a comment that myorelaxants are likely to affect when we talk about treatment effect on EDSS and relapse.
	Dr. Hartung, Dr. Panitch, would you like to comment based on your experience in patients with MS?
	DR. PANITCH:  Well, concurrent/concomitant medications to symptomatically treat MS are universally allowed in clinical trials, and I think that the number of patients that we have here is small enough that I don't know if these differences are significant, but I certainly would not expect the commonly used antispasmodic drugs‑‑for example, xanoflex [ph.], to have an effect on the underlying progression of the disease.  They might affect the EDSS, and one usually attempts to maintain a patient‑‑if the patient is taking the drug at the beginning‑‑to maintain the drug and the dose throughout the trial so that you don't change the results during the trial.
	But these kinds of things are so generally accepted in treating MS that I certainly would not expect them to make a major difference.
	DR. GILMAN:  Dr. Swain, do you have anything further?
	DR. SWAIN:  No.  I mean, I agree that they are used, and that's really not the point.  The point is that there are more patients on the placebo receiving them, indicating that they have more severe symptoms, and also, since the time to relapse is not blinded, it is a very biased endpoint, and I have a real problem with using that endpoint and really trusting it.
	DR. GILMAN:  Dr. Katz first, then Dr. Temple, then Dr. Grotta.
	DR. KATZ:  A couple of things.  One question.  I note that the criteria for defining a severe relapse were either a new disability and a greater than 2‑point increase in the Kurtzke, I gather, or a worsening of pre‑existing symptom, and the worsening had to be of at least one point on one of four, or however many it was, functional scales.
	I am wondering if we have a breakdown of how many of these severe relapses by drug group were defined by the first criterion versus by the second criterion?
	DR. GHALIE:  The data was not collected.  The data was collected such that did the patient suffer from severe relapse or not, and whether treatment was given and what type of treatment.  They did not collect data about what defined a relapse.  It may be available in the patient's record, but it was not collected in the case record form, and it is not available to us.
	DR. KATZ:  So, then, we don't know the nature of the disability, or let's say you don't know the nature of the disability that someone called a severe relapse; you just have a box that was checked that said "severe relapse"?
	DR. GHALIE:  Right.
	DR. KATZ:  Okay, so we don't know what the patients looked like clinically.
	I had one other sort of statistical question.  The protocol, as you said, first required that the multivariate analysis be done, or multivariate measure be assessed, and if that was significant, then you went sequentially down, and you only went down as long as the one before was significant, nominally significant.
	I am wondering if blind‑breaking was at work here.  Let's just for argument's sake say that there was a problem there.  When you looked at the multivariate analysis that too would have incorporated that bias, because part of that was a result of blind‑breaking.  So I am wondering from a statistical point of view what is the appropriateness of relying on a measure to determine whether you can do subsequent tests of the individual measures when that initial measure might be subject to the bias introduced by potential blind‑breaking.
	DR. GHALIE:  The data analysis was conducted by a CRO who was hired specifically for that task, and when they did the analysis, they were still blinded to treatment arm.  And it was only when all the analyses were completed that the unblinding was performed.
	DR. KATZ:  I don't follow.  You said the analysis was done at the end of the study.
	DR. GHALIE:  Yes.
	DR. KATZ:  That doesn't get at the problem, I don't think, that I am raising, which is that the data are biased‑‑allegedly, just for argument's sake, assume‑‑so that when those data go into the multivariate analysis, the first screening analysis, if you will, those results might be unreliable.  And it is only the basis of a particular result on that analysis that permits you to go down the list.
	So I am just raising it as a possible concern.  I don't know‑‑Dr. Van Belle, does that strike you as being relevant?
	DR. VAN BELLE:  I think what you are saying is that the overall analysis, the global analysis, could have had a p value that was larger than you would expect because of the unblinding of the third, fourth and fifth outcomes where there was unblinding. Given that the first two blinded outcomes are also significant, I would not judge that to be a very important point.
	DR. GILMAN:  Dr. Temple?
	DR. TEMPLE:  Nothing further.
	DR. GILMAN:  Dr. Grotta?
	DR. GROTTA:  I am just a stroke neurologist, but to my knowledge there have only been a few drugs that have been shown by evidence to affect the number of relapses, so I just need to be sure that none of the patients in this trial received any drugs that were either experimentally evaluated at that time or that have subsequently been approved to affect the number of relapses.
	DR. GHALIE:  This study and Study 902, which I'll present to you later, were both conducted before the Interferon and Latrimeris [ph.] data were approved in Europe, and therefore, none of these patients had received prior and definitely not while on the study any of these agents.  So they were Interferon and Latrimeris [ph.]‑‑and remained throughout the study.
	DR. GROTTA:  And that was true of both studies?  We might as well get that out of the way for the next one.
	DR. GHALIE:  Yes, correct; for both studies.
	DR. GILMAN:  Dr. Penix?
	DR. PENIX:  Going back to the issue of concomitant medications, my understanding is that the patients who were on study drug were treated with the anti‑nausea drug ondansetron, whereas the placebo patients were not given this‑‑they were given a placebo agent.  So what was the decision not to treat the nausea for the placebo group with the same drug, and particularly since 76 percent of the patients on the 12 mg dose of the study drug had nausea and only 20 percent‑‑a significant number of the patients actually got the treatment for nausea whereas the placebo patients did not.  What was the choice for that?
	DR. GHALIE:  As you know, at the time when the study was conducted, mitoxantrone had been used in oncology experience for many years; it is known that one of the effects of chemotherapy is to produce nausea that can last a day or two.  So to protect those patients who were going to receive the chemotherapy, the decision was made to give them an anti‑emetics.  The decision was also made at this time that patients who were going to receive placebo did not need an additional drug that they were going to have side effects from, and they decided to go for the matched placebo.
	DR. PENIX:  Even if they did have nausea‑‑I mean, you were treating the nausea for that, so 20 percent of those patients did have nausea‑‑that was not treated?
	DR. GHALIE:  I would like to ask Dr. Hartung to comment on that, whether patients who were randomized on placebo and did have nausea were still treated with an anti‑emetic beyond the first day.  But the bottom line I would like to come back to before I pass it to Dr. Hartung is that these patients received the anti‑emetic for the day of the treatment, and it is extremely unlikely that ondansitron given on day one would have any effect on effect on days 7, 10, 15, 21, et cetera.
	But I'd like to have Dr. Hartung comment on whether patients who were on placebo and still had nausea eventually got some anti‑emetic versus just the placebo.
	DR. HARTUNG:  They certainly did, but it was the idea, of course, that we didn't want to expose patients who were on placebo to a drug with possible side effects.  That so many placebo patients in actual fact did have nausea was a little bit astonishing to us, but we know this from other placebo‑controlled trials.
	But yes, if they did become nauseated, they did receive symptomatic therapy.
	DR. GILMAN:  So this was not given prospectively, before the infusion.
	DR. HARTUNG:  No.
	DR. GILMAN:  It was given only with the symptom.
	DR. HARTUNG:  No.  Initially, it was given prospectively for those who were randomized to receive mitoxantrone, and ondansitron placebo for the placebo patients.  Only if those placebo patients did become nauseated did they receive symptomatic therapy.
	DR. GILMAN:  So that's a potential clue that patients that the patients being treated with real drug‑‑I think that's your question as well‑‑
	DR. PENIX:  It appears that the placebo patients were given a placebo drug for that.  My concern is that I doubt if there was a treatment effect of taking this drug, but the 76 percent of your patients who were on the 12 mg dose did receive a drug that the placebo patients did not.  Therefore, I just wonder if these was any concern about that‑‑and is that typical for MS trials?
	DR. GHALIE:  I would like to clarify; I think I see where there is confusion here.  All patients who were in this study got a pill before getting mitoxantrone or placebo.  Before getting study drug, they all get something.  The patients who were randomized to mitoxantrone 12 mg per meter squared or 5 mg per meter squared got ondansetron.  Patients who were randomized on placebo got a pill that was a placebo, that looked identical to the Odansitron.
	The protocol also allowed to repeat a dose of anti‑emetic 8 hours after the dose of mitoxantrone administration or placebo administration, and that second dose was also either Odansitron for the mitoxantrone group or a matched placebo for the placebo group.
	Beyond that, if a patient continued to have nausea, or particularly if the placebo patient had nausea, then they were to receive anti‑emetics, no longer placebo.
	So everyone got a pill before getting the study drug, and again, that's to continue the masking.  Now, again, as Dr. Hartung said, the rationale to give patients randomized to placebo a placebo pill as opposed to an active agent was based on why give active agents when we can give a placebo to the placebo patients.  So it was a decision early on for the patients' safety not to give them Odansitron.
	Now, we all know‑‑and the oncologists around this table can mention it‑‑that Odansitron is used extremely commonly in cancer patients.  It is a very potent and active anti‑emetic.
	DR. PENIX: But in a cancer trial, would they also give the same drug to the placebo group?
	DR. GHALIE:  I am an oncologist by background, and I don't think I have ever seen a placebo‑randomized trial in cancer patients.
	DR. SWAIN:  We have many placebo‑randomized studies, but I think that normally, you would not give the active ant‑emetic.
	Do you agree, Bob?  I have never really seen that done.  I understand your point, though, because it could have some activity.
	I have one quick question.  How as the randomization done?
	DR. GHALIE:  The randomization lists were generated by computer program, and the randomization was done on a per‑site basis to ensure balance within each site and the number of patients assigned to these three groups.
	The study was done in 17 centers in four countries, and for the mechanics of it, there were really two randomization centers‑‑they all had the same lists‑‑one in Germany and one in Belgium.  For the Belgium centers, the randomization center was in Belgium; for the German, Hungarian and Polish centers, it was done in Germany.  They would call there, they would get the patient's number assignment, and they would assign the patients.
	DR. SWAIN:  So the pharmacists were blinded at all the centers except the two randomization centers?
	DR. GHALIE:  I'll let Dr. Hartung speak to that.  I presume the pharmacists knew what they were administering, because they knew it was placebo versus mitoxantrone.  Again, the person who was blinded was the person who assessed disability‑‑and the MRI, obviously.
	DR. GILMAN:  Dr. Grundman first, then Dr. Wolinsky, then Dr. Dahut.
	DR. GRUNDMAN:  With respect to the blinding of the person who assessed the disability, 60 percent of the patients were reported to have alopecia and 70 percent were reported to have nausea.  Were there any measures taken to prevent the so‑called blinded rater from noticing that the patient's hair was‑‑
	DR. GHALIE:  There were no measures taken especially to put a cap or a hat or something like that.  However, I must say right now‑‑and we'll get back to this when we talk about safety‑‑alopecia in this trial was really not a complete hair loss as one would imagine with chemotherapy.  It is really hair thinning.  So that although one could tell maybe that a patient was on one arm or the other one, really, the alopecia may not have been by itself a clue.
	As far as the nausea, as I mentioned earlier, if patients knew that they had a lot of nausea, they were asked not to tell the blinded neurologic disability assessor that they thought they were on chemotherapy.
	And lastly, just to conclude my point, chemotherapy is given one day; neurologic disability assessment was done 3 months later for that cycle.  So by that time, anything having to do with nausea, et cetera, would probably have completely resolved by that time.
	DR. GRUNDMAN:  Given that most of the patients who were receiving the active drug knew what they were on, or a good portion of them had that suspicion, is it possible that that might have tainted their effort in performing these ambulation studies?
	DR. GHALIE:  I don't know how we can tell that patients thought they were on chemotherapy or not.  I'm not sure that this was always obvious to them.  As you will see in the safety profile, the drug was [inaudible] acutely, so it may have been that they were really masked to treatment.  They were getting methylene blue, so they had the same kind of blue environment that I can describe about what happens when someone receives mitoxantrone.
	Now, as far as can a patient have a different EDSS assessment based on the fact that they may or may not have inactive treatment, I would like to have our neurologic expert comment on that.  Maybe Dr. Panitch would like to comment on that and then maybe Dr. Lublin or any of the study chairs also could comment on that.
	DR. PANITCH:  I think it is possible for patients to make very variable efforts in cooperating with neurological examination, but don't forget, these were all trained examiners who had been instructed in how to perform the EDSS, who were experienced in it, and should rely on the objective areas of the EDSS in scoring the patients.
	A certain amount of variable effort is possible, but when this and the Ambulation Index are performed and performed correctly, I think that that is minimized.
	DR. KATZ:  Could I just ask a clarifying question?  Which measures of the EDSS are objective in the sense that they don't require patient motivation or participation?
	DR. PANITCH:  Well, they almost require motivation and participation.  Even performance of tendon reflexes can vary depending on how a patient is feeling and how much coffee he has had that morning.  But the ones that are generally considered the most objective are peramital, cerebellar, the brainstem, and one other‑‑visual, I guess, although that requires a patient to read an eye chart‑‑as opposed to sensory and bowel and bladder, which are more by patient report.  So generally, more weight is placed on those.
	DR. KATZ:  Thank you.
	DR. GILMAN:  Dr. Wolinsky had some questions, then Dr. Dahut.
	DR. WOLINSKY:  A small point.  Odansitron, apparently by some, is believed to be useful in symptomatic treatment for tremor.  I assume all of the EDSS scores were done before the administration of the drug, so you will easily assure me of that?
	DR. GHALIE:  Yes.  The answer is yes.
	DR. WOLINSKY:  The second is a little bit more bothersome, and I just think there is no way to get around this, and I'm not sure I'm very uncomfortable with it.  But I assume that all the patients signed a consent form to participate in this study, and I'm sure that the consent form must have stated side effects which were well‑known for mitoxantrone at the time.  And I'm sure that many of the women in this study would have been able to figure out whether they had thinning of their hair, even if the men couldn't, that they would have known if they were developing amenorrhea‑‑although the men might have had a hard time‑‑and that some of these side effects are undoubtedly unblinding of the patients.  I think we just have to accept that.
	DR. GHALIE:  That's correct.  This is why the protocol and the investigators agreed and explained to the patients that if they knew what arm they were on‑‑and I agree with you they may have known‑‑at least that was to be kept to themselves and not inform the investigators who evaluated neurologic disability.
	DR. GILMAN:  Dr. Dahut?
	DR. DAHUT:  I have a quick question about the EDSS.  The main change in EDSS was a worsening in placebo group of 0.23 and an improvement in the mitoxantrone group by 0.13, so a total change of about 0.36, I guess.  Is that a clinically important difference between neurologists, and would variability among the tests explain some of that?
	DR. GHALIE:  It is a difference and a significant difference‑‑
	DR. DAHUT:  Statistically, but is it a clinical difference or just a statistical difference?
	DR. GHALIE:  It is a mean, so it includes patients who got better, who did not get better, who got worse.  This is always why the mean gets to be so hard to separate.  But that was what was decided early on in the study design to do as primary endpoint.  That was the early nineties study design.
	But if you look at all the other EDSS measurements that I presented to you, the one‑point change, the mean change over time every month, every 3 months until the end, they were also significant in favor of mitoxantrone and that gives us more confidence that really, there was an effect on disability which at least for some patients was real.   Again, some people may like to talk about the EDSS one‑point change that was confirmed at 3 months and 6 months.  I presented at 6 months, but 3 months presented the same data.  The proportion of patients who had a worsening of one point was significantly different in mitoxantrone, much lower than in placebo.
	So although the mean change of 0.5 may not be clinically large, by all the other measures that looked at larger EDSS changes were also in the same direction, significantly in favor of mitoxantrone.
	I don't know if other physicians would like to comment.  Dr. Panitch would like to add to that.
	DR. PANITCH:  Your point is well‑taken, and as a neurologist‑‑I'm not going to speak for other neurologists here‑‑a change of half a point on EDSS for an individual patient is not significant and is not replicable either by the same examiner or by some other examiner.  But if we're talking about group data and we're talking about statistics, then it becomes more relevant and, in my view, more compelling.
	Nevertheless, even for group data like this, half a point is not a lot; it is when it is put in the context of all the other trends and significant outcomes that it becomes convincing.
	DR. GILMAN:  Dr. Ghalie, it is now 10:15.  With your permission, can we take a 15‑minute break and then come back to Study 02?
	DR. GHALIE:  Certainly grant this permission; I would love that.
	DR. GILMAN:  We'll reconvene in 15 minutes for the open public hearing.
	[Short break.]
	DR. GILMAN:  Since the time of the break, we have been joined by Dr. Howard Weiner, who will introduce himself.
	DR. WEINER:  My name is Howard Weiner.  I am at the Multiple Sclerosis Center at the Brigham and Women's Hospital, Massachusetts General Hospital in Boston, at the Harvard Medical School.
	DR. GILMAN:  Thank you, Dr. Weiner.
	Let's resume, then.  Dr. Ghalie, would you continue on, please?
	DR. GHALIE:  I will continue my presentation where we left off by presenting now the data for Study 902, beginning first with the design and efficacy results.
	[Slide.]
	Study 902 is a prospective randomized corticosteroid‑controlled trial.  It was conducted in five centers in France.  It enrolled 44 patients.  Professor Edan, who is with us here today, designed and chaired the study.
	The first patients were enrolled in April of 1992, and the study closed in March of 1995.
	[Slide.]
	The main inclusion criteria are listed on this slide and consist of patients age 18 to 45; a disease history of less than 10 years; and what is defined in the protocol as a "highly active disease" as defined by an EDSS progression of at least 2 points or at least two relapses in the 12 months preceding enrollment.  So that's a highly active or rapidly deteriorating MS.  Also, the baseline EDSS had to be 6 or less.
	[Slide.]
	The exclusion criteria as listed in the protocol are shown on this slide as well.
	[Slide.]
	Let me now describe the study design.  Patients eligible for the study based on clinical criteria‑‑meaning the 2 EDSS point progress or the two relapses or a combination thereof‑‑underwent a 2‑month triage lead‑in period which is shown here.  During this period, they received methylprednisolone one gram intravenously every month for two courses, and they underwent MRI evaluation before each of these two courses of methylprednisolone.  Only patients who had active gadolinium‑enhancing lesions detected on these two MRI scants were then allowed to be randomized into the trial. So to be enrolled in the randomized part of the study, patients had to have active disease based on both clinical criteria and active MRI gadolinium‑enhancing lesions.
	Patients were randomized either to continue on methylprednisolone alone, continuing on the same schedule, one gram intravenously every month, or to receive methylprednisolone at the same does plus mitoxantrone.  Mitoxantrone was given at a fixed dose of 20 mg per course.
	For those of you who are not familiar with the shift from meter squared to fixed dose, a dose of 20 mg in an average adult is very similar to 12 mg per meter squared.
	Randomized treatments were given monthly for a total of six courses.
	[Slide.]
	Patients underwent monthly evaluations, both clinical and MRI evaluations.  Dr. Miller in London reviewed all the MRIs of this study, and as you know, his center is the reference center for European MRI evaluation, and in 1991, he published "Guidelines for Conducting MRI Scans for Patients with Multiple Sclerosis."
	During his review, Dr. Miller was masked both to study drug and to patients' clinical outcome.  He just had a list of patient numbers and the MRIs that he reviewed.
	In this study, the physicians were responsible for patient management, study drug administration, assessment of safety evaluations, as well as assessment of neurologic disability and relapse.  These patients were unmasked to study drug.
	[Slide.]
	The goal of this study was to assess treatment effect on inflammatory lesions in the CNS using MRI scan as the marker.  These scans were done monthly in this study, as I have mentioned.
	The primary MRI efficacy endpoint as defined in the protocol was a comparison between the two groups and the number of patients who had new gadolinium‑enhancing lesions on monthly MRI scans from Month 1 to Month 6.  So that was the primary endpoint‑‑patients with new Gd‑enhancing lesions.
	A secondary MRI endpoint was defined as a comparison between the two groups and the number of new Gd‑enhancing lesions.  So the first primary endpoint was patient, and we're now talking about new Gd‑enhancing lesions, again on monthly MRI scans from Month 1 to Month 6.  And there were also secondary clinical efficacy endpoints as measured by the EDSS scale that we described earlier and relapses.
	The number of patients required for the study was 21 per group, and that was again based on published data from Miller et al. for an MRI‑based study design such as this one.  With these 21 patients per group, it was estimated to be possible to see a 50 percent difference in the number of patients with new Gd‑enhancing lesions during this treatment period.
	DR. GILMAN:  May I ask a question at this point?  When you talk about the number of new Gd‑enhancing lesions monthly, do you mean relative to the previous month or relative to any of the previous months?  What do you mean by "new"?
	DR. GHALIE:  "New" in this protocol and in the analysis I will present to you today is relative to the preceding month. Clearly, we have done evaluation now for any Gd‑enhancing lesions, so it really doesn't take account compared to the previous month or to baseline.  And I have all this information available.
	DR. GILMAN:  So it is relative to the previous month only?
	DR. GHALIE:  Right.  It is new compared to the previous month because one can conceive of patients have MRI lesions at one month, disappearing and coming back.  In this case, it is considered something not good, so it is a new Gd‑enhancing lesion.
	DR. GILMAN:  Please, Dr. Grotta.
	DR. GROTTA:  Just one quick methodological question. So the patients would come in, they assumed they would get their MRI scan before they were dosed with the study drug and steroids?
	DR. GHALIE:  Correct.  And it was specified in the protocol to be done before the corticosteroid to be sure that it does not affect the MRI scan that would be performed at that time.
	DR. GILMAN:  Dr. Grundman?
	DR. GRUNDMAN:  Again, just a methodological question.  The person who was looking at the MRIs did not look at the MRIs independently; is that correct‑‑he had access to the previous month, so a whole series of those MRIs were collected and given to the rater.
	DR. GHALIE:  Yes.  These scans were all done in these five centers in France, and they were all sent to London, where Dr. Miller reviewed the scans at the end of the study.
	DR. GRUNDMAN:  And this was done at the end of the study.
	DR. GHALIE:  Right.
	DR. GRUNDMAN:  And how was the order of those scans given to the rater?  Was there some sort of deliberate randomization process, or were they just given in order of subject number?
	DR. GHALIE:  They were sent in two batches.  The first series was for about half of the patients enrolled in the study, and the other series was for the other half.  And they were all analyzed at the end of the study.  And again, the patients were identified only by their initials or a coding system, not by what treatment arm they were in.
	In the efficacy results I will present to you today, we are going to focus on Month 6 at the end of the study as the primary comparison for some of the p values‑‑but in fact I will present all the data, so you can look at all the data.
	[Slide.]
	I will present first, then, data on patient disposition and demographics.  Forty‑four patients were randomized onto the randomized part of the study. Two patients, one from each group, withdrew from the study after the first course of therapy and before they underwent their first MRI evaluation.  Therefore, these patients did not have efficacy evaluation available.
	Thus, 42 patients of these 44 are evaluable for efficacy, 21 in each of the two groups.  Of these 42 patients, 37 completed the 6 months of treatment and all associated procedures.  All 21 patients were randomized to mitoxantrone plus methylprednisolone, and 16 patients were randomized to methylprednisolone alone.  Five patients were randomized to methylprednisolone who discontinued treatment and withdrew from the study before completing the six courses of treatment.  They withdrew at Month 4 or Month 5.  All of these five patients withdrew due to lack of efficacy and symptomatic and neurologic deterioration.
	[Slide.]
	There is no difference in demographics at baseline between the two groups.
	DR. GILMAN:  Excuse me for one second.
	Dr. Kawas?
	DR. KAWAS:  Just a quick question.  The patients who withdraw from the prednisolone group because of lack of efficacy‑‑did they know that they were in the controlled group, essentially?
	DR. GHALIE:  Yes, indeed.  These patients were not blinded, because there was a group that was receiving the blue chemotherapy and methylprednisolone, and the other group methylprednisolone.  So here, the patients and the physicians were unmasked, so they knew which treatment.  However, when they withdrew from study, there was clear evidence that they had a high number of relapse, and EDSS worsening, and therefore, the physicians treating these patients decided it was time to withdraw them from study.  We have data on these five patients.
	DR. KAWAS:  Thank you.
	DR. GHALIE:  Again, these are the baseline demographics that show there was no significant difference between the two groups at baseline.  About 80 percent of the patients were considered retrospectively as having  relapsing remitting multiple sclerosis based on the fact that at the time of enrollment, they had at least two relapses in the preceding 12 months.  These patients, even though they had relapse and were considered relapsing remitting, also had progression of their EDSS as well.  The other 20 percent of the patients were considered to have secondary progressive MS because their reason for being enrolled in the study was a 2‑point EDSS progression in the preceding 12 months.
	A typical patient enrolled in the study was a 31‑year‑old patient who had a disease history of about 6 years.  The patient population as a whole had an average of three relapses in the year preceding enrollment, and the mean baseline EDSS was 4.5, which, as in the Phase III study, represents a disability severe enough to impair full‑day activity.
	[Slide.]
	I will now turn to the efficacy endpoints of the study, beginning with the primary efficacy endpoint.  Again, that is the number of patients with new gadolinium‑enhancing lesions during the 6 months of treatment.
	Fewer patients in the mitoxantrone group had new gadolinium‑enhancing lesions over time.  This became evident, as you can see on this slide, at Month 2 and persisted for the remaining period of their treatment.
	[Slide.]
	If we look now at Month 6, two of 21 patients randomized to mitoxantrone plus methylprednisolone, which is 10 percent of the patients, here in yellow, had new gadolinium‑enhancing lesions compared to previous months, compared to 11 of the 16 patients randomized to methylprednisolone who were still on study.  That is 69 percent of the patients.
	This difference represents an 86 percent decrease in the number of patients with new gadolinium‑enhancing lesions at Month 6, and the p‑value for Month 6 is presented here as p equals 0.001.
	[Slide.]
	If we turn to the secondary MRI endpoint, which is the mean number of new gadolinium‑enhancing lesions, again, one can see that in the mitoxantrone group, it steadily declined from Month 1 to Month 6, in yellow.  In the placebo group, it was more or less unchanged.  And again, if one looks at the p‑value at Month 6 for the mean number of new lesions, p equals 0.001.
	Again, this is a primary and secondary endpoint of MRI done by masked evaluators.
	Dr. WOLINSKY:  Can you tell me‑‑usually, when one does a study like this, somehow or another, one or more scans don't get done that should have been done.  So how much of the data are we looking at?  Did you actually have all of it?  And the other question which goes along with that is for those patients who withdrew, I assume there was no last observation carried forward, and if there was a missing scan, was there a last observation carried forward or not?
	DR. GHALIE:  To the first question, for this study, we have data for every cycle where the patient was on study, so it is really a full database for all the months where a patient went on study.
	To question number two, what did we do for those five patients who dropped out‑‑we did both analyses.  The analysis I presented to you today is having the patient with last value available presented, and for the month where they withdrew, they were not included in the presentation.  That's the most conservative way.
	If we included now for these patients last value carried forward, the difference becomes even larger, because those patients were getting worse when they withdrew.  But we haven't presented that.  The data is available, and again, it shows even more significant difference.
	DR. WOLINSKY:  You don't know whether they would have gotten worse‑‑they would have gotten worse clinically, but you don't know what the MR showed.
	DR. GILMAN:  They withdrew indeed because clinically, they were getting worse‑‑correct‑‑it was felt at that time that one could not keep them on treatment with worsening EDSS‑‑
	DR. WOLINSKY:  I understand, but you can't make any assumption about the MR changes, because they weren't done.
	DR. GHALIE:  Right.  And this is why we felt the most appropriate evaluation to show was for those patient with the MRI data available.
	[Slide.]
	Now I will turn to the clinical evaluation in the study, beginning with EDSS.  In the mitoxantrone group, the mean EDSS score improved by 1.1 point, from baseline at Month 0 to Month 6.  Mean EDSS remained more or less unchanged in patients randomized to methylprednisolone.  And again, I would like to add what I mentioned before, that patients who withdrew in Months 4 and 5 in the methylprednisolone group, that data is not included here as last value carried forward, so it is exactly the patients who remained on study who are shown here.
	The p‑value for this comparison at Month 6 is equal to 0.013.
	DR. GILMAN:  Let me ask a question about that‑‑go ahead, Dr. Van Belle.
	DR. VAN BELLE:  Clearly, one issue is whether the clinical scores are correlated at all with the physiological scores.  Did you do any correlation at all of the EDSS with such things as the number of lesions?
	DR. GHALIE:  We did in fact two analyses, and one of them was for each patient‑‑and there are 42 patients here‑‑a correlation on individual patients between the number of gadolinium‑enhancing lesions‑‑so any gadolinium‑enhancing lesion‑‑and their EDSS score at that month.  So for each patient, we had a correlation for that series of values.  And then, we did the average for these 42 patients, and we compared that between the two groups.  There was a correlation between EDSS value and the number of new lesions, and this is available on a slide if you would like to look at it.
	We also looked at another analysis, a much simpler analysis‑‑and I recognize that with a small number of patients, it is hard to draw a conclusion, but at least we looked at it‑‑where we looked at patients who had EDSS worsening by one point or less, and whether they had gadolinium‑enhancing lesions or not.  We did this table, and again, with a small number of patients, it is hard to draw any conclusion, but that data is available if you wish to look at it.
	DR. GILMAN:  I wonder if you would address the question that Dr. Katz raised, which is‑‑as I recall the numbers, 15 of these patients had relapsing remitting, and 6 had progressive MS‑‑how does that play with your request that the drug be approved for progressive multiple sclerosis?
	DR. GHALIE:  Really, what we are looking at in this study and when the study was designed, the rationale behind designing the study as it was designed was to take patients who really had very active disease and to be able to treat them with the treatment and see very quickly whether these patients had any effect with mitoxantrone.  Therefore, they elected to take patients who had very active diseases, and therefore, patients who had a lot of relapses were more readily available to enroll in that study.
	In fact, that had to triage 85 patients to end up with 44 patients who were randomized and 42 who were evaluable.
	Now, to answer your question specifically, the majority of the patients who were called relapsing remitting also had EDSS worsening.  It is not like their EDSS was stable over the preceding year.  Clearly, patients who had secondary progressive, which was 20 percent of the patients, had at least a 2‑point EDSS progression.
	DR. GILMAN:  Wait, now‑‑are you saying that these were remitting progressive patients, or that they were relapsing remitting, some of whom had progression?
	DR. GHALIE:  They were really defined as relapsing.  Again, this study‑‑just to make a small parenthesis‑‑was also designed before the new classification of MS in 1996, so the patients were defined as having a number of relapses of at least two, or EDSS progression of at least 2 points.
	DR. GILMAN:  That still doesn't address the question. The question specifically is whether the 15 patients who were defined as relapsing remitting did have progression month‑to‑month.  In other words, in the current classification, were they remitting progressive?
	DR. GHALIE:  These patients were defined, again, based on their relapse, but they again had some progression of disability.  Dr. Edan, who was the study chair, would also like to comment on that, please.
	DR. EDAN:  We studied relapsing patients at the very bad period of their disease.  These patients were selected as having at least two relapses within the previous 12 months, relapses with sequelae, which means worsening of EDSS during that time, or secondary progressive patients with an increase of at least 2 points EDSS, whatever the number of relapses during this 12‑month period.
	So the way to select the patients was really to‑‑all the patients started their disease with relapses, and we selected a group of relapsing patients at a very bad period of their disease.  They were in at least two different situations.  Either they had at least two relapses with sequelae within the previous 12 months, or they moved to secondary progressive with rapid worsening of EDSS.
	DR. GILMAN:  Well, I am still struggling to understand this.  You had 15 cases that had relapsing remitting disease.  Which number of this 15 had what in current terminology would be relapsing progressive disease?
	DR. EDAN:  They were relapsing remitting disease with worsening of EDSS after the relapse within these 12 months.
	DR. GILMAN:  But subsequently, did their EDSS return to its previous level?
	DR. EDAN:  No‑‑they had an increase of their EDSS during that period compared with the 12 months before, for most of the patients.
	DR. WOLINSKY:  Probably Dr. Lublin will help us with our confusion later, Sid, but I think we are going to stay confused on this forever.
	DR. WEINER:  I would just make a point.  I think there is this transition period in MS where people are moving from many relapses into the secondary progressive stage, and I think this is an important point that we will discuss later, because you have people who might be called secondary progressive who aren't really having relapses, who are slowly progressing, and the issue is whether those patients are different from the patients who are having relapses.  Also on MRI scan, the patients who enter the secondary progressive stage and are slowly progressing do not have as many MRI‑enhancing lesions, and I think this will become an important point in terms of if the drug is approved, what is it really approved for in terms of which patients are going to be treated.  But I would also echo what Jerry said, and Fred has struggled with this‑‑the MS Society has tried to segregate into different categories, but it may not be that possible.
	But I guess if we were to ask‑‑and we could ask the presenters or whatever‑‑if you had to classify the patients in this trial as either relapsing remitting or secondary progressive, would they be more in the relapsing remitting category or would they be secondary progressive?
	DR. EDAN:  They would be relapsing remitting MS.
	DR. GHALIE:  Eighty percent are the relapsing remitting.
	DR. EDAN:  Eighty percent, correct.
	DR. GILMAN:  So we have to remain with the numbers, that 15 of these 21 patients were relapsing remitting, and 6 were progressive; correct?
	DR. EDAN:  Yes.
	DR. GILMAN:  I think we have to take that series of numbers.
	DR. GHALIE:  I think Dr. Lublin, who was going to comment on that later, may also add a little bit.  We can introduce that topic right now and then come back to it later as well.
	DR. LUBLIN:  Yes.  When I do, I can go through the whole classification and tell you where I think these patients fit in, but I think that what Drs. Weiner and Wolinsky have said is essentially correct, and the conclusion is that those 15 patients are relapsing remitting patients.  And then I'll show you how that fits in terms of the worsening and so on.
	DR. GILMAN:  Thank you.
	Dr. Lipton?
	DR. LIPTON:  Actually, I just wanted to take the presenter up on his offer to show us the relationship between the clinical measures and the MR measures.
	DR. GHALIE:  Okay.  I would like to have Slide B‑130, and then we will look at Slide B‑131, which looks at the correlation.
	[Slide.]
	DR. GHALIE:  Again, with these small numbers, it is hard to make a determination, but again, this is EDSS deterioration during these 6 months.  Patients who did not have a deterioration, in the methylprednisolone group, 4 had negative scans, 11 had positive scans at month 6.  For the mitoxantrone group, they did not have deterioration in EDSS during the 6‑month period; 17 had negative scans, and 3 at some time had positive scans.
	So the negative‑negative seems to be a reasonably good correlation.  When we look at positive‑positive, 6 patients in the methylprednisolone group worsened, and their scans were positive.  Only one patient worsened, if you recall‑‑actually, I will present the data in a moment; you haven't seen that‑‑and this patient's scan was negative.
	So again, this is a very small number, and it is hard to make a determination based on that, but I think perhaps the clearer evaluation is when we did the correlation, which is actually the next slide, B‑131.
	[Slide.]
	DR. GHALIE:  As I mentioned, for each patient‑‑now, we have more data‑‑for each patient, we look at the correlation between their MRI results and their EDSS gadolinium‑enhancing lesions, any type of lesions, and we then average these 42 patients for which we had data.  The mean correlation for all the groups together was 0.21, and the p‑value was significant. So in other words, when there was gadolinium‑enhancing lesion, the EDSS seemed to be higher, and where there was no gadolinium‑enhancing lesion, EDSS seemed to be lower.
	DR. GILMAN:  Dr. Katz?
	DR. KATZ:  Yes.  I just want to remind the committee that the clinical data with which the MRI has been correlated is unblinded data.
	The first slide you showed, the one prior to this, looked at the‑‑
	DR. GHALIE:  B‑130.
	[Slide.]
	DR. KATZ:  I just want to make sure I read it correctly.  It looked at patients who had a one‑point deterioration‑‑not more than one point, just one point‑‑is that correct.  The other question I had was, as in the first trial, do we have data on what the nature of the relapses was in this?  We apparently didn't have that data for the first trial.  Do we know what the nature of the relapses was in this trial?
	DR. GHALIE:  This protocol also defined clearly the three categories of relapse, whether mild, moderate or severe, and also determined when to treat them.
	DR. KATZ:  I understand that, but I mean the actual relapses that occurred.  Do we know‑‑
	DR. GHALIE:  The numbers?
	DR. KATZ:  Well, beyond the numbers‑‑do we know clinically what these people looked like?  I gather we didn't have that information for the first study, and I am just wondering whether we have it‑‑
	DR. GHALIE:  Maybe Dr. Edan would like to describe what was a typical patient with relapse in his study, but again, I can also show you the slide showing how it was defined in the protocol.
	Dr. Edan, would you like to tell us in your study how you defined relapse and give us an idea about these patients' relapses?
	DR. EDAN:  We defined relapse according to the consequences of the relapse on daily life and the consequences on EDSS, and we separated mild, moderate, and severe groups according to these two criteria.
	DR. KATZ:  Do we know how many were in each category in this study?  Again, I gather you didn't know that the first time around in the first study.
	DR. EDAN:  Yes, we should know that.
	DR. GILMAN:  Dr. Katz, what was your question?
	DR. KATZ:  Do we know‑‑I mean, there is moderate, there is severe,, and there are different criteria for diagnosing‑‑I am just wondering how many patients met what criteria, and how many were moderate, how many were severe, that sort of thing.  I am just trying to get a sense of‑‑again, because blind is an issue here‑‑are we talking about minor changes that are potentially questionable, or are we talking about big league changes?
	DR. EDAN:  Only patients with moderate or severe relapses received methylprednisolone for 3 days.  We have the exact number of patients who were treated with methylprednisolone in each group.
	DR. KATZ:  I don't want to beat a dead horse, but in the first study, there were at least two criteria by which a severe relapse could be diagnosed‑‑either a new lesion with an increase of at least 2 points in the Kurtzke, or a worsening by only one point in a previously existing sign.  And again, we didn't know the breakdown of which relapses met which definition in the first study, and I'm just trying to get a handle on whether we have that sort of data for this study or whether we do not.
	DR. EDAN:  Our goal was not to treat patients with light relapses, so the physician had to measure the consequences of the relapse on daily life and on EDSS, and only if they considered that relapse had consequences on daily life, with a significant change in EDSS, did he decide to treat the patient.  We have this data in the publication.
	DR. GHALIE:  Slide B‑135 in fact describes the number of patients who received corticosteroid for the relapse, as well as the number of corticosteroid‑treated relapses.  So if one follows what Dr. Edan said, they treated only patients who in their opinion had a severe relapse.
	This is for the methylprednisolone group.  Eleven patients received corticosteroid, and they received 21 courses.  In the mitoxantrone group, six patients received corticosteroid‑‑and again, this was during the 6‑month period‑‑for a total of seven courses.  So one patient had two courses.
	So that addresses a little bit your question about what was the severity and the degree of relapse in this patient population, and these are the corticosteroid‑treated relapses.
	DR. GILMAN:  Dr. Wolinsky?
	DR. WOLINSKY:  If I could ask a couple more questions about these relapses, especially when patients are seen monthly‑‑I guess I would like to know how many of these relapses occurred between visits, and how many of them wound up being defined at visits and whether or not the neurologist who was declaring these relapses and deciding whether or not to treat them was making reference to the MRIs which were done on these visits.
	DR. GHALIE:  Dr. Edan, please answer.
	DR. EDAN:  We had some patients who had their relapses at the time of the MRI, but for practical reasons, it was impossible to change the date of the MRI. So we performed the MRI even if the patient had received methylprednisolone 2 or 3 days before.  And remember that most of the patients were in the group with methylprednisolone, so this should have improved the results in the group with methylprednisolone, as we know that methylprednisolone the day of the injection did decrease the number of lesions if the MRI is performed at the same time as methylprednisolone.
	So doing so did not break down the validity of the MRI analysis‑‑on the contrary.
	DR. WOLINSKY:  The question actually was a little bit different, and that is did the physician who was declaring a relapse have access to the MRIs which were done, and did that influence whether or not a relapse was declared?
	DR. EDAN:  No.  He didn't have access to the MRI data.  He decided only on a clinical basis.
	DR. WOLINSKY:  So that the MRIs were kept from the investigators at the site and just shipped off to London; is that correct?
	DR. EDAN:  Yes.
	DR. WOLINSKY:  Thank you.
	DR. GHALIE:  I would like to continue the presentation.
	[Slide.]
	The next slide looks at another measures that physicians like to see for EDSS deterioration, which is they categorized one‑point EDSS change as to whether it improved, remained stable, or worsened by one point or more.
	[Slide.]
	Again, there was a difference seen between patients randomized to mitoxantrone plus methylprednisolone compared to the control group.  One patient on mitoxantrone worsened by one point during this time period versus six on methylprednisolone.  This is the p‑value.  
	If we look now at patients who had improved EDSS by one point during the 6‑month period, again, we see a significant difference between the two groups, 57 percent versus 14 percent.
	[Slide.]
	And to come back now to the issue of relapse assessment which we already approached earlier, here again, one can show a significant difference with mitoxantrone plus methylprednisolone, compared to methylprednisolone alone, and that is looking at the annualized relapse rate.  Here, I have put the baseline in the first row to compare, so you can look at how it was at entry, and then the annualized relapse rate on study, which is the second row, and you can see that there is a significant difference between the two groups.  The annualized relapse rate dropped in the patients with mitoxantrone from a 3.1 mean relapse rate per year in the year preceding enrollment to 0.7 for the year they were on study‑‑rather, for the 6 months on study‑‑whereas it was unchanged for methylprednisolone.  And the p‑value here is a comparison between the two groups, 0.7 versus 3.0.
	And if we look at patients who remained free of relapse during this 6‑month period of study, again, there were 67 percent of patients randomized to mitoxantrone versus 33 randomized to placebo, a doubling of the proportion, and the p‑value was also significant.
	[Slide.]
	So in conclusion, this study, Study 902, shows that mitoxantrone plus methylprednisolone given every month for 6 months significantly reduced gadolinium‑enhancing lesions at monthly MRI scans; slowed neurologic impairment, as seen by EDSS evaluation; and decreased the relapse rate.  This is in patients with highly active or rapidly deteriorating multiple sclerosis.
	I would now like to turn to the safety data on the use of mitoxantrone for patients with multiple sclerosis.
	DR. GILMAN:  I wonder if you would handle a few questions now related to the data you have just covered for the two studies, 02 and 01.
	DR. GHALIE:  Certainly.
	DR. GILMAN:  Dr. Katz asked whether you had actually shown a change in basic progression of the disorder, and he made the point in his narrative that if there were a change in progression, to evaluate this, you would have to look at the patients after they had stopped the medication and look to see whether the group that was on drug returned to the level of the placebo‑treated group or whether they formed parallel measures over time.
	Would you address that question?
	DR. GHALIE:  I will begin with Study 902 and say that the data is not available.  So let's go to Study 901, which is our Phase III study.
	During the 2 years on treatment, clearly, patients who were on mitoxantrone had less EDSS progression and the other Ambulation Index.  But we also have data on Month 36.  Almost all patients who completed Year 2 ended up coming at Year 3 for their evaluation, and as I have shown you on that slide, patients who were randomized on placebo still had less EDSS progression between baseline and Month 36 than patients who were randomized to placebo.  And that was true for the EDSS, the Ambulation Index, and the SNS scores.  We can come back to that slide, if you wish, to make the point.
	DR. GILMAN:  Please do.
	DR. GHALIE:  That is Slide M‑43.
	[Slide.]
	DR. GILMAN:  Dr. Katz has another question.
	DR. KATZ:  Just two points about that.  One, in the design that you are talking about and that I have mentioned, as you point out, in order for a true effect on progression, at least by this paradigm, you would have to maintain that parallelism that you talked about.  The question here, as we will see, is whether they were still different at 36 months or whether they were approaching each other.  In other words, were they still as different as they were at the end of the double‑blind.  That is number one.
	Number two, again, I will remind the committee that the Month 36 data are unblinded\‑‑I believe that's what were told‑‑so that should be taken into consideration.
	DR. GILMAN:  Dr. Temple.
	DR. TEMPLE:  I just want to comment a little further on that issue.  This comes up in cardiovascular evaluations also, where people would like to treat a condition like heart failure with a drug like an ACE inhibitor and find improvement over a period of time, that is, find that some measurement of heart failure is better at the end of a period of time, and suggest that there has been a change in the heart.  We have generally said, well, that's nice, but to show that there has been a change in the heart, you need to have people off therapy, because we already know that ACE inhibits treat symptoms.  So the fact that you are better at that period could mean that you are treating the symptoms; it doesn't necessarily mean you have changed the heart.
	So in response to that, there is a trial of people who have had a heart attack who were given an ACE inhibitor for 6 weeks and were then evaluated at 6 months‑‑that is called the Gissey II [ph.] trial‑‑and it makes the case that ACE inhibitors given early really do have an anatomical effect on the heart.
	But it seems worth pointing out that that issue arises when the drug in question has both a potential claim for changing the underlying disease and also has the potential for symptomatic improvement. So that, for example, in Alzheimer's disease, we have been very rigorous in saying that before you want to claim anything other than a symptomatic benefit, like that we slow the rate of progression, you have to show what the results are off‑therapy, and when that was done with Aracept [ph.], there was no effect off‑therapy.  People came back to the baseline.
	It is just worth saying, without trying to prejudge the answer, that how worried you are about that depends a little bit on mechanism.   So that if one used an antibiotic, for example, to treat coronary artery disease, it isn't too plausible that an antibiotic has an effect on angina other than on its effect on fundamental atherosclerosis.  So the question is a little less forceful when the mechanism doesn't seem to have a potential for symptomatic benefit.  Now, you have to make the judgment whether this mechanism has a potential for just improving symptoms transiently, but that does get factored into how important that question is, I think.
	DR. GILMAN:  Well, I think that clearly this drug would be expected to have a symptomatic effect based on what we know about the immunologic basis of multiple sclerosis and the effectiveness of other immunosuppressive agents.
	Dr. Grotta was next, and then Dr. Weiner.
	DR. GROTTA:  Well, I guess this bears on this question, and that is whether the drug sort of has a nonspecific effect on MRI lesions.  Maybe the oncologists can tell us from the oncology experience in patients who have, say, brain metastasis in whom the drug is given.  Is there an effect on the MRI scan, or has that ever been observed, or can we be convinced that the changes that we are seeing in the gadolinium‑enhancing lesions are actually an effect on MS activity?
	DR. SWAIN:  I think that's a very good question, and I don't really know the answer.  I actually tried to find out some of this information before I came, and one question I had was how much of the Mitoxantrone actually gets into the CNS and into intracerebral tumors, and the data is very minimal and it shows actually it doesn't get into the tumors very much; it is more in the surrounding brain tissue.  And if there is not a disrupted blood brain barrier, it actually doesn't get in much at all.  And I assume that in MS, you do have a disrupted blood brain barrier, so you would get drug in there, but I wanted to later have the company comment on that.
	For Mitoxantrone particularly, I don't know of any data looking specifically at brain metastasis in a study.
	DR. GHALIE:  I would like to have Dr. Alberts comment on that, and then I will come back and answer your question, Dr. Swain, about the systemic effect versus the central nervous effect of Mitoxantrone.
	Dr. Alberts?
	DR. ALBERTS:  I think Dr. Swain is on target here.  The studies that we have suggest that Mitoxantrone does not get through the blood brain barrier to any extent.  The effects on MS, on the other hand, are not related to the Mitoxantrone effects directly on the lesion; they are related to the immunologic effects that they are having.
	So I don't think that we have any data to suggest that Mitoxantrone directly would affect lesions seen on MRI scan.
	DR. GILMAN:  But the lesions on the MR scan reflect breakdown of the blood brain barrier, so is there a possibility that the drug has an effect upon the vessels rather than the nervous system?
	DR. ALBERTS:  Well, I think we are in a very gray zone area of the pharmacology of Mitoxantrone and, for that matter, most of the antineoplastic drugs.  I think the only real data that bear on this are looking at CNS levels or actually cerebrospinal fluid levels of Mitoxantrone after intravenous injection, and in fact, studies have not been able to determine levels or pick up levels of the drug in cerebrospinal fluid in cancer patients.  I think that's the closest I can come to answering the question about whether it's really getting into the brain itself.
	DR. GILMAN:  Thank you.
	Dr. Penn, then Dr. Weiner.
	DR. PENN:  I had a follow‑up immunology question and then I had another question I wanted to raise.  Is there any data in MS patients‑‑and I know some of this was presented earlier‑‑regarding levels of Interferon gamma or TNF or other regulatory‑type cytokines, et cetera, in patients treated with Mitoxantrone in multiple sclerosis?  Do we have any data on that?
	DR. GHALIE:  There are data available both in animal models and in patients.  There is a lot of data from the models that were done in the seventies and eighties that show effect on cytokine, and there is data also on patients that shows a decrease in B‑lymphocytes, a significant decrease in B‑lymphocytes, to a lesser extent a decrease in T‑lymphocytes, particularly T‑helper lymphocyte, CD4.  There is also data, although more limited‑‑and Dr. Hartung is intending to do this in his own Phase III study‑‑looking at cytokine, where there is also a decrease IL‑2, Interferon gamma and TNF alpha. 
	DR. WEINER:  So there is a decrease in IL‑2, Interferon and TNF alpha.  That was done in‑‑
	DR. GHALIE:  In a small number of patients.
	DR. WEINER:  Another question that I have‑‑if there is a shift‑‑with some of the other chemotherapy drugs, for example, cyclophosphamide, where you have a decrease of Interferon gamma, et cetera, and you might have a shift more toward a TH‑2 or TH‑3 response, in the bloodstream, there is actually an increased number of eosinophils which is seen on the white blood count which would indicate an immunologic effect. Was there a change in eocynofils [ph.], or was that looked at in MS patients treated with Mitoxantrone?
	DR. GHALIE:  We have no information on eocynofil [ph.] counts.  That may be something we can look at later.
	DR. WEINER:  Okay.  That was just a follow‑up immunologic question.  The other question I'd like to address is related to the 901 study, and it relates to page 081 which was provided by Immunex to the committee, where analysis is done based on the type of MS.  There, from the 901 study, we have remitting progressive patients and secondary progressive patients, and they are broken out.  I have a number of questions I'd like to ask.
	First of all, based on the classification of patients as remitting progressive or secondary progressive, how many patients, then, in the 901 study were classified as relapsing remitting?
	DR. GHALIE:  Yes, that's something we addressed earlier in the morning.  Remitting progressive are patients in that study defined as patients who have relapsing remitting disease with incomplete neurologic recovery after relapse.  That represents about half of the patients enrolled in the study.
	DR. WEINER:  The other question I wanted to ask, and I don't know if any statistics are presented, is is there a statistical difference between the placebo and the Mitoxantrone 12 mg per meter squared in the secondary progressives when you compare placebo 23 versus Mitoxantrone 15?
	DR. GHALIE:  With respect to which endpoint?  I'm sorry.
	DR. WEINER:  Well, there are a number of endpoints listed‑‑EDSS, AI‑‑
	DR. GHALIE:  Okay, for the efficacy endpoint, no, there was no difference in baseline between the two groups.  As far as treatment effect, again, we are talking about patient subsets here, and there were no significant differences, but there was a trend, as you can see, in favor of Mitoxantrone 12 mg per meter squared.
	DR. WEINER:  The last question I would like to ask is a very important issue in terms of patients with secondary progressive disease is that the longer they have secondary progressive disease, the less likely they may be to respond to immunomodulatory therapy, and if this is used in patients with secondary progressive disease, some patients who have had disease for long periods of time might be treated.
	Do you have any data on the response in terms of subgroups in terms of how long the patients were secondary progressive‑‑in other words, those who were progressive for a year or two years versus those who might have been progressive for five years?  Do you have any data on that?
	DR. GHALIE:  We have read, Dr. Weiner, your paper which was published in December 1999, and I knew that was going to come up as a question.  The data was not collected, so unfortunately, I will not be able to answer whether there is a relationship between duration of the secondary progressive part of their disease.  We have the duration of their disease overall, and here there was no relationship.  But as far as the duration of secondary progressive, we don't have that information.  That may be something that Dr. Hartung may have some information on.
	DR. HARTUNG:  Yes.  This is obviously an important question bearing on the possible differentiation of differences between the various forms of progressive MS.  We have tried to go back and look at the 14 patients enrolled in the Wurzberg [ph.] Center, and we found, if I remember correctly, that those patients classified as secondary progressive had disease for something between 1.5 and close to 4 years.  We don't have information from all the centers, but I am trying to somehow retrospectively get that data.
	DR. WEINER:  Thank you.
	DR. GILMAN:  Dr. Penn, then Dr. Grotta.
	DR. PENN:  I just want to make sure that I am clear on a few points.  I think the committee is going to have a lot of discussion about the claim of progression and whether your drug helps to avoid progression of the disease.  Is the only data that supports that the 36‑month data which you show on your Meyer‑Kaplan curves?  Is there anything else that we should consider other than mechanistic types of arguments that you don't have data for that we should take into account as we debate that point?
	DR. GILMAN:  Can we see that slide as you answer the question, please?
	DR. GHALIE:  The only data I can present to you today on a slide is this Month 36, and again, we can go back to that slide.
	[Slide.]
	DR. GHALIE:  Again, I mentioned in the beginning for full disclosure that our protocol allowed physicians and patients to be unmasked to study drug during the third year of follow‑up.  That was the most conservative way, and in fact, in many centers, that was not done.  In other words, patients and the EDSS disability assessor remained masked.  But I can't add to that how many were.
	So that's the only data we have for that study.  We don't have follow‑up beyond Month 36.  In fact, this is happening these days beyond 36.  So this data is not available.
	There are two other sets of information that are available that were not submitted to FDA, so I cannot present it to you as fact with a slide, but at least I can mention it to you.
	There is one publication that I referenced very early in my presentation by Nili Firini [ph.] and collaborators.  This is a study that was done in Italy published in 1997, a randomized trial with 57 patients with relapsing remitting disease who were randomized to receive Mitoxantrone or placebo.  In that study, patients were given Mitoxantrone or placebo on a monthly basis for one year, and they had EDSS assessment relapse and MRI results.  The patients were seen a year later at Month 24‑‑and again, in this publication which is in the briefing document you have received‑‑at  Month 24, there was still a difference between the two groups in EDSS progression.  Again, that is one year after stopping treatment.  I don't have the raw data to share with you, but that was in the publication.
	DR. KAWAS:  Was that study masked?
	DR. GHALIE:  This was masked.  It was a placebo, and the EDSS evaluator was masked; correct.  It is in the paper.
	DR. GILMAN:  How do those scores compare with the status at Month 24‑‑the SNS, the AI, the EDSS, for example?
	DR. GHALIE:  What I am hearing is that you would like to see what happened between Month 24 and Month 36.
	DR. GILMAN:  The differences between treated at 12 mg per meter squared and placebo.
	DR. GHALIE:  It is Slide B‑25.
	[Slide.]
	DR. GHALIE:  Now, this is only in the year of treatment, Month 24, again in the three groups.  For the SNS, Ambulation Index, and EDSS‑‑and that is EDSS progression during the third year of treatment for those patients followed for a total of 3 years.  That's the mean change also, not total EDSS.
	DR. GILMAN:  So there is essentially no change in EDSS between Months 24 and 36?
	DR. GHALIE:  They were relatively stable, correct, the three groups, here for EDSS, Ambulation Index, and then SNS was higher in the placebo.
	Dr. Lublin has a comment here.
	DR. LUBLIN:  Thank you.
	Let me alter the perspective.  This is a relatively new definition of progression in the field of MS that Dr. Katz has posed.  So what you are looking at is the very best data extant in any study done anywhere in MS that matches the criteria he is trying to put up.
	The nature of this agent is such that none of us would have thought of this as being a symptomatic therapy in the way we used symptomatic therapy, such as baclofen and tisadidine [ph.] and things that alter things.  And the nature of EDSS is also such that we don't view it as a measure of symptoms in MS.
	The thing that we get worried about that this panel has been worried about in the past is whether the change that we are seeing over time in EDSS is reflective of true alteration of the underlying disease or alteration of intercurrent relapses.  And that's why we've used the sustained EDSS to try to take the issue of relapses out.  But we have never thought of it in terms of disease coming back.  That's something that we just don't expect to see, either with the measure of the EDSS in this type of disease and over this time period or with this type of agent.
	DR. GHALIE:  I would like to complete my answer to Dr. Penn.  You had asked if there is other data out that I have not presented.  In fact, there is also data from Dr. Edan's Study 902.  In his own site, there were 17 patients enrolled in this study, half of whom were treated with Mitoxantrone, half with placebo.  He had looked at these patients long‑term now, obviously‑‑these are his patients.   Clearly, we can't present these data today because they were never submitted to the FDA, but Dr. Edan had shown us the data yesterday, and he had graphs on those where he showed in these graphs that once he stopped treatment with Mitoxantrone‑‑and again, it is 6‑month treatment‑‑up to 3 years post‑treatment for those patients who have 36‑month follow‑up, the EDSS was stable compared to what it was at the time he stopped treatment for patients with secondary progressive MS.
	So there is some information accumulating suggesting that patients who stop Novantrone do not have a disease rebound; it stays where it is.  How long this is going to persist will be addressed by following patients longer in the future.
	DR. GILMAN:  We have some questions now.  First, Dr. Katz, then Dr. Wolinsky‑‑were you through, Dick?
	DR. PENN:  I think we ought to discuss this topic as much as possible, and then I want to ask another question after that on a different topic.
	DR. GILMAN:  Let's stay with this topic, then.
	Dr. Katz?
	DR. KATZ:  Again, I would just point out that all this post‑treatment data when we're talking about rebound is unblinded data, so that has to be factored in.
	Also, when we talk about progression or symptomatic, I am a little nervous when people talk about what their expectations are in terms of how the drug is working or what sort of effects it has based on what we think we know about what it's doing, and what the EDSS reflects and what we think that reflects.  That's why it is useful to have some sort of an operational definition of progression that you think makes sense, like this blinded withdrawal sort of phase, and see whether or not the disease returns under those conditions.
	This way, we don't have to worry about the mechanism of action, because we don't really know, as was pointed out earlier, what the mechanism of action is.  That's why I think we ought to‑‑I mean, it's worth discussion, but I don't think it is absolutely germane to the question, because it is based on a whole bunch of assumptions for which we don't really know the truth.
	DR. WOLINSKY:  Maybe I got confused, particularly around these issues of what we are calling these patients, because I think you just referred to Dr. Edan's subset of patients in the French study as secondary progressive, when I was under the impression that he had referred to them as relapsing remitting, some with accumulating disability.  This is not a small issue.
	Now, as I look across these two studies, one of the things that strikes me, since one of the things that is in common is at least a baseline MRI, is that the group of patients selected to be included in the French study were, albeit enriched for the presence of an enhancement on one of the two MRIs coming into the trial, they did what I would expect patients with relapsing remitting disease to do, that is, based on the clinical criteria, about half of them had an enhancement.
	What strikes me in the other study‑‑the multinational study‑‑is that the enhancement frequency was only about 24 percent even though the patients were stated to be rather aggressive in their phase of disease.  This surprises me.  I would have thought it would have been closer to 40, 50 percent.
	Again, trying to get a feel for what kind of patients we really want to hopefully approved these drugs for, what are the similarities and differences between the patients who were entered into these two trials in terms of type.
	DR. GHALIE:  Let me first address your first questions about Dr. Edan's patients.  And again, I feel uncomfortable talking about this, because this is data which was not submitted to the agency, and we have not analyzed it.  This is follow‑up data that Dr. Edan‑
	DR.  WOLINSKY:  What they were when they started is submitted.
	DR. GHALIE:  No, no‑‑I'm saying that in the data we looked at, he had data on patients who were classified as relapsing remitting, patients defined as primary progressive, and patients defined as secondary progressive.  So it is not only the patients in Study 902, it is the patients in his practice.  And I don't want to talk any longer about that; I would like Dr. Edan to comment briefly about that. But I didn't want to give the impression that it is only 902.  It is 902 plus other patients he has in his practice.  And again, we don't have the data to show you, and I apologize for that; I think we could do that.  But Dr. Edan, very briefly, if you could tell us.
	DR. EDAN:  Yes; it shows our experience.  At the present time, in the MS clinical frame, we have the experience of 106 patients who were treated with Mitoxantrone monthly for 6 months.  Our concern was to know what happened with these patients after the induction treatment, and we found 52 relapsing remitting patients; 35 secondary progressive patients, and 19 primary progressive patients.
	We had a follow‑up period of 3 years, and what we observed openly is a clear‑cut effect of Mitoxantrone during the induction treatment, allowing the patient to improve quite a lot the EDSS level, beneficial for the next 3 years.
	But I have to confess that most of these patients were treated after the induction treatment also by immunosuppressive or immunomodulatory agents.  They were treated by betaseron, they were treated by methyltrexate.  So just to tell you my experience with the effect of an induction treatment for 6 months, followed by less aggressive treatment, we have very clear‑cut, good results for a 3‑year period after this attitude.
	DR. GILMAN:  These were not blinded cases; you were not blinded?
	DR. EDAN:  No, no.  It is our experience.  It is not a study; it is the experience of my center.
	DR. WOLINSKY:  To follow up on that just a small amount, so in the patients in 902, who obviously didn't disappear from France at the end of the study‑‑
	DR. EDAN:  No.
	DR. WOLINSKY:  ‑‑and even though this is anecdotal, and we don't have the same level of rigorous anecdote that we have from the multinational study, what happened to them?
	DR. EDAN:  Yes.  We published that two years ago at a meeting in Stockholm.  In the five French centers, we had two different attitudes.  Half of the patients were then treated with Mitoxantrone every 3 months for 2 years, and another attitude was to give no treatment at all‑‑that was for the patients included in the trial.
	What we observed were quite similar results for the two groups of patients.  It was the reason why some of the French centers decided not to continue to treat every 3 months with Mitoxantrone in that group of patients after that.
	DR. WOLINSKY:  That brings me back to a question I had before, which is what is the appropriate way to use Mitoxantrone in patients with, to use newer terms, transitional or very active MS.
	DR. GHALIE:  That is something that we would like indeed to discuss as I go along in our presentation. But in a capsule, what I am getting to is the two studies that I am presenting to you today, in our opinion, show that Mitoxantrone has an effect on patients with multiple sclerosis.  These two studies were designed differently.  The drug was given on a different schedule.  But what we are seeing is an effect on EDSS progression as well as relapse and MRI.
	And in our opinion, where we are proposing the use of Mitoxantrone, it is to slow neurologic disability in patients who have what we call progressive forms of multiple sclerosis.  And I don't want to add a new classification to MS; that's what Dr. Lublin will address.
	Really, it is, in our opinion, what was tested in the Phase III study‑‑patients with secondary progressive MS or patients with relapsing remitting MS with accruing disability following relapses.  In our opinion, that's where we had the strongest data about the role of Mitoxantrone, and that's what we propose as an indication.
	DR. GILMAN:  Dr. Grundman first, then Dr. Grotta.
	DR. GRUNDMAN:  I think the question of dosing is actually a key question.  If you look at Slide M‑38 in the main presentation book, you can see that after 6 months of treatment with Mitoxantrone at 12 mg per meter squared, they perform no better than placebo.
	Now, when you use the induction phase that was just described and which was performed in the 902 study, there was an effect, so kind of an interesting question, getting back to Dr. Wolinsky's point is what is the appropriate way to treat these patients, and I'm not sure we know.
	DR. GHALIE:  The data we have on the larger study, the randomized trial, the one that has the blinded EDSS evaluation, is the one where it was given every 3 months.  And I am not sure I follow what you said, but the placebo patients are the ones in gray, so indeed, at the 3‑month evaluation, which is only after one course, there was no difference between the two groups, but after that, the line separates.
	DR. GRUNDMAN:  I thought it said 6 months there.
	DR. GHALIE:  This is 3 months after one course; this is 6 months after two courses; and after that, the curves do separate, and the patients on placebo get worse, and the patients on Mitoxantrone improve.  So it could be that one needs one or two courses of Mitoxantrone for a population of patients with MS to separate.  For individual patients, some of them may respond sooner; some may not respond.  It is always hard to do on a mean result, but clearly, the curves separate at that point.
	DR. GILMAN:  Dr. Grotta, then Dr. Temple.
	DR. GROTTA:  Notwithstanding some of these confusions we have just been discussing, at least from my perspective, I am becoming convinced that there is some clinical effect here, but I need to come back to the MR data, because that's what you are presenting from the second study as confirmatory evidence, and I'm still not certain about this.
	I am still bothered by the fact that the main outcome you were looking at in the MR studies were gadolinium enhancement, and it bothers me that these patients were getting monthly high‑dose steroids in both groups and that that is not a nonspecific effect.  So I would like to‑‑and this reflects my own ignorance of what is the best thing to follow on MRI, but to me, when you see T2 abnormalities, long‑term differences, that might be somewhat convincing.
	I noticed in Study 901 that while it wasn't significant‑‑this is on your Slide M‑50‑‑there appeared to be some changes in the T2‑weighted lesion load in the first study, 901, and I wondered whether the same thing was looked at in Study 902 and whether any of those were looked at long‑term even beyond the end of the dosing period and whether maybe you even combined the data from Study 901 and Study 902 to increase your numbers.
	DR. GILMAN:  As you point out, in Study 901, we present the T2‑weighted lesion data, and there was at least a trend that one can see.  In the Mitoxantrone group, they were stable, and in placebo, they were worsening.
	I did not present the data for Study 902 because it was not written in the protocol as one of the secondary endpoints.  However, it was done, and the look at the data was available to us.  In fact, it is on Slide B‑129.  This is the data for T2‑weighted lesions, and they are small lesions, and that changed in T2‑weighted lesions at baseline versus Month 6 at the end of the study.  And the lesions were classified as small, moderate, and large in size, and then, the combination of all these lesions.
	If one looks at the change between‑‑we have mean and median shown for you here‑‑in the Mitoxantrone group, for the small lesion, it had increased by 0.6, and for the methylprednisolone, 1.7.
	Now, if one looks at moderate to large lesions, the difference is more significant, and these are the p‑values. 
	Again, those are the data.  I didn't want to present them up front because they were not part of the protocol‑defined criteria, but clearly, that was looked at.
	As far as your first question, or at least the introduction to your question, about the effect of methylprednisolone on MRI results, this is something that I would like to have our consultant comment on, but my first answer to that is that methylprednisolone may have an effect on MRI when it is given immediately before, within maybe a day or two prior to, doing the MRI.  In this study, MRI was done, and then methylprednisolone was given.  Then, the patients were scanned another month later.  So any potential effect of methylprednisolone on MRI is not going to be a month later.
	DR. GROTTA:  I thought that that was what the protocol stated, that if the patients deteriorated or had a relapse during that month, the physician might have given them steroids for symptomatic treatment prior to their coming in for their MRI scan.  I guess I'm just not‑‑maybe it's just me‑‑but I'm just not 100 percent certain that the gadolinium enhancement done monthly was that precise a measure of disease activity.
	DR. GHALIE:  Actually, I would like to follow your reasoning.  Indeed, there are a few patients who may have had methylprednisolone given to them prior to MRI, within a few days, but if you recall the data I presented to you, there were more patients in the methylprednisolone group who had relapse treated with corticosteroid.  So if it is in any way going to impact the study results, it is going to be in favor of methylprednisolone.  Again, this is an observation that one can think of.
	DR. GILMAN:  Dr. Temple, do you still have a question?
	DR. TEMPLE:  Yes.  I just wanted to get back to the dose question.  The second study does, as was pointed out, appear to show a neurologic difference as early as Month 1, and it raises the question of whether there is still more to explore about how best to use this agent.
	You have evidence that you have provided that makes you believe, anyway, that the effect is long‑lasting‑‑that is, even after you stop the drug, you still see improvement relative to the untreated patients even in the year after treatment‑‑now, that's not blinded; leaving aside those reservations.  It really does raise a question of whether a loading dose approach in the long run is better and actually leads to more rapid benefit and perhaps even less toxicity in the long run.  I mean, one doesn't really know until one looks.
	Do you have further studies ongoing of any of these questions, or plans?
	DR. GHALIE:  Allow me to answer your question in two parts.  Number one, on why this schedule was selected, every 3 months, there were a number of rationales.  One of them was that the pilot studies which were done and were published in the early nineties showed that every 3 months works.  And the investigators knew that this was a treatment that eventually had a cumulative dose that you cannot exceed, so they wanted to stretch treatment as much as possible, and every 3 months seemed to work, so it made sense to do it in the Phase III study, and this is the data we have, and we would like, at least for the time being, to consider this as the appropriate dose and schedule for Mitoxantrone.
	Now, to answer your question number two, whether there are currently ongoing studies to evaluate other schedules, Dr. Edan indeed and investigators in France and Italy are currently conducting a study which looks at this induction regimen with Mitoxantrone for six courses, monthly for six courses, and then, either stopping Mitoxantrone and going to Interferon; and the other arm is Interferon alone.
	So in his group‑‑and it just started recently‑‑there were about 25 patients enrolled out of 200‑‑the question of induction regimen will be studied.  
	We are also having requests now from investigators who would like to investigate the role of Mitoxantrone, obviously, as you can imagine.  We have an investigator who is evaluating an induction dose with 12 mg per meter squared every 3 months, going down to 5 mg per meter squared on a different schedule.
	So these are things that we will be looking at in post‑marketing if we are given this opportunity.  But at present, the strongest data is what Dr. Hartung's trial showed on the every‑3‑month schedule.
	Later on, we will get to Dr. Mauch's retrospective analysis and his experience with 500 patients, and as I will describe to you, there is an alternate way that he has given Mitoxantrone that can also tell you about some of these methods one can use.  But again, we would like to focus on our Phase III trial as at least the dose and schedule.
	DR. GILMAN:  Dr. Penn, then Dr. Penix.
	DR. PENN:  I see the other major thing that we are going to be debating is the relationship between our surrogate marker, or so‑called surrogate marker, and clinical progression, and I am wondering whether at this point you might want to speak not with your own data but present something that will either convince us or not convince us that this is a good surrogate.
	DR. GHALIE:  Really, I would like to refer this to the neurologist experts at this table; I would not like to myself get into that debate which, as you may know, is ongoing in the neurology field.
	So I would like perhaps to hear first from Dr. Lublin about how he views the MRI and how can this be viewed as a surrogate marker for pathology of MS, and after that, Dr. Panitch, please, and then Dr. Smith.
	DR. PENN:  It isn't just as a surrogate marker for pathology, which is, of course, very interesting, but also clinical progression.
	DR. GILMAN:  Okay.  Dr. Lublin, please.
	DR. LUBLIN:  Let me start with that issue first, because this is one that has become an issue of great interest for us in the MS community and a source of considerable discussion.  
	My view is that the fairest way to view MRI is that in fact it is reflective of the underlying neuropathology, and that the clinical scales that we use are also reflective of the underlying pathology.  We have had this discourse, because some of the regulations say you have to show clinical benefit and such, and that is of course very important, but some of us have the underlying bias that any changes going on in the brain are bad for you, and that the most reflective measure of those changes, at least demyelinating disease, is the MRI scan.
	Having said that, there are a number of studies which show correlations between, for example, gadolinium‑enhancing lesions early in disease and time to different levels of disability, even in individuals who have not yet made the clinical diagnosis of MS, but with the first symptom, what percentage are going to go on and have it, and that data is not bad.
	There is also in the literature relatively unimpressive correlations between, say, T2 lesion load and levels of disability, and we have been arguing over that as to what that means as well.  But I think again, if one goes back and says, well, it is showing us the underlying neuropathology, that most would agree that growing white spots in your brain are inherently a bad thing, and that is the view we take.
	The other issue, of course‑‑and I'm sure some of your experts here are going to bring this up as well‑‑is each different measure is looking for something different.  So the gadolinium‑enhancing lesions are measuring breakdown of the blood brain barrier.  In MS, that is thought to be the equivalent of inflammatory lesions.
	T2 lesions, which we also have a measure of here, are a measure of a number of things‑‑inflammation, demyelination, astrocytosis, edema‑‑a whole bunch of different things.  So it is a little hard to pin that down.  There are other more recent measures that have come into use but that weren't either available or weren't part of these studies, so they don't give us any added information.
	DR. GILMAN:  Nevertheless the point remains that the location of the multiple sclerosis lesion, the new lesion, is absolutely key with respect to clinical presentation‑‑that is‑‑and Dr. Katz has said this in his narrative‑‑if a lesion happens to cut across the corticospinal fibers someplace, the patient is going to clearly become symptomatic.  Should it be up in the prefrontal region, there may not be a clinical manifestation of that lesion.
	DR. LUBLIN:  There may not be an immediately obvious clinical manifestation of that lesion.  But for example, the best correlate that I know of for white spots presumably representing demyelination in the brain is neuropsychological testing.  So that each one of those is in fact taking its toll; it's a matter of when you are able to measure it with a clinical correlate.
	DR. WEINER:  Let me say a word to your question in terms of how it relates.  We just finished a study that is going to be coming out, and it was NIH contract where we took progressive patients and relapsing remitting patients untreated who were imagined on MRI as many as 22 times over a year; they were analyzed by three‑dimensional imaging and quantitative imaging, both in terms of gadolinium‑enhancing lesions and in terms of T2 volume.  And we do indeed find a correlation between disability as measured by EDSS and Ambulation Index with T2 volume and with disability and relapses as far as gadolinium‑enhancing lesions.
	So I am becoming more and more convinced that the MRI does indeed reflect not only what is going on in the brain but what is happening in terms of disability.  Because there are silent areas of the brain, the R values are not 1; they are somewhat in the middle.  Although we also have positive data, some of it published, some of it we are now putting together, that there are correlations between T2 lesion and volume and cognitive changes by a very sophisticated measure.
	So my own feeling is that indeed the MRI does reflect not only the pathology but clinical manifestations.
	DR. GILMAN:  Dr. Katz, then Dr. Grotta.
	DR. KATZ:  Yes.  An important part of the utility of a surrogate from the point of view of deciding whether or not it is useful for approval of drugs, for example, is not so much only that it correlates with the pathology but that also treatment has the appropriate effect on it and on the clinical outcome of interest.
	So everything we have heard so far about the MRI as a valuable surrogate talks about on treated patients and following them and natural history kind of data.  But what is the data‑‑other than the data we have heard this morning for this drug‑‑that in general, treatment has the effect that you want to the surrogate and also the effect, ultimately, on the clinical benefit of interest?
	DR. PENN:  Well, we are revisiting what we did a number of years ago with the Interferon when we had data on MRI, and it did correlate with progression, as I remember those meetings.  So I think there is substantial data.  And as a neurosurgeon looking at this, I am very glad to see that things are correlating, and they are correlating better when you use the right test‑‑that is, truly volumetric things and take in cognitive impairment, because of course, most of the brain is cognitive, and we are wiping out sections that may not cause obvious neurological symptoms but which are there anyway.
	So the way that I see this discussion going is making this a very powerful surrogate marker, because it is all fitting in the same direction‑‑although we always have to worry about exactly which measures and that it is being done in the same way.  That's why I think the fact that it was read blind in England by somebody who is expert in doing this really gives us some power in this particular case.
	DR. GILMAN:  Dr. Grotta first, then Dr. Wolinsky, then Dr. Temple.
	DR. GROTTA:  This is very useful.  So I am reassured that these MRI measurements among MS experts, both T2 and gadolinium, are now being recognized as reflective of real disease activity.  How dependent is this upon the methodology of carrying out the measurements, and are we convinced that the methodology used in this study is comparative to those carried out in centers like yours, Dr. Weiner, that find these correlations?
	DR. WEINER:  Are you asking me?
	DR. GROTTA:  I am asking whoever knows how‑‑do we need to explore how the measurements were made in London; do they do all the three‑dimensional measures and things like that, and is it possible that‑‑I look at T2‑weighted lesion load, and I see a mean score change of 3 or 4, and I don't know what that means.
	DR. WEINER:  My analysis of the data that is presenting here is that it was done in an appropriate way, with the appropriate measures, et cetera, and is indeed valid in terms of showing changes, both in terms of T2 volume and in terms of gadolinium lesions.
	DR. GILMAN:  Dr. Wolinsky?
	DR. WOLINSKY:  I don't think we can address very easily in this particular meeting the notion of MRI as a surrogate, as I understand the FDA is raising it, and I don't think there is any data here that allows us to look at it as the perfect surrogate.  Certainly, nothing that predicts what these patients are going to do in the future based on what we are seeing across the course of either the short or the longer study.
	But I am very encouraged when I see clinical data and MRI data which  convincingly goes in the same direction.  I would be very bothered by data that goes in opposite directions, and that is the kind of data we are presented today.  So I think as much as I would like to argue for the importance of MRI in other arenas, I think the issues for us today are not technical on how do they read this, not do they show effects in both areas, but how in the world are we supposed to use this.
	DR. GILMAN:  Dr. Temple?
	DR. TEMPLE:  Surrogates are not expected to be perfect substitutes for clinical outcomes‑‑they hardly ever are.  People have written a fair amount about this; we have written only a little bit.
	The initial hope that a surrogate endpoint or putative surrogate might be useful can never be based on correlation with outcome results, because you do not have any outcome results yet.  So in the case you have here, you have only a few drugs that work, and the best you could hope for is a modest degree of association with clinical outcome and the putative surrogate.
	Before one gets to that, however, there is a phase where you look to the available data you have of an epidemiologic nature and see if at least‑‑I think this relates to the last comment‑‑the natural history of the disease seems to serve some correlation with the surrogate and the real outcome.  If it didn't do that, then it wouldn't be a very good candidate surrogate.
	What I think Dr. Weiner was saying is that he feels there is growing evidence at least at that level that there does seem to be a correlation with outcome and the MRI findings.
	The ultimate conclusion that it is a really, really, really solid surrogate sort of depends on looking at a large number of drugs that have effects on both, finding that it always works, showing that patients who have a better response on MRI have a better response clinically, and all kinds of stuff that you can't possibly have yet.
	But I want to emphasize that the Committee is a judging group, not just a data analysis group, and that one of the reason we come to you is for your judgment on the quality of a surrogate like that, even with imperfect information which, heaven knows, is what we have.
	DR. GILMAN:  Are there any other questions from Dr. Ghalie at this point?
	[No response.]
	DR. GILMAN:  If not, Dr. Ghalie, with your consent, I think it would be good for us to have a lunch break, because at one o'clock, we are expecting some patients to be here, and we don't want to keep them waiting.
	Let me ask that the Committee members refrain from any discussion of this agent in any way over lunch.  All of our discussion should be in public.  There is a place reserved in the dining room for Committee members, so please, let's herd together there.
	We'll take a one‑hour break and resume at one o'clock.
	[Whereupon, at 12 o'clock p.m., the proceedings were recessed, to reconvene at  1:10 p.m. this same day.]
‑ ‑ ‑

A F T E R N O O N  S E S S I O N
[1:10 p.m.]
	DR. GILMAN:  We are now going to hear from three people.  The first person who would like to speak is Frank Vanik.
	Mr. Vanik, please.
	MR. VANIK:  Good afternoon.  My name is Frank Vanik, and I am diagnosed with secondary progressive multiple sclerosis.  I live in White Marsh, Maryland, right outside of Baltimore.
	I am here representing the National Multiple Sclerosis Society and the third of a million people it serves annually.
	I am having trouble in that one symptom of my MS is that my vision is kind of blurred, so I am going to just put this statement down and talk to you.
	I have been an athlete all my life.  When I was a senior in college, I noticed that I seemed to step slowly in basketball, and I was tripping a lot over my feet, so I began to worry.  I went first to an orthopedic doctor, and to make a long story short, it took three doctors over two years to get the diagnosis of multiple sclerosis at the age of 22.
	I graduated from Virginia Tech with a degree in mechanical engineering in 1989 and began work as a maintenance foreman at Bethlehem Steel.  About 2 years after I was diagnosed with MS, I started walking with a cane, and I progressed to where I used canadian crutches, and within 4 years of being diagnosed, at the age of 25, I was using a wheelchair most of the time to conserve my energy.
	I had to stop working.  It is kind of tough to work in a steel mill in a wheelchair, so I stopped working there and went on to look for a second career of some sort.
	MS has changed every dynamic of my life.  I tell people off‑handedly that the only part of my life my MS has not affected is my appetite.  You name it, I have experienced it.
	One of the affirming things about living with MS has been that I have found out that I really have a great family.  My father brought me here today, and there is not a day that goes by that one of my sisters or my parents or my friends aren't calling and asking me if there is anything they can do‑‑more times than not, there is, so I am very grateful for that.
	About 5 years ago, I took a part‑time job working for the Maryland Chapter of the MS Society, coordinating recreation and social programs for other people in Maryland with MS.  In addition to that job, that paid employment with the MS Society, I have found a lot of good things to talk about that the MS Society does, and I have kind of found myself appointed as an ambassador of the Maryland Chapter of the MS Society.  I would like to mention here that they have been wonderful for me and I am sure for the rest of the folks living with MS in Maryland.  If the Maryland Chapter is a reflection of how the national organization treats people, then all over the country, we are in pretty good shape.
	One of the things people have asked me about in the past is about my future, and do I want to be a recreation coordinator for the rest of my life, do I want to work part‑time for the rest of my life.  It is clearly difficult for me to answer any questions like that.  It is difficult for anybody‑‑nobody can predict their future‑‑but having multiple sclerosis makes it a little more apparent.  It makes it quicker for you to realize that you cannot predict your future and that it is uncertain.
	I guess that is one of the nice things I have heard about Novantrone‑‑if that is the right pronunciation‑‑and the other thing I should mention is that it seems that my multiple sclerosis has progressed to the secondary progressive stage, and sure, the ABC drugs are wonderful, and my goodness, I hope they work for everybody who is taking them, but the Novantrone, from what I understand, is the first medication that is tailored specifically to people with secondary progressive multiple sclerosis.  And while I hesitate to speak on behalf of other people with multiple sclerosis, I can speak for myself and tell you that if the clinical trials show that it has an impact on people's lives, I just think it is wonderful what you are doing and what Immunex is doing to possibly get this drug cleared to it can be prescribed for everybody living with secondary progressive multiple sclerosis.
	That's about it.  I'd like to thank you for having me here and letting me speak.  I think you all are doing wonderful work.
	Thank you.
	DR. GILMAN:  Mr. Vanik, thank you for coming today.  We greatly appreciate your making the effort to come and talk to us.
	Next, we will hear from Mary Elizabeth McNary.  We have pictures of your two children that we'll pass among the Committee members.
	MS. McNARY:  Thank you.
	I am Mary Elizabeth McNary, and 5 months ago yesterday, I became the proud mother of a pair of beautiful twins, Aidan and Aisling McNary Hickey.  I also work as a counselor at the National Capital Chapter of the National MS Society.
	My career has taken a couple of circuitous turns.  My 1992 diagnosis of relapsing remitting MS, my marriage shortly thereafter to Patrick, who is an international policy analyst with the U.S. General Accounting Office, and our subsequent transfer to Germany have been a couple of the major twists and turns.  
	I have come to believe, however, that everything in life happens for a reason.  Back in 1982, I graduated from Harvard with a specialty in romance languages and literature and Latin American affairs.  I started out in the direction of a law career.  I soon left that path, though, and I worked for several years in the music industry in New York.  I used my knowledge of the law to advocate for copyright protection as a grassroots organizer in the creative community.  
	That experience took me to Washington where I accepted a position with Senator Chris Dodd of Connecticut.  I wanted to develop an understanding of effective lobbying while working from the inside on the Hill. 
	It was here in Washington that I first met Patrick, to whom I remain happily, happily married despite anything that MS has thrown my way.
	As a newlywed in Germany, I used to keep the multiple sclerosis a deep, dark secret.  But after about a year of silence, I decided to use my own experience with chronic illness to help other people, and I began studying for a master's degree in counseling.
	Then, when Patrick and I returned to the States, I accepted a scholarship to study rehabilitation counseling at the University of Maryland.  Upon graduation, I was required to work at a nonprofit organization‑‑so what better choice than the MS Society.  My work with the Society allows me to provide both information and empathetic understanding to others with MS.  I will soon be using my knowledge of foreign languages and law and Latin America to create an outreach program at our local chapter for the Hispanic community, many of whom don't know anything about MS and don't discover anything about it until it hits them, and they read our Spanish language brochures about it.
	I have learned to live with the unpredictable symptoms of my MS, where one day fatigue can make me feel like the only thing running through my veins is water, and the next day, perhaps I can't walk a straight line unless someone offers me his or her arm.  My vision problems make it impossible for me to drive a car; I most likely wouldn't be here today if Patrick hadn't been kind enough to bring me.
	All these symptoms are really frustrating, and they are also hard to explain because I don't really look any different from anybody else.  But what fills me with dread is that I have had a relapsing remitting form of MS for some 10 years now, and that makes me a prime candidate for developing secondary progressive MS.
	Half of all the people who are diagnosed with relapsing remitting disease see their MS turn into secondary progress within 10 years, and of these people, nearly 50 percent will require a walking aid, and 10 percent will need a wheelchair within 5 years.  If my own MS becomes secondary progressive disease, I want to have a treatment available to me.  My babies and my husband need me too much for me to allow this disease to progress untreated.
	Therefore, if the panel believes that the results presented here today support the reported claims that Novantrone can affect underlying disease process in MS for those with secondary progress disease, I encourage‑‑no‑‑I implore the FDA to approve this product with all due dispatch.
	Thank you.
	DR. GILMAN:  Thank you very much, Ms. McNary.
	Is Pat Redondo here?
	MS. REDONDO:  I am so sorry I am late.  We lost the directions.
	My name is Patricia Redondo, and I have been diagnosed with secondary progress multiple sclerosis.  I want to give you a little bit of background on myself.  
	I was diagnosed in 1972.  When I was diagnosed, I had just met my future husband, and we had just bought a house.  We decided, since we were both 28, that we wanted to start a family right away.  In 9 months minus a day, we had our second child.
	Everything was going along great.  I was a program coordinator at the University of Maryland Department of Pediatrics Hospital, and I was in the residency program.  I did the work to make sure that the house staff were running smoothly.  I helped coordinate their beginning and followed them all the way through their third and fourth years.  I helped test them and made sure they were on the right track‑‑I was a proctor‑‑and at the end of their 3 or 4 years‑‑those in the fourth year were usually those people who were chief residents‑‑I filled out the paperwork that qualified them to become certified in pediatrics.  I did that through the dean's office in the School of Medicine, and through that, they went out into the world.
	After about 10 years of working after my diagnosis, I was stricken with what the doctors said was just hip pain.  After a year of living with "just hip pain," I was referred to an orthopedist, and the orthopedist diagnosed me, after x‑rays and so on, with vascular necrosis.  He decided to operate on me, and what he did was pulled blood out of my hip bone, and he decided one of two things‑‑that it was either a success, and I would revascularize on my own; or, two, it would give me the sponge that I needed to walk comfortably.
	I was successfully operated on, and everything went well until I got back to work, and my multiple sclerosis decided to go from relapsing remitting into secondary  progressive multiple sclerosis.  So that happened, and over the course of the next 10 or 15 years, my disease progressed slowly.  Now, I am basically paraplegic from my waist down and almost quadriplegic in that I can't use my left hand and arm; I can barely use my right hand; I can use my computer with two fingers.  It is really not a pleasant situation to be in.
	As you can tell by my speech, I am also suffering from cognitive impairment in that I can see my notes, I can see what I want to say, but I can't get it out.
	I am here to represent what relapsing remitting MS can do to people.  There are 300,000 people in the system at the Multiple Sclerosis Society, and somewhere along the line, probably in about 10 years after there diagnosis, there is a good chance that they are going to go into secondary progressive multiple sclerosis, which is what I am in  now.
	If you can speed up the process of getting this drug on the market so that the people who are yet to go into the relapsing remitting stage can have this drug available to them, they will not have to face what I am facing now.  I have made a good life for myself.  I have volunteered very much.  I have a supportive husband.  He is a saint.  My mother says his halo kind of slips because his head must be so heavy.  I also have two children who are great and supportive of me, and I also have an aide.  I now have to be dressed, I have to be bathed, my hair has to be washed.  Fifty percent of the time, somebody has to feed me.  I cannot write.  I can work on the computer, which is fun. I  can still read, and I can still watch television.
	But you know, there is a better life out there for people who are struggling with this disease.  It is hard enough as it is, but when people go into secondary stages of progressive multiple sclerosis, and you can help them with this new drug, you will be saving so much misery.
	I have a good husband, I have good kids, I have support all around me‑‑but is that really all there is?  I'm sure not.
	So I just want you to consider putting this drug on the fast track.  Thank you.
	DR. GILMAN:  Thank you, Ms. Redondo, very much.
	I'll ask the panel if there are any questions.
	[No response.]
	DR. GILMAN:  Thank you all again.
	Now, Dr. Ghalie, can we resume where we left off? 
	Let me first ask if the panel has any questions about the efficacy of 901 or 902 before we move on to safety.
	[No response.]
	DR. GILMAN:  All right, then, perhaps we can take up where we left off, then.
	DR. GHALIE:  I would like to add a personal note here that is not scripted and has nothing to do with the presentation.
	I would like to salute the patients who have presented to us today.  I admire your courage in the face of adversity; it is an inspiration for me.  So I thank you.
	I would now like to review a little bit where we left off before lunch, which is the efficacy results, just to put together what I presented to you this morning.
	We had presented to you two studies, two randomized trials, that were well‑conducted‑‑Study 901, a large, Phase III randomized trial which has as its primary endpoint clinical endpoints.  These endpoints were met.  There were also MRI results in this study, and they went in the same direction as the clinical endpoints.
	There was also another study which we presented to you, Study 902, which is a study typical of MRI‑based clinical trials.  Its primary MRI endpoints were met.  The clinical results also went in the same direction, and we would like you to keep this in mind as you do your deliberations later.
	[Slide.]
	This slide is in fact at the back of your package, so you may not be able to find it.
	I will now move on to talk about safety.
	[Slide.]
	The safety information I will present to you today is based on three sets of data‑‑the two randomized trials I presented to you earlier, and then a single‑center retrospective analysis.  Altogether, this represents data on 603 patients treated with Mitoxantrone.
	Let's begin with Study 901.  In Study 901, treatment discontinuation due to an adverse event was reported in five patients randomized to Mitoxantrone 12 mg per meter squared, no patients randomized to 5 mg per meter squared, and two patients randomized to placebo.  On the slide, you have the month of withdrawal and the reason for withdrawal.
	[Slide.]
	The next slide demonstrates and describes to you the adverse clinical events that were significantly more frequently observed in the two Mitoxantrone arms compared to the controlled group, the placebo group, with p less than 0.05.  Except for nausea, which was graded as Grade 3 or 4 in 5 percent of these patients, all the other adverse events in the remaining nausea patients had adverse events graded as Grade 1 or 2.
	[Slide.]
	This next slide, which is a busy slide that you also have in the briefing document, now describes all adverse events that were recorded in 10 percent or more of the patients who were randomized in this study.  Here again, most of the adverse events were graded as mild or moderate.
	Now, as you have heard before, Mitoxantrone belongs to a class of agents known to have cardiac toxicity that is related to cumulative dose.  As a result, the effect of treatment on the heart was evaluated carefully, with clinical evaluation and electrocardiograms performed on an every‑3‑month basis and echochardiograms that were performed at baseline, end of Year 1, end of Year 2, and end of Year 3.
	I will present to you some of these results now.
	No patients who were randomized on this study developed congestive heart failure.
	[Slide.]
	This slide shows the distribution of LVEF, or left ventricular ejection fraction, which I will call LVEF from now on, that was equal to or below 50 percent in the three groups at the end of Year 1, end of Year 2, and end of Year 3.  As you can see, there was no significant difference between the three groups based on this factor.
	Now, as you may know, an LVEF of 50 percent, just to clarify what it is, does not represent 50 percent of normal.  It says 50 percent of the blood volume that is ejected during cystoly [ph.].  Cardiologists consider an LVEF of less than 50 percent as indicative of decreased myocardial function.
	[Slide.]
	This is the third year follow‑up for those patients who had discontinued treatment at Month 24 and then had LVEF data available at Month 36.  There were two patients, one in each of the two Mitoxantrone groups, whose LVEF was above 50 percent at Month 24 and declined to less than 50 percent at Month 36.
	There was one patient in the Mitoxantrone 5 mg per meter squared group whose LVEF was less than 50 percent at Month 24, and then, at the Month 36 evaluation went over 50 percent.
	[Slide.]
	Additional safety information‑‑there were no deaths on study for the 2 years of treatment, and in fact, for the 36‑month period.  Two pregnancies were reported on study, although women of child‑bearing age were requested to take appropriate contraception precautions.  One patient randomized to placebo elected to terminate her pregnancy.  One patient randomized to Mitoxantrone 12 mg per meter squared was found to be pregnant during the third course of Mitoxantrone therapy.  She discontinued study treatment and had a normal child delivered.
	[Slide.]
	This slide presents the number of patients with hematologic parameters who were below normal at any time during the 2 years of treatment for the three groups.  As you can see, there were no meaningful differences in the number of patients with low platelets or low hemoglobin in the three groups, and there were no transfusions required in the study.
	Looking at leukocyte count, there were five patients, 15 patients, and 20 patients with low leukocyte count in the three groups respectively.  Now, I must mention right now that leukocyte count decrease in the use of Mitoxantrone is usually transient and reversible.  I would also like to add right now that there were no cases of neutropenic fever detected in the study, and there were no differences in these three groups for hospitalization for severe infection.
	[Slide.]
	Continuing to laboratory results, this slide represents serum chemistries that were above normal at any time in the tour of study between the three groups.  And as you may see again, there were no meaningful differences among the three groups, and here again, most of the adverse events reported were Grade 1 or 2, and they were reversible.
	[Slide.]
	I will now move to the safety results of Study 902, in which you will recall Mitoxantrone was given on a monthly basis for six courses.
	Overall, the type and frequency of adverse events reported in Study 902 were similar to that reported in Study 901 that I presented to you, and they were presented to you in the briefing document.  Adverse events were usually graded as mild or moderate in intensity.  There were three adverse events graded as severe, and they are listed here.  There was one case of amenorrhea, one case of depression with anorexia, and there was one case, called severe, of intolerance to contact lenses.  There were no deaths on study, and there was no clinical cardiotoxicity reported.
	In this study, echocardiograms were performed at baseline at Month 6, and the electrocardiogram and clinical evaluation were done monthly.
	DR. PENN:  I'm sorry.  I'm a little confused as to why contact lens intolerance is a severe reaction.  Didn't you use a standard protocol‑‑
	DR. GHALIE:  The rating for the severity of adverse events in the study followed the WHO criteria, which rates from mild to severe, Grades 0 to 4.  The investigators decided to call this adverse event as severe.  We don't know.  In fact, I agree with you‑‑I can't imagine how severe that can be, but‑‑
	DR. PENN:  I mean, you could buy them a pair of glasses.
	DR. GILMAN:  Dr. Temple, then Dr. Katz.
	DR. TEMPLE:  In ADR land, there is a distinction between a serious reaction, which is life‑threatening or something like that, and a reaction that is not dangerous to you, like nausea, which could be mild, moderate or severe.  So this was a severe reaction of this kind.  It didn't threaten lives, but that would be called severe, that sort of standard.
	DR. GHALIE:  This slide shows the percent of patients with Grade 3 or 4 hematologic toxicity using the NCI criteria, Grade 3 or 5 meaning the more severe hematologic toxicity, which you may have interest in knowing.
	[Slide.]
	DR. GHALIE:  In this study, as you may know, hemograms were performed weekly on the Mitoxantrone group for the 6 months of treatment.  With monthly courses of Mitoxantrone 48 percent of the patients experienced Grade 3 or 4 leukopenia at any time during the 6 months of treatment.  That does not mean it occurred with every course, but at any time, they may have had a Grade 3 or 4 leukopenia.
	Leukopenia usually occurred during the first or the second course after Mitoxantrone administration and tended to result by day 21 after Mitoxantrone administration.
	As with Study 901, there were no meaningful differences in serum chemistries between the two groups, and I am not presenting this today, but again, it is in the briefing document.
	[Slide.]
	To provide additional long‑term safety information on the use of Mitoxantrone in patients with multiple sclerosis, we retrospectively collected data from a single MS center where Mitoxantrone was used extensively over the last 10 years.  This study, designated 903, took place at the Academic Clinic of Ulm University in Germany under the direction of Professor Mauch, who is here.
	This retrospective analysis involved every patient who had received at least one dose of Mitoxantrone in the clinic during the period of November 1998 and September 1998.  Four hundred fifty‑four patients treated with Mitoxantrone were identified.  These patients were not enrolled in clinical trials.  They received Mitoxantrone as part of the standard of care at this clinic.  We did not exclude any patients from this analysis.
	[Slide.]
	A staff that was hired specifically to do the data collection used specifically designed case record forms to collect specific data on safety and efficacy.  An effort was made to collect the most recent forms possible from patients who were not actively followed in the clinic.
	Information on treatments given off‑site during this 10‑year period was not collected for this retrospective analysis.  Dr. Mauch reviewed each and every one of these case record forms for accuracy.
	[Slide.]
	In this clinic, Mitoxantrone was usually started at a dose of 12 mg per meter squared and given every 3 months, and that is based, again, on the pilot study published by Dr. Mauch in the early nineties.  The dose and the interval between courses were then adjusted in certain patients as needed to take into account hematologic tolerance, adverse events, and also treatment effects.
	Treatment was usually discontinued in patients who did not tolerate therapy, in patients who achieved a good MS response and one who stopped treatment, or in women who wanted to become pregnant, and obviously, in patients who elected not to continue treatment.
	[Slide.]
	Patient demographics are shown on this slide.  Mean EDSS for that study was 5.1, which is higher than I have shown in the two randomized trials.  In fact, some patients had baseline EDSS of 8 and 9.
	Mean follow‑up from the first dose to the last contact was 47 months, which is nearly 4 years.  Overall, 80 of the 454 patients, which represent 18 percent of the patients, had received six, seven, or eight courses of Mitoxantrone in the study.  In addition, 49 patients received more than eight courses.  The reason I mention six to eight courses is because that was the range that was studied in the two randomized trials.
	[Slide.]
	No death reported in this series was temporally related to Mitoxantrone administration.  Twenty patients, or 4 percent of the 454 patients, died.  The causes are listed here and are the typical causes of death in patients with advanced multiple sclerosis.
	I would now like to discuss two specific deaths, the two patients who died from heart failure, knowing your interest in knowing more about that adverse event.
	One patient of these two patients who died from heart failure received a single dose at the clinic and then stopped treatment.  This patient then died at least 4 years after receiving this single dose of Mitoxantrone.  It is unlikely that this single dose of Mitoxantrone was responsible for this heart failure.
	The other patient who died from heart failure had received 90 mg per meter squared of Mitoxantrone in the clinic and then went to his treating physician, and the treating physician near home continued Mitoxantrone administration for additional courses.  This patient died later from heart failure.  The contribution of Mitoxantrone to this heart failure and death cannot be ruled out.
	DR. GILMAN:  In that case, do you know the total dose that was administered?  It is not in the narrative that I saw.
	DR. GHALIE:  No, because we were unable to collect data on treatment given off‑site.  We do not know how many more courses of Mitoxantrone were given to that specific patient.  Dr. Mauch intentionally tried to determine that information by calling either the physician treating the patient or the patients themselves to collect that information, and for that specific patient, that information was not available.  The family said the patient had multiple courses, but no number could be assigned.
	DR. GILMAN:  Are you going to talk about the infections?
	DR. GHALIE:  Certainly.
	[Slide.]
	Four pregnancies began during Mitoxantrone administration, and five others occurred after the patients started Mitoxantrone with the intent of becoming pregnant.  Of these nine pregnancies, six resulted in the birth of a normal child, one was ongoing at the time of data collection, which was a few months ago, and the outcome of the remaining two pregnancies was not available to us for collection.
	[Slide.]
	Patients underwent cardiac monitoring as expected.  An echocardiogram was usually performed when the Mitoxantrone dose reached about 100 mg per meter squared.  In addition, patients had additional echocardiograms performed if there was any evidence of signs or symptoms that could be suggestive of cardiac failure.  At that time, Dr. Mauch had a consultation with a cardiologist who worked with the clinic, and echocardiograms were performed and evaluated.
	A cardiac event that was considered clinically significant by Dr. Mauch in his retrospective analysis was identified in seven patients shown here.  Five patients had decreased LVEF of various degrees, and Mitoxantrone cannot be ruled out as the cause of this decreased LVEF.  One other patient had mitral valve insufficiency, and it is unlikely based on what we know from Mitoxantrone in cancer patients that it is due to Mitoxantrone.  And one last patient had tachycardia during administration of the first course of chemotherapy with Mitoxantrone.  This patient did not continue Mitoxantrone, and again, it is unlikely that Mitoxantrone was the cause of this event.
	Additional information is obviously available to us based on the large experience with the use of Mitoxantrone in cancer patients.  The information I present to you is available to us based on reviewing Immunex databases, Lederle databases‑‑Lederle was the company that developed this product years ago‑‑and also, publications available in the literature, including the experience of oncology cooperative groups.  We also know that the FDA briefing document has an extensive description of this information that is available.
	In summary, I can tell you that with a cumulative dose of 140 mg per meter squared, the incidence of congestive heart failure is equal to 2.6 percent, and the incidence of moderate to severe decreased LVEF is 13 percent.  That is in patients who have received Mitoxantrone either alone or in combination with other agents who may have received chemotherapy prior to receiving Mitoxantrone or who may have received chest radiation‑‑and that also includes an age group that goes anywhere from children to older patients.
	DR. GILMAN:  Dr. Swain?
	DR. SWAIN:  I had a question regarding where you got this database.  Was this reporting in CHFs [ph.], or is it from trials that you have completed?
	DR. GHALIE:  This is really a compilation of different databases which are also listed in the briefing document.  There are really three large publications that were published, by Dukart [ph.], Posner [ph.], and by the Schwab [ph.] Group.  They included anywhere between 700 and over 3,000 patients.  Those are a compilation of patients enrolled in clinical trials as well as a postmarketing report.  These publications were done early after Mitoxantrone was put on the market, and that is really where the aggregate of this information is available.  And pretty much nothing new that we know of Mitoxantrone in the last 10 years has changed what we know from that information.
	DR. SWAIN:  So you have data from case report forms asking specifically about congestive heart failure; this is not a retrospective review of patients‑‑is that correct?
	DR. GHALIE:  What we have in our record at Immunex will be database from patients who enrolled  in the two pivotal trials that led to the approval of Novantrone for leukemia and prostate cancer.  There is also the experience with breast cancer that was collected in the eighties, and as I mentioned, there are all the postmarketing safety reports that were submitted to Immunex over the last few years.
	DR. SWAIN:  I guess I'm just making the point, is this under‑reporting‑‑because I know that if you look at doxorubicin, you will actually see more, if you look very, very carefully, than what is reported in the literature.
	DR. GHALIE:  This information I present to you here is really what is in the Novantrone/Mitoxantrone package insert, and that was established early on when the drug was approved, which was based mostly on the randomized trials that were available at that time for approval.
	[Slide.]
	In conclusion, the three studies in Mitoxantrone in multiple sclerosis showed the following.  Most adverse events are mild to moderate.  They are manageable and reversible.  No congestive heart failure was reported for a cumulative dose up to 100 mg per meter squared in the two randomized trial control data we have presented to you today.  Marrow suppression is reversible within one to 3 weeks after chemotherapy administration, and it is not associated with an increased incidence of severe infection.
	Furthermore, the Month 36 evaluation from Study 901 and the long‑term safety database from Professor Mauch indicate that no unexpected late adverse event occurred after Mitoxantrone administration in patients with multiple sclerosis.  In addition, there was no secondary leukemia or myelodysplasia reported in these long‑term patients.
	I would now like to turn to a benefit and risk assessment‑‑
	DR. GILMAN:  If I could interrupt before you go on, just to ask two questions.  One, Dr. Kawas has reminded me that on page 28 of the FDA Safety Review, there is a paragraph about Subject 281, a 42‑year‑old male MS patient treated in the clinic with Mitoxantrone, cumulative dose 155 mg over a 2‑year period.  The patient's family doctor gave an additional 120 mg over a 2‑year period.  Two months after his last dose, he was admitted for cariogenic shock and died of cardiac insufficiency.
	That's a huge dose, 275 total.  Is this the patient that you referred to earlier?
	DR. GHALIE:  Yes.
	DR. GILMAN:  So we do know the dose, in fact.
	DR. GHALIE:  We do know; I had forgotten.
	DR. GILMAN:  Good.  Okay, thank you.
	Also, I wanted to ask you about infections.  Again, the same narrative page 27 of the FDA's Evaluation of Safety, at the bottom of the page, it says "The sponsor reported that 38 percent, or 171 of the patients in the cohort, had a recognized infection during the observation period.  Eighty‑six percent of these were classified as urinary tract infections, 2 percent upper respiratory, fewer than 1 percent sinusitis, 12 percent unknown.  The sponsor did not report the severity at outcome of the infections and did not state which of these occurred in the setting of decreased white blood cell counts."
	That was my question.  Do you know the severity of these infections; do you know the outcomes of them; and do you know whether they were post administration of drug, and if so, what were the white blood cell counts associated with them?
	DR. GHALIE:  Yes.  You are referring to Slide C‑52, where most of the adverse events in fact called infection adverse events were urinary tract infections and upper respiratory infections.  We did not collect in the case record form that have designed to collect in this study if there was a relationship between the episode of infection and if the patient was neutropening [ph.] at that time.
	Maybe Dr. Mauch, who reviewed all of these case record forms, could comment on that, please.
	DR. MAUCH:  Most of our patients had urinary tract infections, and they were completely reversible and had no influence on further disability of patients, and there was no reason to stop treatment.
	Also, we collected at every contact the patient had with the clinic the leukocyte counts.  I think these data are not available, but sometimes, we could see that we had high leukocyte counts without further information as to what kind of infection it was.  That was the majority of these 40 patients with unknown infections.
	DR. GILMAN:  So if I understand what you just said, the severity was such that the urinary tract infections responded quickly to treatment; is that correct?
	DR. MAUCH:  Yes.  They were treated with antibiotics after we had tested the urine, and they recovered completely from these infections.
	DR. GILMAN:  And you do not know their white blood cell counts at the time of the infection?
	DR. MAUCH:  Yes, we do‑‑
	DR. GILMAN:  You do know?
	DR. MAUCH:  We do know.
	DR. GILMAN:  But you have not analyzed the data.
	DR. MAUCH:  We have not, I think, in the plan to present, but we have in our data also the leukocyte counts.
	DR. GILMAN:  Can you tell us anything about it?  Was the leukocyte count down in most of these patients who had urinary tract infections?
	DR. MAUCH:  No.  In many patients, the leukocyte count was increased.
	DR. GILMAN:  Increased‑‑you mean within normal limits?
	DR. MAUCH:  Yes.
	DR. GILMAN:  Can you tell us about the length of time between the last treatment and the occurrence of the urinary tract infection?  Were these often soon after treatment?
	DR. MAUCH:  I looked through all the data we presented, and it was my impression that we had frequent urinary tract infection in highly disabled patients, and in my impression as a treating physician, the percentage of urinary tract infections did not differ from our treated patients to patients treated only symptomatically for their MS.
	DR. GILMAN:  That is helpful.  And of course, people who were impaired with mobility and so on do develop such infections.
	DR. MAUCH:  Yes.
	DR. GILMAN:  The question is whether there is any relationship between the treatment and the onset of the urinary tract infection, the timing.
	DR. MAUCH:  Yes.  There was more relationship between immobility than with therapy.
	DR. GILMAN:  Dr. Grundman?
	DR. GRUNDMAN:  Again, I think there was almost a threefold increase in the frequency of urinary tract infections among patients treated with Novantrone compared to the placebo patients, so wouldn't that prima facie be evidence for an association of the urinary tract infection with the drug treatment?
	DR. GILMAN:  That would be the impression, but we are not hearing that.  I am not sure I am getting the question directly answered, though.
	DR. KATZ:  There are no placebo patients in this cohort.
	DR. GILMAN:  No.
	DR. GRUNDMAN:  I'm sorry.  I was referring to page 49 in Study 901, which‑‑
	DR. GILMAN:  This is retrospective data on treated patients.
	DR. GRUNDMAN:  Yes, but in their actual study that they presented prospectively, there was a threefold increase in UTIs among the treated patients.
	DR. GHALIE:  This is something that indeed we have looked at and have presented the data.  The cause of that is at present undetermined.  Whether that can be due in part because patients had a dip in leukocyte account and therefore had maybe a higher incidence of UTI, or the physicians being unblinded were more susceptible to that and more frequently likely to report this as a UTI than patients who were not.  At present, I don't know what is the interpretation for that observation.
	DR. GILMAN:  Dr. Swain?
	DR. SWAIN:  I just have to comment that even though your percent of leukopenia in that 01 study was only 20 percent or something like that, you did not mention nadir count, which you normally do in oncology.  It's probably much, much higher than that.  In your second study it was extremely high; it was 86 percent.  I really find it hard to believe that you had no reports of febrile neutropenia.
	DR. GHALIE:  I will describe to you how Study 901 was designed and what was asked to be done and where the data was obtained, and then I will move to Study 902.
	For Study 901, as you mentioned, there was a CBC that was required before each course of therapy.  In addition‑‑and the protocol was very clear about it‑‑there was a requirement to do a CBC at the time of the expected leukocyte nadir‑‑in fact, the treating physicians, as you know, were unmasked, so they knew when the expected leukocyte nadir was‑‑to do repeated CBC in a patient who may have an episode of infection or something that would be suggestive of infection.  So even though it was not required to do at Day 14 or 20‑‑and again, those are masked patients that go back home, and they are not necessarily actively seen as oncology patients every 3 to 4 weeks‑‑so that incidence that we show is for those patients who had a CBC done either every 3 months or at the exact time of neutropenia nadir if they had any episode that was suggestive of infection.
	In Study 902, indeed, Mitoxantrone was given on a monthly basis more as when it is used in cancer patients, and indeed, the incidence of neutropenia was higher in this study than in Study 901.
	DR. SWAIN:  In Study 902, were those patients also followed by their local physicians?  Are we missing data here, because I just cannot believe there is no febrile neutropenia.
	DR. GHALIE:  For Study 902, because the treatments were given on a monthly basis, they were also closer to the site where the treatment was given. Most of the patients came back to that specific clinic to be followed.
	I know that Dr. Alberts has a comment here.  Dr. Alberts?
	DR. ALBERTS:  I just wanted to comment that Mitoxantrone came on the market in oncology as the safest drug that we have seen, and I think the reason is that as a single agent, at 12 mg per meter squared, even though you get a nadir, and you can get a very significantly lowered nadir, these nadirs usually last 3 or 4 days at the most.  So febrile neutropenia is an extremely rare event, at least in the cancer patient.
	DR. GILMAN:  Dr. Wolinsky?
	DR. WOLINSKY:  If I read it correctly, in the SNS that was done in Study 901 and not in the other studies, one of the scoring systems talked about residual urine volumes.  Were those measured by ultrasound, or were they by catheterization, and did manipulation have anything to do with the UTIs in that patient population?
	DR. GHALIE:  I would like to invite Dr. Hartung to answer that question, please.
	DR. HARTUNG:  This was done by ultrasound measurement.
	DR. GHALIE:  I understand your concern as a committee about potential infection in patients with multiple sclerosis and receiving Mitoxantrone, so I would like to ask for Slide C‑16, which looked at the randomized Phase III study, which looked at the three groups‑‑placebo, Mitoxantrone 5 and 12 mg per meter squared.
	[Slide.]
	DR. GHALIE:  We have here the two events that are of interest‑‑what happens when the leukocyte count goes down, infection, and potential for bleeding.  As you can see, the percent of infection in the three groups‑‑and that includes any type of infection‑‑really is reasonably similar among the three groups.
	If we look at severe infections or infections that led to hospitalization‑‑and again, it is unlikely that this is going to be underreported when there is a hospitalization‑‑and you look at the difference among the three groups, it is really minor.  And if you can read the little font at the bottom, that tells you what was the reason for hospitalization for each one of these patients‑‑tonsillitis, and for the 12 mg per meter squared group, which is the higher dose of Mitoxantrone, one case of tonsillitis, two cases of urinary tract infection, one case of endometritis.
	We looked very carefully at all the patients enrolled in this study to see if there was any episode of neutropenic fever, what oncologists call neutropenic fever, meaning low white cell count, less than 1,000 or 500, and a systemic infection.  There was no report in this study of any patient who had neutropenic fever.
	It is very likely that the every‑3‑month schedule is different than the every‑3‑week schedule as far as patients' tolerance to infection.
	DR. GILMAN:  Dr. Swain has another question.
	DR. SWAIN:  Yes, I have a couple more safety questions.  In the FDA review, there was a report of six patients who had hyperbilirubinemia.  Can you just comment on that, because I know that Mitoxantrone concentrates quite a bit in the liver.
	DR. GHALIE:  Yes, you are indeed very right, Dr. Swain.  Mitoxantrone is metabolized in part in the liver.  And as you also know, the package insert says that patients who have severe liver impairment should not receive Mitoxantrone, or should at least receive a lower dose.
	Patients who had increased bilirubin were all Grade 1 or 2.  In fact, I can bring up the slide that shows the chemistries of Grades 3/4 in Study 902, which is Slide C‑37.
	[Slide.]
	DR. GHALIE:  These are really the Grades 3/4.  That is using the WHO, which is similar to NIH criteria.  Really, there was one patient who had SGOT increase in each of the two Mitoxantrone arms; no patient who got 3/4 bilirubin.  They were mostly Grades 1 and 2, and they eventually came down.
	There was one patient in fact in the placebo who had Grade 3, but that was colithiasis [ph.].
	DR. SWAIN:  So you don't think that the cases reported‑‑I don't remember where they were in the FDA review‑‑were related to drug, that hyperbilirubinemia?
	DR. GHALIE:  They were not reported in the case record form as drug‑related.  They may have occurred at different time points during the 3 months between courses.
	DR. SWAIN:  Then, my last question is on the issue of amenorrhea.  I think 63 percent of the patients had amenorrhea.  In those situations, how often was it reversible, since you did follow patients for a year later?
	DR. GHALIE:  I believe we have the month 36 follow‑up for the menstruation data on Slide C‑40.
	[Slide.]
	DR. GHALIE:  That will give you an idea one year after stopping treatment what was observed.  In the three groups‑‑and these are obviously women; that's why the number decreased from what we had for total population‑‑patients with regular menses‑‑and that is percent of patients‑‑29 percent of the women had normal menses at Month 36, and 54 percent of the placebos.  So clearly, there are some patients who at least a year later had not recovered their menses.  Again, this patient population ranged from 18 to 55; some women were in the stage where they were becoming menopausal.  There was irregular menses quite similar between the two groups; amenorrhea higher‑‑that really compliments the first finding.  Some patients, we had no data available for, and "Other" meaning mostly dysmenorrhea or some other change in cycle length.
	DR. SWAIN:  Thank you.
	DR. GILMAN:  What does "Other" mean at the bottom of that slide?
	DR. GHALIE:  That's what I was saying.  Those are probably dysmenorrhea patients or patients whose cycle was not the regular cycle that you would expect.
	DR. GILMAN:  Dr. Kawas?
	DR. KAWAS:  Just now and also in your text, on more than one occasion you made the comment that it might be that these women were supposed to be already perimenopausal.  Is that because there was an age effect to the amenorrhea, or is there any data to support that?  Is it just that women who were going to be perimenopausal in the next few years might have been hastened, or are these 20‑year‑olds who are amenorrheic a year later?
	DR. GHALIE:  There are young women who can become amenorrheic with Mitoxantrone, but in general‑‑and that is in chemotherapy experience, but certainly with Mitoxantrone‑‑the older the woman, the more likely that if she receives Mitoxantrone, particularly if she is close to menopause, it may accelerate her menopause.
	DR. KAWAS:  And that was also the experience in the study, that it was the older women who were more likely to be amenorrheic?
	DR. GHALIE:  I have to say I have not analyzed data looking age and what happened with amenorrhea.  
	Dr. Hartung, do you have any additional information to add here?
	DR. HARTUNG:  No.
	DR. GHALIE:  No.  We haven't looked at this specifically.
	DR. KAWAS:  Thank you.
	DR. GILMAN:  Dr. Weiner?
	DR. WEINER:  I had a question in terms of the alopecia.  How severe was the alopecia in the patients that you treated?
	DR. GHALIE:  As I mentioned earlier, all adverse events that were reported in the study, more common in the Mitoxantrone group, which includes amenorrhea, were graded as Grades 1 or 2.  So in fact when we see amenorrhea in patients receiving Mitoxantrone as a single agent, it is more of hair thinning as opposed to hair loss‑‑alopecia‑‑I am sorry.  I will repeat my sentence.  When we see alopecia in patients receiving Mitoxantrone, single agent, particularly when it is given every 3 months, it was mostly hair thinning as opposed to complete hair loss.
	And if you like, Drs. Hartung and Mauch, who have seen many patients treated like this‑‑do you have anything else to add to that?
	DR. HARTUNG:  Well, it is my experience that as a physician, I am in most instances unable to detect, being a neurologist and not a dermatologist, alopecia.  I have to rely on the patients' recollection of their hair becoming thinner, but I haven't seen any patchy alopecia or any diffuse, massive alopecia.
	DR. GILMAN:  Dr. Grundman?
	DR. GRUNDMAN:  On page 30 of the Immunex document, there is a table which lists the hospitalizations and quality of life.  It seems that as far as the patients who were hospitalized, the most patients hospitalized were in the placebo group with corresponding decreases as you go to the 5 mg and 12 mg dose.  But the duration of the hospitalization remained stable, or actually, in the case of the 5 mg dose, increased to 49 days.  I recognize that the p‑value was not significant, but the suggestion is that perhaps the people who are admitted to the hospital have somewhat longer stays for the people in the Mitoxantrone groups.
	And there is a footnote which says that many of the hospitalizations were for rehabilitation.  So I wonder if you were able to break these up into hospitalizations that were due to adverse events or side effects to determine whether or not there was a longer hospitalization stay for the Mitoxantrone groups due to adverse events.
	DR. GHALIE:  I would like to have Slide B‑109, which in fact allows all of us now to see that data.
	[Slide.]
	DR. GHALIE:  One difference in the management of MS patients between Europe and the U.S.‑‑and that was really the only one I noticed from reading all the data and talking to experts in the field‑‑is in the hospitalization of patients.
	In Europe, patients are hospitalized to treat any complications of MS and for rehabilitation.  So when you see duration of hospitalization which goes from 15, 20, 30 days, the bulk of that is really to rehabilitate the patient.
	Now, if you look at number of patients hospitalized in the three groups, it was higher in placebo compared to Mitoxantrone.  IF you look at the number of hospitalizations, it was higher.  And the mean days, as I mentioned, are really very likely here driven by the rehabilitation.
	As I mentioned, and I showed you in the prior slide which was also Study 901, the number of hospitalizations for severe infection was very low‑‑in fact, four, two, and one‑‑so this certainly does not drive that duration.  And really, most of the hospitalizations, as you can see, were MS‑related, 81 of 89, 64 of 85, and 34 of 50.
	DR. GRUNDMAN:  The piece that I was looking for is actually not on the slide, which is the hospitalizations that were due to other causes and their mean duration in the non‑MS.
	DR. GHALIE:  Unfortunately, I have to see the document‑‑unless someone who has the document can answer.
	MS. HAYES:  I think you only looked at the hospitalizations for multiple sclerosis.
	DR. GHALIE:  Right.
	DR. GILMAN:  She said that he only looked at the hospitalizations for multiple sclerosis.
	Dr. Penix?
	DR. PENIX:  Are there any recommendations about the total dose that can be given?  Since we can anticipate that a relatively young patient who has MS may require drug treatment for many years, I know that in your Study 903, there were 49 patients, or 11 percent of the patients, who got greater than nine doses.  In that group, are there any who got doses for several years, and do we have any data on how they did; and also, do we have any data from the cancer treatment patients who may have gotten drug for prolonged periods of time?
	DR. GHALIE:  To bring together the issue of duration of treatment, Study 901 looked at eight courses;  Study 902 looked at six courses.  In Dr. Mauch's retrospective analysis, you see the number of patients who went beyond six courses.  In fact, there were six patients who went beyond 140 mg per meter squared, and I have data on these patients.  We obviously looked at them very carefully.  In this subset of patients, these six patients, there was no cardiac toxicity detected and no severe infection.
	Our recommendation, which we are going to present to you in a moment and which I can mention right now, as far as the duration of treatment with Mitoxantrone patients with MS, is to say the following.  We have data for two controlled trials for dose up to 100 mg per meter squared.  That would be the dose that we would recommend for treatment.
	Based on the experience we have from patients with cancer, it is possible to go beyond that dose.  For these patients as a company, conservatively, we would like the physicians to do an echocardiogram or at least an LVEF evaluation before each course.  We as a company are going to recommend to discontinue treatment for patients who reach the dose of 140 mg per meter squared, just to be on the safe side.  The reason for that is because on the cancer experience, we know that once one exceeds a dose of 160 to 180 mg per meter squared, the risk of heart failure takes off.  Therefore, to really be conservative, we are recommending to be very cautious at 100 mg, to do monthly or at least before each course echocardiogram, and we recommend not going beyond that.  And there will be more recommendations that I can describe as we get to that in my presentation.
	DR. PENIX:  And those recommendations would be placed in the package insert?
	DR. GHALIE:  That will be something we will be discussing with the agency to decide in which format this will be presented. We would like it to be in the package insert.  We will also have an educational program when we have this drug on the market for syndication to ensure, hopefully, that physicians get this message and make their decisions based on that.
	It is really a question of benefit and risk assessment that is a physician's decision, but that would be the company's recommendation.
	DR. GILMAN:  Dr. Swain?
	DR. SWAIN:  I just have to say I totally agree with your recommendation.  I absolutely would cap it at 140, because you have a population that really has a normal life span.  All of the data that has looked at doxarubisone and injection fractions and trying to figure out who is going to develop congestive heart failure really shows that the serial testing is not effective to predict who will develop CHF.  So I don't feel comfortable at all, and I think the company is totally right in capping it and not increasing it any more.
	DR. GHALIE:  Dr. Alberts, would you like to add something to Dr. Swain's comment?
	DR. ALBERTS:  Well, in talking to the company about cardiotoxicity, I think there is one other ingredient to making certain that these MS patients do not get it, and that is to exclude any patient who has had prior anthracyclines, those who have had chest radiation, those who have a prior existing cardiac dysfunction, and those who are 70 years of age or older.  Those are the primary risk factors for cardiotoxicity with Mitoxantrone, and in fact if you eliminate that group of subjects, the chance of cardiotoxicity at 140 mg per meter squared is infinitesimally small.
	DR. GILMAN:  Dr. Weiner?
	DR. WEINER:  There may not be an answer to this, but I think it is an important question to ask anyway.  Is there any experience or any theoretical reason to believe that patients who are on the interferon drugs would have an increased risk of toxicity subsequent to being treated with Mitoxantrone, either cardiac or otherwise?
	DR. GHALIE:  As I mentioned earlier, the two randomized trials I presented to you today were done in patients who were Interferon‑naive.  So I do not have data to present to you on that.
	However, Dr. Mauch's experience as well as Dr. Hartung's and Edan's, and in fact Dr. Smith in Seattle, have used Mitoxantrone now in patients who failed Interferon, and based on what they will be able to tell us right now, in their opinion, there is no increased incidence of toxicity due to the fact that they had received Interferon previously.
	Having said that, as a company, we have been approached already by investigators wanting to study Mitoxantrone in patients who had failed Interferon therapy.  So there are two ongoing studies right now, pilot studies, safety studies, very carefully designed to look at safety.  I do not have the data yet.  These studies are currently ongoing.
	DR. WEINER:  The second part of my question is is there any theoretical or pharmacological reason to believe that patients on Interferon would have more likelihood of having toxicity from Mitoxantrone?
	DR. GHALIE:  I am not aware of any theoretical reason, but I would like to ask any of our consultant experts who have used Interferon.  
	Dr. Lublin, you have used Interferon‑‑please.
	DR. LUBLIN:  No relationship to this.
	DR. GILMAN:  He has nothing to say.
	DR. GHALIE:  Dr. Alberts has something to say.
	DR. ALBERTS:  I can't comment on betaseron, but with alpha‑Interferon, there are large databases in patients with multiple myeloma who have had high doses of doxarubisone followed by long periods of alpha‑Interferon, and that also applies to non‑Hodgkins lymphoma, and there has not been any known evidence of an interaction between alpha‑Interferon and the anthracyclines.
	DR. GHALIE:  Dr. Smith, who has some patients who have been treated, would like to comment as well.
	DR. SMITH:  We have had two patients from Alaska who were started on Mitoxantrone and told us after initiation therapy that their betaseron had been continued until we found that out and stopped it, and there was no difference in their hematologic profile.  That was after 2 months in one patient and 3 months in the other patient.  So we do have some experience with combined therapy.
	DR. GILMAN:  Dr. Lacey?
	DR. LACEY:  You propose if this drug is approved to cap the cumulative dosage of Mitoxantrone.  In the United States, considering how medicine is practiced, where both physician and patient are quite mobile, do you expect to do anything other than the patient package insert to help to facilitate this capping of the drug with patients?
	DR. GHALIE:  As you rightfully mentioned, in the U.S., the physician decides how and when they want to treat their patients.  The best we can do as a company is to bring forth the information we have in the package insert and the educational material.  In addition, there will be postmarketing databases or studies that will be performed by Immunex to try to collect postmarket information on safety, and we will be able to tell, if there are some patients who go beyond that dose, what will occur to them if anything.  So that will be something that we will be proactively looking at.
	DR. LACEY:  I guess I am more concerned with the preventive aspect of it going beyond the 140.
	DR. GHALIE:  The best we can do as a company is make it very clear in the package insert as well as in educational material and publications that will be published.
	Dr. Mauch has a comment here.
	DR. MAUCH:  I would like to make a comment on this very important question you have asked.  We manage our patients giving them a sort of "passport."  At the start of Novantrone therapy, the patient is handed a passport, and every dosage is registered in this passport, and even if the patient changes to another doctor, he is quite informed about the dosage, about the last leukocyte count, about ECG information, or if echocardiography is executed.  And in Germany, the patients are not so mobile as your patients are, but I think this would also be a good idea to manage your patients.
	DR. LACEY:  So this is something that could possibly be considered as a recommendation.
	DR. GILMAN:  Yes.
	DR. GHALIE:  Dr. Ann Hayes, the senior executive in the company, would also like to add her comment to that.
	DR. HAYES:  Yes, I think I would like to comment that we are trying to be proactive on putting a cap on this to try to indicate that you should not go above this in these patients in our opinion.  We fully realize that physicians make a choice and patients make a choice, but I think that as a company, we will certainly try through the MS Society and the various branches to make sure patients are educated, too, on the potential dangers of cardiotoxicity if they go above these doses.  So it is not just physician education, it is also going to be patient education.
	DR. GHALIE:  Dr. Alberts, please.
	DR. ALBERTS:  Just briefly, I think it is remarkable that etched in the minds of oncologists because of educational programs are the doses for doxarubisone and Mitoxantrone not to go beyond because of cardiotoxicity issues.  So that educational program, at least in oncology, I think is very, very successful.
	DR. GILMAN:  A question from Dr. Lipton, then Dr. Katz, then Dr. Temple, and then Dr. Van Belle.
	DR. LIPTON:  Given the long survival of people with MS and given the toxicity that we have been talking about and given the benefit of the 5 mg per meter squared dose in your first study where, if anything, the benefits were numerically superior on EDSS with the lower dose, why did you choose to recommend the higher rather than the lower dose?
	DR. GHALIE:  This is indeed one of the questions that Dr. Katz raised, and were obviously ready to answer that.  You are right to mention that the EDSS evaluation for the 5 mg per meter squared for the results appears to be better than 12 mg per meter squared; although there was no significant differences between the two, they were both better than placebo.  That was the only evaluation in fact EDSS where 5 looked better than 12.
	If you look at the five primary efficacy endpoints, all five of them were significantly better with Mitoxantrone 12 compared to placebo.  Number two, two of the five were significantly better with Mitoxantrone 5.  So we recommend now going to 12 mg per meter squared for the following reasons.
	One, that was a dose that was always significantly better than placebo.  Two, it is the test dose in this pivotal trial.  The 5 mg was an exploratory dose; it was not sized for that dose.  Three, this is also the dose that was tested in Study 902.  As I mentioned, 20 mg fixed dose or 12 mg per meter squared are very similar, so we have information from two independent studies that this dose worked.  We don't have information from independent studies for the 5 mg.  And finally, the majority of the experience in cancer patients is based on doses around 12 mg per meter squared.  So that is why we recommend 12 as the dose for that indication at present.
	DR. LIPTON:  The thing that strikes me, though, is that the variables where the 12 mg per meter squared dose has the greatest difference relative to the five are the variables that were rated by an unblinded rater who could be influenced by the greater adverse event profile of the drug.  So that is at least part of the context in which I look at these data.
	DR. GILMAN:  Dr. Katz?
	DR. KATZ:  Yes, one comment and one question.  The sponsor was beginning to discuss some possible ways if the drug is approved to prevent its use beyond 140 mg per meter squared‑‑labeling, education, that sort of thing.  The Committee will just have to discuss, if you think it is approvable from the effectiveness point of view, whether or not those sorts of warnings and educational efforts will actually prevent its use above 140.
	Obviously, we have a number of examples where labeling has been excruciatingly clear about how a particular drug shouldn't be used, and then, of course, it is used in that way.  So that is something that we'd like to hear what the Committee thinks about.
	Then I had a question about this so‑called passport which you use which accompanies the patient.  I just wonder if you have any evidence about how successful it is in informing another physician when the patient does move?  You said it works out well‑‑the patient takes the passport, and the next physician is well‑informed.  Do we know if that's true?
	Dr. MAUCH:  We try to prevent the patient moving among several doctors.  If a patient comes far from our clinic, we try to see that he has a certain doctor and only one doctor who continues therapy.  This passport is mainly for information between our clinic and the outside physician, and it is not the intention to let the patient move among a lot of doctors.
	DR. KATZ:  Okay.  So presumably, the success of this passport system is not so much dependent upon the existence of the passport but the fact that the patients are fairly restricted in whom they go to and in terms of the number of physicians they go to.
	DR. MAUCH:  It does not have the power to restrict a change in doctor; it is intended to have very valid and complete information about therapy, and it is intended that this information is only between treating doctor outside and the clinic.
	DR. GILMAN:  Dr. Temple?
	DR. TEMPLE:  One can imagine a registry system, depending upon how serious one is going to be about this, that actually tried to accumulate dose and perhaps interacted with a patient passport record.  Those are probably all things that one should talk about.  
	I just want to make one observation on the low dose effects.  There aren't nominal p‑values given for the low dose placebo comparison, but my look at it would say that only the EDSS would be statistically significant if you actually did look.  The others are leaning in the right direction, and it is tempting to think that, at least for some people, the lower dose might work.  But if one is looking for at least‑‑do we have nominal value‑‑sorry‑‑so the actual values show what I guessed from looking at it‑‑only the EDSS is nominally significant‑‑AI is not so far.
	DR. GILMAN:  Dr. Van Belle?
	DR. VAN BELLE:  I was going to discuss the same point mentioned by Dr. Lipton.
	Could you put up Slide M‑40 for us, please?
	DR. GHALIE:  Yes.  M‑40, please.
	[Slide.]
	DR. VAN BELLE:  Just one small point.  The 22 percent associated with improved should actually be 28 percent.  There is a mistake in that table.  So that certainly, the Mito‑5 looks at least as good as the 12 dose.
	The other thing is that, as was already mentioned before, this index plus the Ambulatory Index, which if you look at the data is virtually identical to the 12 dose, I don't see on the basis of these two blinded outcomes anything to choose between Mito‑5 and Mito‑12.
	DR. GHALIE:  We did an additional analysis to determine the dose‑response effect, the John Curry [ph.] test, which I do not even want to try to explain, but our statistician will be happy to discuss with you.  He explained to me that comparing placebo 5 and 12, there is a trend in the dose‑response effect when looking at all patients.  That is why we are feeling more confident in recommending a dose of 12 mg per meter squared.
	DR. VAN BELLE:  Then, I assume that that test was not significant for this particular outcome, for the EDSS?
	DR. GHALIE:  It was done for the EDSS valuable, and Mike Butan [ph.] may want to comment further on that.
	MR. BUTAN:  Actually, it was significant for this variable also.  I think that that is driven, though, by the low placebo rate. So you are smoothing out that response due to a placebo group.  So you have a significant test even though the 5 was numerically higher than the 12.
	DR. LIPTON:  But I assume you didn't test for differences between the lower active and higher active dose.
	MR. BUTAN:  Oh, yes, we did.  That was non‑significant.
	DR. LIPTON:  All of them were non‑significant?
	MR. BUTAN:  A few of them were significant, occasionally‑‑I don't recall specifically; we have done so many analyses.  I think perhaps one of the time to relapse was significant, but by and large, they were non‑significant.  We are seeing consistently strong results for 12 versus placebo, and we are seeing very good results for 5  versus placebo, but not nearly the magnitude.  So we do see consistent dose response throughout all endpoints.
	DR. GILMAN:  Dr. Wolinsky?
	DR. WOLINSKY:  Isn't the time to attack in terms of the dose response very heavily driven by the few attacks which occurred very early in that group, and then the curves are very parallel?
	MR. BUTAN:  I believe a log ranked [ph.] test is actually going to be more sensitive to sensoring later on in the curve, whereas the Wilcoxin [ph.] would be more sensitive to early ones.
	DR. GILMAN:  All right.  Let's move on to risk‑benefit, then, please, Dr. Ghalie.
	DR. GHALIE:  Yes.  I am done with the data, so now it is going to be more a benefit and risk assessment of the use of Mitoxantrone in patients with multiple sclerosis.
	[Slide.]
	The acute and long‑term adverse events of Mitoxantrone are well‑characterized and manageable.  I will present guidelines, some of which we have discussed so far, on how to monitor these effects.
	Mitoxantrone is effective in a well‑defined subset of patients with multiple sclerosis which also I will describe.  Overall, we believe that Mitoxantrone's benefits outweigh its risks in patients with progressive forms of multiple sclerosis who have limited therapeutic options.
	[Slide.]
	The adverse events of Mitoxantrone given at 12 mg per meter squared were well‑characterized in the two randomized trials and in thousands of patients with cancer who received this agent.
	In general, mild or moderate nausea and/or emesis may occur in about two‑thirds of the patients.  They do not happen with each course of therapy.  That is important to know.
	Number two, they tend to resolve a day or two after Mitoxantrone administration.  This is not something that persists for the 3 months between courses.  They can be managed with standard emetics, and we mentioned the ondansetron before as a potential treatment.
	Severe alopecia is not seen, as we have already earlier mentioned, and alopecia usually consists of hair thinning and in many patients resolves after treatment is discontinued.
	Severe leukopenia, based on what we have seen in Study 902, occurs in less than 50 percent of patients, and when we have looked in 902 on a weekly basis, we can tell you that leukopenia usually occurs between Days 7 and 14 and tend to resolve by Day 21.  During this window of time, based on the two randomized trials we showed you, the risk of neutropenic fever is low.  However, it is not impossible to develop neutropenic fever when there is a neutropenia nadir.
	[Slide.]
	We recommend that patients undergo serum chemistry before each course of therapy, including liver function test, as mentioned by Dr. Swain.  We also recommend that a hemogram be performed before each course of therapy.  In addition, we recommend that the hemogram be performed at the time of expected leukocyte nadir, meaning anywhere between Day 7, 14 or 21, in a patient who may have evidence, or at least clinic signs or symptoms, suggesting an infection.  This is very similar to what the recommendation and experience is in cancer patients.
	[Slide.]
	Let's now discuss what we are talking about with cardiac toxicity in patients with multiple sclerosis.  This risk was well‑evaluated in the two randomized trials I have presented to you today.  There were no cases of congestive heart failure at doses up to 100 mg per meter squared.  We have no evidence and there is no evidence that the risk of congestive heart failure is going to be greater in patients with multiple sclerosis compared to cancer patients.
	So a conservative recommendation in our opinion is as follows.  We recommend doing a baseline LVEF evaluation and another LVEF evaluation when the patient reaches 100 mg per meter squared, which represents 2 years of treatment with a 3‑month schedule.
	[Slide.]	
	DR. GHALIE:  Again, as I said, we recommend doing a baseline LVEF examination, and then, when the dose reaches 100 mg per meter squared, which is 2 years of treatment with a 3‑month schedule.
	Based on the oncology setting we discussed earlier, it may be possible to go beyond this dose.  Continuing dosing should be addressed on an individual patient basis, and for each patient, weighing the risk of benefits of continuing therapy and the potential risk of cardiac events.
	In this situation, as a company, we recommend repeating LVEF before each course of therapy.  Continuing therapy in patients who have an LVEF that declined by more than 15 percent from the baseline should also be determined on an individual basis.  In other words, to state it differently, if you have a patient whose LVEF declined by more than 15 percent, before the next course of therapy, we recommend doing an LVEF evaluation and then deciding whether to continue treatment.
	We recommend as a company to discontinue Mitoxantrone in two conditions‑‑if the LVEF declined to less than 50 percent and when the cumulative dose reaches 140 mg per meter squared.  We also recommend excluding from therapy‑‑and this was discussed by Dr. Alberts‑‑patients who already have cardiac dysfunction to begin with, who are above the age of 70, who have received chest radiation or doxarubisone, which I recognize the latter two are going to be rare in patients with multiple sclerosis.
	[Slide.]
	As already indicated in the package insert, Mitoxantrone should not be used in patients who are pregnant or are attempting to become pregnant.  That is on the label, and that needs to be known by the physician and by the patient.
	[Slide.]
	I will now turn to the benefits of Mitoxantrone in patients with multiple sclerosis.  Study 901, the Phase III study, shows that Mitoxantrone slowed the progression of neurologic disability as shown by an EDSS progression reduction by 64 percent compared to placebo.  It decreases the number of treated relapses by 69 percent compared to placebo.  It also decreases gadolinium‑enhancing lesions on the early MRI scan.
	[Slide.]
	Study 902 in our opinion supports the findings of Study 901.  It shows that Mitoxantrone significantly slowed one‑point EDSS progression by 83 percent compared to the control arm, decreased the relapse rate by 77 percent, and decreased the number of patients with gadolinium‑enhancing lesions by 86 percent compared to the control arm.
	Study 903 indicates that with appropriate monitoring, it is possible to use Mitoxantrone in a clinical practice setting.
	I would now like to present Immunex' perspective on the question raised by Dr. Katz in his introduction.  We have already addressed some of those before, but I will go through them again, one by one.
	[Slide.]
	First, to the question asked by Dr. Katz, were the two studies presented today adequate and well‑controlled, our answer is yes.  Study 901 was a randomized, placebo‑controlled trial.  It had prospectively‑defined entry criteria, efficacy endpoints, study size, and statistical analyses, all prospectively defined.
	All five primary efficacy variables consisted of a well‑characterized disability scale and standard definition of relapses.
	MRI evaluations were prospectively defined to be done in a subset of patients enrolled in the study.
	[Slide.]
	Study 902 was also a randomized, controlled trial.  It had prospectively‑defined entry criteria and efficacy endpoints.  It had the typical design of an MRI‑based trial.  It also included evaluation of clinical endpoints, including the EDSS scale and relapse.
	[Slide.]
	The second question that was raised by Dr. Katz was is there evidence that Mitoxantrone slows the progression of neurologic disability.
	DR. GILMAN:  Could I interrupt for a second?  I actually wanted to stop you there, anyway.  But you would agree no doubt that Study 902 was unblinded, and therefore, there has to be some question about the objectivity of those data‑‑clinical data, that is.
	DR. GHALIE:  In Study 902‑‑to indeed follow up your question‑‑the primary endpoint was masked.  The EDSS and the relapse were unmasked.  In our opinion, these results are robust despite this unmasking for the following reasons.
	Number one, the magnitude of effect was quite large to be just a coincidence or a bias.  Number two, they are consistent with the MRI results, which was a blinded assessment.  And number three, if we see the two studies together, the magnitude of effect of Mitoxantrone in both studies is very similar‑‑in fact, the effects on EDSS and on relapse were about the same magnitude‑‑which in our opinion indicates that Study 902 clinical endpoints are also robust, albeit unblinded.
	DR. GILMAN:  Dr. Katz?
	DR. KATZ:  Yes.  Maybe you will get to this, and maybe I should wait, but the first two slides you showed were not in response to any question I had asked.
	Just to clarify, the first question I asked was whether or not there was replication or substantial evidence of effectiveness in a particularly well‑defined population‑‑progressive MS patients.  Maybe you will get to that.  But I think we thought that the two trials were adequate and well‑controlled.  There were certainly clearly blinding questions that we need to talk to you even more about, but as far as their meeting the primary outcome, it wasn't really a question for us.
	DR. GHALIE:  Indeed, I will be getting to the issue of the patient population.
	[Slide.]
	The third question to address is is there evidence that Mitoxantrone decreased the relapse rate, since it was done by unmasked physicians.  And our answer, based on the two sets of data, is also yes.  Now, we recognize, and we have discussed this before, that the treating physician was ummasked to study drug in both studies.   However, as I mentioned, despite this unmasking, we believe that the data on relapse is robust, and I have already said that a minute ago, but I will repeat it.
	First, the definition of relapse in the two studies, particularly the severe relapse that required treatment, was well‑defined, and there is no evidence that the physician did not follow the definition of relapse.
	Second, the effect of Mitoxantrone on the number and time to first relapse treated with corticosteroids was highly significant, so it is unlikely that it will be biased just by knowing the arm for which the patients were randomized to.
	Third, and as I mentioned earlier for the EDSS, there were very consistent results between the two studies on effect on relapse, which again lends some robustness to the results in both studies.
	And lastly, no matter how we look at relapse, whether it is treated relapse, severe relapse, relapse seen by the physician in the clinic, or relapse seen by the physician near home, all the results show Mitoxantrone being better than placebo.
	So it is the combination of all the data on relapse that in our opinion provides the robustness to the interpretation of the relapse data in these two studies.
	DR. GILMAN:  Dr. Temple, a question?
	DR. TEMPLE:  Do I recall correctly‑‑you don't actually have the descriptions of patients at the time they supposedly had a relapse, so that although you indicated there were criteria, you cannot say on your own‑‑you can trust your investigators, but you can't say on your own‑‑that you know whether the criteria were followed; is that right?
	DR. GHALIE:  This is always true in a clinical design.  We have to trust the investigators to do the right assessment‑‑
	DR. TEMPLE:  No, no, that isn't‑‑I am not unsympathetic to your point of view necessarily, but what you just said it not true.  You could have them fill out a little form explaining how they decided to treat, how it met the criteria; they could check whether the criteria were met.  So please don't say that all studies have this lesion.  Yours does.
	DR. GHALIE:  No, no.  I'm going to add to that.  I'm sorry.
	DR. TEMPLE:  Okay.
	DR. GHALIE:  I hadn't finished my sentence.  I was going to say that in addition, there was an audit that was done to determine whether the relapses that were called severe relapse or other were also documented by what we find in the patient case record form.
	Thirdly‑‑and this is something that Dr. Hartung would like to describe now‑‑there was a form that was filled out that addressed the  description of the relapse in patients randomized in his studies.
	So, Dr. Hartung, please clarify how we can be confident with the relapse data.
	DR. HARTUNG:  All the relapses examined by the treating physician‑‑or the treating physicians in each and every instance recorded the EDSS and then, based on the stipulated criteria, whether this is a severe relapse or not a severe relapse, ticked a box in the CRF.
	So the EDSS data is available.
	DR. TEMPLE:  Now, this was the treating physician's EDSS?
	DR. HARTUNG:  Treating.
	DR. TEMPLE:  So that would be different from the blinded one that was done.  But you are saying it could serve to show that the nominal criteria were met.
	DR. HARTUNG:  Yes.
	DR. GILMAN:  But it doesn't address the situations in which the physician treating the patient at a long distance was not similar to the treating physician.  And we saw there were a fair number of cases in that category.
	DR. TEMPLE:  No, it doesn't do that.  It answers one of the possible questions, namely, that there were standards and that you can say, well, the apparent standards were met.  If you don't look, you don't even really for sure know that, although you might believe it because you trust your investigators.  That's a different answer, though.
	DR. GHALIE:  Next, I will discuss the MRI findings in this filing.
	[Slide.]
	In Study 901, MRIs were performed in a subset of patients who were randomized under the study.  Patients were not stratified based on baseline MRI.  That was a decision made early on.  And the study was not sized to correlate MRI findings with clinical findings as we have already discussed earlier.
	However, despite these limitations, there is a clear reduction in the number of patients with gadolinium‑enhancing lesions as well as the number of lesions that are gadolinium‑enhancing in this study, and these results were similar, in the mae direction and consistent with the clinical findings of the study.
	Taken together, the clinical findings and the MRI findings suggest a biologic effect of Mitoxantrone on the inflammatory process in the CNS in patients with multiple sclerosis.
	[Slide.]
	Let's look now at Study 902, which had the design typical that we see today for MRI‑based clinical trials.  The results of the MRI data were highly significant, and they were consistent, as I mentioned, with the clinical results of the study.  And the magnitude of the MRI results in both Study 901 and Study 902 are very similar.
	So taken together, Studies 901 and 902, in our opinion, provide further support to the activity of Mitoxantrone in multiple sclerosis.
	DR. GILMAN:  Well, there is the question about the differences in the cases.  In 902, you had 15 relapsing remitting cases and 6 progressive  cases; whereas in 901, most and essentially all were progressive cases.  So there is a difference.
	DR. GHALIE:  There are differences in the patient eligibility and the type of patients enrolled, and this is what Dr. Lublin is going to discuss in fact imminently.  I will discuss the dose and maybe I can go into the target patient population and why we believe those data are supportive.  Is it possible, or would you like me to‑‑
	DR. GILMAN:  Dr. Grundman?
	DR. GRUNDMAN:  I have a question regarding the MRI results.  Can I refer you to Table 6.1.2.a on page 27 of the FDA review?  It is in section 4. 
	The question has to do again with the comparability of the two groups with respect to their entry into the study.  One can see that at the month prior to baseline, the standard deviation of the number of lesions, as well as the median range of the lesions, was much greater in the methylprednisolone‑alone group compared to the Mitoxantrone‑plus‑methylprednisolone group.
	I am just wondering to what extent subjects who had many lesions on their MRI, or the lack of many lesions on their MRI, contributed to the mean response that you have seen.  Did you make any attempt to stratify the results in terms of the number of lesions that were present either at Month Minus‑1 or at Month 1?
	DR. GHALIE:  This study was not designed to stratify patients based on baseline MRI.  Again, that was a 42‑patient study, and stratification would have been difficult.  And when we look retrospectively at the data, we looked at the data.  We have not looked at this analysis based on the number of lesions at baseline.
	Dr. Edan, who designed and conducted this study, has a comment here.
	DR. EDAN:  We perfectly know that there is a great variation between patients concerning the number of lesions on MRI.  This is the reason why the primary endpoint was not a reduction of new MRI lesions, but the percentage of patients with no MRI lesions at all, month after month.  What impressed us when we saw the results was that it was month after month that the number of patients without any new activity of MRI increased in the group of patients with Mitoxantrone.
	So it is not only the result of mean number of lesions, but we took the most robust primary endpoint for MRI analysis, which was patients with not one MRI lesion, which is much more difficult to reach.
	DR. GILMAN:  Please continue.
	DR. GHALIE:  Finally, I will address the issues raised by Dr. Katz about the dose and the target population.
	[Slide.]
	We propose that the approved dose of 12 mg per meter squared, which is approved in cancer patients, also be approved in patients with multiple sclerosis.  The proposed schedule in multiple sclerosis is clearly different than cancer patients; it is going to be once every 3 months compared to once every 3 weeks, as used in cancer patients.  And as I mentioned to you, the rationale for proposing the dose of 12 mg per meter squared is as follows.  It was the test dose in the Phase III study; all five primary endpoints and the secondary endpoints were significantly better with this dose compared to placebo.  The fixed monthly dose of 20 mg that was tested in Study 902 is essentially identical to 12 mg per meter squared.   Again, as I mentioned, this is the dose that we have the largest safety experience with in patients with cancer.
	[Slide.]
	Based on the results of Study 901, Mitoxantrone in our opinion was shown to be effective in patients with progressive forms of multiple sclerosis excluding primary progressive MS, and they were not tested in this trial.
	Dr. Lublin will now address in his remarks current thought about the continuum of patients with multiple sclerosis and the rationale for this proposed patient population.  As you know, Dr. Lublin was the lead author in 1996 for the new classification of multiple sclerosis in these four disease categories.
	I will come back at the end of Dr. Lublin's presentation to conclude.
	DR. GILMAN:  Well, again, I have to comment on this last slide.  Still, Study 902 consisted primarily of patients with relapsing remitting.
	DR. GHALIE:  And I believe this is where Dr. Lublin will be able to shed some information on that specific question that you have.
	DR. GILMAN:  Thank you very  much, Dr. Ghalie.
	Dr. Lublin?
	DR. LUBLIN:  Good afternoon.
	In 1993, this panel recommended and subsequently this Agency approved the first treatment for relapsing remitting multiple sclerosis.  Since then, two additional agents have been approved for relapsing remitting and relapsing forms of multiple sclerosis.  There is currently no approved agent for progressive forms of MS, including the 50 percent of relapsing remitting patients that are expected to convert to the secondary progressive form, especially for those in the higher disability scores.
	Multiple sclerosis is a disease that can be categorized into several different clinical course subtypes.  These have been derived by a consensus from a survey of physicians specializing in research and treatment in multiple sclerosis and published in 1996.  We have heard a bit about this during the course of the day, but let me run through the types for you.
	[Slide.]
	The commonest course of presentation is relapsing remitting.  This is acute flare‑ups, exacerbations of multiple sclerosis followed by a period of disability, followed by improvement which can be either complete, as in the top part here, or incomplete.  If the improvement is incomplete, then there is stepwise accrual of disability.
	Over time, approximately 50 percent of this group will then convert to the secondary progressive form.  The difference between relapsing remitting and the progressive forms of disease is in the baseline between attacks.  In relapsing remitting disease, there is a stable baseline between attacks, and in all of the progressive forms, there is gradual worsening.
	The secondary progressive form is an outcome from primary progressive where they go into a gradual progressive form either with superimposed exacerbations or without.  They start out as relapsing remitting; they are then secondary progressive.
	The least common form in this categorization is the progressive relapsing form.  They start out as gradual progressive disease punctuated by occasional clear‑cut exacerbations, so they have some relapses.
	In the primary progressive group, which has not been tested in any of the studies mentioned today, there are no acute exacerbations, just gradual progression, worsening of disease, which may occur at a variable rate.  
	It is important to not that there are no reliable radiologic, immunologic or biologic markers to distinguish these different types of multiple sclerosis.  Some feel that primary progressive may in fact be a distinct subtype, but this is not yet proven.  Most recent clinical trials have utilized these designations to obtain better homogeneity of their experimental groups.
	Currently‑approved therapy for MS is limited to relapsing remitting form or relapsing forms of MS and provides partial benefit as measured by reduction in relapse rate and/or lessened disability.  There is no approved agent for progressive forms of disease.
	[Slide.]
	Worsening of disability in MS occurs via two mechanisms.  There is stepwise worsening in the relapsing remitting form which is characterized by incomplete recovery from successive attacks.  And then there is the gradual progressive worsening that occurs independent of relapses in the progressive forms of disease.  The latter is generally considered to be the greater contributor to patient disability although it is still unclear whether the mechanisms of worsening are actually distinct or not.
	[Slide.]
	If one looks at the progressive phase of the disease, we don't actually know whether it is truly gradual progressive disease or rather the summed effect of multiple mini exacerbations, each one of which is not necessarily  expressed as clinical disease.
	[Slide.]
	Despite the lack of proven agents for the more devastating forms of MS, many patients are subjected to treatment with potentially toxic therapies without the benefit of supporting, well‑designed, randomized clinical trials.  These treatments are administered by well‑intentioned clinicians who are confronted with patients who have entered an aggressive phase of deterioration.  This is especially troubling for patients who have already failed one of the currently approved therapies such as Interferon‑beta and gluteramir acetate [ph.].
	[Slide.]
	In this slide, we show the groups of patients that would be appropriate for more aggressive forms of therapy and correspond with the groups of patients who are presented here today‑‑that is, patients with relapsing remitting disease who are undergoing stepwise deterioration, patients with secondary progressive disease anywhere along this course, and even patients with progressive relapsing disease which wasn't named until 1996, so it is hard for me to tell, looking back into the database of patients, whether any of these were there or not, but they fit in our hands into a similar pattern as this.  But clearly, these two groups of patients have been included in the studies today, and both are undergoing worsening of their disease.
	[Slide.]
	The data presented today are consistent and robust.  They demonstrate that Mitoxantrone is an effective treatment for slowing disability and reducing relapse rate in patients who are accruing disability and are in the higher range of EDSS.  There is no approved, proven effective agent for this group of patients, and thus, Mitoxantrone provides a very reasonable therapeutic option.
	Thank you.
	DR. GILMAN:  Thank you.
	Dr. Wolinsky?
	DR. WOLINSKY:  I wonder if Dr. Lublin could enlighten the Committee as to what kinds of patients were actually included in the pivotal trial for Betaseron, the pivotal trial for Avanex, and the pivotal trial for gluteramir acetate.  That is, how would you distinguish the proportion of patients in those trials who were relapsing remitting without accumulated disability, relapsing remitting with some accumulated disability, and relapsing remitting with some amount of progression in between?
	DR. LUBLIN:  In the Betaseron group, it was all, at least at the start, relapsing remitting, as you will recall.  And they were from‑‑
	DR. WOLINSKY:  Did we have the wisdom of your definitions then?
	DR. LUBLIN:  No.  In fact, for none of those studies were the current definitions.  But the definition that was employed for relapsing remitting disease would have excluded patients who had progressive disease in the Betaseron study.
	In the Avanex study, that was not the case, and in fact, when presented here, it was mentioned that there were in fact some patients who they thought could have had progressive disease in addition to relapses, and I think that that in fact affected the labeling.  Copaxone, again, the definition was such that I would be confident that those were relapsing remitting patients.
	How many ended up accruing disability‑‑they all did.  If you look a the Kaplan‑Meyer curves, over time, the patients were getting worse in all groups, just less worse in some groups.
	DR. GILMAN:  Dr. Katz?
	DR. KATZ:  So as I understand it, your assertion is that the patients in Study 902 were relapsing remitting, but with an accumulating deficit that wasn't resolved.  Is that it?
	DR. LUBLIN:  This again comes from conversations with Dr. Edan.  When you look at his definition, his definition is active relapsing remitting patients having two or more attacks over a year's time, or progressive patients that have increased by two points on the EDSS.  HE tells us that in fact in the relapsing remitting group, they were stepwise accruing deficits, but that wasn't necessarily in the definition.
	DR. KATZ:  No, no.  I know it wasn't in the definition, but the assertion at this point after the fact is that in fact they were patients who, although you would still call them relapsing remitting, in fact had an accumulating deficit; they might have been stable between attacks, but‑‑
	DR. LUBLIN:  That's absolutely correct.  That is one of the mechanisms of worsening.
	DR. KATZ:  I understand that.  I'd like to know what the evidence is for that assertion.
	DR. LUBLIN:  For which assertion?
	DR. KATZ:  For the fact that these patients were relapsing remitting with an accumulating deficit.  As I understand, you're trying to make the point that in some sense, even these patients, even the relapsing remitting patients in Study 902, were progressive.  And I am trying to just see what the evidence is to support that.
	DR. GHALIE:  If i might intervene here, Dr. Edan, could you repeat again in your protocol the definition of enrollment in the study, which again was written long before the 1996 classification.  And as you will hear from Dr. Edan, the way the eligibility criteria was, it will include the patients Dr. Katz has asked about.
	DR. EDAN:  Yes.  We include a category of patients who within the previous 12 months have had at least two relapses with sequelae, and these patients reached the high level of handicap.  If you remember, the levels they had after 5 years of the disease, the irreversible EDSS at that time had been at least one month after relapse, were at 4.5, which is very high for a relapsing population 5 years after onset of the disease.  So it is clear from my experience and from the study we did that the population who were treated with monthly Mitoxantrone were mostly relapsing remitting patients, with sequelae.
	DR. GILMAN:  Now I am confused.  I thought earlier you said these were all relapsing remitting patients, period, without accumulating disease burden.  There were 15‑‑
	DR. EDAN:  No, no.  They were with accumulative disability within the 12 previous months after each relapse.
	DR. GILMAN:  All of the 15 that were called relapsing remitting.
	DR. EDAN:  Yes, yes.
	DR. GILMAN:  All of them were relapsing progressive.  Is that what you're saying now?
	DR. LUBLIN:  No.  We like to avoid that term, Dr. Gilman.
	DR. EDAN:  It is confusing, the term "progressive," I understand, but there was worsening of the EDSS after the relapses.
	DR. LUBLIN:  Just for clarification, they worsened their EDSS after relapses, and they did not go back.
	DR. EDAN:  Yes, that's right.
	DR. LUBLIN:  So they stayed worsened, and then they were‑‑
	DR. EDAN:  Yes.
	DR. LUBLIN:  Can I have my first slide?
	[Slide.]
	DR. LUBLIN:  There it is.  This group here.  This is still relapsing remitting, because the baseline between attacks is stable.  But if they don't return to their prior baseline, they are accruing disability.  This is what used to be called relapsing progressive by some, but then some also called this relapsing progressive, and that's why we did away with it.
	DR. WOLINSKY:  Can I again have a little bit more clarification, then, because if we stick to this religiously, then patients who are the top blue line could only get into a study if, between attacks, they were EDSS zero, and we would only have‑‑this is the way it's shown‑‑
	DR. TEMPLE:  No.  The second line are relapsing remitting, but they don't get back to zero.
	DR. WOLINSKY:  I understand that they are relapsing remitting with accumulated disability between attacks with stable periods.  What I am trying to drive at‑‑and I think this is not trivial, because I actually have a very sympathetic feeling for what I believe the investigators treated in Europe, but I think in terms of trying to help my colleagues in the field, when or if they have this drug, they need to know what to treat.  So my problem is that, at least in my own mind, the only way I can really be sure how these groups are different is to know how I cut them by EDSS score and the fact that they at one time or another had enough attacks to get into trial.
	DR. LUBLIN:  You may very well be right.  This is a very common form of MS.  Any patients who comes into study with relapsing remitting disease of 1, 2, or 3 has been in here.  They haven't returned to a baseline of zero at some point.  So you are right, one has to know more than just relapsing remitting disease with accrual of deficit.  It is perfectly reasonable to say what else do you have to qualify that with to have aggressive forms of therapy.  If that is the point you are getting at, I agree with you.
	DR. WOLINSKY:  It is very much the point, because the potential extension‑‑and it may be absolutely where we should go; I don't know the answer to this‑‑is to take a patient at first diagnosis and begin Mitoxantrone.  But we will hit our cap fairly quickly.
	DR. GILMAN:  Dr. Temple, do you want to ask your question now?
	DR. TEMPLE:  I guess for the certified non‑neurologist here, to look at those lines between exacerbations and try to figure out whether they are ever so slightly rising or absolutely flat seems a very daunting task.  Does everybody really believe you can do that?  Again, I know nothing about this; that is important to realize.
	DR. GILMAN:  I wonder if Dr. Lublin wants to answer that.
	DR. LUBLIN:  Well, I see some heads shaking no, but yes, I absolutely think you can.  We follow these patients, especially the ones on therapy now, so we follow patients a lot more closely, and you have a pretty good idea‑‑even a very good idea‑‑from month‑ or 3‑month to 3‑month period whether the patient is changing or not.  I don't think this is that difficult a task.
	DR. GILMAN:  Dr. Grotta?
	DR. GROTTA:  I guess maybe I'm missing something, but I don't really see the confusion.  I recognize that people in that second line are included in this study, but not all of them.  They had to have had more than two relapses in the last 12 months or they had to have had an EDSS progression of greater than or equal to two points.  So not everybody on that second line would have gotten into that.  It would have been the relapsing remitting patients who didn't return to normal between attacks who had particularly frequent episodes of relapse.  So I don't think it's all that complicated‑‑plus the other patients who were in the study were those who were progressing, who had the progressing baseline in between attacks.  
	So I think that that should be the guideline.  I think that what has been proposed is that that group of patients, then, would benefit from this treatment and did seem to benefit from this treatment in Study 902 by MR criteria.
	DR. GILMAN:  Dr. Lipton?
	DR. LIPTON:  Yes, but granted what you said, here is my problem as someone who is far from an MS expert. We are being asked to use the evidence in the 902 study to make a judgment about whether or not this treatment works in progressive MS, and some proportion of the patients enrolled in that study have something that we would now call progressive MS, and some of them don't, and in order for me to apply the data in 902 to the judgment we are being asked to make, I feel the need to know how treatment works in a group that we would call progressive MS, not looking at those who have something else.  It sounds like a subgroup analysis to me based on reclassification of patients blind to treatment group.
	DR. GILMAN:  When I read the narrative that Dr. Katz and the Division prepared, it sounded as if there were 15 patients in Study 902 who had relapsing remitting, and it was undisclosed whether they were the cases that you would see on the first line or on the second line.  We now hear that all 15 would match the second line, if I am understanding what the sponsor is telling us.  Therefore, it sounds as if all the patients in 902 had a progressive form, even though 15 out of the 21 had relapsing remitting symptoms also.
	DR. GHALIE:  That is correct.  I probably should have been clearer when I presented the patient population and enrollment criteria.  Patients, to be enrolled, if they had relapsing remitting, they had to have‑‑as Dr. Edan said, and it was spelled out in the protocol as well‑‑they had to have sequelae, meaning EDSS progression.  So they do fit under blue line number two, correct.  And this is why as a company we propose the words "progressing forms of MS," which is patients who have the orange line as well as the second blue line or the yellow line as well, and we clarify excluding primary progressive.  So that is really the patient population enrolled in 901 and 902.
	DR. GILMAN:  Dr. Weiner?
	DR. WEINER:  Could you put back on Slide M‑112?
	[Slide.]
	DR. WEINER:  Okay.  I guess I'd like to make a couple points and then ask a question for those who have used the drug.  If you look at the forms of MS that one wants to use the Mitoxantrone for, the top one, which is relapsing remitting, and the second one, which is secondary progressive with attacks would actually qualify for treatment with Betaseron or Avanex or Copaxone, because these are people with relapses and remissions, even the progressive relapsing form on one level.
	So I am just thinking about the label and the claim that this is just for progressive forms, because those two actually would fit if you wanted to prescribe something for relapsing remitting patients.
	The next question that I'd like to ask those who have used the drug‑‑and in this case, what Dr. Wolinsky said in terms of where it really is effective‑‑and I do believe the drug is effective, and I hope it can be approved, and we'll talk about that later, for the appropriate papulation‑‑but I get the feeling that the patients that it really is effective in are the blue line, the relapsing remitting, and the top line of the secondary progressive people who are having relapses and that the patients who are more slow‑chronic‑progressive, that secondary progressive, may not be helped as much by this drug.  I would be interested in the comments of the physicians who have used it and put people into the studies and what their comments are and the response of the patients in the top two lines and the third line, which is a lot of patients.
	DR. LUBLIN:  Let me just stress your first issues, Howard.  That is why, when I made this slide, I avoided the word "progressing" disease and used "worsening," because I don't know that there is any real difference biologically or any other way between this kind of worsening and this kind of worsening.  If someone is ending up with a walker or a wheelchair or whatever, I am looking for something that is going to halt that.  So I like "worsening" forms, because it doesn't lock you into anything.
	DR. GHALIE:  I'd like to address Dr. Weiner's question which was in two parts.  We presented earlier this morning a slide that looked at the five primary endpoints including EDSS, Ambulation Index, and the SNS score, based on whether patients had relapsed or not prior to going into the study and whether they were classified as relapsing remitting or secondary progressive.  And again, looking at subset analysis‑‑I did not want to present p‑values‑‑these slides show that Mitoxantrone patients were better than placebo whether they had or had not relapsed prior to enrollment.  So that is to provide information for you about which one of these patient lines fit.
	I'd now like to address and indeed direct my question what you had wanted to hear from physicians who have used this drug in patients to elaborate on how they see which patients fit.  So I would first like to have Dr. Hartung, who did Study 901, and after that, Dr. Smith, who is a practicing physician who saw that data and is making decisions now about when to use this treatment in his patients.
	DR. HARTUNG:  Well, my answer is in two parts.  First, the data that I can oversee that has been collected in the trial, and this was both patients in fact with active disease, whether they had relapses or not, but active progressive disease with deterioration.
	Second, in my experience with some 30 or so patients who were treated outside the context of the trial, I got the impression that patients with active disease whether or not, again, they had superimposed relapses benefitted from the therapy.  
	So in my opinion, I think this is a therapeutic option that we should be able to offer patients with any type of active progressive disease so as to hopefully stabilize them by time‑‑3 years, 4 years, whatever‑‑and perhaps make them responsive again to other kinds of immunomodulatory therapy, although I would very sincerely hope that you can agree that there is a place for Mitoxantrone in the treatment of multiple sclerosis.
	DR. WOLINSKY:  Peter, if you wouldn't mind elaborating a little bit before we go on to the next.  I think I heard using this drug for patients who fail‑‑and I know these are very difficult questions, but of all the people who are going to talk to us, I think you and Dr. Edan have the most experience, practically.  So do you see this as your first choice for what kind of patient and your first choice for what other kind of patient?  Could you give that to us?
	DR. HARTUNG:  Again, I think I have to differentiate in my elaborations whether or not I'm talking about data obtained in the trial or experience I collected over the years with the drug.  I think we cannot right now, based on the data, say that this drug is also useful in patients who fail to respond to established therapy because we have not tested that in the trial.  
	However, I have in the meantime seen patients who received‑‑since Beta‑Interferon is approved in Europe for the treatment of secondary progressive MS, other than here in the United States‑‑that patients who did not respond either initially or after wide Beta‑Interferon did receive benefit from Mitoxantrone therapy.
	So I see in actual fact two scenarios.  In patients with very active disease, rapidly progressive, I would consider or at least provide the physician as well as the patient with the option to use Mitoxantrone as a kind of induction and also would consider its use, if you like, as a rescue therapy in those patients‑‑and they are certainly not few‑‑who may have responded initially to Beta‑Interferon or any other immunomodulatory therapy but fail to do so.  And also, as you know, there are probably nonresponders from the beginning where this would also be an alternative to be considered.
	DR. GILMAN:  Dr. Penn?
	DR. PENN:  I think we are getting to the slipper slope at this moment, because what we are asking our colleagues to do is to tell us how they might use this outside of the data that we have for the drug.  If we get into this, it will be extremely interesting, but it won't answer the question we have to address as a regulatory advisory committee, and that is:  Do we have the data now to approve this drug on the basis of its efficacy and safety for what now, at least in my mind, is becoming fairly clear the clinical situation in which it has been tested.
	So I think all of this is what we would do with the drug later on, but we should stick to the point because we can start talking about all sorts of experience, and then we're going to have trouble.
	DR. GILMAN:  Dr. Katz?
	DR. KATZ:  That's pretty much what I was going to say.  If you do recommend approval, the indication will describe or be closely related to the population that was studied once we think we can define that, and then, as far as second line, if you recommend that it be approved for progressive forms of MS, there is nothing else in this country approved for those forms, so it can't possibly be second line in that case, because once a drug is out there, as you say, people can use it for anybody they want‑‑of course, it is out there, as it turns out, but you get the point.
	DR. GILMAN:  Dr. Penix?
	DR. PENIX:  Clearly, there is a problem with semantics.  It appears that the sponsor has proposed to have the drug approved for the indication to slow the progression of neurologic disability and reduce the relapse rate in patients with progressive multiple sclerosis.  That second progressive is the thing that bothers me, certainly.  When I look at the testimonials of the three patients, each of these patients has secondary progressive MS, and two of the patients have indicated their interest in having a drug, if we agree with the reported claims, to be approved for secondary progressive MS.
	Again, I think that certainly, that was my initial concern, and my recommendation would be for us to maybe either get rid of that second progressive or to change it to something like "moderate" or "severe," because clearly, my impression from the patients is that they are thinking that this is an indication for secondary progressive MS.
	DR. GILMAN:  I'm not sure we're going to be able to change that issue right now.
	Dr. Katz?
	DR. KATZ:  Also, half the patients in the first study were diagnosed with secondary progressive MS, if I am remembering correctly.  The other half had something else.
	DR. GILMAN:  All right, then.  Can we turn to Dr. Ghalie for his final comments?
	DR. GHALIE:  I really essentially concluded my presentation of the data and our view of the role of this agent in the treatment of multiple sclerosis.
	What I have tried to present to you today is that we have two studies.  They were not identical; they were designed with different endpoints in mind.  One has clinical endpoints that it met, and the MRI data supported that.  One had an MRI endpoint that it met with the clinical data that went in the same direction.  You have discussed at length what kind of patient population might fit in this disease category.
	But in our opinion, we have two well‑designed, randomized trials that were conducted that show Mitoxantrone effectiveness and that it is usually well‑tolerated in patients with multiple sclerosis.
	Based on the data for the Phase III study, when Mitoxantrone is given by short intravenous infusion at a dose of 12 mg per meter squared every 3 months, it slowed progression of neurologic disability, it reduced relapse rate‑‑and that is in patients, not to go into nomenclature, who have progressive forms of multiple sclerosis.
	With this dose and schedule, Mitoxantrone can be given for about 2 to 3 years based on the dose that we have decided to propose as a cap.
	In our opinion, this will still provide a substantial clinical benefit for patients who have a disease with no therapeutic option available to them and who are suffering from a serious illness.
	Thank you.  I am ready to take any additional questions you may have.
	DR. GILMAN:  Dr. Temple?
	DR. TEMPLE:  The data here are a cornucopia of things you'd like to know but don't yet know.  Could you elaborate a little on any of your future study plans‑‑in particular, the cap at 140 is obviously fairly onerous for people whose lives go on and whose disease goes on.  That is potentially susceptible to study, with close monitoring of cardiac function.  Do you plan that, or can you say anything about that?
	DR. GHALIE:  I can tell you about the studies that are currently ongoing and what we have proposed to the agency, in fact, to Dr. Katz' group, about what we intend to do in the future.
	We have currently three studies.  One was initiated about a year ago when the first of these data were available to investigators.  That is a study conducted currently in patients with primary progressive MS.  It is a pilot study, an d we have no data to share with you.
	The other two studies are pilot studies that are conducted in patients who have‑‑
	DR. TEMPLE:  Does "pilot" mean no control group?  Is that what that means?
	DR. GHALIE:  It is a placebo‑controlled study.  It is not powered as a Phase III study, but it is placebo‑controlled.
	DR. TEMPLE:  Okay.
	DR. GHALIE:  It is a methylene blue, as a matter of fact, controlled.
	The other two studies are single‑arm studies in patients who have failed Interferons.  As you know, there are two Interferons currently available, and each of these studies look at patient populations that have failed Interferon, the first one and the second one.  Those studies are really focusing on safety data first, but they include frequent MRI evaluation based on what we have learned from the experts in the field, to try to look at whether there is also efficacy assessed there.  There will also be EDSS evaluation.
	The other currently ongoing study‑‑and it is presented in the briefing document as well as in our discussion with Dr. Katz' group‑‑as a company, we are willing to do a post‑marketing registry to collect data long‑term on several hundred patients who receive Mitoxantrone in clinical practice, collect safety information on these patients long‑term while on Mitoxantrone or after they completed Mitoxantrone.  That hopefully will provide further safety information on this drug as you wish.
	DR. TEMPLE:  What about doses beyond 140?  I think Dr. Alberts said there was some suggestion that a protectant athiol [ph.] might be beneficial.  Does that seem like an area you plan to pursue?  We may ask you the same question in other fora, but I wonder if you want to say anything about it now.
	DR. GHALIE:  Certainly as a company we are interested in looking at potential ways to decrease this cardiotoxicity if we can.  These studies, as you know, are very complex to do.  Dr. Swain is really the expert here, and she knows how long it takes to be able to collect that information.  This is not something we can provide right away.  This is something we may have to do prospectively.  And that is again something that we are willing to discuss with you as you wish.
	DR. TEMPLE:  Actually, the candidate group would be people who are getting near their limit, and they probably exist.  At that point, you need to randomize to continue treatment, or continue treatment with athiol, or something.  But the candidate population doesn't have to be collected; it's out there for you.
	DR. GHALIE:  As you know, in the U.S., very few patients currently with multiple sclerosis have been treated with Mitoxantrone, so they are not at that point yet.  We may go to Europe and try to find out if this patient population exists.
	Dr. Alberts has a comment, I understand, presumably about athiol, which is his expertise.
	DR. ALBERTS:  I would just very briefly reiterate what I said before, that there is a very large chance that one could go well beyond 140 mg per meter squared, obviously, in a research setting.  In this population of people where you exclude people with pre‑existing cardiac dysfunction, any prior radiation to the chest, older age, and of course, prior anthracyclines, if you in fact use the population that should be treated, and knowing also‑‑something that I didn't comment on‑‑that dose intensity is involved in the cardiac dysfunction situation with anthracyclines and anthracene dions [ph.], so the point I'd make is that there is every reason to feel that you could go beyond this, and in fact, I think studies need to be designed to look at that.  And yes, I think athiol has a real potential role in this area.
	DR. GHALIE:  Thank you.
	DR. GILMAN:  Are there any other questions for Dr. Ghalie or the sponsor?
	DR. WEINER:  I'd just like to ask a question of Dr. Swain.  If you‑‑and I don't know if you can answer this or not‑‑but if you took 10,000 people, MS patients, between the ages of 20 and 30, who had no cardiac history or problems, and you treated them with 140 mg per meter squared of Mitoxantrone, how many of those would you expect to get into any cardiac problems?
	DR. SWAIN:  Well, all I can do is base a number on the information that was presented by Dr. Ghalie.  It would probably be in the one percent range.  You're still going to see it even at low doses.  You'll occasionally see it idiosyncratically, but it is not going to be high.  As Dr. Alberts said, the older age group is more susceptible‑‑although I would have to make a comment that your patients that you treated with this compound, I am sure none or very few of them had radiation, they were not supposed to have low ejection fractions.  They didn't have any of the risk factors that he mentioned.  So really, this is the group you are going to be treating.  It will be present, but it is going to be very low.
	DR. GILMAN:  All right.  Let me ask the sponsor if you have anything further that you would like to present to the Committee.
	DR. GHALIE:  Not at present, but in case some questions come up later and you would like me to come back, I would be happy to do so.
	DR. GILMAN:  Let me ask the Division if there is anything further that you would like to tell the Committee.
	DR. KATZ:  No.
	DR. GILMAN:  All right.  For the Committee, then, there are three questions laid out that we will be voting on; they are in the sheets before you with the agenda.  Dr. Katz has posed a series of questions, and I think it is best for the Committee to go back over those questions and see if we can at least succinctly respond to those issues that were raised.
	Yes, Dr. Weiner?
	DR. WEINER:  I am a non‑voting member.  If I have comments that I want to make regarding my view of everything, is this the time to say that before we are voting, or will there be a time later?
	DR. GILMAN:  You are certainly welcome to comment at any time during these deliberations.  You are a consultant to the Committee and as such, we would hope you would participate in the discussion.  You will not participate as a voting member, however.
	DR. WEINER:  Right.  Are we going to vote now?
	DR. GILMAN:  No, we are not going to vote now.  We are going to go through each of the questions that Dr. Katz wanted us to deliberate.
	DR. WEINER:  Right.  I just want to be able to give some views about it before the voting.
	DR. GILMAN:  You are certainly welcome to do that.
	DR. KATZ:  You won't have an opportunity after the voting, so speak now, please.
	DR. WEINER:  So, do you want me to speak now or wait?  I'm just asking that question.
	DR. GILMAN:  I think it's best if we go through each of the questions that Dr. Katz has posed.  We would like to hear your views if you have any about those questions, and then, when we come to the vote on the three questions before us, perhaps you'd like to make additional comments if you wish, and anybody around the table among the consultants can do so.
	Dr. Van Belle?
	DR. VAN BELLE:  Could we take a short break?
	DR. GILMAN:  Dr. Van Belle has asked for a short break.  It is 25 minutes of 4, and I know there are a lot of airplanes that are going to be taking off shortly that some of our members need to be on.  Maybe we should have a very short, 5‑minute break.  I don't want you to be uncomfortable during the deliberations.
	Let's take a very fast break, and please, be back here in 5 minutes.
	[Recess.]
	DR. GILMAN:  Let us start again, please.
	Dr. Katz has laid out a series of issues which I have abstracted, and we'll go back through, and we'll take these one at a time.
	Of course, he wants to know what our opinion is regarding the controlled trials supporting the sponsor's claim‑‑that is, does Novantrone slow the progression of neurologic disability and reduce the relapse rate in progressive multiple sclerosis.
	He expressed the concern that Study 902 included mostly relapsing remitting multiple sclerosis patients, not progressive multiple sclerosis patients, and therefore, he wanted to know whether there are two independent trials that demonstrate efficacy.
	So that's a question for the Committee.  Now, in light of what we have heard, I believe there are two trials that showed an effect in progressive patients.  I am now hearing that 902 cases, even though they are called relapsing remitting, those 15 cases were in fact showing progression.
	Is that a debatable question before the Committee, Dr. Katz?
	DR. KATZ:  Yes.  Just a clarification.  You said that there are two studies that show an effect in patients with progression.  I don't think we're up to the point yet where we know there is an effect‑‑just in terms of keeping things in order.
	DR. GILMAN:  Thank you.
	DR. KATZ:  I was first concerned about whether there was an appropriate population enrolled so that a claim, if one was granted, could be made in that population.
	DR. GILMAN:  Thank you.  I didn't say it right.  It now appears that in both studies, the patients had progressive multiple sclerosis, and that's the question before the Committee.  Is there a disagreement about that question?
	[No response.]
	DR. GILMAN:  Seeing no objection‑‑good‑‑let's continue on.
	Dr. Katz wanted to know whether relapsing remitting and chronic progressive multiple sclerosis constitutes a continuum of disease, or are they distinct pathophysiologically and in their responses to treatment.
	You will recall that in the Beta‑Interferon studies, the cases were limited to relapsing remitting, and as far as I know, there are no studies as yet of the Beta‑Interferons in chronic progressive cases.  All the same‑‑
	DR. WOLINSKY:  I think that's not exactly right, Sid.
	DR. GILMAN:  Okay.  Let's hear about that, then.
	DR. WOLINSKY:  If what we mean by chronic progressive is secondary progressive, then the answer is that there are studies which are complete and reported, studies which are complete and in the pipeline for reporting, and studies which are complete and under analysis, and studies which are in progress.
	DR. GILMAN:  Are the results available to us now?
	DR. WOLINSKY:  The only studies which are in the published public realm that I am aware of at the moment are the studies in secondary progressive that have been done in primarily Europe and I think with a few Canadian centers with Betaferon, which is basically the European brand name for Betaseron, and those show the now well‑expected reduction in attack rate, reduction in MRI activity, and a modest slowing of disease progression.
	The studies from Rebif [ph.], which is similar to some other drugs, have been publicly presented in a number of forums but have not yet been published, and those show similar things in terms of relapse rate and in terms of MRI activity but failed as an overall to reach their primary goal of slowing progression.  They did show some benefits in subgroups.  The other two studies are not available.
	DR. GILMAN:  Thank you.  That is helpful to my own way of thinking.  But I'd like to hear further about the question of whether these are different entities, relapsing remitting and the various forms of progressive disease, primarily primary progressive.  
	I wonder if we could have some discussion about those questions?
	DR. WEINER:  I think there is a continuum, but I think there is a differential between the relapsing remitting forms and the progressive types of disease that do have either relapses or regular progression with them.  And I think another point that helps distinguish them‑‑and we didn't talk about it‑‑is that if you're looking immunologically, there are certain changes that occur in the immune system in terms of chemokyne [ph.] receptor expression, interferon‑gamma secretion in IL‑12.  It is seem more in the progressive forms of the disease than in the relapsing remitting forms, which would imply that the progressive form from an immunologic standpoint is also more active and may represent a different form or type of the disease.
	So I think there is evidence that there are two different broad forms.
	DR. GILMAN:  Jerry?
	DR. WOLINSKY:  I could argue it the other way around.
	DR. GILMAN:  Suffice it to say there is not universal agreement.
	DR. WOLINSKY:  There is no question, at least in my mind, that as one gets into patients who have increased amounts of clinical disability, they have increased burdens of disease on their MRI, less of the acute measures of activity that we are used to seeing, like gadolinium enhancement and easily‑defined clinical attacks, and probably‑‑my bias‑‑have accumulated more easily‑found abnormalities in their immune system.
	DR. GILMAN:  Does any other Committee member or consultant want to address that question?
	[No response].
	DR. GILMAN:  Well, Dr. Katz, you have heard the two sides of this.
	DR. KATZ:  Yes.  In my view, anyway, I think the question takes on a little less urgency given that the Committee has answered the first question in the affirmative.  In other words, the question about how close they are pathophysiologically was designed to get at the question of if these were two different patient populations studied, could we take strength from one, from the relapsing remitting, to make an overall claim for progressive patients.  But I gather the Committee thinks that both studies included progressive patients, which was the primary question I was concerned about.
	If I could  just back up to that question, if I could just hear some discussion about what the evidence is on which you would base your conclusion that the patients in 902 were progressive, whether you call it relapsing progressive or‑‑well, they would be called relapsing remitting‑‑but is it the EDSS at baseline?
	DR. GILMAN:  As I heard the presentation by the sponsor, these patients had an EDSS that increased, that worsened over time.  In other words, these patients did not return to baseline and therefore would be viewed as having progression‑‑worsening.
	DR. WOLINSKY:  I think it's fair to say that these patients have aggressive disease in the mid‑portion of the EDSS scoring range.  It is very hard to differentiate beyond that in group data.
	DR. WEINER:  I would think that one could easily argue and be confident that there was a progressive component to the 902 as well when you define progression as accumulated disability in a disease that is moving in the individual patient, causing more neurologic impairment.  And that's what progression is.
	DR. GILMAN:  Dr. Temple?
	DR. TEMPLE: I'm sorry‑‑I thought I had learned that there was a difference between people who go up, up, and stay up, and people who inch up slowly.  You are saying that a) that is hard to discover and b) it may not matter so much?
	DR. WEINER:  I am saying that obviously, there is a semantic issue here, and obviously, you are in a transitional phase, and because you are in a transitional phase, it is not going to be all one or all the other.  But if you are talking about treating an MS patient, and you are talking about the fact that the problem with the disease is that it is a progressive accumulation of neurologic disability, even though we may argue about the semantics of an attack and coming back or whatever, in my view, the people in the 902 are progressive in the sense that they are getting a progressive neurologic accumulation disability.
	DR. TEMPLE:  So they are transitional.
	DR. WEINER:  They are worsening.
	DR. TEMPLE:  And we don't want them to worsen.
	DR. GILMAN:  Dr. Grotta?
	DR. GROTTA:  But at the same time, I am also hearing that this treatment is not advocated for the patient who has a relapsing and remitting‑‑not all patients who have a relapsing and remitting course who have accumulated an abnormal Kurtzke score‑‑in other words, the patient who has a hemiparesis and doesn't completely return to normal‑‑there has to be some amount of disease activity over the last year in the sense of multiple attacks.
	To me‑‑and I guess that's what I am struggle with, is whether that needs to be spelled out‑‑and to me, the key conceptual slot is the one that Dr. Lublin presented where he was showing the fact that the progressing slope can be either an intermittent one or a progressive one, but it is sort of the fact that patients are deteriorating or progressing, and I think we are struggling, or at least I am struggling, with how to get the proper wording for that.
	DR. GILMAN:  Dr. Temple?
	DR. TEMPLE:  My understanding was that half of the people in 901 did not in fact have exacerbations in the last year, although they were in one way or another worsening or had achieved a state where they were reasonably bad off, but they didn't actually have attacks.  Isn't that correct‑‑that you could divide it into two groups‑‑although the mean number of attacks was in the neighborhood of one‑and‑a‑half, half of the population didn't not have any during the preceding year?
	DR. GROTTA:  But they were worsening.
	DR. TEMPLE:  Oh, yes.
	DR. GROTTA:  In other words, they were going up on a steady way, or they were going stepwise.
	DR. TEMPLE:  Right, right.
	DR. GROTTA:  But the fact is that over the last year, they were getting worse.
	DR. TEMPLE:  Yes.  I thought I heard you say that they had had exacerbations, but if you didn't, forget it.
	DR. GILMAN:  Dr. Penix?
	DR. PENIX:  The study was performed with specific exclusion of patients with primary progressive MS.  There is evidence that some patients with relapsing remitting MS may benefit from this.  And again, I hate to belabor this, but I am having a problem with this indication in patients with progressive multiple sclerosis.  Perhaps, since we have a subtype of MS that is called secondary progressive MS, and it appears that these patients will benefit from the drug, I just wonder if there will be confusion‑‑obviously, there may be some confusion from the patients who presented their testimonials, because they specifically say that they want us to look at this drug for treatment of secondary progressive MS.  And again, you say that you excluded patients with primary progressive MS.
	So again, perhaps patients with worsening MS would help solve some of these issues.
	DR. GILMAN:  Dr. Katz: 
	DR. KATZ:  Well, yes.  What I wanted to hear was whether or not, whatever you call these patients, there is general agreement that the studies looked at the population that was worsening or progressive.  Knowing that, we can work on the actual‑‑assuming that you recommend approval and that we approve it‑‑we can work on the specific language.  But we will try to make clear in labeling who these patients were.
	DR. GILMAN:  All right.  The next question is whether these two trials show slowing of progression.  And again, Dr. Katz is referring to a design that specifically shows slowing of progression, that is, by having an effect upon the fundamental pathology in the disease, in which case one would expect to see a trial that went on after cessation of drug, with an evaluation of the patients at endpoints post‑drug administration, to determine whether the placebo group ran in parallel to the drug‑treated group, or did the two connect very quickly after cessation of the trial, suggesting a symptomatic treatment alone, or symptomatic effect alone.  Let's have some discussion about that from our consultants.
	Dr. Penn?
	DR. PENN:  Yes.  I feel moderately comfortable with that data, but clearly, if we were going to look carefully at that, it would take more patients and a study design that, as far as I am concerned, can't be done very easily.  That leaves us with a clear‑cut dilemma of do we say on the basis of not really solid facts, just on one study, whether or not looking at that one‑year period that we have, that is enough for us to feel that that is the case.
	My general impression is that, yes, I would be willing to give them that, but I think we're going to vary in the  Committee about our judgments on that.
	DR. GILMAN:  Dr. Lipton?
	DR. LIPTON:  The evidence that we have before us that speaks to that issue is the evidence from the blinded assessments of the disability scales, the evidence that following open‑label withdrawal, there wasn't exacerbation, and if we accept the MRI as a surrogate marker, the evidence that accumulation of MRI lesions was slowed.
	The one thing I would want to see that is missing is blinded withdrawal as opposed to open‑label withdrawal from treatment, and the evidence is sufficient for me, although I would like to see that blinded withdrawal piece.
	DR. GILMAN:  Yes.  The MRI will be another set of questions for us, actually.
	Dr. Temple?
	DR. TEMPLE:  I'm not sure how critical that question is, so you are hearing a slight disagreement between us.  The question of whether you change the course of the disease has arisen principally when there was a pharmacologic effect that made some sense as a possible source of the improvement.
	Treating someone's lymphocytes doesn't make a really persuasive case for improving the neurologic symptoms of something.  So I am not as obsessed with that as I usually am.
	I do want to observe, though, that the fact that there is a limitation on dose currently at 140 gives a perfect opportunity to test this very question, because we don't know yet whether it's better to keep treating after 140 or not, so you get a chance to see something about the persistence of effects afterward, the possible benefits of continued therapy, and a whole raft of things.
	So I want to push again for the possibility that that is something that can be explored rigorously.
	DR. GILMAN:  Dr. Katz?
	DR. KATZ:  Yes, there probably is a little bit of a disagreement between Dr. Temple and myself, because as I said earlier, I am hesitant to make a claim for a particular phenomenon, let's say progression, based on what we think we understand about how the drug is working, because we never really understand that very well, and that's why I would prefer some sort of an operational definition, some sort of a study design that will just get at that question empirically, without having to rely on assumptions that we can have a test.  So perhaps there is a disagreement.
	I think the question of the progression is an important one, because it will have an important effect on how the thing gets labeled if it is approved and subsequent marketing and everything else.
	DR. GILMAN:  I have a similar view to Dr. Katz, but perhaps after we discuss MRI as a surrogate marker, we could get back to this question, because I think the evidence is pretty good that MRI is a good surrogate marker, and we are finding an effect upon MRI.  Therefore, it does appear that there is an effect upon disease progression as indicated from the MRI.  But I think we should next turn to the MRI.
	Dr. Dahut?
	DR. DAHUT:  I too would agree with Dr. Katz, especially when you have a drug which at this point we believe we can only give for a fixed period of time at a fixed dose.  If, 2 to 3 years after the drug is stopped, regardless of what therapy people went on, if people came back to thes mae point, it would be tough to justify using the drug, particularly‑‑although the toxicity profile in this study was very good‑‑we have to remember the patients were young; 45 was the top of one group, 55 in the other‑‑and eventually, there will be older patients who will want the drug.   In the prostate trials, there was 20 percent incidence of congestive heart failure; in an older population, I understand.   So if, 2 to 3 years after the drug, basically, the curves came together at that point, any type of lifelong toxicity would be tougher to justify.  So I think it is an important issue.
	DR. GILMAN:  Dr. Temple?
	DR. TEMPLE:  How long the effect lasts, whether it persists, whether there is a catch‑up phase‑‑those are all very interesting questions, and I certainly would not dismiss them.  But it is not easy for me to see how a drug that affects your lymphocytes and things like that can be doing anything but slowing progression during the time it is being taken.  That is in contrast with a drug that has a pharmacologic effect where it might be doing nothing at all to the underlying disease, and you still might look better.  Maybe you think this is a distinction without a difference and isn't worth talking about too much, which is also a possible interpretation.
	DR. GILMAN:  Dr. Katz:
	DR. KATZ:  Yes, I think that's just a different definition of progression.  To say that it prevents progression while it is being given, I would not view that as a progression sort of claim.  It could very well be what I would call a symptomatic effect.
	DR. TEMPLE:  Let me give you an analogy, and then I'll forget it.  If you could show that an antibiotic could slow the progress of coronary artery disease, which is a hypothesis that is going on right now, it would not be plausible to think that the symptoms of coronary artery disease, like angina and things like that, were being treated by the antibiotic, because an antibiotic affects bugs, not people.  The effect might be short‑lived.  The bugs might grow back as soon as you stop the drug.  That would mean maybe you wouldn't think it was very good because you would have to be on the antibiotic all the time, but it would challenge the question of whether you had slowed progression; you have just slowed progression while the drug was there.
	In contrast, if you slow heart failure by giving an ACE inhibitor, someone is entitled to ask you are you merely treating the heart failure before it got there, which is a slightly different issue and really goes to the question of whether you are preventing actual changes in the heart muscle. 
	I think they are two fundamentally different situations, but it may not matter that much.
	DR. GILMAN:  All right.  The intermediate question before we get to the question about MR scanning is that the trials were unblinded, in a sense.  Study 901 used blinded evaluators, and 902 did not.  Diagnosis of relapses in 902 is made by neurologists aware of treatment assignment.  So the question posed to us is what is the effect of unblinding on treatment outcomes in these two studies.
	Dr. Grotta?
	DR. GROTTA:  Well, I think we'd all rather have all of the endpoints blinded, but the primary endpoints of both studies seem to me to have been blinded and were robustly positive.  So for instance, the clinical scales in the first study and the MRI reading in the second study were both done in a blinded fashion.  So I am not that bothered by the blinding issue.
	DR. GILMAN:  Let me leap ahead to the question of whether there are two well‑controlled, placebo‑controlled trials, with appropriate blinding, then, that show clinical efficacy in that one of the trials, 901, had blinding to clinical outcome, and 902 did not.
	Dr. Katz?
	DR. KATZ:  Yes, 901 we learned did not have blinding with regard to relapses, and since the sponsor is requesting sort of two indications, in a sense, an effect on progression, which we will get back to, and an effect on relapses.  So I asked the question whether there is a bonafide effect here on relapses.  Both studies are unblinded with regard to relapses.
	So if you could discuss that matter first, I'd like to hear that.  The other thing‑‑and Dr. Grotta has already given his opinion on this‑‑the other measures in 901 were ostensibly blinded‑‑the EDSS, the Ambulation Index.  The treatment effect sizes were relatively small, and there were some that people have discussed, some potential breaks in the blind because of very high instances, for example, of nausea, vomiting‑‑or, nausea, anyway‑‑alopecia, amenorrhea.
	So when we are dealing with treatment effect sizes that are in the range, let's say, with regard to the means, anyway, that we have seen in 901, I would be interested to know what people think about the potential effects of unblinding even on those.  But first, if we could look at the relapse question, that would be my preference.
	DR. GILMAN:  All right.  Let's deal with the relapse question.  That is just fine.  I think it has to be said that neither trial had blinding for relapses.  That is what we have heard, anyway.  I don't think there is going to be disagreement on that point, and I see asset around the table, so I think that's the answer to your question.
	DR. KATZ:  Well, yes, that's a factual‑‑but does the Committee think that nonetheless they should be entitled to a claim to treat relapses?
	DR. GILMAN:  Well, I think we should get to that question, ultimately, that is obviously before us.
	Dr. Grotta?
	DR. GROTTA:  Well, I agree that the clinical relapse rate was unblinded, and I guess I'd like to hear from the MS authorities as to how closely‑‑and I think we heard at least a beginning discussion‑‑as to how closely does the MRI appearance of gadolinium enhancement correlate with clinical relapses, because we did see a significant reduction in the incidence of new gadolinium lesions on the MRI scan in the second study that was a blinded assessment, and one could argue that the appearance of gadolinium‑enhancing lesions is a form of relapse.
	DR. GILMAN:  Dr. Weiner, Dr. Wolinsky?
	DR. WOLINSKY:  Probably the data that speaks to this test is a meta analysis that Ludwig Kapos and other investigators have done across fairly large datasets in which serial MRI is available, or MRIs at baseline and relapse rates.  So the relative risk‑‑whether you want to look at relative risks or whether you want to look at correlations, there is a correlation between the amount of enhancement you see on a particular scan and the likelihood of a subsequent relapse‑‑but it is not high.
	DR. WEINER:  First of all, if you look at all the studies of correlation between MRI and clinical outcomes in multiple sclerosis, the strongest correlation that is seen in virtually every study is a correlation between gadolinium‑enhancing lesions and relapses.  There is some debate in terms of T2 volume and progression and other things, but the strongest correlation, although it may not be perfect, because there are silent areas, is between gadolinium‑enhancing and relapses, and that's something that we saw in our study as well.
	DR. GILMAN:  Dr. Lipton, then Dr. Katz.
	DR. LIPTON:  I guess my question to the MS experts‑‑since I don't do MS trials, I don't know this‑‑is to what extent do you think relapse can be assessed in open‑label fashion without bias.  How powerfully could knowledge of treatment influence the assessment of relapse in this setting?
	DR. WEINER:  You're talking about the clinical relapse, not the MRI?
	DR. LIPTON:  Clinical relapse.
	DR. WEINER:  Yes.  Of course, it depends on how the relapse is defined, but I think that if the relapse is rigorous defined as it was defined here, and there are clear neurologic findings like intranuclear ophthalmaplegias [ph.] and optic neuritis and ataxia or whatever, I think that it is pretty clear.
	DR. WOLINSKY:  I think we have seen an effect on what are called severe attacks, and I am convinced that those are the ones that are easy enough to count, hard enough to get too confused about.  If the only effects we saw were on, quote, "mild" attacks, those can be much more easily affected by the extent of blinding.
	I think the fact that there was a bonafide attempt to provide some level of blinding, even though it will never be perfect in any study, assures me.  And while I don't like the tightness of the connection between the activity on the MRI, that is, gadolinium activity, and relapse rate, the fact that both of them are going in the same direction is quite reassuring.
	DR. GILMAN:  With respect to the problems in blinding clinically when a patient being treated has nausea, vomiting, hair loss, I don't think any trial could possibly deal with that, no matter how large the series, in a drug such as this.  So the point is a good one, Dr. Katz, but I don't believe that the sponsor could be expected to do a perfect study in the light of those side effects.
	Let me ask our oncology consultants if they have any other comments about that?
	DR. SWAIN:  No.  I would agree with you.  You don't want to give the placebo group something metagenic just to make it unblinded‑‑or blinded.
	DR. GILMAN:  Dr. Dahut?
	DR. DAHUT:  I would point out at least in the blinded trial of Sermin [ph.] in prostate cancer‑‑and Sermin is a drug where there is a well‑known side effect‑‑about 30 percent of the patients were wrong, and the physicians were often wrong, too.
	So there is a very powerful placebo group.  People will often develop side effects that they believe the drug has.  So I think it can be done.  If there is total alopecia, and there is not, that's fine.  But I think that actually, it can be blinded, but it is going to still be a minority of the patients.
	DR. GILMAN:  Dr. Katz:
	DR. KATZ:  I had a question for Dr. Wolinsky.  Suppose a study is done that has no MRI in patients with exacerbations.  Would you be comfortable in the future permitting a trial or concluding a trial, in effect, on relapses if it was unblinded?
	DR. WOLINSKY:  I would have to look very,k very carefully at the design and the conduct.  I might, but then I would also look very carefully at the magnitude of the outcome.  And if you are saying there is no comparator group, as opposed to unblinded, no, I have no confidence in that whatsoever.
	DR. GILMAN:  Dr. Temple?
	DR. TEMPLE:  Just to be sure I am hearing it right, what I heard was at least some view that if the exacerbations are reasonably well‑defined and are serious ones, it is at least moderately credible that blinding would not influence that outcome too much and that people are at least somewhat buttressed in their slightly warm feeling about that by the MRI data.  And we should tell everybody that you should try to blind the determination from now on about whether an exacerbation has occurred.  It is possible to do it‑‑it is a little more difficult‑‑but it ends a lot of questions.
	DR. GILMAN:  It would make our task easier, I must say.  
	All right.  Coming back to the question about unblinded trials, I believe we have one trial in which clinical outcome was blinded, or clinical status was blinded, and one in which it was not.  I wonder if there is any debate about that question?
	[No response.]
	DR. GILMAN:  All right.  Let's move along, then.  The next question has to do with use of MRI as a surrogate marker.
	Dr. Katz mentioned that it has not been validated‑‑that is, an effect on the MRI has not been shown to predict clinical effect.  Can we hear something about that?  You have touched on it slightly, but not specifically to this kind of question.
	Dr. Weiner or Dr. Wolinsky?
	DR. WOLINSKY:  I think it depends on how you look at it.  I think we have had a number of trials now, both successful and, unfortunately, unsuccessful trials in which the MRI correlates with clinical effects have been very good.  We have had an occasional trial where the correlates are not so good‑‑that is, where an effect, particularly on gadolinium enhancement, seemed not to support a clinical effect as there was no clinical effect.
	The question, though, that I think you are raising is a much more complicated question, and that is can we take to the bank‑‑at least, this is the way I would see it‑‑the data from 902 which showed an almost complete ablation of enhancement activity after the course of 3 months of treatment, to believe that that will always correlate with good outcome one or two or three years later.  I don't think we have any data that speak to that.  And that is a predictive surrogate rather than a surrogate which is, if you will, just a supportive piece of evidence of drug effect.
	DR. GILMAN:  Dr. Weiner?
	DR. WEINER:  I don't know what the question is exactly in terms of the surrogate or the MRI.  I guess the question is with the changes on the MRI, does one expect that to translate into benefit for the patient‑‑is that the question?
	DR. GILMAN:  Dr. Katz?
	DR. KATZ:  Yes.  Basically, the predictive surrogate is the sort that the regulation talks about and that in general people talk about, but here, there is no sense from the sponsor, anyway, that they had anticipated that it would be a surrogate in the sense of predicting what happens two or three years down the road.  That is why we talked about the concept of the so‑called contemporaneous surrogate, which is is it a reflection of the underlying pathology at the moment, and at that moment‑‑let's say at six months‑‑does that mean the patients are better off given the response on the MRI, clinically, importantly.
	DR. WEINER:  I think the answer to that is yes, in my mind, anyway.  And there is data that is accumulating that the MRI is also a predictive surrogate; some studies that look at MRI lesion burden, et cetera, and how the patient is 10 years later, and there are correlations that patients whose MRIs have more lesion burdening, et cetera, 10 years later don't do as well.  So those aren't perfect studies, but that data is beginning to accumulate, so things are moving in that direction, and I think I can confidently say in my own mind, anyway, that what was shown in the study here with MRI shows that during the time of treatment, the disease process itself was lessened.
	DR. GILMAN:  Well, that becomes key, because 902 did not have blinding to clinical status, and if we are hearing that in fact the MRI serves as a good contemporaneous surrogate for disease and therefore clinical status, then some of our concerns about the lack of blinding in Study 902 are somewhat assuaged.
	DR. WOLINSKY:  I think the level of understanding or insight into what MRI is telling us‑‑I think we are far enough along to be able to say, particularly with where we think a drug like Mitoxantrone would be working, and what we are seeing on the MRI evidence in these cases is that the influx of new cells into the brain to initiate a new lesion and create a new T‑2‑weighted abnormality is clearly being stopped.  It doesn't say anything is getting into the brain, and of course, the level of MRI analysis here was not adequate to tell us whether we are having any effects on pre‑existing lesions.
	DR. WEINER:  I would just like to turn your comment around, Russ, in terms of a study that only had clinical.  I think we are beyond that.  I don't think there can ever be a study now testing a drug that has a putative anti‑inflammatory action in multiple sclerosis without MRI.  I think it has come that far.
	DR. KATZ:  Let me just ask a question that's not necessarily on the table for this application.  Have we come far enough to say that if you had a trial that showed an effect on MRI and did not show an effect on clinical outcome that that would be‑‑
	DR. WEINER:  You were at the meeting.  We had a big meeting to discuss that in terms of the MRI as surrogate marker here in Washington.  The feeling of most of the people who came was that as far as gadolinium‑enhancing lesions, they felt that that did reflect attacks, et cetera.  There was still some debate on some of the others.  But I would predict, rightly or wrongly, that we will one day get to the point where the MRI could be a surrogate marker and that it will be, because it will be linked, and it will not be possible to have changes on MRI not linked to clinical.
	DR. GILMAN:  Dr. Temple?
	DR. TEMPLE:  That all seems like a really important discussion, and because of the people listening, it seems worth saying that the potential use of MRI here in this case is in support of one study that has a clinically meaningful endpoint.  That is very different from the conclusion that the MRI data alone, without any clinical data, might support approval, and I wouldn't want anybody out there to forget that distinction.
	Before you can accept a surrogate, you have to have some idea of the quantitative relationship.  You have to know what a given change might mean clinically‑‑otherwise, how can you weigh it against the risks?  So that's a significant additional step.
	The burden the surrogate is being asked to support here is considerably less.  I'm sure everybody here knows that.  I just worry about the outside world.
	DR. GILMAN:  Thank you.
	Dr. Grotta?
	DR. GROTTA:  I'd just like to make the plea that‑‑I'd hate to see trials, certainly in stroke, and I would think in MS, too, to be done without a clinical correlate.  And I don't really want to spend the time to debate this at this point because I have a plane to catch.  But the fact of the matter is we need to know what to go back and tell our patients about the effect of a drug.  I can say from Study 901 that if one of these patients of the two who had the secondary progressive, and perhaps the third one, who testified before us today, received this drug‑‑that those patients had a 25 percent chance of deteriorating by one or more points on the Kurtzke scale in the next two years with placebo, and with this treatment, they have an 8 percent chance of deteriorating one or more point on the Kurtzke scale.  To me, that is understandable; that is something patients understand.  They don't understand the number of MRI lesions.  I think we need to keep the clinical scores.
	DR. GILMAN:  Let me turn to a subset of those issues, which is that the treatment may interfere with the measurement itself.  That is, is there any evidence, or are we suspicious at all that the drug interfered or interacted with the lesion or the MR scan itself, namely, with the gadolinium, I guess is the question.  I don't know of any such evidence.  Can anybody comment on that question?
	DR. WOLINSKY:  I think that sets a new hypothesis that is for me beyond belief.
	DR. GILMAN:  Theoretically, it is possible.  Is there any other comments about that?
	[No response.]
	DR. GILMAN:  I think we will leave it there, then.  The third subset question is the drug conceivably could have a benefit on the surrogate marker but not on the disease itself.  That is, the drug could conceivably even benefit the surrogate but worsen the disease.
	As I have seen the data, there is no evidence of that in these two trials, but I want to hear from the rest of the Committee about that question.
	DR. LIPTON:  I thought it was a valuable cautionary note, that in a context where the surrogate and the clinical measures improve together, it seems unparsimonious to think that's what is operating here.
	DR. WEINER:  I would agree.  Just getting back to your question and your comment as well, I agree 100 percent that all of our trials need to have a clinical outcome.  There is no question about that.  I think the surrogates can be used in Phase I and Phase II.  Also, the point I was making is that I would be very reluctant to approve something in multiple sclerosis in Phase III that didn't also show something on MRI in addition to the clinical.  And I don't think that necessarily would happen, but I agree with what you and Dr. Katz said about the clinical.
	DR. GILMAN:  The next subset of that set of questions would be what specific MRI measure reflects what specific brain pathology.  In other words, what are we seeing when we see gadolinium enhancement was the question.
	I think the answer is that it shows a breakdown of the blood brain barrier.  Are there other comments about that question?
	DR. WOLINSKY:  This is picking up some measure of the inflammatory process that we currently believe is an important early event in lesion formation, at least for some lesions.  And there is good histologic evidence for that now, and there is good correlative pathologic evidence.  It probably doesn't pick up all lesion development early.
	DR. WEINER:  I would agree with that.
	DR. GILMAN:  Thank you.
	Next is the hypothetical situation in which the effect of the surrogate marker is so small that it can never be reflected in a meaningful clinical benefit, irrespective of the sensitivity of the marker.  As a consequence, what are the Committee's views on the utility of MRI as a marker?
	I think we have addressed that issue pretty well thus far, unless there is any other comment about that.  There clearly was a set of changes in the MR scanning with 902 as a blinded study, and the effects were fairly substantial.
	Dr. Grundman?
	DR. GRUNDMAN:  Just one quick question.  Can anybody explain to me why going from Month Zero to Month One, the number of mean MRI lesions could double, say, from 5 to 12 in Study 902, but the EDSS score only went up by 0.01 point, if the correlation is that good.
	DR. WOLINSKY:  The correlation is not that good, and I could show you many patients that we followed with serial imaging and spectroscopy where the total enhanced tissue volume has been in excess of 7 mls, which is more than the T2 lesion burden in many of the patients in the study, and they have had no symptoms at the time.
	DR. GILMAN:  It's an anatomical issue, isn't it?  It depends upon where the lesion is located with respect to the principal motor and sensory pathways.
	DR. WOLINSKY:  With all due respect, Dr. Gilman, it is much more complicated than that.
	DR. WEINER:  I was going to make another point that we haven't discussed that I think is very important.  It is not only an anatomical issue, but the brain has a lot of plasticity, so that if you have damage to one area, other areas can then take over.  So if you look at someone with optic neuritis who recovers, and you do functional imaging, there are other parts of the brain that are now picking it up.  So what is happening is that you are using other parts of the brain, but then, as the disease progresses, you go over that threshold, and then you get an irreversible deficit.  So I think things are happening and putting the patient at risk later on for neurologic disease or deficits.
	DR. GILMAN:  All right.  Is there any other discussion about MRI as a surrogate marker or the results of theses studies?
	[No response.]
	DR. GILMAN:  All right.  hearing none, Dr. Katz, I believe we are close to asking the question whether the sponsor has proven efficacy, and I am ready to address these questions.  So, are there other issues that you want to ask us about?
	DR. KATZ:  Yes.  You were going to get back to the question of progression of disability claim after the MRI discussion.
	DR. GILMAN:  Thank you.  You are quite right.
	Then, just to paraphrase, in fact, is there evidence of a chance in progression from what you have heard‑‑let me ask the consultants and let me ask the Committee also, if the consultants want to comment first about the claim of a change in progression contemporaneous.
	DR. WOLINSKY:  There was a lesser amount of accumulated disability at the end of the study than there was in the beginning of the study in the patients who were treated.  This concept of progression is a very thorny issue, and I am not sure exactly how to define it.
	I do know that the EDSS scores were different, and I think that's all I could say.  I am not clear about the concept of progression.  It is likely that there was some meaningful, statistically meaningful, and perhaps for the patients, important, change in the tempo of their disease that happened temporarily with treatment.
	DR. WEINER:  Yes, I think there was an effect on progression.  I actually liked Dr. Lublin's slide‑‑and maybe this is some wording we might get into, or it might be recommended‑‑that rather than an effect on secondary or progressive disease, worsening forms of relapsing and progressing disease.  I think that that's the key‑‑it is the worsening of the disease and the worsening form of both the relapsing or the progressive disease, and I think that that was shown.
	DR. GILMAN:  Dr. Katz?
	DR. KATZ:  Again, the word "progression" has been thrown around a lot, and it occurs two places in effect in the sponsor's proposed labeling.  I think we have already dealt with the question of who the patients are and what sort of disease they have.  We can figure out a word to describe them.  What I'm talking about here is the effect of the drug on the disease, and the use of the word "progression" could describe that.
	I agree with you, and obviously, I think Dr. Temple and I even have a disagreement about how it best ought to be defined or at least looked for.  So it's a complicated matter.
	DR. GILMAN:  Dr. Kawas?
	DR. KAWAS:  Somewhat in that same vein, I am a little bit surprised that I am about to say I have come to the conclusion that this drug probably does have a clinical effect.  But I don't understand how it is different from the clinical effect for the drugs that are already approved for MS right now, and I wanted to ask the two MS experts on our panel if, when they are talking about progression and that there is an effect on progression of functional disability or progression of whatever, is that different from the other drugs that are available?  Is this a different effect on the disease, or do you think we are looking at something similar to the Interferon in terms of clinical significance and magnitude?
	DR. WEINER:  Well, I think if the disease is one disease or a subset of diseases, and there are immunomodulatory therapies that are affecting it, they ultimately have to be working through similar pathways.  And I would believe or like to believe, and there are theories, that the way the Interferons are working or the way the Copaxone is working or the way the Mitoxantrone is working will ultimately be in a similar area, whether it is decreasing IL‑12 [ph.], whether it is decreasing migration of lymphocytes, whether it is decreasing TNF, if we believe the immune hypothesis of the disease, which is what the current feeling is.
	So I think that they ultimately have to be working in a similar way.  Where does it fit in terms of the other drugs?  We only would know that if they were compared directly against the other drugs.  There is some suggestion from the data presented that the Mitoxantrone might have stronger clinical effects because it was used in more active patients.  Whether that will be shown to be true if you compare them directly to the other drugs, I don't know.  We'd have to see a direct comparison.
	DR. KAWAS:  So, by your definition of progression, does Betaseron affect progression?
	DR. WEINER:  Betaseron‑‑I would use the word "worsening" and progression, and I would say yes.
	DR. KAWAS:  Thanks.
	DR. GILMAN:  You'd say yes, based on what?
	DR. WEINER:  This is again a hypothetical question, but I would say yes based on the fact that, for example, if you look‑‑again, we are not now talking about controlled trials, which is comparing one thing to the other‑‑but if you look, there are linkages, for example, between the number of attacks people have and later disease progression or predicted value of how they are doing.  And although it may be a certain article of faith that if you are decreasing relapse trait or whatever, you are affecting progression.  Again, I interpreted the question as more of what I thought or what I would postulate, not what necessarily the hard evidence is, and that hard evidence only comes with direct comparison and long‑term studies.  But there are linkages between number of attacks and how people do later on in their disease; there are linkages between MRI lesions and how people do later.  So I think the disease‑modifying drugs, although imperfect, if they are affecting gadolinium lesions and if they are affecting T2 volumes, and those are shown to be linked, although imperfectly, they ultimately are going to affect progression or worsening of the disease.
	DR. GILMAN:  That may be, but what we have seen in the two trials, the Avanex and the Betaseron trial, has been reflected in only relapses, not in progression, except for the study that Dr. Wolinsky mentioned.
	Go ahead.
	DR. WOLINSKY:  I think it depends on what the various review committees accepted as a definition of progression when those particular studies were presented in a room like this.  I think it is fair to say in the Betaseron trial, the original one, that there was a trend that suggested a reduction in accumulated disability‑‑I'll use the same term I used a while ago‑‑but the size of the study was probably inadequate to be statistically significant.
	I think the trial for gluteramir acetate showed a magnitude of an effect which is very similar to what we are seeing today, but we are looking across slightly different patient sets, so I don't know how translatable that data is.
	The European secondary progressive trial reached statistical significance for this kind of outcome measure.  So in my own mind, because of my problems in how I define progression, feel that we probably are seeing a third class of immunomodulator, one with very respectable toxicity, or toxicity to be respected, which provides another alternative for trying to modify the disease course in patients with MS, and it will be our problem, I hope, to figure out how wisely to use these.
	DR. GILMAN:  Dr. Temple?
	DR. TEMPLE:  We like most what's actually in the labeling, and Copaxone does not have any claim to reduce the level of disability.  You could say that they were moderately close to such a claim, but they weren't given it.  And one of the Beta‑Interferons has a claim for prevention of progression or whatever you want to call it, but only in relapsing remitting disease.
	Now, to the extent that that's a mixed bag, who knows what they really have, but at least at the moment, there isn't anybody who has a claim for prevention of whatever this is in worsening disease‑‑not yet.  That doesn't mean those don't have an effect, it's just that they are not labeled that way.
	DR. WOLINSKY:  That's why I tried to be very careful with that answer.
	DR. GILMAN:  Dr. Dahut?
	DR. DAHUT:  Just one quick comment on this.  I think Slide M‑39, which shows the number of patients in each group whose EDSS showed a greater than 1.0‑point deterioration over 6 months, is probably the most important group in my mind, because we said earlier that a one‑point deterioration was meaningful clinically, and this was for 6 months, so I think that's an important endpoint.
	Now, it is important to know that while it was statistically significant, it was at 0.045, and you have small numbers, which means if you had one more patient in the Mitoxantrone arm who didn't reach that, it wouldn't have reached statistical significance.
	So I think we have to be aware that we only have 62 patients treated in the 2‑3‑month treatment arm, and just one or two patients a few ways may change our perception of the data.  So while I think there is sort of a bias and an accumulation of information that something good is probably going on, it is certainly not overwhelming under any one particular test.
	DR. GILMAN:  All right.  We're going to come next to the three questions before us unless there is anything else, Dr. Katz,  Dr. Temple, that you wanted to hear from the Committee.
	DR. KATZ:  Yes.  Again, just on the progression, I am trying to get a sense of how the Committee in general feels about that.  I don't think I got a clear sense about that.
	DR. PENN:  Shall we just take a vote on whether we think there is some evidence, substantial evidence?
	DR. KATZ:  Well, the first question asks if you think they have substantial evidence to support their proposed claim and if you think‑‑
	DR. PENN:  And that is part of their claim.
	DR. KATZ:  ‑‑that is part of their claim‑‑so if you think it does, and you think relapses are involved in that‑‑
	DR. TEMPLE:  Would people be happier if it said "neurologic progression" or something like that?  Does that remove the implication of something eternal?  I mean, what else‑‑that doesn't make any difference?
	DR. GILMAN:  No, no.  The request for approval is to slow progression of neurological disability‑‑the first part of the statement.
	Dr. Grotta?
	DR. GROTTA:  I think the problem is still the use of the word "progression," and I think‑‑and I don't want to put words in your mouth‑‑but I think what you are wrestling with is that that implies a biological effect on the disease, and we are talking about a clinical change.  I think that probably if you just change that first progression to some other term, and Jerry suggested "accumulated neurological disability," but I guess you're going to wrestle with the wording of the claim.
	DR. GILMAN:  Right.
	DR. GROTTA:  I guess my point is that I feel comfortable with the notion that it affects and reduces the accumulated neurologic deficit, the clinical progression.  I don't know about the biological progression, but I don't care.
	DR. KATZ:  Okay, but I care.  From the point of view of labeling, I think it's important.  I want to know whether or not the Committee thinks that there is an effect on the underlying biology, pathophysiology, structural, if you will, effect and whether you think there is evidence that that effect is transient, and when you take the drug away, it goes back to the way it was had you never been on drug, or whether you think that's a permanent change.
	DR. GILMAN:  We don't have data that bear on that question, in my opinion.
	DR. WOLINSKY:  I can't answer the second part of that in terms of whether or not it goes away.  The MRI data convinces me that there is an effect on a fundamental aspect of the underlying pathology.  If that's what we use, which is not what patients really care about, then yes, they've got it.
	DR. GILMAN:  Dr. Grundman?
	DR. GRUNDMAN:  I would agree.  I don't think there is evidence presented here that it affects the underlying structure.  So if the word "progression" is an issue, I could live with the idea of reduction in clinical disability compared to the control group if I actually believed that, and I'm not sure I believe that because I still have problems with the blinding of the study overall, and also with the clinical remissions, as long as we are on the subject.  Despite what we have heard here, I don't know if we want to set the bar that low for future studies that we would approve a drug for relapses that weren't conducted in a blinded fashion.
	DR. GILMAN:  Dr. Penn?
	DR. PENN:  Okay.  I think that an MRI that shows a hole in the head shows something about the biology.  Let's put it that simply‑‑that a gadolinium positive scan does say something about biology.
	I live in the world of dealing with these scans and deciding whether to do surgery or not on the basis of them, for example.  So I don't think there is a question about that.  But we would all like to have evidence of how it works biologically that would make us feel happier about it, and we have some sense of immune responses and so forth that are modified.  In fact, that's why we think it might work like the other drugs work, but we don't have comparable evidence with the other drugs.  As I thought I said before, we have some moderate evidence that meets your operational criterion of stopping progression‑‑that is, the one‑year‑out study that was not blinded‑‑so I find that, plus the MRI evidence, which I really give strong weight to, convincing enough to give them the phrase affecting progression of disease as well as we can define it now.
	But that's a very forceful "pro" statement, and I'm not sure that all my colleagues would agree with that in that form.
	DR. GILMAN:  We'll soon find out.
	Are there any other comments about that question?  Yes, please.
	DR. WEINER:  Since I don't vote, let me just‑‑and I won't take a long time‑‑tell you my own personal view of the data and where I think it fits in terms of multiple sclerosis as someone who has been treating patients with the disease for 25 years and has actually used other chemotherapy agents that can only be used for short periods of time, et cetera.
	First, in my own mind, I don't think there's any question that the Mitoxantrone affects the underlying pathology of the disease while it's given, and also is beneficial clinically.
	Second, there is also no question my mind that it will add something to the armamentarium of the neurologist who is confronted with MS patients, especially‑‑and I liked these words‑‑the worsening forms of relapsing remitting or progressive disease.  We hope‑‑if you put someone on Copaxone or one of the other drugs, and they do well and don't need anything else, that's fine, but we know that that's not true, and Mitoxantrone will serve a need.
	I also want to warn that I think this is going to create false hopes among multiple sclerosis patients.  There are going to be MS patients who are severely disabled or who have very slow progression or are not that actively progressive who now think that there is a drug that is going to have a major impact on their disease.  There are lots of people that that won't happen.  So I would put a word of caution to both the MS Society and to the company, who I applaud for all their work, to be careful about this, because actually, if you look at Table 40, you will see that it doesn't stop things in everybody; there are people who are worse, most people are basically stable, and the number of improved is not that great.
	The other thing I would mention to you as someone who deals with the disease and doesn't just see patients for 2 years but sees patients over 10 or 20 years, the ultimate issue is to keep a 25‑year‑old person stable and without disability over the long course of their disease, and I think that the Mitoxantrone will give us the opportunity to help stop the disease early, and the fact that it can only be given for 2 years is a weakness.  However, the strength of the biologic effect will it to be used in combination not necessarily with other drugs being given, but other drugs being given sequentially.  And we know in medicine, whether it is cancer or any other disease, that we often use drugs in sequence or in combination.  So I think it is going to have an effect in that particular way.
	DR. GILMAN:  Thank you.
	Are there any other comments?
	Dr. Wolinsky?
	DR. WOLINSKY:  No.
	DR. GILMAN:  Dr. Lipton?
	DR. LIPTON:  At the risk of perseverating, I continue to be impressed with the fact that the evidence that the 12 mg per meter squared is not demonstrably better than the lower dose and that the lower dose might well address your issue of you only get 2 years of treatment.  So in some way, I would like that reflected in the plans going forward.
	DR. GILMAN:  That was true of the EDSS, but it was not true for the other markers that they used, whereas with the 12 mg per meter squared, in fact, it was true with most of the other markers for their primary outcome.
	DR. LIPTON:  Yes.  The summary measure was significant for both, and EDSS was significant, as were relapses treated with steroids, and time to first relapse‑‑so three of them were significant, and the primary was significant, and the others weren't different.
	DR. WOLINSKY:  If I could add, because of the differences in the two studies, because of the differences in the patients, because of the differences in doses, although I am convinced about the biological effect they have shown, I am not sure but what one couldn't get the same effect with 3 months of treatment as was done in the French study alone.
	DR. GILMAN:  Dr. Grotta?
	DR. GROTTA:  Just to remind the group, we are not being asked to answer that question.  We are being asked is this dose that they propose effective or not.  Further study could determine whether there is a better dose or a better way to give the drug.  
	DR. WOLINSKY:  I agree with that, Jim.  I just wanted to go on record as saying there is still a lot of room for potential safer use of this drug.
	DR. GILMAN:  Dr. Katz?
	DR. KATZ:  I think that's right, but there is a dose‑related, if you will, question that was not up on my slide and might not even be in the book, but I talk about it, which is the fact that these two studies used widely disparate dosing regimens, and the MRI data, which is most impressive, comes from one in which the drug was given every month for 6 months.  To the extent that that data makes you feel comfortable about the clinical data in the first study, what can we say about what dose ought to be recommended?
	DR. WOLINSKY:  I think you can't say very much.
	DR. KATZ:  Well, you have to.
	DR. WOLINSKY:  That's why I'm not voting.
	DR. GILMAN:  No‑‑you are not voting because you are a consultant.
	The sponsor has asked for approval of 12 mg per meter squared, and the data that we have are complete for that dose‑‑every three months, yes.  Thank you.
	DR. GRUNDMAN:  Every 3 months for what period of time?
	DR. GILMAN:  Up to a total dose of 140, they are telling us today.   At 100, they do an echocardiogram, but their total dose, they are telling us, is 140.
	DR. GRUNDMAN:  So this would be approved as a treatment regimen for 12 mg per meter squared every 3 months up until 100‑‑whatever‑‑is reached?
	DR. GILMAN:  Well, up until 140, which is their absolute top dose, they have told us today.  There will be points at which the echocardiogram would be examined.
	DR. GRUNDMAN:  And would there be any point before that that we would stop the medication, or would it just be that's the regimen, up to 2 years' worth of treatment?
	DR. GILMAN:  I believe that would be up to the treating physician.
	DR. GRUNDMAN:  Because remember, after 6 months' worth of treatment, it was no better than placebo in the first study at 12 mg every 3 months.  So two doses didn't seem to matter too much, so it seems like you'd have to continue dosing them for maybe up to 2 years to ensure that you are going to get the effect that you are after.
	DR. GILMAN:  They were showing an effect already at the third month, and that effect improved in the 901 study.  It continued to improve, if I recall the data correctly.
	DR. PENN:  At six months.
	DR. GILMAN:  At six months.  Thank you.  Okay.
	Dr. Katz, I think, was first, then Dr. Temple, then Dr. Grotta.
	DR. KATZ:  I'd like to hear from the voting members, then, what they think about the proposed dosing regimen.  I'd just like to get a sense.
	DR. GILMAN:  Dr. Grotta, you fill that bill.
	DR. GROTTA:  Well, I'm not really bothered by it too much.  I think in our current health care system, it's much more likely that people are going to get too little of this drug than too much of it, and I think that you're going to spell out the caveats of when toxicity is likely to occur.  I think the data that we have seen today show that in the dosing regimen that is being recommended with the safeguards that are recommended that the likelihood of cardiac toxicity is very low, and I think the cancer data would support that, too.  So I think we have to worry  more about patients being able to have their insurance cover the drug.
	DR. GILMAN:  I would agree with that assessment that the dose of 12 mg per meter squared appears to have some toxic effects but no "serious" or life‑threatening toxic effects.
	DR. KATZ:  I'm not really concerned, for purposes of this question, about the toxic effects.  I am wondering whether, if you think the MRI findings are very persuasive‑‑most of those persuasive findings come from 902, where the dosing was more intensive‑‑and I am wondering whether you think you need that dosing regimen to confer the benefit.
	DR. GILMAN:  Well, the dosing regimen was different.  We are told it was in the ball park of 12.
	DR. KATZ:  But it was given every month.  It's a much shorter‑‑
	DR. GILMAN:  That's right, that's right.
	DR. WOLINSKY:  If I could come back and reiterate what I said before, I think it is conceivable‑‑but we don't have this data‑‑it is conceivable with the aggressive dosing that was done in the French study, possibly for a less long period of time, that one conceivably could get the same results, but we just don't know that.  So in that sense, voting or not voting, I think the data we have before us certainly gives us some feeling for what the limits of dosing ought to be.
	DR. GILMAN:  Does anybody else‑‑voting members‑‑want to make a comment about that question that Dr. Katz has posed?
	Dr. Kawas?
	DR. KAWAS:  I just want to say I wouldn't have a clue what would be the best dose to give a patient of this drug or the frequency with which to give it.  And even though I am convinced that there is probably a clinical effect of this drug, I think there is a lot of question about the dosing and the frequency‑‑a lot of question.
	DR. GILMAN:  Dr. Temple?
	DR. TEMPLE:  There is no doubt about that.  I can't imagine that by the time people who haven't yet been treated roll around to the end of their 2 years, we can't have reasonable data on what happens if you continue therapy, and I'm sure we'll make sure that those data are collected.  So that at least ought to be known.  Either you do really have to stop at 140, or you don't, and we don't know the answer to that yet.  And it's not exactly undiscoverable.  There are people who must be approaching that dose now who can be studied.
	DR. PENN:  It sounds like the usual FDA thing of wanting to kill the dog to make sure you know where the toxicity is, and I'm not sure that the company will be overjoyed at running studies over 140, so I'm not sure that's going to really get done.
	The question of the exact dose, we can never answer.  It would take many studies to try to do that.  That's why they had their Phase I and II, to make a guess.
	DR. GILMAN:  Dr. Grundman?
	DR. GRUNDMAN:  Just going back to the EDSS scores on M‑38, you know, the Mitoxantrone at 5 mg had a more rapid and more consistent effect than the Mitoxantrone at 12 mg, and we don't have data on the MRI on the Mito‑5 in the second study.
	DR. GILMAN:  That is absolutely correct.  Again, the sponsor's aim was to use 12, and they wanted to use 5 just to see whether there was a greater effect at 12 than at 5.
	DR. GRUNDMAN:  There was.
	DR. GILMAN:  Well, for that one marker, there was not.
	DR. GRUNDMAN:  The other markers were unblinded.
	DR. GILMAN:  Correct.  But we've dealt with that.  We simply don't know the answer to that.
	DR. TEMPLE:  No‑‑there was a better effect on two of the other blinded markers‑‑somewhat better.  It wasn't all that different, but it was leaning.
	Just as an observation, the third‑year data from 24 to 36 months, if I read it correctly, showed that people began to get worse again; they didn't lose the entire effect, but the trend lines if you were to draw them showed that the disease started to recur, progression started to recur, or whatever the right word is.
	It is hard for me to imagine that people won't be interested in knowing whether they could prevent that.  We don't know the answer yet, but wouldn't that be interesting?
	DR. WEINER:  I think that what you're going to see happening is that one will try to prevent that by using other drugs at that time rather than by using more of the Mitoxantrone is what I would predict.
	DR. GILMAN:  Dr. Grotta?
	DR. GROTTA:  Well, in struggling to try to compare the two studies, if you look at Table M‑40 and Table M‑64, they both look at the same‑‑admittedly, the patients are different in the two studies‑‑but they look at the percentage of patients who change more than or equal to one point on the EDSS, which to me is the most understandable outcome.  That is Number 40 and 64.  And to me, what you are trying to prevent is worsening, so if you look at the percentage of patients who worsened in the Mito‑12 category in 901, it was 8 percent compared to 25 percent in placebo, and in 902, it was 5 percent in the Mito plus methylprednisolone versus 29 percent in placebo.
	Clinically, at least, they are roughly comparable, and I don't think we have enough information to say that one is better than the other‑‑although you are quite right‑‑maybe it is better to front‑end‑load it, but again, that's not the question we're being asked, and I don't really see that much of a difference to say that we shouldn't be at this point approving the dose that is requested.
	DR. WOLINSKY:  Those two tables, of course, have very different time lines.
	DR. GILMAN:  Exactly.  One was monthly dosing, the other was three‑monthly dosing.  Six months versus 2 to 3 years total duration of study.  So I'm not sure they are comparable at all.  All right.
	Again, I have to ask Dr. Temple, Dr. Katz, are there any other question you want us to address, because we are going to come to the question about requested approval.
	DR. KATZ:  One more which has to do with the fact that all the studies were done in Europe, and there were no domestic studies. I'd just like to know if people think that's okay, if patients are the same, the standard of care is pretty much the same, and the results in these studies would be relevant and transferrable to the domestic population.
	DR. GILMAN:  I don't personally see a problem with that.  It appears that Study 901 was well‑designed.  There was some unblinding that I think could have been done a bit better, that is, inappropriately  unblinded aspects to the study, but it looks as if the scales used were the scales that would be used in this country, except for SNS.  We did not hear about validation of that scale.  I can't really comment on it, but it has been used in Germany for 10 years, we hear.  I don't think any of us around this table has a bit of experience with it, anyway‑‑or do we?  Does anybody have experience with the SNS?
	[No response.]
	DR. GILMAN:  No.  But to answer your question, I am pretty comfortable with it.
	Anybody else?
	DR. WEINER:  I would echo that.  I am comfortable with it.
	DR. GILMAN:  Anything else, then?  Dr. Katz, Dr. Temple, anything else?
	DR. KATZ:  No.  Thank you.
	DR. TEMPLE:  No.
	DR. GILMAN:  All right.
	The sponsor now requests approval for the following:  To slow progression of neurological disability and reduce the relapse rate in patient with progressive forms of multiple sclerosis, excluding primary progressive multiple sclerosis.
	So the question that we are asked‑‑that is, the voting members of the Committee‑‑is:  Has the sponsor submitted substantial evidence of effectiveness to support their proposed indication?
	Members of the Committee who are going to vote on this are Drs. Kawas, Penn, Van Belle, Grotta, Lacey, Penix and Gilman.
	I think there ought to be a bit of discussion to lay the groundwork for our vote.
	Dr. Grotta?
	DR. GROTTA:  I assume that our vote does not necessarily endorse this exact wording, but rather the spirit of the wording according to the discussions we have had?
	DR. GILMAN:  Precisely, yes.  They will alter the wording for the package insert if we are in approval, but there are two points to this.  One is the relapse, and the second is disability, slowing the progression of neurological disability.  We could take them separately if anybody wishes to; I think we could take them together myself.
	DR. KAWAS:  Just in terms of the spirit, I planned on voting no for that question, because as it is worded, I feel very uncomfortable with it.  As a neurologist who doesn't take care of MS patients, but I think the average neurologist would interpret it as it is worded right now for a different form the disease to do something for patients differently than the drugs that are currently available, and although I do believe there is evidence of effectiveness of this drug, it is not clear to me personally that it does anything or provides anything other than an additional armamentarium to the neurologist.
	So how this is worded is very important to how I would vote, and maybe I need to have a better idea than what we are really being asked now with Question Number 1 as opposed to Question Number 2.
	DR. GILMAN:  Would it help you if we separated the two parts‑‑to slow the progression of neurological disability, talk about that, and then talk about reducing the relapse rate?
	DR. KAWAS:  No.  Probably the two parts that bother me the most are I don't like "slow the progression of neurologic disability," but I also don't like the "progressive multiple sclerosis" term.  As you have heard today, I think a lot of people interpret that as a different form of disease that provides a completely new indication, whereas the drugs that are available don't do that.
	DR. GILMAN:  How would it sit with you if we said "to slow worsening of neurological disability," et cetera, "with worsening forms of multiple sclerosis"?
	DR. KAWAS:  That's getting better.
	DR. PENN:  I like it as it is for the reasons I have said, but I don't know how everybody else feels about it.
	DR. GILMAN:  We could go around the table and see what people think.
	DR. GROTTA:  I'd recommend we take a vote on how it is, and if it doesn't pass, then maybe we can wrestle with amendments.
	DR. GILMAN:  Yes.  It's going to be wordsmithing, then, which I am a little bit uncomfortable with here.
	Dr. Temple?
	DR. TEMPLE:  Obviously, people think the term "progression" carries extra freight, and we don't have to use that term.  "Worsening" is fine, if that general idea sounds better to people.  And I think we are totally convinced that the term "progressive multiple sclerosis" is ambiguous, so we could substitute "worsening" and put in parentheses the two subtypes, which as I understand it‑‑tell me where I am wrong‑‑are secondary progressive MS or relapsing remitting with worsening, or something like that.
	That describes the population.  It doesn't carry any implication about what you are doing at the micro or histologic level; it just says, I would have thought, what was shown, if that's in fact what you think has been shown.
	DR. GILMAN:  I tend to agree with that.  It is close to the data, so I like that wording.
	Dr. Grotta?
	DR. GROTTA:  In that case, I had written up a slight amendment if you want me to read it.
	DR. GILMAN:  Go ahead.
	DR. GROTTA:  "To slow accumulated neurological disability and reduce the relapse rate in patients with clinically worsening, secondary progressive or relapsing multiple sclerosis."
	DR. GILMAN:  It should be "relapsing remitting"; right?
	DR. GROTTA:  All right.  Close, but no cigar.
	DR. GILMAN:  Right.  We are wordsmithing.  Could we have that again?
	DR. GROTTA:  "To slow accumulated neurological disability and reduce the relapse rate in patients with clinically worsening, secondary progressive or relapsing remitting multiple sclerosis."
	DR. TEMPLE:  The only thing wrong with that is that relapsing remitting comes in two flavors.
	DR. GROTTA:  Well, "clinically worsening, secondary progressive or relapsing remitting multiple sclerosis."
	DR. TEMPLE:  Gotcha.
	DR. WOLINSKY:  What I think was studied in these trials are patients with relapsing remitting and secondary progressive disease with rapidly accumulating deficits.
	DR. GILMAN:  How rapid is "rapid"?
	DR. WOLINSKY:  The trials actually define that.
	DR. KATZ:  Again, my view would be that the use of a modifier like "rapidly" is really open to interpretation, even if in the clinical trials section of labeling we actually say what the data are.  My personal view would be to stay away from that sort of language.
	DR. PENIX:  I like this modification.  It does help clarify the point somewhat.  But there should be some leeway.  Physicians and patients should have some‑‑we can't characterize the intensity of the disease, so I think that if we got rid of that "rapidly progressing," or did not include that‑‑in other words, I support Dr. Grotta's amendment.
	DR. GILMAN:  Yes, I think it helps very much myself.
	Are there any other comments about that?
	Dr. Temple?
	DR. TEMPLE:  Just to get your words right, would you say the very first part of the sentence again?
	DR. GROTTA:  "To slow accumulated neurological disability"‑‑
	DR. TEMPLE:  Okay.  I have a question.  Do you slow accumulated neurological disability, or do you reduce it?  You slow worsening‑‑
	DR. GROTTA:  I'll defer to the group.
	DR. WEINER:  You could say "slow the accumulation of"‑‑that's what you're saying.
	DR. TEMPLE:  Well, it starts to get a little complicated, but I think we could work on that.
	You like the term "accumulated neurological disability" in preference to "worsening neurological disability"‑‑there is a preference there?
	DR. GROTTA:  We are using "worsening" later in the definition because we're seeing clinical worsening, and Dr. Wolinsky proposed that what we are really doing‑‑it's the amount of neurologic disability that accumulates as a result of their disease that we are either slowing or preventing.  I think the drug does seem to slow it.  The rate of development of the neurological deficit seems to be retarded.  Now, the question is it permanently retarded or not, we don't need to address in this, but it does seem to slow it.
	DR. TEMPLE:  Okay. I'm just checking.  You like the concept of "accumulated neurological disability" as opposed to "worsening neurological disability"‑‑I realize the inelegance of using the same word twice in the same sentence.
	DR. GILMAN:  What does "accumulated" mean, though?
	DR. TEMPLE:  Don't ask me.
	DR. GILMAN:  That's a serious question.
	DR. GROTTA:  Well, again, if somebody has visual loss, hemipareses and ataxia, they are accumulating a number of different neurological deficits, so it doesn't prevent any one of them.  In total, your score tests the global function of the patient, and you are preventing their disability.  That's obviously only one way to say it, and if someone has a better suggestion‑‑but it seems to me "accumulated neurological"‑‑
	DR. GILMAN:  I think the problem is that you're saying there is an accumulation of different systems into the mix.  But what about the patient who simply has a worsening EDSS because the gait becomes worse and worse and worse‑‑is that still "accumulating"?  Why not just "worsening," so that you can get around this equivocation or lack of clarity?
	Dr. Katz?
	DR. KATZ:  Yes.  I have a pretty good sense, I believe, even though no vote has been taken yet, of what the Committee thinks the drug does and what the data don't speak to.  I have worded the question this way to get the Committee's sense of what you think the drug does, and I think I have that sense‑‑I think we have that sense.
	If you would permit us, we can work on language with the company and I'm sure we can come to some mutual agreement, incorporating your views about what you think the drug does.  So if you just want to vote to say if there is substantial evidence for a reasonable claim for MS or some generic language, I'd be happy with a vote on that, and we'll work on the language, the specifics, if that meets with your approval.
	DR. GILMAN:  Approved.
	DR. WEINER:  I would just like to make a comment.  I don't know the name of the doctor sitting right next to you‑‑
	DR. GILMAN:  Dr. Kawas.
	DR. WEINER:  ‑‑yes‑‑I would also support some of the comments that you made in the fact that this is not something unique to progressive MS that has never been shown before per se, but I support some of your comments.
	DR. GILMAN:  Well, all the same, I think we should take a vote.  If the voting members of the Committee are comfortable with what we just heard from Dr. Katz, it will be something close to what Dr. Grotta said.  I would prefer not to have the word "accumulating" in there, because that's not clear to me, but if it is "worsening," all right.
	Is there any further discussion, or shall we vote?
	[No response.]
	DR. GILMAN:  All those in favor‑‑there should be seven votes‑‑the question is has the sponsor submitted substantial evidence of effectiveness to support their proposed indication, and the proposed indication is as modified, as we have discussed‑‑"worsening of neurological disability," et cetera.  All right?
	All those who say yes, the sponsor has submitted evidence, please raise your hands.
	[A show of hands.]
	DR. GILMAN:  So it is unanimous.
	Let's move on, then.  If not, then‑‑well, we have, so we can drop Question 2.
	Question 3: Has the sponsor submitted sufficient safety data?
	In my view, yes, but let me hear from the rest of the Committee and from our consultants.
	DR. WEINER:  I would say yes.
	DR. WOLINSKY:  Yes.  I think they have convinced me that they will do a good job in limiting us.
	DR. GILMAN:  Committee members, any discussion of this?
	DR. KAWAS:  Once again for me, at least, the wording is very important.  I think it is crucial that additional data is collected even if this drug were approved and available, in post‑marketing and other ways.  I feel that there are a lot of questions that haven't been answered yet in terms of safety in the long run and maintaining dosage.
	This drug looks to me like it does what other drugs available for MS do, but the toxicity looks to me like it has the potential to be greater in the long run, and we won't know that without looking further.
	DR. GILMAN:  Can you elaborate a little on some of your concerns?  You said long‑term safety data‑‑is that what you are referring to‑‑say, 5 years' experience.  We did hear about some accumulated data over 10 years or so.
	DR. KAWAS:  Primarily my concern would be over a long duration and high‑dose usage, yes.
	DR. GILMAN:  Could you define "long duration"?
	DR. KAWAS:  We have seen data when this was administered over 2 years, and I guess, presumably, that's what would be recommended.  And I guess, presumably, it would also be recommended that nobody get another course of this ever again.  I mean, people with MS have MS when they are 20, and they still have it when they are 40 and when they are 60 and when they are 80, and we don't have any way of knowing whether or not additional dosage regimens or anything like that is appropriate.  Everybody knows that physicians kind of so whatever they want, in spite of what is on the package insert, and I think it would be very useful to have an idea of what would happen if they gave another dosage to this.
	The one patient who received two regimens of this of 155 mg cumulative and 120 mg was a 40‑year‑old who were are told died.
	DR. GILMAN:  Dr. Penix?
	DR. PENIX:  The representatives of Immunex have indicated that they would, but I would certainly like to see a specific cap set and also some guidelines about patient monitoring, in specific, both in regard to the cardiac function and in regard to the hematologic monitoring.
	DR. GILMAN:   Are we ready for the vote?  All right.
	All those who believe the sponsor has submitted sufficient safety data of the voting members, please raise your hands.
	[A show of hands.]
	DR. GILMAN:  Six.
	All those who do not believe that sufficient data on safety has been submitted?	
	[One hand raised.]
	DR. GILMAN:  One.  One opposes that notion.
	Now, are there any other questions that the Division wants us to address?  Dr. Katz?  
	Dr. Kawas?
	DR. KAWAS:  Actually, maybe it's an extension of the safety issue, but I thought the Division also asked us to consider whether there should be restrictions on the way the drug was given out and by whom.
	DR. GILMAN:  Thank you.  Yes, they did.  The question is whether this drug should be administered by oncologists only, or should neurologists who have license, essentially, have the capacity to give it.
	Dr. Penn?
	DR. PENN:  I was hoping you would include neurosurgeons in this category.  I think it is a danger to give specific information like that, to restrict the drug in that way, and it depends on the education of the doctors who do it.  I think that if the company puts an emphasis on education, then there are a great number of people who could potentially use this safely‑‑even nurse practitioners, if you don't mind my saying so.
	DR. GILMAN:  I would tend to agree that, really, it depends upon the education, sensitivity, knowledge base, and care of the treating physician, not necessarily how that person has been boarded, as it were, but let me hear the other members of the Committee talk about that.
	Dr. Penix?
	DR. PENIX:  I agree.  I think that perhaps people are concerned about the lack of treatable diseases that neurologists have taken care of.  But clearly, in our experience, the MS physicians are dedicated and have a great deal of experience in taking care of these patients and also will be primarily responsible for following their clinical outcome.  So I think there should not be any restrictions.
	DR. GILMAN:  Is that unanimous?
	Dr. Kawas?
	DR. KAWAS:  I think it's a mistake to say that this is going to be given out by MS physicians.  I mean, most of us around this table come from academic centers, so we get into this notion of thinking that every doctor takes care of only one disease.  But the majority of this is going to be given out by people who are a little more broad than that, including internists and other doctors.
	I'm not so sure that I would suggest a restriction based on specialty, however, but how about some kind of registry restriction?  I believe, for example, there is a precedent with Clozaril where anybody who goes through the paperwork or whatever potentially can distribute the drug, but going through the paperwork ensures an education process.  Is that an option that perhaps we should be considering?
	DR. GILMAN:  Dr. Temple‑‑that's something that the FDA will address, I suspect.
	DR. TEMPLE:  Yes, we'll explore that.  A recently approved anti‑arrhythmic drug that has to be started in the hospital is available only to people who have taken the training program.  One of the difficulties is that this is a drug that is out there for other uses, and it is not so easy to do that, because it can be prescribed through those other forums.
	But we would certainly think about what kind of training, special packaging, et cetera, would be appropriate here.
	DR. PENIX:  My impression is that with Clozaril and maybe some of the other anti‑arrhythmics, the concern there is because of the potential fatal outcomes, and it appears that there is no increase in fatal outcome with this particular drug.  That may require‑‑my vote would be not to limit it, and I hope I didn't imply before that there should be specialty limitations, because I don't think so.
	DR. GILMAN:  Dr. Lacey, please.
	DR. LACEY:  I would like to speak against limiting the administration of the drug by specialty, based on the geographic area in which I live as an illustration of many areas of this country.  In one‑third of the State of Illinois, the southern part of Illinois, there is often not a single neurologist practicing.
	DR. PENIX:  Nor oncologist, probably.
	DR. LACEY:  No.  We have oncologists sometimes, but not a neurologist.  So if you were restricted on the side of neurologists‑‑
	DR. GILMAN:  Dr. Kawas, do you want to comment further.
	DR. KAWAS:  I guess I just wanted to say in part the reason I voted no on do we have enough safety data is because there were no fatalities in people who just got one course under careful clinical observation.  There was a fatality of an individual who got two courses.  The average patient and his doctor‑‑I mean, patients who live a block from the hospital are told on a regular basis that they cannot come and see me anymore.  So I think we don't know whether two courses of this disease will kill people or not.  So I guess all I want to put a plea in for is some mechanism where that could be controlled.
	DR. PENIX:  Would not the cap on the total dosage‑‑because the dose that the patient got who died, didn't it exceed 140 mg?
	DR. GILMAN:  The patient got 275 mg.
	DR. KATZ:  I don't think‑‑270 mg per meter squared‑‑but in any event, theoretically, in an ideal world, the cap of 140, if that's what we ultimately decide on, would do it.  But as Claudia points out, people go to different doctors; people move around, they want more, and they will try to get more, and they aren't necessarily going to tell their history.  I don't know if this is going to happen, but this is certainly one thing that presumably you could be reasonably concerned about given what we think we know about the toxicity at even minimally higher doses than 140.
	DR. GILMAN:  Dr. Grotta, then Dr. Penix.
	DR. GROTTA:  Well, my experience is that if you put all these warnings and so on about side effects on the package insert, physicians in this country, where there is a lawyer on every corner, are not going to be prescribing this drug unless they are very careful and cautious about it.  You can never totally safeguard against misuse of a drug if someone doesn't pay attention, and I don't think we can do that, so I think we just put the warnings and the side effects on the package insert and the limitations of dose, and that should be sufficient.
	DR. GILMAN:  Dr. Penix?
	DR. PENIX:  I agree with that.  As a stroke neurologist, in my experience, I have never seen anyone exceed the recommended dose of Ticlopidine [ph.] nor TPA.  So I think if we put it on the package insert and make it very clear, physicians would tend not to do that.  But you're right, there is a complication of patients not reporting it to the physicians, and I think that that is going to be impossible to regulate.
	DR. GILMAN:  Do you want a vote on this question, Dr. Katz, or have you heard enough‑‑
	DR. KATZ:  I have heard enough.
	DR. GILMAN:  Would you like to hear anymore about anything else‑‑Dr. Temple, Dr. Katz?
	DR. KATZ:  No.  The only thing I have left to say is to thank everybody.  It has been a long day, with a lot of difficult issues, and I think everybody really contributed, and I want to thank you very much.
	I particularly want to publicly thank Drs. Kawas and Gilman, whose last meeting this is, at least for a while.  They are rotating off the Committee.  You have both been tremendous assets to the Division and to the Committee‑‑it goes without saying, but it is worth saying‑‑you have been courageous at times under very stressful conditions, publicly, and I want to thank you very much.  The Committee will miss you, the Division will miss you, and I personally will miss you.  Thank you very much for your work.
	[Applause.]
	DR. GILMAN:  Thank you, Dr. Katz, and let me thank the Committee and consultants.  It has been an interesting day.
	We will adjourn now.
	[Whereupon, at 5:27 p.m., the proceedings were concluded.]
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