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MAY 3, 2001

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The meeting came to order at 8:00 a.m. in the CDER Advisory Committee Conference Room, 5630 Fishers Lane, Rockville, Md., John Doull, M.D., Ph.D., Chair, Presiding.


John Doull, M.D., Ph.D., Chair

Gloria Anderson, Ph.D., Member

Jay Goodman, Ph.D., Member

Joy Cavagnaro, Ph.D., Member

Government Participants:

Nancy Chamberlin, Pharm.D., Executive Secretary

Daniel A. Casciano, Ph.D., Center Director, NCTR

David Essayan, M.D., FDA

James T. MacGregor, Ph.D., Deputy Director for

Washington, NCTR

Frank D. Sistare, Ph.D., Director Scientist, FDA

Helen N. Winkle, Acting Director, OPS








Call to Order/Chairman's Remarks 3

Dr. John Doull (Chair)

Conflict of Interest 3

Nancy Chamberlin, Executive Secretary

Welcome B- Helen Winkle 8

Office of Pharmaceutical Sciences

FDA Objectives, Dr. James MacGregor 14

Scientific Issues, Dr. Frank Sistare 30

Summary of Subcommittee Activities 45

Dr. Doull

Specific Objectives -B Expert Working Groups 52

Subcommittee Discussion

Dr. Doull

Meeting adjourned 72


























(8:34 a.m.)

CHAIRPERSON DOULL: Good morning. Let me welcome you to this meeting of the nonclinical subcommittee. This is kind of a red letter day for us, we have been engaged in undertaking this project for almost a year now, I guess, and it is now off and running and we are here to celebrate that event and to facilitate the formation of these two new working groups.

We need to start out by doing the conflict of interest activity and Nancy Chamberlin, you'll do that.

DR. CHAMBERLIN: The following announcement addresses the issue of conflict of interest with regard to this meeting, and is made part of the record to preclude even the appearance of such at this meeting.

Since the issues to be discussed by the subcommittee at this meeting will not have a unique impact on any particular firm or product, but rather may have widespread implications with respect to an entire class of products in accordance with 18USC Section 208(b), waivers have been granted to John Doull, M.D., Gloria Anderson, Ph.D., Jay Goodman, Ph.D and Joy Cavagnaro, Ph.D. A copy of these waiver statements may be attained by submitting a written request to the FDA's Freedom of Information Office, Room 12A-30 of the Parkland Building.

With respect to the FDA's invited guests, there are reported affiliations which we believe should be made public to allow their participants to objectively evaluate their comments. Paul Snyder, DMV, Ph.D would like to disclose that he owns stock in Pfizer. He also is the principal investigator on a proposal to study vasculitis in beagle dogs and has received a privately funded grant to study vasculitis in beagles.

Scott Burchiel, Ph.D is a part time consultant to Boehringer-Ingelheim and a principal investigator on a Boehringer-Ingelheim funded study of flow cytometry, detection of vasculitis biomarkers in dogs. Dr. Burchiel is also working on a project involving vasculitis biomarkers in rats. Boehringer-Ingelheim is funding the study through CRADA.

Lastly, William Kerns, DVM would like to disclose that he has interests in SA Pharmaceuticals and OmniViral Therapeutics and Camvite Biopharmaceuticals.

In the event that the discussions involved any other products or firms not already on the agenda for which any FDA participant has a financial interest, the participants are aware of the need to exclude themselves from such involvement and their inclusion will be noted for the record.

With respect to all participants we ask, in the interest of fairness, that they address any current or previous involvement with any firm whose products they may wish to comment upon.

CHAIRPERSON DOULL: Does the committee have any comments, questions, about conflict of interest?

Well, before we hear from our distinguished guests, I think it probably would be worthwhile to go around the room so that everyone knows everyone, so let's do that. Let's start up here. Nancy?

DR. CHAMBERLIN: Okay. We have new mikes and for them to work you press the talk and the red light comes on for these. And for these for when our guests speak over here they're supposed to turn the two buttons on the microphones is all I'm going to say. Okay.

I'm Nancy Chamberlin, I'm Executive Secretary.

CHAIRPERSON DOULL: I'm John Doull. I chair this committee. I'm from KU Med. Gloria, do you have a mike?

MEMBER ANDERSON: Gloria Anderson, Callaway Professor of Chemistry at Morris Brown College in Atlanta, Georgia.

MEMBER GOODMAN: Jay Goodman, Department of Pharmacology and Toxicology, Michigan State University.

MEMBER CAVAGNARO: Joy Cavagnaro, Access Bio.

DR. ESSAYAN: David Essayan, Center for Biologics Evaluation and Research, Food and Drug Administration.

DR. MACGREGOR: Jim MacGregor from the FDA National Center for Toxicological Research and I'm the FDA coordinator for the subcommittee.

DR. SISTARE: I'm Frank Sistare from the Center for Drug Evaluation and Research in FDA.

DR. CASCIANO: Dan Casciano from the National Center for Toxicological Research FDA.

CHAIRPERSON DOULL: Why don't we then start back over here.

DR. ESSAYAN: For people on the expert groups it would be useful if you identify which of the groups you're on.

DR. BURCHIEL: I'm Scott Burchiel from the University of New Mexico and I'm on the vasculitis working group.

DR. HERMAN: Gene Herman from the FDA's Center for Drug Evaluation and Research, I'm on the cardiovascular toxicity group.

DR. HOLT: I'm Gordon Holt from Oxford GlycoSciences and I'm on the cardio tox group.

DR. BLANCHARD: Kerry Blanchard from Boehringer Ingelheim and I'm on the vasculitis working group.

DR. ROSENBLUM: Irwin Rosenblum, Schering-Plough and I'm on the cardiovascular.

DR. SCHWARTZ: I'm Les Schwartz from Glaxo SmithKline on the vasculitis group.

DR. METZ: I'm Al Metz from Pfizer and I'm on the cardiotoxicity working group.

DR. MURPHY: I'm Elizabeth Murphy from NIEHS in North Carolina and I'm on the cardiotoxicity working group.

DR. MILLER: Fred Miller, Environmental Autoimmunity Group, NIEHS, vasculitis working group.

DR. SNYDER: I'm Paul Snyder from Purdue University on the vasculitis working group.

DR. ROBERTSON: Don Robertson from Pfizer, I'm on the vasculitis working group.

DR. YORK: Malcolm York from Glaxo SmithKline, I'm on the cardiotoxicity working group.

DR. WALLACE: Ken Wallace, University of Minnesota, I'm on the cardiotoxicity working group.

DR. KERNS: Good morning. Bill Kerns, Pharma Consulting on the vasculitis group.

DR. NAGARKATTI: I'm Prakash Nagarkatti from the Medical College of Virginia, I'm studying on the vasculitis group.

CHAIRPERSON DOULL: One of the committee members, Ray Tennant, is not here. He's from NIEHS. I think that's all our members.

Well, it's a pleasure then for me to introduce Helen Winkle. She is the acting director of the Office of Pharmaceutical Sciences. Dr. Winkle.

DR. WINKLE: It certainly is my pleasure to welcome the subcommittee. As Dr. Doull said, we've been trying to get this committee up and running for at least a year and probably even more years than that at FDA. It goes back several years. And so it really is an exciting day to start moving forward with the expert working group. I really see that this is a significant group. There's a lot that they can offer to the Center for Drug Evaluation and Research and I'm really excited about the potential here.

This morning I just want to talk quickly about NCSS and where it has been, where it is now and where it is going next. But, first, let me take a minute and just go back to the Advisory Committee for Pharmaceutical Science and I'm doing this because I want to put the subcommittee in sort of perspective as to how it functions within the scope of the center.

The ACPS, or the Advisory Committee for Pharmaceutical Science, serves the role of scientific advisers to the Office of Pharmaceutical Science on various complex scientific issues which affect how we make our regulatory decisions. And the members of these committees, Dr. Doull and Dr. Anderson are both on this committee, serve a variety of different scientific disciplines and they help with these recommendations.

The various areas that the disciplines include are for biopharmaceutists, for chemists, for clinical pharmacologists, for toxicologists, there are also microbiologists on this committee, and we look at a variety of issues in these scientific areas.

We have over the years looked at a variety of issues that have been brought before the committee. These issues include things like individual bioequivalents for pharmaceutical products and determining biopharmaceutics.

We've looked at dermatopharmacokinetics, we've looked at biopharmaceutics classification system which in the last year was just published in a guide, and we've also looked at the reduction of CMC review requirements. So we've brought a lot of issues before this committee and what we're hoping to be able to do was what the expert working groups do through the subcommittee is bring these issues, or the issues you identify and the research issues you identify, we hope to bring those into the advisory committee and make some decisions along the regulatory lines.

Next slide. Let me just go quickly now on the NCSS and where we've been. Basically, and I think many of you here know this, NCSS was actually an offshoot of the CDDI and CDDI was a collaboration on drug development improvement. It was a collaboration that was started several years ago to bring academia, industry, and the government together to make decisions on the development of pharmaceuticals, and its goals were basically to study and advance current and new approaches to substantially improve the efficiency of drug development and the review processes.

And one of the original committees of CDDI was the nonclinical studies technical committee. And, basically, CDDI didn't make it. It was one of those areas where we had a real difficult time moving forward with the different things that we wanted to do in CDDI, but the NCSS did survive. I mean we all agreed that this was a very important thing and through the perseverance of Dr. MacGregor the committee survived. We brought the goals of that committee into the subcommittee and what you see now is an offshoot of that.

I wanted to show you just quickly the drug development process so you would understand where this committee sort of fits in the overall picture. And I thought this was an excellent slide because it shows the various phases of drug development. It show the preclinical research, the clinical studies, and finally the NDA review and you can see from this that basically we're talking about the preclinical research here, and this is the significant foundation for them bringing a product through the clinical studies and the NDA review.

So what we're doing here in this subcommittee and subsequently within the working groups, is extremely important as we move forward in making our regulatory decisions. Next slide.

Basically, and I've already said this, the purpose of NCSS is to serve to develop recommendations on drug development approaches in the nonclinical area. Next.

And the objectives are to provide advice on improved scientific approaches to nonclinical drugs development to the advisory committee, and to help foster the scientific collaboration among FDA, industry, academia and the public. And, again, this is what the original intention of CDDI is that intention continues to be fostered here within the subcommittee and the working groups.

Just quickly where the focus of the working groups and that's already been made clear as we went through to see which working group everyone was one, is for biomarkers for cardiac toxicity and biomarkers for vasculitis. We see these as only the first of the working groups, I'm sure there are other issues that are going to come along over the years and will include working groups for those issues as well. Next.

I wanted to go through the next steps real quickly just to show you where we are going. I think the important thing here today, and tomorrow, is for the working groups' agenda to be finalized, for our direction to be set with the working groups.

Then in July we will have an ACPS meeting and the subcommittee will report back to the ACPS on where we're going and the progress of the working groups.

But, at the same time, we're looking at, and this is an internal discussion that we're having, is to closing out the subcommittee as part of the ACPS and actually moving it into NCTR. We feel that the emphasis of what we're doing here in the working groups, although they affect the drug areas, also go hand in hand with what is happening in the National Center for Toxicological Research and, of course, that has been facilitated by Jim moving to that center. So we're in the process of making some decisions on how we want to handle that, so we're looking at probably in the fall, NCTR taking over the administration of the subcommittee but, again, those issues are still up in the air.

But, regardless of where the subcommittee is in the future, it's very important that NCTR and NCSS work closely with CDER to determine the issues which are most important as we move forward.

So that's basically, I just wanted to give you a real quick overview of yesterday, today and tomorrow and I want to wish all of you the best of luck. I really look forward to hearing where you're going with your working groups and I appreciate all of your commitment to this group. Thanks very much.

CHAIRPERSON DOULL: Thank you. You heard that clear message of support from the Agency for what has happened and what's going to happen with these working groups.

Let's move then to discussion of the FDA objectives and role in what it is we're doing, and Dr. MacGregor is going to give that.

DR. MACGREGOR: Well thanks, John. As John and Helen have both said, I think this is a landmark meeting of the subcommittee because there's a lot of history that Helen went over briefly, and in a moment I'll go back over some of that history and kind of try to give you a little bit more comprehensive feel about the discussions we've had and the objectives and where we think we're going as a subcommittee.

So, as I've said, the primary focus of this meeting is to really now establish functional working groups that really come to grips with the practicalities of the scientific issues that we'd like to address and make progress in. And so we're going to spend, we have two days scheduled for the expert working groups, or a little more than a day and a half actually, we're going to spend this first morning with the subcommittee, delineating a little bit of history, laying out the expectations of the subcommittee and providing then an opportunity for both public comment and questions and discussion between the expert group members and the subcommittee and the public, and anyone else that would like to comment, to be sure that we all have a common understanding of our goals and what we're trying to do.

And then when we finish with that, the expert groups actually will go to work and they'll work individually as the two expert groups, meeting separately through lunch time tomorrow, and then after lunch they will come back together in a plenary group to report back to a joint meeting of the two expert groups together what they've accomplished, where they think they're going and what the next step should be.

So I'll go through those things in a little bit of detail. And then I'm going to call on Frank Sistare to give a little bit of the scientific background and rationale that brought us to these two particular expert groups as the first groups that we put together to move toward our goals.

I'd also though before I get into that, like to just spend a couple of minutes on logistics, just to lay out the plan for the day so everybody knows what they're doing and where they're going and how to get food when the appropriate time arises.

I think everybody on at least the subcommittee and the expert groups has received a copy of this map of the local area. If anyone has not, either Nancy or Brenda Gomez, ah okay, over here, can provide you with copies of this. If you have that, if you want to pull that out right now I'll tell you some things about the logistics of where we're going to go and meet during the day.

So you've all managed to find the advisers and consultants meeting room which is here, that is on your map, and if you'll find that our plan is we're scheduled to run through noon today, although I suspect that we may finish up a little bit earlier than noon.

And then we're scheduled to begin working group meetings at one o'clock, so our plan is to simply walk to the Parklawn cafeteria for an informal lunch after we finish, whenever that might be. This is on your map and the way you get it is you go out this door right here to the parking lot, turn left and you'll be facing an obvious entrance to the Parklawn Building on your left across the parking lot. If you go through the security at that entrance, you'll be standing right in front of the cafeteria and there are a lot of large group tables there and we can just all get our lunch and we can commandeer a few tables and be able to meet and talk among each other.

Then at one o'clock, if you ask either one of us from FDA or the security people outside the cafeteria to direct you to the main lobby of the Parklawn Building, directly across the street from the main lobby, across Fisher's Lane, we'll have some cars available for those of you that are on the vasculitis group to bring you to your meeting room. The vasculitis group will meet at the Ramada Inn, the cardiotoxicity group will meet back here in this very same room that we're in.

So if you're on the vasculitis group, or if you're not on the vasculitis group and you'd like to attend and listen to the proceedings of that group, everyone is welcome to do that and I'll talk a bit about the logistics of how the meetings will be run in a moment.

If you go out there at one o'clock we'll have some transportation available to bring you over there.

Then for dinner tonight we have an informal dinner planned at the restaurant called That's Amore, which is directly across Rockville Pike from the Doubletree Hotel. I think most people are staying at either the Doubletree or the Ramada and this restaurant is just a few steps from either hotel. So we'll convene there for a seven o'clock dinner and we'll need to get a count, and maybe we can do that right now, of the approximate number of people that would be joining us for that dinner.

We have space available and maybe we could just have a show of hands right now for people that would plan to attend that dinner tonight at seven. Okay, got it.

Okay. Now tomorrow we will continue with working group meetings and, again, they'll be meeting in the same places so those of you can easily walk over to the Ramada, and if you like a brisk walk over here in the morning you could do that or we can discuss at evening if people would like to ride over, we probably can find a couple of people to drive people over in the morning from the Doubletree.

DR. CHAMBERLIN: If there's a few people that need to switch hotels because we book them at two different hotels, I can help you transport your luggage prior to lunch time.

DR. MACGREGOR: Okay, so if you need to do that catch Nancy this morning and let her know.

Now everyone should have picked up outside the two agenda, there are actually two separate agendas, one for this meeting and one for the expert group meeting so if you didn't get those two, they look like this. Make sure you get one at the break.

Okay, any questions or comments about logistics?

Okay. So what I'd like to do now is I'd like to just provide a little bit more background on this subcommittee and the objectives of the subcommittee and these two new expert groups that have just been formed. Next slide.

I think the general concept of this committee is really that that's illustrated in this slide, and that's to address the question of really how should FDA be focusing its resources and partnering in a way that leverages the resources that are available in order to capitalize on new scientific opportunities and bring those opportunities to a practical application in the regulatory process.

And so to that end, we've created this subcommittee and the general concept here, I think, is one that if successful could be expanded well beyond this particular advisory committee. And the general concept that is perhaps all of the focus the advisory committees could assign a subcommittee of people to address these general questions of what might be improved scientific approaches, in this case to nonclinical drug development and in the case of other advisory committees to their particular functions.

And then to go a step beyond just providing that advice and actually to play a role in helping to foster and facilitate scientific collaborations among FDA, industry, academia and the public, to bring these ideas and approaches to fruition. So that's the basic idea and the basic thing that we're trying to achieve.

Now, as Helen has already gone over, the specific objectives of this committee, the nonclinical study committee, is to recommend approaches and mechanisms to improve nonclinical information for effective drug development that could improve the predictivity of nonclinical tests for human outcomes, and that could provide a linkage between nonclinical and clinical studies.

And then, importantly, in addition to making these recommendations and providing advice, to actually play a role in facilitating collaborative approaches to advancing the scientific basis of drug development and regulation.

Now Helen's already gone over some of the early history and, as she said, it began with the concept of the collaboration for drug development improvement and eventually came to fruition with the formation of this nonclinical study subcommittee as part of the advisory committee for pharmaceutical science.

This is a history of the subcommittee, the subcommittee actually first met informally in August of 1999 to develop the concept, discuss the rationale and advisability of forming such a subcommittee. The group that met, as Helen said, was really a spin-off from the CDDI and included all the people that had been involved in the CDDI nonclinical study subcommittee.

People universally though it was a good idea and so in September of 1999, the concept was presented through the advisory committee for pharmaceutical science, which endorsed the concept. Then in December of 2000, the subcommittee met and at that meeting selected two general areas of focus that it felt would be fruitful to pursue, and that was the area of accessible biomarkers of toxicity and non-invasive imaging approaches. And the reason the non-invasive imaging came in was that it was felt that as biomarkers were identified and developed that eventually in order to be able to conduct the human studies that would be necessary to link the nonclinical together with the clinical, that eventually imaging technology might be brought into play in combination with molecular biomarkers to be able to make analogous studies in the human to link the nonclinical information.

Then in March the committee met again and discussed how it might proceed more specifically within these two general areas. And, at that time, it was decided that we should focus in two very specific areas, bring together experts in those areas, and then try to formulate a specific plan with those areas to see how the whole process worked. And the two focus areas that were selected then at that meeting were cardiotoxicity and vasculitis, that led to the solicitation for nomination for these two expert groups and then the selection process which I'll talk about in a little more detail.

Now, just back to the general picture, the current groups that are actively participating in the subcommittee and that have representatives sitting on the subcommittee are listed on this slide. The initial concept began with two of the FDA centers, CDER and CBER, the initial CDDI steering committee was composed of the two center directors from CDER and CBER, as well as representatives from PhRMA, from BIO and from academic institutions.

As we began to talk about FDA's role and the impact of the activities of this committee on FDA, it became apparent that we were moving toward nonclinical toxicology studies and that NCTR should be included, and they were added. It became clear that NIH had many activities in the area of molecular biomarkers and that they should be included, and Ray Tennant was added during the past year to the committee as the NIH representative and Ray is also the chair of the new national toxicogenomics program that's part of NIEHS and NTP.

So, hopefully, we've established a good linkage there between the activities of this committee and the national toxicogenomics program.

Now, these are the two meetings that I've already mentioned. Actually, I guess I've already gone over this. I think we can skip this, I think I've already gone over that one.

Now, the next two slides I think are really key slides. These are the things we need to focus on today and be sure that we all really have a clear and common understanding. And this is, what's the role of the subcommittee, what's the role of the expert groups, and what does each expect the other to be achieving?

So this slide deals with how we envision the role of the subcommittee. And we see the role of the subcommittee as being comprised of people from the various stakeholder groups involved in initially pharmaceuticals, although as Helen said, we're now beginning to think about possibly even expanding beyond that area in the near future. But within those areas people that would be involved in the process, knowledgeable about the science and the area and able to identify and recommend those key focus areas where activity should be focused.

In terms of mechanism, it's recognized by the subcommittee that the subcommittee itself does not contain all the technical expertise necessary to really identify all the specific opportunities and formulate specific plans and approaches, and so the subcommittee recognized that it would need to form expert working groups to develop specific options.

And the process for that is something we just have gone through with these two committees, was to announce as widely as we could the opportunity to serve on these groups, and to that end there were announcements in the Federal Register. We approached people on the subcommittee and the groups that are involved in the activities and asked them to nominate individuals, and we specifically wrote to and solicited nominations from a number of professional societies.

So with that process and with the expert groups in place, the subcommittee would then serve as the steering committee to oversee the expert groups, the expert groups will be reporting back to the subcommittee, and that should this whole process lead to collaborative processes, then the subcommittee is envisioned as the steering committee that would oversee these collaborative projects, and the body that would support workshops, reports, output from the various activities.

Now the expert groups, as I've already said, are experts within the areas specifically identified by the subcommittee, and the role of the expert groups is to identify specific scientific opportunities that could improve our regulatory methods and regulatory approaches. To decide, within those opportunity areas, what information is really needed to translate the opportunity into regulatory practice, to lay out some specific plans about how that could be achieved, to think about resources and expertise that would be needed to implement the plans and identify those to the subcommittee. And, again, to think specifically in terms of appropriate collaborators, individuals, resources that could actually bring things to fruition.

So the whole focus here is to try to be practical and proactive and to think beyond just advice. We don't want to just hear wouldn't it be nice if we could measure all the relevant biomarkers in both animals and human and that would be great. What we really want from the expert groups are specific opportunities and specific identification of specific ways in which those opportunities could in fact be brought to fruition.

This is just an expansion, really for the record, of how we went about the identification and recruitment of these groups. Following the meetings that I indicated in July of this year, the Federal Register Notice published and essentially simultaneously letters went out to scientific societies, announcements were made within FDA, subcommittee members made contacts and announcements were made at public meetings to recruit nominations.

And then an FDA committee was formed with representation from CDER and CBER and NCTR and appropriate individuals within those groups involved in the areas of the expert groups, that then reviewed the applications and selected the membership, with attention to achieving a balance among the various constituency groups to be sure that we had representation from all the areas.

Now, in terms of process and this is what we're going to implement beginning this afternoon, as I've already said, the expert group will be reporting to the nonclinical study subcommittee, hopefully we've provided guidance to you on what we'd like to have from you. If that's not clear, that's what this morning is for. Ask questions and be sure we go out of this meeting with a common understanding of what we want to achieve.

Then you, as working groups, need to define your own milestones, when you're going to produce your report and so on. The expert groups may meet independently of the subcommittee and the full advisory committee, you're a working group, you identify facts for the subcommittee and the full advisory committee, those are the groups that actually make recommendations to FDA.

We encourage you to solicit external input. As I've already said, I hope we can keep the expert group meetings open to interested parties as much as we can, so that people can come. I think it will be up to the chairs of the expert groups to be efficient and to decide if it may be necessary to limit discussion just to the working group in order to move along, and that I think can be done on a judgmental basis by the chair. And I think leaving it up to the working group to form its own working process and milestones and select its own chair, who would then be responsible for providing summary minutes of all meetings to the subcommittee.

Okay. So that's essentially the background on the history, what we're trying to achieve and so on, and now I'm going to go to Frank Sistare and ask him to provide some scientific background on what led us specifically to these two groups.

Are there any -- should I take any specific questions at this point, or should I, does anybody have any question or comment?

DR. SISTARE: It just might be helpful to know can the expert working groups meet without advertisement in the Federal Register ahead of time?

DR. MACGREGOR: Yes. I thought I had said that but I'll repeat that. Part of our process here, you know, I mean we spend a lot of time thinking within FDA how we can meet all the requirements for public availability of information, input from all stakeholders, and still be able to get something done in a timely fashion because, as those of you that have been involved with advisory committees know, there are many requirements. Everything has to be public, advisory committees cannot even meet unless everything is previously announced in the Federal Register and so on and that takes a lot of time.

So we've looked a lot into these operating processes. The expert groups may meet on their own, without public announcement, although we do encourage and hope that to the extent possible, the meetings will be announced and that interested parties will be able to attend and hear what's going on.

Then the expert groups will report back their proceedings to this subcommittee, and that all must be part of the public process. So everything they do will immediately get reported back to the subcommittee and that will all be part of the public process announcement in the Federal Register and so on. And there'll be full minutes of those meetings, whereas the expert groups may meet and just provide summaries of their conclusions and proceedings.

Now, if I've misstated, and I see Nancy leaning at her microphone and I've probably misstated something.

DR. CHAMBERLIN: We will advertise expert working groups, like we did this one, in the FDA calendar events, not in the Federal Register.

DR. SISTARE: As Jim pointed out, he asked me to give just like a ten minute overview of some of the scientific issues, how we got to where we are today with respect to the focus being on vasculitis and myocardial injury. Next slide.

It came forward to the NCSS, I think it was December 1999 and then again about a year ago from today and I'm going to give you a summary of that. This is essentially overheads that I used for those two meetings.

In terms of biomarkers of toxicity, the general hypothesis is that there exist a more optimal panel of toxicity biomarkers in biofluids and that we can easily access, be it plasma, urine, or circulating leukocytes that can act as sentinels, that we're not presently incorporating into our studies, either routinely and sometimes maybe not even as special end points that could be used.

These panels of biomarkers are measurable, can reliably herald the onset of drug-induced system specific damage prior to visible morbidity or significant irreversible insidious damage. So that's the overall hypothesis, that these things exist and we're maybe not using them optimally at the present time. Next.

So why do we feel this? What are some of the indications that more and better biomarkers linking exposure to toxicity are needed? Well, overall in general, biomarkers of toxicity haven't changed much in the last 40 years. We're still using a lot of the same biomarkers, or clinical end points, that we've been using for the last 40 years.

There is obviously attrition of pharmaceuticals from clinical phases of development. We can't always say that that's because there were biomarkers in the animal that we didn't have and didn't have to go into the clinic, but to some extent I think we can point to that as a possible reason.

Number of drugs, approved drugs, have been removed from the marketplace. Again, maybe biomarkers, improved biomarkers are not the answer to all those, but I think it's quite possible that if we had better sets of biomarkers we'd have a better handle and these kinds of things would happen less often.

There's quite often a questioned relevance of certain animal findings for nonclinical studies. What's the relevance to man? So the ability to go into the clinic and extrapolate from species to species remains a gnawing issue at times.

There are perceptions of inconsistency across drug review divisions. Some review divisions maybe being accused of being more conservative than others. And possibly it's because the science just isn't there. We don't have the biomarkers to answer some of these issues. Often, not often, occasionally, drugs are placed on clinical hold and oftentimes that's because we just don't have those biomarkers to tell us again whether these animal findings are relevant. And that addresses the last point, questioned relevance of certain animal models as well. Next.

So in terms of using biomarkers of toxicity, accessible, system specific biomarkers of toxicity research in that area, the objective would be to define biomarkers with an improved ability to profile a prioritized set of system specific damage endpoints covering a variety of mechanisms and different drug classes.

The goal we might establish is to establish again a more optimal set of these easily accessible biomarkers, to allow us to progress with greater confidence from animal studies into, and through the clinic, to herald early onset of toxicities prior to morbidity and irreversible damage.

In terms of general considerations as we approach these issues, we need to focus on biomarkers that are mechanistically related to the pathogenesis of insidious toxicities. We don't want correlative, we want things that are mechanistically linked.

We need to choose toxicity of interest to both regulators and sponsors to encourage partnering, and a lot of why we're here today, is I think we've succeeded in identifying a couple of areas that are really of shared concern.

We need to choose practical biomarker strategy that will allow this extrapolation across from animals into man. I guess I've made that point a few times haven't I.

Okay, in terms of where we can gain, where we can access these biomarkers, I think we have to keep a very open mind. But they need to be accessible. We have to keep in mind that we can do a lot of things in animals that we can't do in people. We can't pull out lungs and we can't pull out livers and things like that that we can do in animal studies.

So we need to those sort of goal endpoints of histopathology that we see in animal studies and be able to extrapolate what's going on in accessible tissues, circulating blood elements. Can we look at cellular RNA? Can we look at proteins that are expressed on the surface? Can we look at alterations in DNA?

Accessible clinical biopsies, if they're easily accessible, things like skin.

Serum components, be they unregulated secreted proteins, lipid products, steroids. Again, we need to keep an open mind what to look at.

Tissue specific proteins that might be released when membrane integrity of a specific organ of interest is compromised.

And then components of other body fluids, like cerebral spinal fluid, like urine, saliva. Again, we need to keep an open mind. Next slide.

Now in terms of the evaluation of biomarkers, and getting into a lot more detail but just in terms of the kinds of challenges that we have ahead of us, there are a number of phases that we need to take into mind. The clinical chemistry phase. Is the assay accurate? Is it precise? Is it robust? Is it reproducible? What's the sensitivity specificity and dynamic range of the particular clinical chemistry, just the assay itself.

Then as you move into the nonclinical phase of the development and the evaluation, you need to look at things like dose-response, the identification of the action threshold, at what point does this increase mean that you've gotten into a point of morbidity, at least in the animal study you can establish that.

Establish the cause-effect relationship. Again, not correlative but actually in the line of the cause-effect relationship mechanistically. Is it sensitive? Is it specific? Is it predictive? Again, there sensitivity, we're talking about drugs, better known to cause the toxicity versus drugs that are know not to cause the toxicity. We have to make sure we can pick up the sensitive but it's not non-specific.

And, again, issues of the relationship between the biomarkers and whether it's telling us anything about whether we're still in a reversible phase or have we crossed into a state of irreversibility. So there's a lot of challenges there.

And then, obviously, we've got to come up with a strategy of how we're going to show that these things are clinically relevant, and we have to confirm that aspect of things. So there's a lot ahead of us.

So, again, back in March last year, being the good bureaucrat that I am, I wanted to make sure that these weren't just personal ideas, that we had sort of a consensus from our center. And we have a research subcommittee to the Pharm Tox coordinating committee and we posed these issues, you know, in terms of toxicities that we see, that are recurring that we still wrestle with, if we could develop a better panel of biomarkers that would help us as we move into the clinic, to establish better monitoring strategies, what would they be? Where are the sort of priority areas?

And I'm going to give you that feedback. I have it broken up into three tiers.

In Tier 1, priority. They felt, again, cardiac toxicity, myocardial injury as I have in (a), but also the issue was raised about the whole QT issue, drugs that prolong QT. There is a parallel effort going on to deal with that so it was felt that for this committee, the myocardial injury would be more appropriate.

Vasculitis. Again, the need for biomarkers was endorsed there and the committee encouraged, maybe not even just focusing on vasculitis, but as we look into that area, look into biomarkers of a general immune system activation, keep that window open. Next.

The Tier 2 and Tier 3 advice that came from the subcommittee was we still wrestle with issues relating to neurotoxicity. Peripheral damage, neurotoxic damage, are there plasma markers that can reflect that? Central damage, are there again serum markers or CFS markers we could use? Non-invasive imaging, again Jim already related to that, so that is sort of on the table in that other effort.

Hepatoxicity, the feeling was to wait and not bring to the NCSS at this point. The FDA/PhRMA conference which was just held just held a short time ago, I can't remember which month it was. But there was some advice coming from that, and there will probably be some efforts as a result of that as well. But, as of March of last year, the thing was to wait for that, and that is something that either the NCSS or some other parallel structure will probably work toward biomarkers to better predict and diagnose heptatoxicity. Next.

And the third tier, things are sort of in the wings. Photocarcinogenicity, we have animal models, there's a general feeling that we would also like to have biomarkers, and here again maybe skin is a possible place to look for biomarkers of whether we have a relevant human photocarcinogen.

And renal toxicity. There is an ongoing ILSI initiative focused primarily on genomics, but samples are being saved from those studies and proteomics for looking at biomarkers is a possible spin-off there. So that could be coordinated with that initiative and ILSI is looking for ways to move forward.

There's also an NMR consortium working through the Imperial College and I believe a number of the members in the audience today are a part of that consortium as well. So these things are going on. But we felt that vasculitis and myocardial injury really deserved some attention that wasn't being met elsewhere. Next.

So just in terms of giving you a feel for some of the kinds of issues that are out there and, again, I'm preaching to the choir a little bit here because I know some of our members have wrestled with these issues firsthand, trying to develop drugs that have caused vascular injury in their nonclinical studies.

This is an example that was published, this was presented at SOT a couple of years ago. This was a drug, PDI 747, that was developed by Novartis. It's a phosphodiesterase type 4 inhibitor being developed for inflammatory skin diseases.

As you can see, they found positive vasculitis findings after just two weeks and 13 weeks in the GI tract and also myocardial necrosis was seen.

In terms of a safety margin, the doses they want to get to in the clinic were going to be 25-fold higher than the doses that were causing the toxicity in the rat.

The dog, they also saw vasculitis and myocardial necrosis, myocarditis. There, the doses they wanted to get to in the clinic would have been 50-fold higher than the doses that were achieving this toxicity in the dog.

The mouse was listed as positive, the minipig was also positive in the mesenteric; the monkey was also listed as positive, I don't know the information in terms of the site of predilection. In the rat, it was also listed as a positive.

So every single species they looked at it was positive. One could still ask the question, is it going to incur in humans? And we may never know. But they felt that it would not be wise to develop that compound at this point in time. Next slide.

Here's something that's maybe a little bit tougher and we have a company Y that's developing a drug X and mesenteric vasculitis and death is seen in the rat study. The company is not seeing clinical efficacy in their phase 2 trial and they want to increase the dose. They want to increase the dose to either meet or exceed the AUC that was in the rat that was shown to cause mesenteric vasculitis. So you have an impasse, and largely because there's no clinical biomarker to monitor for these findings in the clinic.

The histopath clearly shows early injury to rat vascular endothelial and smooth muscle cells, and what we have done is we've initiated proteomics approach in our laboratories and we have a number of collaborations going with people to try to address this kind of issue. But this is not atypical, the kinds of things that have been seen in submissions and it cuts across class. Some phosphodiesterase inhibitors, some will be endothelial recipient B- some will be reverse transcriptase inhibitors. There's a number of different classes. Some basoactive, some not so obviously basoactive compounds for which vasculitis findings were seen. Next slide.

In terms of switching over to myocardial injury, there we're a little more advanced in our tools that we have available to us. So myocardial injury biomarkers do exist, we have isoforms of B- we have isoforms of LDH that we can monitor, and these have been shown to reflect acute myocardial injury as a result of myocardial infarction, for example.

When it comes to monitoring for drug induced cardiac toxicity, we have evidence that Troponin T may be even more promising biomarker of drug induced cardiotoxicity, both acute and chronic. Here, I'm just showing a representative example of some of the data that's come out of Gene Herman's lab in my division, showing Troponin T increasing as weekly doses of DXR, and one milligram per kilogram are given to a rat model that he's developed over the years, showing a nice increase with time and Troponin T. What I haven't shown you is that the myocardial injury histopath also reflects very nicely the increase that's seen in Troponin T.

Now Gene has developed data not just showing this, but looking at differential sensitivity between males and females. Again, the correlation is very good between histopath and the biomarker, cardio protectin, pre-administration of cardio protectin reflects again that Troponin T is working as a nice predictor, that is inhibited by the cardio protectin as is the histopathology. He's done other classes of drugs on both acute myocardial injuries and as chronic and it's looking quite promising.

So the question is with this particular approach, with this particular question, is what do we need to do to get this into routine practice in terms of the drug developers? With vasculitis, there's a wide open field. We don't really have anything at the present time. But with myocardial injury we have a few candidates and we feel that we have a better one than the ones that can be measured sort of routinely, but we sense a reluctance on the part of the industry, citing reasons for not using it. So what we do we have to do collectively?

And there are other ones. There's Troponin I, there's Troponin T, there are biomarkers of response, hypertrophic response that we'd be able to like to use on non-invasive. So there are other things there.

What do we need to do collectively to get these into practice? Next slide.

These are some of the thoughts. Again, sensitivity/specificity. How many different drugs do we have to look at that are known myocardial injurors.

How many drugs we have to look at that are known not to injure the myocardium, but maybe injure the kidney and not the myocardium. Do we see a Triponin T increase? So that we can at least know how predictive and what are the limitations of Triponin T if we choose that as something that we want to look at. What's the robustness, reproducibility, dynamic range, the half life of the biomarker? These are very practical questions that we need to address. Related dose exposure and time, as we choose the agents that we want to test.

Then look across species, across different strains, across gender variations and relate to the "gold standard" histopath observations. This is sort of a primitive strategy that I put there that would probably need to be applied. Next.

So the question that was posed to the NCSS back in December of 1999 and again in March of 2000, was who should assume the costs of biomarker identification and evaluation? Is this an FDA responsibility? Is it NCTR responsibility? Is it CTER responsibility? Is it Pfizer's responsibility? Is it Lilly's responsibility? How do we start, how do we prioritize. Is it the academic's world responsibility?

Well the vision that we shared with the NCSS and the NCSS picked up on was that this should be a collaborative effort to define improved panels of biomarkers for specific toxicities that cut across species and built into a very practical format that's easily implemented. Next, and I think my last.

So the impact of achieving this vision will be to assess the relevance, or irrelevance, of animal toxicity findings, to accurately assess doses that are associated with toxicity. To maximize a favorable impact on public health. To minimize regulatory dilemmas impasses. To improve selection of candidates for drug development and reduce candidate attrition rates. To accelerate drug development, minimize resource consumption and make for a more perfect world.

I think that's the last slide. Is that my last slide? Yes. Okay. Thanks. Any questions? Do I take questions now?

CHAIRPERSON DOULL: Sure, why don't you, Frank.


CHAIRPERSON DOULL: Questions for Dr. Sistare? A more perfect world.

Well, you've heard from Helen and Jim how all this got started and how we have all ended up here together, and you've heard from Dr. Sistare about why we selected cardiotoxicity and vasculitis as the two working groups to start off with.

This is a novel, a new approach for Food and Drug and it's as you can tell I'm sure from listening to these presentations, it's been difficult to do this. We had all sorts of ideas initially about how this would happen. We thought, for example, a subcommittee would appoint the working groups; it turns out officially we can't do that so the subcommittee gave input to Food and Drug so you were actually appointed by Food and Drug.

We thought it would happen very quickly. As you can see, it's taken quite a while. But it's very important because this sets a pattern, in a sense, what has been accomplished by forming these groups, emphasizes something Food and Drug has said for a long time, we want to do cooperative things with industry and with academia that benefit us all in the development of new drugs and in the testing of drugs.

We need a mechanism that makes this work, and this is an opportunity for us to demonstrate that there is a mechanism, that it can be used, and that in fact it does hopefully will work. That's really what we'd like to demonstrate.

I might also say in regard to the -- our subcommittee has two goals, one is a scientific goal and you've heard about that, we want to find biomarkers that are more predictive than what we now have. Those biomarkers actually could be very helpful in the development of new drugs. They could be very helpful in pre-clinical testing of drugs that have come along that far.

We heard the speaker talk about the possible use of biomarkers to identify people who have a genetic fault, or for some reason or other are more susceptible to that particular drug and some examples for that. So there are lots of scientific opportunities for us to work together to develop biomarkers so they're more useful.

And the other aspect, which I've already mentioned, is of course the collaborative one. It's very important I think that we figure out how to get around the difficulties and make a collaborative effort of this nature work.

I might just say a word about Dr. Sistare's presentation. The subcommittee, as he indicated, has met several times and we've looked at a lot of different areas that we could get into and form working groups and so on. And he showed you several of those, a neurotox for example. The subcommittee talked a great deal about genomics and proteomics and other "omics" and the need for a working group in that area. We're all very excited about that and think it has great potential in toxicology as well as development of drugs.

But our subcommittee did not really feel we were at the stage where a working group would really be very profitable in the "omics" groups, and we do have very good links, courses, the leader of that group for NIEHS and Dan, of course, is aware of what's going on at NCTR. So as soon as that gets to a stage where it would be useful to have a working group, hopefully the subcommittee will be able to do something in a way that would be helpful.

Another area that Jim mentioned is the non-invasive, the imaging techniques, and we've had some beautiful presentations on PET scan, for example, and NMR and how they can be used as biomarkers to locate drugs and to look at distribution and so on. And those are also very exciting developments.

PET scanning is very expensive, there aren't a lot of machines out, and it kind of is at the stage where it's a demonstration technique. It really does some things very elegantly, but the subcommittee felt after a lot of discussion, although we initially recommended that maybe we should have a working group to do PET scanning, that we probably weren't quite ready to get into that. There wasn't enough mass out there to make that a go situation and also for NCTR or for NMR.

We talked also about kinetics at some length. I think there was a lot of enthusiasm amongst members of the committee for a kinetics area, pharmacokinetics, pharmacodynamics, pharmacokinetics, the modeling sort of techniques. But the ones that we selected, I think, represent what the agency and what this committee felt were the most likely ones to give us some bang for the buck.

In thinking about this, I've gone back and looked at definitions for biomarkers. It's interesting that that term does not go back a long ways. If you look in medical dictionaries, for example, some time ago you don't find biomonitoring or biomarkers and so on. It's a relatively new term. And so I looked for a definition, and I found the Academy has a definition which they used in 1989 but Elaine Kaufmann and her committee on developmental toxicology just recently restated that definition.

I think because of the fact that we're dealing in a whole bunch of different areas, imaging, genomics and what have you, we need to have some concept about what biomarkers really, you know, what we mean by that term. And let me just read the Academy definition.

Indicators, signaling events in biological systems or samples. There are three classes of biomarkers; biomarkers of exposure, biomarkers of effect and biomarkers of susceptibility. A marker of exposure is an exogenous substance or its metabolite, or the product of an interaction between a xenobiotic agent and some target molecules or cell that is measured in a compartment within a organism. A marker of effect, which would be more like what we're concerned with in cardiotoxicity and vasculitis, is a measurable biochemical, physiological or other alteration within an organism that depending on magnitude can be recognized as an established or potential health impairment or disease. And a marker of susceptibility is an indicator of the inherent or acquired limitation of an organism's ability to respond to the challenge of exposure to the specific xenobiotic substance.

Like most Academy definitions, they're pretty wordy, but I think one of the things that your groups could do would be to think about how we define biomonitoring and biomarkers in a way that's broad enough, for example, to encompass what it is we really need to talk about.

Regine Henderson, a couple of years ago she had an article in Critical Reviews in Toxicology and she pointed out that we need to think about biomarkers not as a process or a test or something, but as a piece of information, and that that is really how we're using it, as a piece of information which has high predictivity for whatever it is we want to know.

The CTECH people talked about biomarkers and it was interesting because they talked about so-called gold biomarkers. Those are ones which are highly specific and the example they used was cholinesterase, for example. Cholinesterase is inhibited by OPs or whatever, but that's a gold biomarker in that it's very specific for a chemical. ALA would be the same thing for lead, for example. Things that are really compound specific and in that sense are what they would call a gold biomarker.

They talked about silver biomarkers and there they're talking about things like DNA addicts, which are generally less specific than like, say, cholinesterase. And for bronze biomarkers, the lowest category, they talked about things like P450, zip one and zip two, which occurred with a whole bunch of different enzyme changes in general.

So that's something also you might think about is the usefulness, or the quality of the biomarker if that's a useful kind of thing that you all might get into.

We have not in this process defined exactly a task. In the Academy, for example, it's customary when we form a new committee that we give them a statement of task. But on the back sheet of this background material, background document, there is a page of proposed objectives which are specifically for this committee. You all may need to look at those, you may need to modify them, but those were some of the ideas that we thought might serve as a working recommendation.

And let me just quickly go through those. First, to identify the areas of science which are of common interest to both FDA and the stakeholders so that they may collaborate effectively to advance methods and techniques by which to identify and prevent drug induced cardiotoxicity and vasculitis, which focuses on that collaboration which is clearly one of the major goals.

Second, to define specific objectives within the fields of cardiotoxicity and vasculitis that could be achieved by collaboration, and also to identify resources, effort and the time required to achieve specific milestone determined by each group.

Third, to identify potential collaborators who have resources and interest in achieving these objectives.

Fourth, to identify mechanisms by which a collaboration could be effected, and I would add enhanced.

And, fifth, to define benefits to be realized by agreeing upon these objectives.

Those are very general but are kind of guidelines, if you will, that the NCCS would like to give you all to start off this task.

Let me ask other committee members for comments.

MEMBER GOODMAN: I think one thing that's also important to consider is overall philosophically to not just look to add new tests, but to see if anything that is currently being done maybe can be eliminated and done better, as opposed to just simply adding to the list of tests.

CHAIRPERSON DOULL: Jay is speaking from experience. A couple of weeks ago, several of us were at a meeting, an ILSI meeting, to see if we couldn't simplify the testing. It happened to be for pesticides, but the toxicity arguments are applicable across the board.

Old tox tests are like old soldiers -- they just never go away. They just keep on and on, and we add each time. We need a system whereby we can look at what we do and say is that really the best way to determine whether this material is going to have an adverse effect in the public. We don't do them any great service by simply adding a whole bunch of new tests.

CHAIRPERSON DOULL: Other comments? Joy?

MEMBER CAVAGNARO: Just one comment and I note that we have representatives from companies and perhaps international flavor, and I think that, you know, as we move forward since this we're in a global environment now, that I think it's going to be important to see how this impacts actually globally. If there are recommendations from this committee and how not only do we move forward and to try to get acceptability, as Frank said, in terms of development programs, but a consideration about how we move forward in a global setting I think is going to be pretty important as well.

MEMBER ANDERSON: I would like for you to comment on the objectives which you just did from the background paper, and the role and objectives here. How these two relate. This is very general and this one was very specific.

CHAIRPERSON DOULL: Okay. Gloria -- Dr. Anderson B- is talking about the objectives, Jim, that you had in your slides which are somewhat different than the ones that are at the end of the backgrounder. DR. MACGREGOR: Okay. I think that what I'm trying to lay out is, in a way, a parallel to the objectives that John just read. You're referring to the ones that I presented versus the one that was in the backgrounder that John just read.

And I think actually they're not incompatible and mine is just, as Dave just said, really a checklist of things that need to happen today, and that the groups need to address. I think that's what I was intending to lay out in a general sense. The overall thing we want to get out of these groups, and the subcommittee, are the objectives that John just read.

MEMBER ANDERSON: I was concerned, and I guess you've answered it, that these are very general so I guess this would be general down to the specific ones, so this will not supercede the specific one that you have here. Is that correct?

DR. MACGREGOR: Yes, I think that's correct. And in a sense, I guess, in my mind personally as a personal comment is that both of these sets are fairly general. That is that I think that the subcommittee has come to the point of considering information and case histories and been convinced that these are important areas in which progress could be made, but that the subcommittee did not really possess in depth expertise in these technical areas. So these are purposely left general enough that when we bring together these experts that we now have, that they would have the latitude to put forward their views on really what are the best opportunities and either confirm our thoughts or extend them, or come up with a better set.

CHAIRPERSON DOULL: We could, in fact, get a recommendation from you guys that we ought not to be doing this, that it's premature or that there isn't enough information out there, whatever. And that certainly is an acceptable recommendation. We've made our best guess as to where the possibility for some good recommendations might come forth but, you know, we rely on you to tell us whether that was a wise recommendation and how to implement it.

I'm sure over the period of time we're going to have a lot of concerns about the mechanism of all this. How we get the meetings. You've already heard about do we have to have it in the Federal Register. Well, we don't have to do that. But we will need to deal with the mechanics of all this, how we arrange to keep track of what you're doing and whether you want to have meetings with this committee or how we keep in communication and so on.

We intend to be fairly active in following along what you're doing because it's important to us and it's important to the Food and Drug.

So do you all have any questions for the committee?


DR. ROSENBLUM: Is it working? I was curious about another activity that's ongoing, it's an ILSI sponsored, I think it's called nonclinical clinical toxicity correlations, and that's been meeting for a couple of years now.

It seems to me that the progress of that committee could significantly impact the objectives of this committee, and I was wondering was there any attempt to bring those two functions together or to correlate them somehow?

DR. MACGREGOR: Yes. Could you give your name for the --

DR. ROSENBLUM: Oh, I'm sorry. Rosenblum, Schering-Plough. Sorry about that.

DR. MACGREGOR: We had at our, I forget which meeting, Denise Robinson from ILSI to come and talk about some of the ILSI activities. We are trying not to reinvent the wheel. ILSI, for example, has a big liver ongoing activity and, as Frank mentioned, that's one area that we have avoided somewhat.

I'm not familiar specifically with the one you're talking about.

DR. ROSENBLUM: Could I just extend that. What was particularly of interest to me was that the ILSI committee activities were attempting to get at predictivity of toxic findings in animal models as it relates to human safety, and it seems to me that that's very germane to what we're trying to accomplish here.

DR. MAGREGOR: I agree.

DR. DEGEORGE: I'm Joseph DeGeorge. The ILSI effort though is a slightly different effort. It's actually designed to look at -- the current effort is designed to look at the pharmaceuticals in development now, what findings are observed in animals and whether or not those findings are then observed in the clinic, if in fact it comes to fruition. That's a little different than trying to identify improved better biomarkers, for example for cardiac toxicity, that might be more predictive of the outcome in the clinic, over whether you are getting any changes in the clinic at therapeutic doses that might be predictive that if you went higher, you would see a cardiac toxicity, for example.

I mean the ILSI effort won't be able to tell us whether the model is predictive, other than the fact that you observe cardiac toxicity in the animals at some dose level, and at some other dose level you do not yet observe cardiac toxicity. The biomarkers might actually improve that prediction by allowing you to extend and say, well, if you double the dose clinically, which you don't have to do, you would in fact see the cardiotoxicity or some early signs of it in humans.

So they're somewhat, they're parallel to both important efforts but this takes on a different focus. In fact, I think the topics that were chosen as areas were also areas where it was felt from the original ILSI effort that there was very little predictivity, given our current techniques.

CHAIRPERSON DOULL: Thank you, Joe. You know, that's something that if it would be helpful certainly we could facilitate, you know, communicating that information either through Food and Drug people on that committee or through ILSI itself. If that's something that would be helpful to you all. Yes?

DR. MACGREGOR: I was just going to comment. I think the point is well taken that there in fact are a number of different collaborative activities that are going on that these groups need to pay attention to and try to coordinate with that.

As John pointed out, we did have Denise Robinson and also Gwyn Morgan, who was at the time chairing the genomics initiative in the ILSI consortium, come and talk about those activities. And, in fact, those types of activities were considered when we chose the initial two general topics and, in particular, when we went to the theme of accessible biomarkers, because there are a number of different groups that are using genomics, i.e. gene expression chip approaches, which is really in some of our minds, I would say in my mind, more of a, it's a useful tool in discovery and it's kind of a discovery tool for clinical and accessible nonclinical biomarkers.

But in general your nucleic acids are not accessible and because there really wasn't a consortium that was approaching the accessible markers, which when identified could be immediately brought into use. That was part of our thinking in going to the accessible marker theme to try to focus there for those two reasons because there were things going on and also because by approaching the accessible markers you'd have things that would be a little faster to bring into practical application.

DR. ESSAYAN: There's another issue that has been raised by some of the comments here, and that's that there are sort of two levels of approaching this problem. There's the discovery level and then there's the validation level. I think one of the things that this committee is interested in looking at is not just the identification of the biomarkers but the ability to validate them in a way that will be useful.

The validation part as a regulator becomes a very central point in what we need to do here. Identification can be done prospectively but there may need to be some retrospective data collected in the circumstance where we know a toxicity occurred to look at whether we can validate the preclinical homologue and the clinical data that can be acquired. And then potentially raising that to the next higher level of structure function homology and whether we can detect classes, or structures, that may then predispose to these adverse events.

CHAIRPERSON DOULL: It occurs to me we should, we can get a copy of your slides to the committee and some of the material from the August meeting might be helpful also. I'm just thinking of things that we have talked about, for example, that might be helpful to you all. We can certainly facilitate that. Yes?

DR. ROSENBLUM: Frank nicely pointed out some of the progress on the Triponin T as a potential biomarker. I would like to ask Frank is it appropriate to review some of the progress on the so-called genomics front, i.e. microarray work that's been conducted over the past many months. And, in fact, I think Frank you yourself have looked at doxorubicin in terms of gene expression analysis.

I'm just looking for sort of updates on some of the newer technologies that are not yet in published journals but data is floating around.

DR. MACGREGOR: Yes, Rosy, you're hitting a big question and I'm not sure exactly how we're actually going to do that. All of us have data that we have that would be very good to share amongst ourselves in terms of our own experiences. I know Roger Brown at Glaxo has done some really nice stuff with doxorubicin and looking at -B leucocyte gene expression changes, for example. We have to figure out how we're going to do that in some sort of a systematic way. I don't know the answer to that.

I just touched on and very briefly talked about some of the experiments that we had done and just gave you the one slide. You know, we could spend hours probably going over all the details of what we did and I don't know how we're going to do that in the expert working groups. We do need to sort of, everybody needs to share what they're doing, where they are, how they're doing what they're doing, who they're working with. That's a big question.

CHAIRPERSON DOULL: It's a lot easier to deal with a working group than it is with a subcommittee.

DR. SISTARE: And I think that's an appropriate question for the expert groups to address. DR. JOHNSON: I have a separate but related question. Dr. Sistare, you mention I believe that the QTC prolongation is going to be covered in a parallel effort. Can you qualify that? And I guess in sort of a related way, is the cardiotox group expected to address that specific issue?

CHAIRPERSON DOULL: Identify yourself for the record, please.

DR. JOHNSON: Oh, I'm sorry. Robert Johnson, Schering-Plough.

DR. DEGEORGE: Again there are actually -B Joseph DeGeorge, FDA. There is an industry and FDA effort, actually there's an international effort ongoing look at evaluating appropriate test systems for QT sorts of efforts. In fact, the industry is testing a number of pharmaceuticals that they've picked out with both positive and negative outcomes in humans to derive appropriate animal models to address that.

I think it was felt by at least the Pharmtox coordinating committee's research subcommittee that that effort was being addressed, and to have another group try to do the same thing would not really facilitate getting to an answer. Again, industry's already investing a significant amount of research effort into that. The FDA is working with them on that effort within CDER. Internationally there's an effort underway under the ICH to generate an evaluation of current methods. So there's already a lot of activity on that. The direct cardiotoxicity effort is one which no one seems to have picked up and which we clinically run into problems with and nonclinically run into problems with. So trying to get an effort there was thought to be a better use of limited resources.

DR. JOHNSON: What was the formal name though of that group?

DR. DEGEORGE: The formal name I am not sure, but it's part of the subcommittee that is doing that under the safety pharmacology group.

CHAIRPERSON DOULL: Other questions? Concerns?

DR. SISTARE: Let me make one thing clear though. That list that I gave you is like a Tier 1, Tier 2, Tier 3, those were the recommendations that were brought from a research subcommittee that's part of the Pharmtox coordinating committee which Joe is the policy head on that. So those were the recommendations that I brought forward to the NCSS, then the NCSS from this banquet or, you know, from this plate of possibilities, they agreed that the Tier 1, those two were the most appropriate. And, because of the parallel effort that Joe talked about, let's not deal with QT in this group. Let's focus on biomarkers of myocardial injury and possibly response to injury with time.

So the cardiotox group is not to focus on rhythm issues.

CHAIRPERSON DOULL: But that's not a restraint. If you guys feel that you need to look at that or talk about it or consider it, then obviously you know whatever makes it work.

We are extremely anxious for it to work with these two committees because we have a lot more possible advisory committees that we're thinking about down the road, and that we would like this to be a model to help us make them all work. Yes, sir?

DR. ROSENBLUM: Well, insofar as many cardiotoxic drugs are toxic by virtue of functional changes and not necessarily structural changes, I don't see how you can separate the two areas really.

DR. SISTARE: Well, you could ask the question and it would be a fair question. If you have a drug which causes a rhythm disturbance, will you be able to monitor that by looking at some -B biomarker? I mean I'm open minded, you know, that's possible. I'm not suggesting that may be the best way to pick it up, but it's quite possible.

But, again, the focus was on, you know, compromising the integrity of the myocardial injury per se. You know, it may be that these things with continued injury may result in fibrosis that ultimately does result in a rhythm disturbance or electrical disturbance. You know, these are great questions to bring up and you shouldn't throw anything out, at least in the early part.

DR. HOLT: Gordon Holt. In playing off of what Frank suggested about the value of being able to share data, an obvious impediment to that is confidentiality. And I know that my company certainly has a lot of contractual obligations that certainly would complicate sharing of data.

I wondered if it's possible, I appreciate that this forum can't be under CDA, I wondered if there's a possibility of taking some segment to the working groups into a confidential setting so that we can share actual data and actual experiences.

DR. MACGREGOR: Well, Nancy, do you want to comment on that?

DR. CHAMBERLIN: We have a transcriber for the morning session and that's being videoed. We were trying to do the working task force in an open session and initially for the first meeting to get the ground rules going, you can do open session. But at some point, if you do want to choose to do confidential information, you can set your ground rules there. But we were trying to be upfront in the public, but in order for say confidentiality, I mean that's your call.

DR. HOLT: Should we discuss that in a working group or could I persuade you guys? I feel with great confidence if we polled real quickly here that everybody would say we'll make a lot more tangible decisions if we can, not for the entire working groups, but just at some point we can say from here on this is confidential information.

DR. MACGREGOR: Why don't you take it up in the working groups early on and we can then decide how to proceed.

CHAIRPERSON DOULL: Nancy says we have no requests for public comments, but are there any public comments that anybody would like to make, either to the working groups or the subcommittees?

Well, I think we know at least where we're at which is not all that well formulated but we've left it loose intentionally because we're not sure how the best way to make it work. And that's what we're going to explore this afternoon.

Do you have any other additional details? You've taken care of the administrative things, lunch and so on?

DR. MACGREGOR: Yes, I mean my only question would be if we're about to wrap up we can obviously begin working earlier, so we'll just have to think about our logistics since the plan was to have one of the groups go to a remote site. We'll just have to check on our transportation and maybe take a short break and then formulate a plan on that.

CHAIRPERSON DOULL: Yes, why don't we do that. Why don't we just take a ten minute break and we can talk about that and then figure out how best to do our afternoon sessions.

(Whereupon, the proceedings went off the record at 10:08 a.m. and resumed at 10:34 a.m.)

CHAIRPERSON DOULL: I think we'll start our working group meetings early and Dr. MacGregor is going to fill us in on how we're going to do that.

DR. MACGREGOR: Okay. Since we're done, there'll be a slight amendment to the general plan that I announced earlier. We're going to begin the working group meetings right away before lunch so you'll have some time to discuss and get organized before lunch. And because the meeting for the vasculitis group, it's not far away but it's not right here either, I think it's going to be easier not to try to get everyone together for lunch.

So what we're going to do is we have arranged for transportation for those of you that are in the vasculitis group to go over to the Ramada Inn. There's a meeting room there, Nancy what is the meeting room number?

DR. CHAMBERLIN: I think they changed it to the Georgetown Room. Originally it was the --

DR. MACGREGOR: Georgetown Room, okay. So Georgetown Room at the Ramada Inn. And we have the transportation arranged at approximately 10:45 but we won't leave until we have you all, to bring people over there. So people that are in cardiotox group will stay right here in this room and we'll reconvene in about ten minutes after John closes this meeting. And then at about that same time we'll have transportation for the vasculitis group.

Now the transportation will be a van that will hold four people, so the first four of you see Nancy. Nancy, raise your hand. The first four people that see Nancy, she'll just take you out this door right here and there'll be a van. But the people that have cars can't get in that parking lot. So the rest of you go upstairs to the main lobby of this building, and the main lobby faces Fisher's Lane. Go out the main lobby and walk across Fisher's Lane to the other side of the street, because that's where the cars can pull up and there'll be three or four cars of people going over there.

So first four go with Nancy, the rest of you in vasculitis go upstairs, across Fisher's Lane and there'll be cars there to bring you over. There are a number of restaurants right adjacent to the Ramada and Dave Essayan, who's our liaison to the vasculitis group, will make sure you find one of those restaurants and eat. And I'll be staying with the cardiotox group here, and we'll just follow the original plan of going over to the cafeteria.

And also a reminder, seven o'clock everyone that would like to come together for lunch, seven o'clock at That's Amore restaurant, which is directly across the street from the Doubletree Hotel, directly across Rockville Pike and in the same parking lot actually with the Ramada. So just ask if you have any confusion, the people at the hotel where is That's Amore, and we'll see you at seven.

CHAIRPERSON DOULL: When we introduced the working group members we neglected a couple of the Food and Drug reps. So we'll -B Tom and Elizabeth.

DR. MACGREGOR: Yes, an oversight in my introduction that we also in setting up these groups recognize that each of the FDA centers that's involved really ought to have liaison contact with these expert groups. And we gave each of the three centers that are now actively involved, CDER, CBER and NCTR, the opportunity to appoint liaisons to these expert groups.

And CDER has appointed one to each group, Tom Papoian, Tom are you here from CDER, to the vasculitis group and Elizabeth, Liz Hausner to the cardiotoxicity group. So they'll be liaisons to CDER. For the moment I will be functioning as the NCTR liaison to both groups and Dave Essayan the CBER liaison to both groups. And we also have, Dave and myself will be keeping track of the groups as part of our function of being the NCTR and CBER liaisons, FDA liaisons actually with the subcommittee group.

CHAIRPERSON DOULL: Okay. One final thing. When you meet in your working groups, why don't we start out with Jim being in charge of the cardiotoxicity one, just to get it organized so you can do your thing. And Dr. Essayan being in charge of the vasculitis one, and he can help you then get it organized.

Is there any additional business that needs to come to this committee? Then I would like to thank all of you for being here to day to help us get this business started. Thank you very much. We're adjourned.

(Whereupon, the above-entitled matter went off the record at 10:38 a.m.)