There is only an hour left and there are a few key things I would like to get to. Although I have a couple more discussion questions that I would like to bring up, before we get to those, I wonder if I could propose a couple of ideas that I culled out of discussions last night and this morning as key clinical trials questions. One of the goals I thought we ought to have at this meeting would be to say what are some fundamental clinical trials that we want to see done, things that people should work on in producing trials. So I would like to propose a couple to you and see what you think. Then we can go back to general discussion questions as you like.

One of the questions that came up is whether in vitro diagnostics can be used as a substitute in some ways for surveillance cystoscopy in follow-up patients. And or can surveillance be done at less frequent intervals for lower risk cases. There was considerable discussion about that in breakouts yesterday and I don't expect we can say how these trials should be done - maybe we can - but I don't think we can nail that down this morning. Would people agree that this is an important issue for us to address in clinical trials fairly soon? Show of hands, people who agree that that is an important set of issues. How about people who think it is not going to be very important or particularly possible. One or two. Okay go ahead and discuss it. Brent?

DR. BLUMENSTEIN: Your alternative there, not important versus not possible - that is a difficult question to answer. I think it is potentially important, but the thinking I have done about the trial design there leads me to feel that this trial has to be based on a progression type of endpoint. The reason is that it is very complicated. Anything less than progression does not really show a patient benefit and it is confounded by the fact that you are treating with different kinds of surveillance, with cystoscopies at a different rate and you are going to see disease at different rates. Also, any kind of a trial like that would scream out for some kind of a quality of life or health preference state assessment that would be important to do.

DR. SCHOENBERG: If you accept that design, which is very germane in that particular context, you axiomatically select a group of patients in which progression is very rare. Therefore, you impose on trial design a tremendous n. The question then is, is that really the underpinning of your impossible supposition? It may be the Catch-22 that makes the trial impossible, if you use progression as the endpoint.

DR. SANDLER: That was one of the points that I thought was important for this particular question. The other one was if there is a limited amount of resources to do clinical trials, I am thinking that trials that focus on patients who have an appreciable risk of death from bladder cancer should take priority over studies where the risk to any individual patient of death from bladder cancer is very low, which is the kind of patient who would be put onto this trial.

DR. KAPLAN: One thing that was discussed yesterday was the possibility that you could address questions of surveillance, questions of markers and questions of secondary chemoprevention all in the context of one large study that would involve several of those issues, and yield information about some of those things.

DR. LERNER: That is exactly right. The proposal was made, and I would be very interested in Brent's and Richard's comments in the context of the Dave Woods perioperative cipro trial. That has an accrual goal of 900 and has 100 patients enrolled. Accrual has been difficult. We are sort of befuddled as to why. But could we add onto that, for instance, a biomarker study in a subset of those patients in institutions that can support that. And since this is a low risk patient population for progression, you could very easily and ethically randomize those patients to a surveillance strategy of, for example, what is written in there, every three months, versus every year. Then answer several questions that I think are very relevant for urologists and patients.

DR. KLOTZ: Two comments. To address what Seth just said, the problem I can see with the trial design is that if your endpoint for the cipro study is recurrence, which I believe it is, and you get a difference between them - there is obviously going to be some bias towards detecting earlier recurrence in the surveillance arm, if you make that a two by two trial. You may make it difficult to identify your endpoint, the primary endpoint of the study.

DR. KAPLAN: You might be able to construct some sort of landmark analysis that addresses that complexity.

DR. KLOTZ: The other point I wanted to make is that I would rather see those two first bullets disaggregated because I think the second one, we have the data and we know enough about the natural history to know the answer to that one. It clearly can be done at less frequent intervals and there has been Marcove modeling of surveillance intervals based on clinical parameters that I think have really answered that question adequately, even though we don't have a large Phase III study. So I would support the first one, but the second one, I think we would be putting a lot of resources into answering a question for which we already know the answer.

DR. KAPLAN: Would you like to see this State of the Science meeting propose a statement on that topic and see if we can use that statement as a starting point for discussions with various groups, such as the AUA and standards setting consensus groups?

DR. KLOTZ: Definitely.

DR. LERNER: But, Laurie, you could answer both questions with one trial - randomize it to follow-up with in vitro diagnostics and, say, once a year cysto, do the in vitro diagnostics in both arms so you have the data from both arms and the other arm is regular cysto. That is a question to the trial design experts.

DR. JEWETT: An answer to your question is can the second question be abandoned because we know the answer? If we know the answer, why are cystoscopies not being done at less frequent intervals? So I would say this in fact is a very major issue from a societal perspective and we should not abandon that as a question for some form of trial. What is defying us is the endpoint to use in such a trial.

DR. VAN DER MEIJDEN: If we believe in evidence-based medicine we should do such a trial. It is the only way to convince our urologic community in what we all believe but what we all don't do yet. So it is necessary.

DR. SCHOENBERG: Let me just say one other thing which will corroborate these two statements. After all, in Campbell's, the standard text from the last edition, the recommendation is not do what you are assuming. Just to quote Don Coffey, we really should not assume what we could prove and we could prove it pretty simply. It would take a lot of organization but it wouldn't be complex and we obviously need to agree on the endpoint. I think it would be dangerous for this forum to make a recommendation that flies completely in the face of standard urologic practice. I think we should not do that.

DR. GROSSMAN: I personally have a healthy skepticism of any models. You can set up a model any way you want and what you are doing is basing it on the best available retrospective data and we don't believe retrospective data in the first place. We need to do prospective trials, so how can you believe any statistical model that you make out of it. The only way you are really going to convince people has already been said, and that is in some prospective clinical trial. It certainly is doable. I think maybe as the initial point, instead of surveillance cystoscopy, what you want to do is dramatically decrease the frequency of cystoscopy, maybe to once a year for a couple of years. But these are fine tuning points of discussion for a protocol that we don't need to get into. But I think that kind of trial is going to be very useful and helpful to the patients.

DR. KAPLAN: In the interest of time - obviously there is more to be said about this and we won't resolve it and we won't get to the other questions either - do you agree that these top two bullets are something that should appear in the minutes of this meeting as potentially important clinical questions to be addressed appropriately? You would have to work out what appropriate means and how it should best be done. But do you agree that they are important? Okay.

DR. BLUMENSTEIN: I just wanted to say one thing. Michael Jewett and I discussed this kind of thing yesterday and just as an idea that occurred to me during the discussion, we might think about approaching such a trial as a group randomized trial. What I mean by that is, instead of randomizing each patient between follow-up schedules, we would randomize clinical sites to use one schedule of follow-up versus another. This has been used successfully in a number of different settings, especially things like smoking cessation programs where you randomize communities or schools or things of that nature. It has some advantages in management, but it also raises issues about trial size and so on that are kind of difficult, but not impossible to address.

DR. KAPLAN: That sounds attractive to me except for something Adrian said before about some difference in recurrence rates in particular sites. I guess if you randomize you should address that issue, too.
Okay, let's try to move on. Another key clinical question that seemed to emerge from yesterday and from this morning's presentations is that we need to encourage further investigation of period timing for both intravesicular and systemic chemotherapy. Is that something that everybody agrees is a kind of key setting for clinical questions to be done and try to stimulate some thought?

DR. VAN DER MEIJDEN: As a European, could anybody in this audience update me about the valrubicin study that is being done in the US? In fact, we do have two large studies done in Europe, one by MRC and one by EORTC. I don't know whether this is enough to convince you, but there are two large studies.

DR. BLUMENSTEIN: As you recall, SWOG sent in a study concept for doing this about five years ago and it was turned down by CTEP because it was regarded at that time as being more or less uninteresting.

DR. KAPLAN: That is not a precise characterization, but in any case that is why we are having this meeting.

DR. BLUMENSTEIN: I think part of the turn-down had to do with the fact that it did not include enough science and other things like that, to be fair. But it would seem to me to be a fairly interesting study and possibly a quick study to do provided one accepted an endpoint of three months as to whether the disease was present or not, and one was careful about a blinded application of the immediate perioperative therapy so it would not influence the intravesical therapy used in the first three months. Adrian asks a good question about whether the European data is sufficient or not. It would seem to me that it is. Nonetheless, we are not using it, so perhaps we do need to do the trial to convince US people that it is important to do.

DR. KAPLAN: My point of putting it here was not does the European data convince us of something. The whole question here is do we think that the European data and everything else we know about the biology of the disease is adequate to say that this is an appropriate framework for clinical trials to be done. I think we all agree on that, whatever conclusion we have about the European data thus far. That is the important point in this particular context.

The issue you raised about the design of that trial you mentioned is very important because there are issues of regulatory approval. When you get regulatory approval having to compete with scientific interests in the study, you get a lot of potential conflicts in goals and objectives and needs. That is really the kind of thing we got hung up on at that point. Obviously, from the standpoint of any industrial sponsor, the fastest endpoint and the endpoint that is most achievable is very desirable. From the regulator's point of view, getting a drug on the market, with all of the promotion that goes with it, and changing practices, one would like to be sure that the endpoint you are going to use in those trials is not just feasible, but actually potentially valuable in the overall course of the disease for patients. That is a very hard question, one that we cannot answer here today. It does make the design complex for this sort of trial and any others.
Can I move on?

DR. COTE: Richard, just one thing on the endpoint? On your previous slide, based on my understanding of what we are talking about, the previous discussion, where you say based on progression endpoint, I think it is based on progression endpoint in some studies and on recurrence endpoint in other studies. It depends on the question that is being asked. I would just make that modification.

DR. KAPLAN: I will do that. I put that in before the discussion was completed. It seemed to me that I heard a lot of recommendations that we need to follow up on - the leads leading to lower dose BCG use, on the multivitamin approaches, and I think people have said this for a long time. This may be a more prominent forum in which to say people should work on these issues. Is that something that we should list here in this category? I think I hear nodding on that, either off or in agreement.
We probably want to try to confirm or address some of the promising data on BCG/interferon that Michael O'Donnell was talking about yesterday. I am not certain that I understand the status of all those data at this point, but presumably that is something that bears some follow-up discussion and planning of additional trials as appropriate, if you all agree. Of course I have listed the COX-2 inhibition approach to what we might call secondary chemoprevention or for that matter primary chemoprevention, as being highly attractive from many standpoints, having come up in several of the breakouts yesterday. So shall we list that as well here?

DR. COTE: Again, in terms of the second two questions, that these also represent opportunities to do correlative studies. In other words, in the BCG/interferon trial it would be very reasonable to look at angiogenic status and recurrence and progression. Obviously in the COX-2 inhibitor trials, it would be not only reasonable but critical to establish the level of COX-2 expression in the marker tumor. I think these are nice clinical questions and they are ones that lend themselves to marker related and correlated studies and perhaps even at some point marker-driven studies in terms of looking at selection of secondary chemoprevention agents in intravesicular treatment of superficial bladder cancer.

DR. VELTRI: Also in Breakout A we mentioned that we would break up the biomarkers into host-determined biomarkers in terms of the immunologic response versus tumor-associated marker alternations in response to either the dual or single therapy.

My other question is if you do dose titration for BCG to modify the active treatment dose, does that mean that that information would be translatable over to the combination therapy for immunotherapy? Would that be a part of what is being addressed here? Or would you just use standard of care plus interferon?

DR. KAPLAN: I was not thinking specifically exactly how we would structure that, but I would assume that the modifications might very well carry over in the design of combination studies.

DR. VELTRI: That is where the cascading approach would be beneficial.

DR. FRANGIONI: I wanted to mention that the best pre-clinical data, which is probably Debbie Knapp's dog model, wasn't COX-2, but a non-specific COX inhibitor. That may be as important.

DR. LERNER: Just a follow-up - in any chemoprevention study design we would have to take into account confounding variables, such as the high prevalent use of complementary and alternative medication which may have an impact on disease. A significant issue was raised, even an ethical issue was raised, regarding our obligation to counsel patients on stopping cigarette smoking and trying to get our arms around the benefit of that and the impact of continued cigarette smoking on risk of recurrence and potentially progression.

DR. KAPLAN: I will try to take these points that are emerging from the discussion and include them in the slides that will be the output of this eventually. I think those are what I had listed as things that clearly emerge as key clinical questions. I think you may suggest some additional ones if you would like.

DR. BLUMENSTEIN: I was hoping Richard would say something, but the EORTC has a trial currently open addressing the first of those issues up there. I think that it is important to get that fact into the minutes, that they have a two by two design. Richard, I better not try to describe your trial.

DR. SYLVESTER; We have a two by two factorial design. It is not designed under the assumption there is no interaction. We are looking at two different questions. One is standard dose BCG versus one-third dose BCG. The second question built into the same study is one year of maintenance versus three years of maintenance. So we are looking at both the dose of the BCG and the duration of maintenance. Hopefully with this we will be able to answer a few of these questions concerning how much BCG is necessary. We have 1,300 patients needed and I think there are somewhere between 700 and 800 patients entered into the trial now, so the trial will probably remain open to entry for another couple of years.

DR. KAPLAN: Are there other key clinical questions we should list under this category?

DR. VAN DER MEIJDEN: In general, chemoprevention is very essential to me - chemoprevention in superficial bladder cancer.

DR. COTE: I think there are a couple more things. First of all, I think we have an opportunity for marker-driven, if you will, clinical trials that I would say would be similar in concept to the p53 MVAC trial that is currently going on. I think we have enough data on the biology of bladder cancer to actually start to think about stratifying patients on the basis of specific biological characteristics of those patients. Frankly, if we don't do it, we are losing a major opportunity and a lot of time.

That is one thing that I think we really need to be thinking about and really focusing on. This is an area where particularly the NCI can be very beneficial in providing the impetus and resources to actually allow those kinds of trials to go forward and encourage the cooperative groups to bring forward.

The other thing is that we have a critical need to develop better and more sophisticated modeling systems, in particular animal models in these diseases. I think there is an opportunity to fund the development of that and to use these animal models in the ways we described, to look at efficacy of multiple targeted therapies and the use of surrogate biological target-driven endpoints. I think those would be two issues that would be important issues for future development and funding as well.

DR. KAPLAN: I did not mean to neglect those. I think that is something that we have got in the minutes of the output of this. It is not a clinical question, per se, but we definitely need to include that.

DR. AU: We have worked on intravesicular therapy for a long time, but we are also interested in systemic therapy. I would like to make a point on the model we used, and the model basically told us that when you maximize drug delivery, in the case of mitomycin, around 40 percent response. That is all we are going to get, because the rest has to come from manipulating the biology. We also talked about bFGF and aFGF both being very important factors in resistance. I think the next way to go is to try to capture what we learned from the biological factors that cause the drug not to be effective and therefore I think now with some of the data we have in lung cancer and prostate cancer and also in the bladder cancer cell lines, we certainly are at the point now where we can do at least single institution Phase I and Phase II trials in bladder cancer using Suramin as a blocker of the FGF's. It is not key in the sense it is not yet at the Phase III step, but I think the next big wave in improving chemotherapy efficacy will have to come from biology and not just changing doses. Marginal increase is not going to be the best way to go at this time.

DR. GROSSMAN: Related to the last three points is the fact that targeted therapy is important and chemoprevention is important. But all these things are going to need to start getting away from single-targeted therapy to multiple targets, either along the same pathway or even better, using complementary pathways to maximize the effect. The multivitamin study did not just use one vitamin. It was a compilation of a rationally selected choice of vitamins and particularly in chemoprevention I think we are going to need to address multiple pathways to yield real benefit.

DR. KAPLAN: I think that is an excellent point that has been made several times. It is a critical point in the development of novel therapeutics really all across the board. We have to find ways to study these things appropriately from the earliest stages of development, in combination, so that we can somehow compress the current path to effective use of combinations in human beings which takes ten years for one drug and another seven years to add a second drug to it. That is just not acceptable.

DR. BOCHNER: One of the things to keep in mind is that some of the agents we have been talking about, particularly the COX-2 agents, may have multiple effects and therefore affect a variety of pathways. I think before we begin to add multiple layers of drugs that are going to need to be tested, it is probably very important in these chemoprevention trials to keep a very open mind that we are not sure what the mechanism of action is. You should not necessarily penalize studies that are going to look at a variety of markers that may not necessarily seem related. You may need to look at cell cycle and angiogenesis factors and apoptotic factors to really begin to sort these mechanisms out.

DR. KAPLAN: I am conscious that we have a very short period of time left. There is at least one issue here that I don't think we should fail to address again. It is the bottom issue here. I would also like to discuss what Peter Jones asked yesterday - is it really a field defect in this disease and where is the evidence? That would be interesting, but we don't have to answer that today. But it has been proposed that we do need separate clinical trials infrastructure for bladder cancer studies in general to make them practical. I am not sure I see the immediate path to accomplishing that. But part of that is I am not sure we have explored all of the possible ways to do things as thoroughly together as we could have. So I would like to ask that question. Do we need a separate infrastructure? Why can we not build on some the infrastructures that already exist? Mark or others may want to begin to address that.

DR. VAN DER MEIJDEN: One of the most important things that brought me to this meeting is that the time is over that EORTC or MRC or SWOG or whatever can embark on a trial without knowing from each other or without helping each other. I do think that if we would embark on trials on surveillance and we would need thousands of patients on that, if we would think about chemoprevention we would need thousands of patients on that - there is no other possibility than cooperating. I think that we resuscitated the GU-Global group a couple of years ago. Laurie Klotz is the chairman of that. I do think if we make an effort to look to these new ways and strategies, we should do this together.

DR. KAPLAN: I absolutely endorse that, but it is a somewhat different question that the one being asked. That is overwhelmingly important.

DR. RAGHAVAN: I think, picking up from what Adrian said, we have just had the exercise, in what I think is pretty much record time, through the GU-Global group, launching two studies that I think are going to be two of the major studies asking seminal issues in bladder cancer today. There has been no impediment to the development of correlative science. The impediment has been the impediment of the non-medical politics of moving specimens around. The benefit of using the established trial mechanisms is that you can then amplify the impact of the group. So you get a bunch of committed trialists from different groups who get together under Laurie's chairmanship - and it is a rotating chairmanship, so whoever it might be - and I think we have been very mature in putting to bed the issues of power and control and actually collaborating well. So I am actually a bit of an exponent of keeping the current mechanisms in place and not developing trial groups that are focused to that extent. I think there is one benefit and that is that you get the interplay of so much more information from other tumor types. So you have the interaction of RTOG or SWOG or whatever of the non-bladder clinical trialists working with the bladder or GU trialists, and then they focus their efforts up to the GU-Global group. I am not certain and I think Richard Cote and I don't have a common view on this, although we don't fight about it. But I think the fact that, for example, Richard was able to approach SWOG and other groups to join the p53 trial, which was a little slower than I would like to have seen, but the mechanism was there. I think the more we do this, the better it will work. Then you can use the trial groups to enhance interest in the various trials. If you have a little cabal of people who just sit around talking about bladder cancer all day, A, they become incredibly boring and B, they don't have the ability to move those ideas out into the community as quickly.

DR. COTE: I hope everybody understood that Derek was implying that I am slow. I think that I would not disagree with the interplay between the clinical trial groups. In fact, one of the efforts that we have made recently, along with SWOG, is to try to create an interaction with the American College of Surgeons Oncology Group. I think what I heard Mark saying and what really was part of the reason for the existence of our p53 MVAC trial, was that there was a group of people who were interested in these questions. Not that these questions would then be isolated within a particular trial network, but that there could be a nidus - and Derek used the word cabal - but there would be a nidus for the development of protocols that would then very reasonably and in some cases, particularly in superficial bladder cancer, essentially be brought into a much larger clinical trial network. So in a sense I would almost advocate both scenarios, where we have a group of individuals very often, as with our group, that are involved with many of the other clinical trial groups, that can actually focus on some of these issues with the intent of either doing proof of principle studies, which are very important prior to devoting the huge amount of resources that would be involved with intergroup trials as we currently see it. So that is number one.
Secondly, to bring the well developed ideas into the worldwide now mechanism of the inter-trial group and to do that in an effective and efficient way. So I kind of see there would be synergy between these ideas rather than competition between these kinds of groups.

DR. KLOTZ: I agree with Richard. Many of the national groups have disease-oriented groups within them. Obviously the EORTC was the originator of that concept. In Canada we have copied them. We have superficial and advanced bladder cancer disease oriented group national chairmen and so on. So I think it is always good for people with shared interests to get together. The national group structure can be unwieldy. So I support the concept of having a network in bladder cancer which also works within the existing large cooperative clinical trials groups. I think most people who would be in the bladder cancer network would also be a member of a cooperative clinical trials group.

DR. SCHOENBERG: The idea of cooperating and being inclusive is very attractive. The fact that Laurie is here, as chairman of the GU-Global, is evidence of the fact that the bladder cancer community is actually pretty small. When you go to the AUA you see a lot of the same people you see here. They also turn out to be the people who are in marker networks. So in a sense, cabal sounds somewhat pejorative, but the same group of people have been hanging out with each other for years now talking about these issues. One of the things that has been expressed though is the frustration that, despite this interaction and familiarity with one another, for various reasons we have not done the studies that we think are important. There must be some fundamental interaction between the ideas that could generate a forum like this and informal conversation at meetings that takes advantage of the very important bureaucratic advantages of the cooperative groups. Clearly some interaction is going to be key. But a network of people have to keep talking to one another in order to get these high priority items on the agenda and the studies performed. The very fact that the GU-Global was able to quickly bring to the public or to investigators relevant study protocols is obviously very important and should be used and probably will be in this context.

DR. JEWETT: When we use these words, infrastructure, I am not sure what they mean. They traditionally connote offices and staffers and so forth. With the informatics systems that we are now using, it seems to me that you could argue that we already have such an infrastructure. It is just a virtual networked infrastructure. We don't have to necessarily think of these concepts as new resources. It is just ways to organize existing resources. I wonder if this is really a salient issue right now?

DR. COTE: The only difference in terms of the virtual infrastructure that would exist versus the established clinical trial networks is that, if there was a function of doing, for example, preliminary proof of principle studies, then a more formal infrastructure of a bladder cancer network might actually be an appropriate and reasonable thing. So that would take it a step beyond that virtual infrastructure, which probably already does exist in one way or another, and take it to a more formal infrastructure that actually requires administration and funding. Then use that as the structure to bring it to interact with the larger groups.

DR. GETZENBERG: I don't know. I have not worked at all with the different groups that are around, but I think as far as markers are concerned, we have not done a very good job at doing trials to really address the critical questions about markers, some of which we talked about today. I don't know how easy they can be incorporated or do we have to have a different entity that is going to do that. But we need to somehow address some critical questions in the marker area that we have the tools now to address.

DR. KAPLAN: It is a very difficult set of problems overall. I think everybody in this room recognizes, Richard Cote and his colleagues have put together the p53 MVAC study, and they have essentially done what we all needed to have done. They have done the prototype of a key type of trial that needs to move forward. It didn't happen within an established and funded network already. They applied for funding separately and got things initiated that way. But the big difference between a virtual network, using the current resources and that sort of thing, is the question of funding another new and separate initiative. Ultimately, if we are going to establish something that is ongoing, we at NCI would have to find some way to find the funds to have what amounts to a sort of separate cooperative group dedicated specifically to bladder cancer. The track record over the last couple of decades with disease-specific NCI cooperative groups has not been a great track record. They started out with full plates of things to do, took a couple of years to get active, did a couple of trials and then they ran into trouble as they had to be self-perpetuating mechanisms, even when there was not a mature idea ready to go that day. Even if there needed to be a gap of a year or two before there was something to really occupy them, you had to keep the mechanism in place. It was very fiscally inefficient. Sometimes it was scientifically inefficient as well, and so basically what we had to do was find ways to fold those functions back into larger scale cooperative groups which could shift their resources when needed to other diseases - let that committee start doing its pilot or whatever else and eventually get back to a Phase III trial without having to waste resources in the meantime. So it is very hard for us to figure out ways to initiate a brand new and permanent ongoing continuous funding mechanism for something which is very disease-specific. That does not mean that we should not do it. It means that you have to make a case very well for the particular need, if that is what the need is. Or we all have to work together to try to accomplish as much as possible of that same goal within the context of some of the other structures that exist, and make a virtual bladder network that works closely within the auspices of, say, ACOSOG or some of the other groups or some sort of supervening structure that is sort of linked to the GU-Global and thereby all the Cooperative Groups. This is going to take some real brainstorming from my point of view. But we need to accomplish it somehow.

DR. BLUMENSTEIN: As long as we are discussing infrastructure, I think it is important to recognize that one of the things the existing cooperative groups offer is the nuts and bolts type of infrastructure - data acquisition, data quality control, data and safety monitoring committees, talented statisticians like me. I think these are not things you create overnight or necessarily function within a smaller group - not to say they can't. But I think there is a certain critical mass that comes about when you have people together who are working on a common methodology like cancer clinical trials. There is an economy of scale there, to a point. The point probably has to do with what can be supported at a single institution that hosts such an infrastructure and so on.

I have done a lot of thinking about this and I think that taking advantage of that network is not difficult to do, but I think the major inhibition is the kind of thing being addressed by the NCI initiatives. It is access to the infrastructure, not from the point of view of using the nuts and bolts of it, but from gaining a mind share of that group, getting an idea moved forward and getting the consensus developed and so forth. It is very difficult to work within one of these groups if you don't know how to do it. It is even difficult if you do know how to do it. The idea of getting consensus and carrying an idea forward is one of the things that we are finding very challenging in this new group in the American College of Surgeons. We are having to train people how to operate within that framework and it is challenging and fun and so forth, but I think we have to pay attention to the new NCI initiatives and how new ideas are generated. We should not lose track of the fact that there is nuts and bolts infrastructure in place, several of them. They are all pretty good and they are ready to manage the trials. It is the flow of ideas is where the problem is.

DR. LERNER: One of the benefits of having such an infrastructure, be it virtual or real, would be the opportunity to quickly execute and conduct Phase I and Phase II trials. I am just thinking about some personal experiences. Say things like Jessie's idea of Suramin/mitomycin C, studies looking at intravesical gemcitabine, gene therapy - we all have lots of ideas. We have generated pre-clinical data. The typical mechanism is you do it at your own institution, depending on the trial size it might take a year to two years to get done. Could such a group execute those kinds of studies in a collaborative way quicker? My understanding of cooperative groups is that they are really designed and organized to carry out large Phase III randomized trials that answer key clinical questions. That cooperative group mechanism would serve as an infrastructure to then take the ideas that are coming out of these earlier phase studies and get them into the cooperative group mechanism. Just a thought.

DR. RAGHAVAN: Two quick points. One is, very early in the piece I would like to make a point about being very cautious about bracketing Phase I/Phase II in the sense of multi-center trials. I think Phase I trials done in multi-centers, unless they are extraordinarily carefully structured are incredibly dangerous. If you look at the history of Phase I development, most of the disasters have been in that context, where you don't have tight enough linkages to identify toxicity and trends and problems, where you accrue patients at toxic doses too quickly. So I think that is one thing that this group should be very careful about.

The second thing is if it ain't broke, I am not sure you have to fix it. I look again at what we have achieved in the last year. If you look at the way the GU-Global has worked, the number of trials and good ideas that have been put out into the community in a rapid period of time is spectacular. I think the criticism that we, as a community, have been slow to do this is absolutely correct. But I think that the reconstituted GU-Global has been incredibly effective. It is almost an un-North American thing to say, but it has been cheap. So in that context, the amount that has been done on a relatively low budget is just astonishing. It may well be that the NCI could look at the mechanisms in place that these guys have put up. I take no credit for it. I am just an admirer of what they have done. Start to look at cost effective ways of translating ideas.

There are two issues. One is infrastructure and the other is ideas. I don't think the government needs to control ideas. It needs to control infrastructure to some extent. So it may well be that government can actually make money available to let the ideas factory work, which is working extraordinarily well at the moment and provide a mechanism to make it easier for this group to meet and exchange the ideas.
The other thing I would say is the criticisms that I have been hearing are a function of what happened in the past. I think from the point of inception of ideas, the laparotomy trial, the renal studies, it is not just bladder cancer. There are a bunch of really good studies that are being developed internationally. NCI can foster that by removing some of the obstructions at the level of CEP.
The other issues that relate to the concerns about Phase II - groups respond to CTEP and there is absolutely no doubt that through financial management CTEP has discouraged the groups from doing Phase II trials over a period of time. I notice now, having seen Phase II trials in SWOG, some of which were awful ideas and some of which weren't bad, I notice some of the CTEP people say, how did that happen? Who did that? Why did your groups not do Phase II trials? And it was a money thing. So I think the Phase II trials can easily be done in groups like SWOG and ECOG and elsewhere if CTEP wants to broker them.

My point in summary is I am not sure the whole mechanism that is in place at the moment is a bad one. It really allows a lot of different things to happen with the GU-Global being the glue. The problem is money. SO NIH may want to look at that mechanism as one that it could participate in on an experimental basis and see how good an idea amplifier it is.

DR. KAPLAN: I just want to respond to a couple of those points. There was a lot you covered. It doesn't seem feasible at this point, for the first reason you covered, which is the government does not want to control the idea but try to help with the infrastructure. We have built a lot of the ideas of the clinical trials restructuring based on sort of competition between groups to get trials through. The CEP in that context is a key implementing tool for that. It is very hard for me to see a way where we could get to the point where we use even as good an entity as the GU-Global to plan all trials and not have any competition, because people could collaborate and say this is what trial we are going to do. So it somehow goes outside the CEP and does not have a true peer review by people who have not produced it. Admittedly you guys are a kind of peer review because that is how the ideas rise to the top in GU-Global. We understand that, but we also understand it is a place where, if politics have not supervened much yet, even if politics have actually been helpful to you in the recent past, it will not always be the case. So I don't think we can yet abandon the experiment of CEP because it helps us use a competition of ideas. Otherwise I think there are good points in what you said.

The other thing I wanted to say is that, for the cooperative groups to do Phase I and II trials, particularly Phase II trials, it wasn't really funds that was limiting. It was what peer review and the groups felt was the role of the groups themselves. It was not that we said you could not use the money for that. It was the fact that they knew if they used the money for that instead of Phase III trials, they got dinged next time they came to peer review. So we have had to address that at the peer review level. We are trying to send out the message from CTEP that that is an okay, even very worthwhile use of group resources, and we have to get the peer reviewers to actually function as if it is that way, because it isn't us that does the peer review. I think it can proceed and I think when you do subsets of limited institution pilots within the cooperative groups, you can get around some of the issues, the safety issues, the speed issues that have to be addressed to make it feasible within those groups.
It is five minutes to twelve. Are there any other burning points that people want to make before they dash?

DR. AU: I think one thing we have learned through these eleven years of study of mitomycin C, taking it from the bench to the clinic to prove the point that delivery is very important. I want to make sure those lessons we learned in that particular paradigm is not lost. I don't know if this is the place to bring that up, but there has to be some way to educate, in terms of compliance, and I don't mean giving a dose, but watching out for the urine, dehydration status and so forth, mundane stuff. But turned out to be very important obviously. I don't know how to bring that through. And I know the group made a question that should the optimized mitomycin C be a new standard for chemotherapy in that regard.

DR. KAPLAN: I don't know if anybody wants to comment on that. They may not feel able to do so until they have seen a peer reviewed manuscript. Does anybody want to comment?

DR. RAGHAVAN: I think Jessie's work has been very creative and very important, but I think that one always needs to be careful about introducing ideas in a forum like this. I think the issue of peer review, the issue of validated randomized trials needs to be in place before a group like this endorses any concept. We have had a lot of really interesting ideas coming from many people. I think the good thing is that people have tended not to push their own concepts to be endorsed here, but rather to put them up for further evaluation. I think it would be a mistake to pull out any of the ideas we have heard and give them the endorsement of this meeting, short of a couple a major principles that have come through that everybody has completely agreed upon.

DR. AU: Let me just clarify. The randomized trial has been done. The peer review article, I agree. We should wait until the paper is accepted and in print. That part I agree.

DR. RAGHAVAN: That is my point. It needs to be peer reviewed.

DR. KAPLAN: First of all I want to thank you all for this discussion this morning and your participation in this meeting, which has been extraordinary. Most extraordinary of all has been the fact that this has been the best planning committee, and group of breakout chairs I have ever worked with. I think this has been a very gratifying experience for me and I want to thank them especially and all of you for participating.

(Whereupon, at noon, the meeting was adjourned.)

TOP