ATDEPARTMENT OF HEALTH AND HUMAN SERVICES

> FOOD AND DRUG ADMINISTRATION
>
> CENTER FOR DRUG EVALUATION AND RESEARCH
>
> **WORKSHOP ON PEDIATRIC ONCOLOGY DRUG DEVELOPMENT**
>
> Thursday, July 18, 2002
>
> 8:30 a.m.
>
> Advisors and Consultants Staff Conference Room
>
> 5630 Fishers Lane
>
> Rockville, Maryland
>
> [C O N T E N T S]{.underline}
>
> Welcome: Louis Z. Cooper, M.D.
>
> President, American Academy of Pediatrics 4
>
> Welcome: Janet Woodcock, M.D.
>
> Director, CDER, FDA 8
>
> Welcome: Mark Ellengood, M.D., Deputy Director, CBER, FDA 12
>
> Summary of Pediatric Oncology Activity at FDA:
>
> Steven Hirschfeld, M.D., Ph.D. CDER, FDA 15
>
> **Panel 1 - Early Development of New Therapies**
>
> **for Pediatric Oncology** 48
>
> Co-Moderators:
>
> Wayne Rackoff, M.D., Johnson & Johnson PRD
>
> Alla Shapiro, M.D., CDER, FDA
>
> Panelists:
>
> Peter Ho, M.D., CDER, FDA
>
> David Poplack, M.D., Baylor
>
> Wayne Rackoff, M.D., Johnson & Johnson PRD
>
> Greg Reaman, M.D., COG
>
> Alla Shapiro, M.D., CDER, FDA
>
> Malcolm Smith M.D., NCI
>
> Susan Weiner, Ph.D., Children\'s Cause
>
> Presentation: Malcolm Smith, M.D. 50
>
> Presentation: Greg Reaman, M.D. 61
>
> Discussion \--
>
> Public Comment 99
>
> **Panel 2 - Designing Clinical Oncology**
>
> **Studies for Children** 111
>
> Co-Moderators:
>
> Susan Blaney, M.D., COG
>
> Joseph E. Gootenberg, M.D., CBER, FDA
>
> Panelists:
>
> Susan Blaney, M.D., COG
>
> Joseph E. Gootenberg, M.D., CBER, FDA
>
> Anne Hagey, M.D., Abbott
>
> Michael Hurley, Abbott
>
> Wayne Rackoff, M.D., Johnson & Johnson PRD
>
> Susan Shurin, M.D., COG
>
> Richard Sposto, Ph.D., COG
>
> Diane Traynor, Alliance for
>
> Childhood Cancer
>
> [C O N T E N T S]{.underline}(CONTINUED)
>
> Presentation: Susan Blaney, M.D. 115
>
> Presentation: Richard Sposto, Ph.D. 128
>
> Presentation: Susan Shurin, M.D. 148
>
> Discussion 160
>
> Public Comment 185
>
> **Panel 3 - Access to New Therapies**
>
> **for Childhood Cancer** 198
>
> Co-Moderators:
>
> Ed Forman, M.D., Alliance for Childhood Cancer
>
> Ramzi Dagher, M.D., CDER, FDA
>
> Panelists:
>
> Ramzi Dagher, M.D.
>
> Jerry Finkelstein, M.D., American Academy
>
> of Pediatrics
>
> Ed Forman, M.D., Alliance for
>
> Childhood Cancer
>
> Ruth Hoffman, Candle Lighters
>
> Michael Hurley, Abbott
>
> Carl Huntley, Ph.D., NCI
>
> Anna Meadows, M.D., COG and NCI
>
> Dale Shoemaker, Ph.D., NCI
>
> Grant Williams, M.D., FDA
>
> Presentation: Grant Williams, M.D. 200
>
> Presentation: Dale Shoemaker, Ph.D. 209
>
> Presentation: Ramzi Dagher, M.D. 215
>
> Discussion \--
>
> Public Comment 248
>
> **Summary Discussion**
>
> Co-Moderators:
>
> Patricia Keegan, M.D., CBER, FDA
>
> Richard Pazdur, M.D., CDER, FDA
>
> Panelists:
>
> Susan Blaney, M.D.
>
> Ramzi Dagher, M.D.
>
> Ed Forman, M.D.
>
> Joe Gootenberg, M.D.
>
> Wayne Rackoff, M.D.
>
> Alla Shapiro, M.D.
>
> Summary Discussion 264
>
> [P]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
> [E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
> [N]{.underline} [G]{.underline} [S]{.underline}
>
> **Welcome**
>
> DR. COOPER: Good morning. I am Lou Cooper. I am the current President
> of the American Academy of Pediatrics. It is my pleasant opportunity
> to welcome all of you to this workshop on Pediatric Oncology Drug
> Development. I certainly want to acknowledge and thank our partners,
> the FDA, the NCI, the Children\'s Oncology Group and the Alliance for
> Childhood Cancer. I understand this has been put together in record
> time. That could not have been done without tremendous cooperation
> from all parties and, for that, we are grateful.
>
> That I am here as the Academy\'s President tells you how important we
> think this workshop is, how important we consider the issue of
> appropriate drugs and drug development for children\'s cancers are.
>
> I have some prepared remarks but I can\'t resist the opportunity to
> tell you a personal comment as I was coming down and reflecting on
> this meeting. I realized it was forty years ago this month that I, a
> second-year fellow, in infectious disease got assigned to be the
> consultant on a pediatric-oncology unit. It was one of the most
> depressing periods of my life because, in fact, no matter what we did,
> we couldn\'t manage the children\'s infections and we also couldn\'t
> manage the children\'s cancers.
>
> You know that the outlook today is dramatically different from what we
> faced forty years ago. What has been most important, I think, in that
> progress has been the remarkable ability of pediatricians and
> pediatric oncologists to come together to do the kinds of trials, to
> use the kinds of protocols, that have given us answers that have
> helped make the treatment of childhood cancer more effective and safer
> for everybody.
>
> I am at an age now where I have to think about those old men\'s
> cancers, prostate cancer and so forth. It is very frustrating to me
> that our adult colleague have not been able to bit the bullet and
> eagerly engage in the same kinds of studies that are our pediatric
> colleagues have done over the last I don\'t know how many years. When
> did the Oncology Group start? The difference is dramatic and I just
> want to, on behalf of the American Academy of Pediatrics acknowledge
> and thank those of you in this discipline who have had the wisdom to
> do that.
>
> There are many things in which I wish the adult medical world would
> follow the pediatric practices. This certainly is one of them. You all
> know the Academy\'s mission. You all know how committed we are to both
> the Best Pharmaceuticals Act and also the Pediatric Rule. You know how
> we have worked, I think aggressively but, most importantly,
> cooperatively with the FDA and with Congress to make sure that our
> laws and our regulations move toward what every pediatrician needs
> which is clear understanding of how to use the drugs that are out
> there for kids and, most importantly, what do we need to do to make
> sure that those trials, that those studies, are done on the front end
> so that kids can have the opportunity to have access to appropriate
> drugs as quickly as their adult counterparts.
>
> You and I know that there are lots of drugs in the pipeline and,
> especially in oncology, an increasing number of drugs are going to be
> biologic products as well. We want to make sure that pediatric testing
> takes place not after the fact but that it is part and parcel of the
> progress.
>
> As you know, this session will bring us to the discussion of three
> major areas in pediatric oncology, early development of new therapies,
> how to design clinical-oncology studies for children. Then we will
> touch on matters such as whether potential cancer therapies need to be
> developed in adults first before being made available to children.
>
> Then, finally, you will discuss new therapies in cancer. It has been
> almost a year and a half since the Academy helped to sponsor the last
> meeting on pediatric oncology. It is terrific to see so many of you
> representing key activities within both the federal government and the
> private sector here. It is nice to have a distinguished roster of
> speakers.
>
> We are delighted to be able to help sponsor and move this meeting
> forward. It is my pleasure now to introduce Janet Woodcock, as you
> know, the Director for the Center for Drug Evaluation and Research.
>
> By the way, I would like to stay for the rest of the meeting but,
> guess what? I have other places I have to go so I will say now thank
> you all for coming. I look forward to hearing the results of the
> meeting and thank you, Dr. Woodcock.
>
> **Welcome**
>
> DR. WOODCOCK: Good morning. When I was asked to make some opening
> remarks for this meeting, I got some information from the Oncology
> Division about pediatric cancer that was of great interest to me. I
> think this is partly and educational experience for me.
>
> The people we have gathered here this morning, all of you, I think are
> deeply committed to development of treatments for pediatric tumors.
> You probably understood this better than I but what Steven told me
> each year there are over 12,000 new cases diagnosed in children in the
> United States and that more than 20,000 children right now are under
> treatment for cancer every year.
>
> By age twenty, one child or adolescent in 330 is diagnosed with
> cancer. So it is incredible. Childhood cancer is this number-one
> disease killer of children and adolescents in North American and is
> just behind accidents in overall cause of mortality.
>
> So this is, obviously, an extremely important issue for the whole
> community in the United States. There has been a distinguished
> history, obviously, of drugs used to treat cancer and FDA has been
> approving cancer therapy since 1948. Of course, you all know better
> than the history that was just alluded to where there was nothing,
> moving from having nothing, to having treatments available to
> prolonging life, to having cures in many children cancers today.
>
> But we can\'t sit on our laurels. We can\'t stall or slow down the
> progress that has been made. I think that is why all of you are here
> today. In the drug area, the last new drug to treat pediatric cancer
> was approved in 1990. There haven\'t been any pediatric-oncology NDA
> submissions to the FDA since 1990.
>
> We have established numerous initiatives and we have been working with
> the American Academy in the academic sector and the private-industry
> sector to try and stimulate drug development in cancer and make sure
> that children are included.
>
> Of course, everyone worked together with Congress to get the pediatric
> incentive program that was in the FDA Modernization Act is now called
> the Best Pharmaceuticals for Children Act. A number of years ago, I
> worked with David Kessler and others to get the Pediatric Rule
> published. There has been, obviously, a lot of history and issues
> around the Pediatric Rule which is still in effect and being
> implemented by the agency.
>
> We have now an Office of Pediatrics within the Center for Drugs. We
> have pediatric-specific advisory committees. We have education on
> pediatric initiatives. We train our staff in each division. Diane
> Murphy is here. We are training everyone on the pediatric initiatives
> that we have so that our staff are thinking as they interact with
> sponsors during drug development.
>
> They are thinking about children, thinking about the needs of
> children, how will product development be interleaved within the Drug
> Development Program. We have issued guidances. We have had workshops
> and conferences, obviously, and we really are trying to stimulate
> pediatric drug development specifically in this case a drug
> development for children with cancer.
>
> Obviously, the hope of the future is that there will be more
> treatments coming through that will be very specific, that a new
> science is going to be applied to the treatment of children cancer and
> adult cancer, that this will result in much more targeted therapy that
> will curative or produce long remissions without the toxicity that we
> currently have with a number of available therapies.
>
> We are really committed to make this happen. But, of course, there are
> a number of barriers that remain. Those are what this workshop is
> going to address today, try to identify those so that we can move on
> and, perhaps, have further meetings, advisory committee meetings,
> workshops, whatever, around the issues.
>
> Ethics, for example, is always something that we have to address in
> the pediatric realm, the ethics of trials. There are a variety of
> societal opinions on this, as you all know. What we need to do is
> arrive at some sort of consensus or at least understanding of the
> various opinions of different groups so that people can know what the
> parameters are when trials are done.
>
> Trial design is another issue, the timing of initiation of pediatric
> studies with respect to adult studies is another issue that needs to
> be addressed. Endpoints, the extrapolation of adult results to
> pediatric diseases is a general issue that we are dealing with and is
> a specific issue also for pediatric cancer.
>
> So it sounds to me, by looking at the agenda, like you are going to
> take up many of these issues today, discuss them. All the various
> sectors are here, the advocacy groups, pediatricians, people who study
> pediatric cancer as well as FDA.
>
> If issues that are not resolved or need further work can be
> identified, we can take those and move forward with them in the
> subsequent months. So this is a very important meeting for that
> purpose to keep this ball moving.
>
> So I welcome you all. Your agenda is packed. So I won\'t take up any
> more time, and thank you very much. I would like to introduce Mark
> Ellengold who is the Deputy Director of the Center for Biologics. That
> center regulates many of the promising new biological therapies that
> we are looking at now.
>
> Mark?
>
> **Welcome**
>
> DR. ELLENGOLD: Thank you Janet. Just in case there is any confusion, I
> am not Kathy Zoon. If you want to use standard Kathy Zoon units, by
> mass, I am probably two.
>
> First, let me apologize for Kathy. There was an issue that came up
> early this morning and she has actually been up next door at Parklawn
> with Dr. Crawford since about 7:30. She just couldn\'t break away and
> she was really looking forward to welcoming you for this discussion.
>
> Now, let me apologize for myself. I found out I was going to be doing
> this about forty minutes ago. My office is at the NIH Campus. As I
> raced up Rockville Pike, I had all the time in the world to prepare my
> remarks while watching the garbage trucks and the lane closures.
>
> Kathy said, \"Don\'t worry. Here are my notes.\" I can\'t read them so
> that is not going to help. I just want to welcome you. Fortunately,
> Janet covered most of the things that need to be covered. This is a
> very important workshop. You are here to do very important work.
>
> Cancer is always tragic. At my age in life, several of my friends and
> relatives have recently become afflicted. That is always bad. But it
> is even more heart-wrenching and important when it involves children.
> Children, as we now know, are not just small adults. Studying them,
> developing products and using products is a whole art and science. I
> am glad you are all here working on it today.
>
> CBER has always been involved with child health. Our notable success
> with vaccines in eradicating many infectious diseases. Many of the
> younger physicians have never seen cases of these diseases. That is a
> tribute to the work done on the vaccine industry.
>
> Another big triumph in child health I know over my generation has been
> the use of clotting factors to treat hemophilia. A hemophiliac child
> today can actually expect an almost normal life where thirty, forty
> years ago, that would have been impossible.
>
> The work you are doing here and the work in the Pediatric Rule, the
> work of the pediatric legislation, is all-important and nowhere more
> important than cancer. I would just like to also thank you for taking
> your effort. Over my thirty-plus years with the Food and Drug
> Administration, I always have been impressed by both the advisors who
> serve on our advisory committee and the members of the public and
> other professionals who come to workshops like this to work together
> on a problem such as this, particularly the advocacy groups\--thank
> you for being here.
>
> As Janet said, you have a lot of work to do so I don\'t want to take
> up your time. Feel free to contact any of us at CBER if we can be of
> assistance to you.
>
> Thank you.
>
> **Summary of Pediatric Oncology Activity at FDA**
>
> DR. HIRSCHFELD: We have an excellent shot at remaining on schedule so
> I will try to keep us that way. My name is Seven Hirschfeld. I am a
> medical officer in the Center for Drug Evaluation and Research. I am
> uniform because I am a member of the U.S. Public Health Service. That
> gives me extraordinary flexibility and the great privilege to be able
> to work in multiple places.
>
> One of those is the Division of Oncology Drug Products. The other is
> the Office of Pediatrics. The workshop that we have today is a
> byproduct of the excellent cooperation between that division, that
> office, and our colleagues in many places in the FDA, some of whom I
> would like to recognize. Some of the people who were particularly
> active in putting this workshop together are Dr. Joe Gootenberg from
> the Center for Biologics, Drs. Ramzi Dagher and Alla Shapiro who will
> be chairing sessions, all three of them, later today from the Center
> for Drug Evaluation and Research.
>
> Our Director and Deputy Director, Dr. Richard Pazdur, Dr. Grant
> Williams, Dr. Donna Grieble who has just returned from Aspen Colorado
> helped us out. I want to make particular mention of the
> extraordinarily efforts of Ms. Iris Khalaf of the Office of Training
> who is in the corner there and who helped us set several world indoor
> records in terms of establishing this meeting and getting notices out,
> and her staff, and Olivia Pritslaf.
>
> In the Academy of Pediatrics, in the back of the room there, is Elaine
> Holland-Vining who, probably more than anyone, represents the
> conscience of pediatrics here in Washington, D.C., has been invaluable
> in helping us put this workshop together, getting everything
> coordinated, making the handouts and getting all the people here.
>
> For the Alliance for Children Cancer, we have Dr. Ed Forman and Ms.
> Diane Traynor here who also were instrumental in helping plan this
> workshop and from the Children\'s Oncology Group, we have the Director
> of the Children\'s Oncology Group, Dr. Greg Reaman, who will also be
> on the podium later, who has been an extraordinary ally of children\'s
> health in general but also working with the FDA in supporting some of
> the important initiatives and legislation in the past.
>
> So all these people, I think, deserve special recognition for putting
> this event on in such a short period of time.
>
> I am going to speak on issues which may sound technical and arcane.
> That is on some of the legislation and some of the initiatives and
> regulations which have supported pediatric development. But there is a
> theme that ties them together and that theme underlies one of the
> fundamental missions of the FDA which is to protect the vulnerable.
>
> So, using that as a framework, then, I know that it will be a rapid
> pace and it will be reasonably technical. But we have some material in
> the background to help you digest it if you want to look at it
> afterwards. When we finish it, then we will touch on the themes and
> what we hope to accomplish in the workshop.
>
> We have heard our opening remarks and welcomes and we were especially
> honored to have such a distinguished panel of physicians introduce
> this workshop. After these introductory remarks, we will have three
> panels.
>
> The first panel will deal with early development of new therapies for
> pediatric oncology. The comoderators will be Dr. Wayne Rackoff from
> Johnson & Johnson. I want to make a special mention of the pioneering
> work that Wayne has done. Prior to a meeting that the American Academy
> of Pediatrics sponsored in February, 2000 there was no organization or
> network in the pharmaceutical industry of pediatric oncologists.
>
> In fact, pediatric oncologists were often lost and not identified as
> pediatric oncologists. Subsequent to February, 2000, Wayne and his
> colleague, Raj Malik, who is now with EM Merck, more or less, by
> themselves, organized a large consortium and identified people in the
> industry which now measures in the dozens and have been very active
> and have been attending all of the Children\'s Oncology Group meetings
> and have acted as focal points for communication between the
> investigators and the pharmaceutical industry. There is no role model
> for this. They have been developing it all along and they have been
> doing it with competence, good humor and, I might say, grace. So thank
> you, Wayne, for your pioneering efforts.
>
> Alla Shapiro is with us and if I might just say a word about Alla.
> Among many things she has accomplished, she has the extraordinary
> experience of having been the pediatrician who dealt with the children
> after the Chernoble incident and has shared with us some of her
> experiences in that regard.
>
> So we are going to focus on early development. There will be some
> didactic components. The format of the workshop will be that we will
> have some short talks from distinguished leaders in the field on
> issues which will give us a common ground in terms of vocabulary and a
> common ground in terms of information.
>
> Following that introductory material, a number of questions will be
> proposed to each panel. Each panel has, as its calling, not to answer
> the questions but to refine the questions but to refine the questions,
> to identify them, to elaborate on them, to help define issues which we
> collectively can move forward so that, at the end of the day, we have
> an agenda which we are in agreement with, which we are comfortable
> with and which we recognize the importance of and we can use it to
> build on further activities, both joint workshops, individual
> activities and some of the FDA-sponsored activities
>
> So the discussion issues for the first panel are are special
> formulations needed for treating children with cancer, what methods
> are available to prioritize new and emerging agents within the same
> class for clinical studies in children with cancer and among various
> classes.
>
> Our panelists, as you see on the screen, will be Dr. Malcolm Smith
> who, himself, has defined the role of what a government advocate can
> be for children\'s cancer. Prior to Malcolm, there was no program at
> the NCI that had the profile or the scope or the responsibilities that
> Malcolm has undertaken and developed. I think everyone in the field
> recognizes his past and his ongoing contributions.
>
> Dr. Greg Reaman, whom we have introduced. Dr. David Poplack, who has
> been a personal mentor to me for over a decade. Dr. Susan Weiner from
> the Children\'s Cause. Dr. Peter Ho, who, at one time in his career,
> passed through the FDA and has special perspective because he has been
> at the NCI, the FDA and in the pharmaceutical industry. Dr. Shapiro
> and Dr. Rackoff we have already introduced.
>
> Following each panel will be an opportunity for public comment. This
> is not an accident. This is something which we, at the FDA and I know
> at the highest levels in the FDA, welcome, endorse and encourage. We
> want to hear from the people who are affected by what we do. We want
> to hear people who have experience that they can convey to us so that
> we can best understand our mission and our role.
>
> We are so committed to it that we have a special office established
> for this, the Office of Special Health Issues which is in the
> Commissioner\'s office. Joanne Miner and Patty Delaney, who have spent
> the bulk of their careers focusing on cancer issues are here today and
> will help us out during these public-comment periods.
>
> After each panel discussion, the panel comoderators will make some
> brief logistical comments on how the public-comment period will
> evolve. Public comments can be and ought to be addressed to some of
> the issues that the panel discussed but could also encompass other
> issues. So, if there is something on your mind, something in your
> heart, don\'t hesitate to share it.
>
> The second panel will be focused on designing clinical oncology
> studies for children. The comoderators will be Dr. Susan Blaney, whom
> we have had for many years overlap in our training and careers and
> interests. Susan has developed as one of the preemininent phase I
> clinical pharmacologist investigators and has been a significant
> contributor to the COG, which is the new national children\'s
> consortium in the phase I studies.
>
> Joe Gootenberg, after a productive academic career in the area, came
> to the FDA and is now with the Center for Biologics.
>
> The didactic components are summarized here. No need to read them, but
> the discussion issues which we will touch on : do potential cancer
> therapies need to be developed in adults before being made available
> for testing in children; how can adult and pediatric development plans
> be coordinated to improve access for investigators to the most
> promising new cancer therapies during the drug-development cycle; what
> are the constraints to obtaining reliable answers in pediatric-cancer
> trials and how can they be overcome; and are there ethical or other
> aspects of requirements, particularly for tissue biopsy sampling, that
> should be considered in pediatric phase I trials of targeted
> therapies.
>
> Our panelists, in addition to the comoderators, will be Dr. Richard
> Sposto, a statistician who has been working with previously the
> Children\'s Cancer Group and now the Children\'s Oncology Group came
> to us all the way from California. Dr. Susan Shurin, who has had a
> special interest in ethics and heads the Ethics Committee in the
> Children\'s Oncology Group. Ms. Diane Traynor, we have mentioned
> before, except we didn\'t mention of her support, her very generous
> support, in terms of time and other commitments to pediatric brain
> tumors and her work with the Pediatric Brain Tumor Consortium.
>
> Mr. Michael Hurley who is joining us from Abbott and who came highly
> recommended and left a very strong impression of interest and
> commitment when he was part of a workshop that the NCI sponsored on
> intellectual property transfer. And we have a surprise panelist whom I
> would like to introduce and that is Dr. Anne Hagey from Abbott, also,
> who came last night and we wanted to take advantage of her skills as a
> pediatric oncologist. She trained at UCLA and has been working with
> Perry Nissen for the last couple of years. So she will join us on that
> panel.
>
> Lunch will be on your own. It will be very quick and there will be an
> announcement on the details right at that time. We will reconvene at
> 1:30 and discuss access to new therapies for childhood cancer. Our
> comoderators, we have discussed to some degree. Dr. Dagher is someone
> that I met initially at a camp for children with cancer. I was so
> impressed with his energy and his analytic skills that we recruited
> him to come to the FDA. He accepted and has been with us and has been
> an important contributor since then. There will be an educational
> component. The discussion issues will be what mechanisms are used to
> treat children with cancer off-protocol and what is the role of
> product labeling for pediatric oncology. Our panelists will be Dale
> Shoemaker who heads up the Regulatory Affairs Branch from the National
> Cancer Institute, Dr. Williams, whom we introduced already and then
> Ruth Hoffman from the Candlelighters Foundation who manages to squeeze
> about thirty hours of energy and activity into every 24-hour day and
> has been an uncompromising advocate for children with cancer.
>
> Dr. Anna Meadows is getting on a train in Philadelphia right now but
> she has had a lifelong commitment to pediatric cancer and is coming
> down from the Children\'s Hospital in Philadelphia. She has an
> important liaison position with the National Cancer Institute as well
> as her work with the Children\'s Oncology Group and at the Children\'s
> Hospital in Philadelphia.
>
> Dr. Jerry Finkelstein started the Children\'s Oncology Group in his
> garage and has been contributing to it ever since but has\--that
> wasn\'t a serious comment, but Jerry has been a contributor to
> pediatric studies, particularly in the areas of leukemia for several
> decades and has been one of the guiding forces in forging a link
> between the broader American Academy of Pediatrics community and the
> pediatric oncology community and has served for many years as a very
> effective chair of the Pediatric Oncology Section of the American
> Academy of Pediatrics.
>
> Dr. Ochs sent us a notice that she, unfortunately, can\'t make it, at
> the last moment, so she will be substituted again by our colleagues
> from Abbott. Then Dr. Carl Huntley will come from the NCI. He is a
> pharmacist who has a lot of experience with off-protocol access.
>
> The summary discussion will then be in the format of asking each of
> the comoderators to bring those issues that they felt were of
> interest. They won\'t be expected to capture or filter every word or
> every idea that came forward but just bring those issues that they
> felt were of particular interest from their panel, from their
> discussion, from the public comments and present those at the end of
> the day. Then we will look at each of the comments from each of the
> three panels and see if we can, from that, fashion not only some
> consensus issues which we would all wish to address but, if there are
> particular issues that we can bring to the FDA and which the FDA might
> have some ability to act as a catalyst or to move forward in special
> ways.
>
> So that will be chaired by Dr. Richard Pazdur and Dr. Patricia Keegan
> from the Center of Biologics.
>
> Now, after those introductory comments, we will go into some more
> technical\--which I will try to work my way through as clearly but as
> concisely and quickly as possible so that we can get to the meat of
> the discussion.
>
> We have two goals in pediatrics. We would like to provide adequate
> product information for drugs and biologicals that will be used in
> treat children and we would like to have to establish some mechanisms
> for the safe and effective development of pediatric medications.
>
> For those who are not familiar with some of the nuances of vocabulary,
> the fundamentals of government are that we laws which are established
> and changed by the legislative branch, which is Congress. These are
> effective until they are changed or expired. We have regulations which
> are interpretations of laws initiated by the Executive Branch. We,
> then, the Department of Health and Human Services and we, the Food and
> Drug Administration, would be responsible for issuing regulations
> because we are under the Executive Branch.
>
> Then we have guidance documents which, depending on your perspective,
> are either commands or suggestions or something to be considered. But,
> in any case, what these documents represent is the thinking that is
> current about a particular issue. While legally not binding, they
> represent what the expectations are, both on the position of the FDA
> and the position of someone who might be submitting material to the
> FDA.
>
> Our principles are founded on three which evolve through the Twentieth
> Century. This is an entirely different discussion but I find a very
> interesting one and would argue that all three principles were based
> on pediatric public-health scandals, but they are adequate labeling
> with arose at the early part of the Twentieth Century. About one-third
> of the way through the Twentieth Century, the principles of safety
> were established.
>
> Then, about two-thirds of the way through the Twentieth Century, the
> principle of efficacy was codified into the Food Drug and Cosmetic
> Act. The focus from the FDA, Food and Drug Administration, perspective
> is on a product and product development which is different from the
> way most of us were trained which is to look at disease and disease
> development.
>
> So, given that perspective, it is important, then, to recognize what
> our position may be.
>
> To address what were perceived to be and documented to be inequities
> in the availability of therapeutic products, medications, whether they
> were drugs or biologicals, the FDA has been looking at this for about
> a quarter of a century in a series of graded maneuvers which have led
> up to our current pediatric initiatives.
>
> In 1979, a principle was annunciated that said that the pediatric use
> for drugs and biologics that were approved for adults on the basis of
> adequate and well-controlled clinical trials in the same disease may
> be labeled for children on the basis of safety and dosing studies.
>
> This was the first articulation of a principle of extrapolation. It
> didn\'t state how it could be done but it stated it could be done.
>
> In 1994, to address what Dr. Harry Shirkey termed the therapeutic
> orphans of the world but, in this case, America, the 1994 Pediatric
> Rule was issued. The 1994 rule stated that the FDA is willing to
> provide a pediatric indication for those cases where the illness and
> its course and the\--and I substituted here for clarity, drug or
> biologic\--and its mechanism of action of sufficiently similar in the
> pediatric and adult populations to permit extrapolation from adult
> efficacy data to pediatric patients if the sponsor voluntarily submits
> data.
>
> The key points were that there was some aspect of extrapolation that
> could be invoked and that there was a voluntary submission. We
> monitored the situation carefully and found that the volunteerism was
> at an ebb at that time and so there was another approach taken, in
> fact, a complex approach to look at an incentive program and a mandate
> program. We will discuss the mandate program initially.
>
> The mandate is known as the 1998 Pediatric Rule. It became effective
> April 1, 1999 because a statutory lag time between when a rule is
> issued and when it becomes effective, and then there is a further lag
> between when it becomes effective and you actually have to comply with
> it.
>
> So it became effective the second of December, 2000. I make that point
> because the experience we have with it is relatively limited from the
> time people had to comply with the rule, it has been only eighteen
> months. So, if one asks the question what has the impact of the
> Pediatric Rule been, we don\'t have a long time frame. We are going
> back to the 1st of April, 1999 to look at the mandatory compliance
> with the rule.
>
> The scope of the rule is it applies to marketed drugs and biologics.
> These are listed here. Those of you who picked up the handout can see
> it. There is no need to go into detail through the list. It also
> applies to new drugs and biologics.
>
> For the marketed drugs and biologics, there are two conditions that
> must be satisfied in addition to this extrapolation or sufficiently
> similar condition. So that is one. That is not stated explicitly in
> the slide, but I will state it explicitly here. The rule is only
> invoked when the extrapolation can be made.
>
> If the extrapolation can be made then, if there is, in addition,
> meaningful therapeutic benefit and the absence of labeling poses a
> risk or substantial use in the absence of labeling poses a risk, then
> the rule would be invoked.
>
> The rule for new drugs and biologics, because we don\'t have a
> marketing history yet, is somewhat different in that it is, again, the
> extrapolation must be invoked and, once the extrapolation is
> established, then its meaningful therapeutic benefit or projected
> substantial use.
>
> How do we define\--and the absence of labeling poses a risk is
> excluded\--meaningful therapeutic benefit. It is defined as
> significant improvement in the treatment diagnosis or prevention of a
> disease compared to marketed products adequately labeled for that use
> in the relevant pediatric population, or the drug is in a class of
> drugs for an indication for which there is a need for additional
> therapeutic options.
>
> Substantial use is defined as a therapeutic product that would be used
> by more than 50,000 children for the approved criteria and this came
> from a calculation based on the definition of orphan drugs and the
> absence of adequate labeling would pose a risk.
>
> There is absolutely no intent and no history of products for adults
> being delayed because of the Pediatric Rule. That was anticipated and
> there is a mechanism to defer compliance with the rule. The deferral
> can be for a new drug or biologic and it can deferred if safety
> concerns exist, if there is no appropriate formulation or for other
> reasons which are taken up on a case-by-case basis.
>
> So our expectation of the course is to have the pediatric data but
> there is no intent to delay the adult release for marketing. There can
> also be waivers. Waivers are granted if there is neither therapeutic
> advance nor substantial use. So those who are familiar with clinical
> protocols will say the eligibility criteria were not met.
>
> Then, if the pediatric studies are difficult or impossible due to too
> few children or geographic dispersion, if the product is not safe or
> available in a form for children, and there are partial waivers
> available for specific age groups which may not have the disease, may
> not have an appropriate formulation, or other reasons.
>
> There is another initiative which appeared potentially
> contemporaneously. But, before I go into that, I just want to comment
> on the impact of the Pediatric Rule. It is very difficult to
> ascertain, and it is an issue which is being examined now and I won\'t
> make any further comments other than to say that it has been invoked
> multiple times within the Center for Drugs, the Center for Biologics
> and it has been invoked for specific oncology products.
>
> The Food and Drug Administration Modernization Act of 1997, Section
> 111, introduced a concept into a realm other than orphan drugs and
> that is to give for a special population, in this case, children, an
> incentive by lengthening the period of marketing exclusivity by six
> months.
>
> It is voluntary. It applied to the entire product line. There was no
> restriction on eligible pediatric diseases. It could only apply when
> there was an underlying patent or exclusivity protection and medical
> devices, most biologics and some antibiotics are excluded from it.
>
> I don\'t know if this is quite visible but, in essence, there are
> three steps formally to the process. The FDA issues a written request.
> That request, then, would result in protocols. The protocols would be
> reviewed by us and then studies would commence. When the studies are
> completed, then study reports are submitted to the FDA. These must
> contain data that has not been previously submitted to the FDA.
>
> Following the submission of the study reports, the FDA will make a
> determination. If the determination is that the study report is in
> compliance with the written request, regardless of the clinical or
> scientific outcome, but if it addresses all the issues, if it provides
> the information requested because that is what we are asking for
> information that answers a perceive public-health need. Then the
> exclusivity determination would be favorable and the exclusivity
> period would be lengthened.
>
> We don\'t have the resources and some would say we don\'t have the
> wisdom to anticipate every pediatric potential use so we solicit
> pediatric proposals for people to propose uses for products in a
> pediatric population. And we review these carefully.
>
> Sometimes we issue, and in oncology in particular, we have issued
> written requests without receiving proposals because there was a
> perceived public-health need. But there is a mechanism whereby someone
> outside the FDA can initiate the process or we can initiate it
> internally.
>
> We have received\--and these are data which were current as of a
> couple of months ago. Last night, we got some new data but I didn\'t
> update the slides because it would have put us out of sync somewhat.
> Approximately 250 proposals. We have sent out approximately 200
> written requests and approximately 40 products have been granted
> exclusivity extensions.
>
> Breaking it down in terms of the written requests that have been
> issued according to various divisions, again, this program only
> applies to drugs. Oncology drugs has issued twenty-eight, which is
> commensurate with some of the more active divisions.
>
> The types of studies is approximately a third have been efficacy and
> safety, approximately a third have been pharmacokinetics and safety
> and the other third have been a mixture of safety, PK/PD, exposure
> response and others.
>
> So I won\'t read through this list but here is a comparison of the
> Pediatric Rule and the Incentive Program. I identified it as the
> Incentive Program because the FDAMA Section 111 Program expired
> December 31, 2001 and was replaced January 4, 2002 by a new program
> which is incorporated in the Best Pharmaceuticals for Children Act.
>
> I will note that there is great interest on the other side of the
> Atlantic in developing parallel initiatives but they are a little more
> modest and they have called their initiative the Better
> Pharmaceuticals for Children approach. But we are Americans and we
> have the Best.
>
> The major provisions are that there will be continuation of the
> pediatric exclusivity until October, 2007. There is an establishment
> of procedure to study medications that lack exclusivity or are
> off-patent and establishment of procedures to ensure proper pediatric
> labeling.
>
> Additional provisions are adverse-event reporting and tracking,
> pediatric plan for the availability of investigational drugs for INDs
> and special reports to Congress. The American Academy of Pediatrics
> was instrumental in having this legislation enacted and has kindly
> provided, for those who are interested, on the outside table, copies
> of the entire act.
>
> There are further provisions in the act which include the
> establishment of an FDA Office of Pediatrics, a dispute-resolution
> mechanism, a new Advisory Committee for Pediatric Pharmacology and
> codification of two existing subcommittees, the Pediatric Subcommittee
> of the Infectious Disease\--I want to welcome its chair, Dr. Joan
> Chesney, who has come all the way from Memphis, Tennessee to be with
> us this morning. So, welcome, Dr. Chesney\--and an Oncology
> Subcommittee, several members of which have come here, too.
>
> Then, the National Institutes of Health is to publish a list of drugs
> for further pediatric study. There are some process changes which are
> more of interest to the FDA and, I think, to the pharmaceutical
> industry than to this workshop so I will skip over that and focus on a
> new provision which is a program to address drugs without marketing
> exclusivity or patent protection.
>
> This program is somewhat complex requiring a series of interchanges
> between the National Institutes of Health and the FDA and all the
> mechanisms are still in the process of the details being worked out.
> But the general outlines are that the National Institutes of Health,
> in consultation with the FDA, is to develop a list of approved drugs
> for which pediatric studies are needed.
>
> The FDA, then, will issue written requests based on this priority
> list, to all the current suppliers. The current suppliers have a right
> of first refusal and have thirty days to make that decision. There is
> no incentive for them monetarily in the program. They don\'t get any
> patent extension or exclusivity extension in this so it is anticipated
> that most will refuse.
>
> If the current supplier declines development, then the NIH will issue
> a request for proposals to perform the studies under contract and then
> the study reports will be submitted to the FDA for evaluation and,
> hopefully, inclusion in the product label.
>
> For drugs with marketing exclusivity patent protection, the program
> remains very similar to the program that expired last year. I won\'t
> go into those details other than to note that the innovator has 180
> days to respond and should respond specifically with plans and a time
> table. One of the themes of the Best Pharmaceuticals for Children Act
> is that there is dissemination of information so that important
> pediatric data is available to all who might have a need to use it.
>
> If the innovator declines to respond, then there is a mechanism that
> would allow a foundation, not the National Institutes of Health
> directly, but a foundation linked with the NIH, to fund studies by a
> grant mechanism.
>
> As mentioned, the dissemination of information is one of the paramount
> features of this act. The FDA can publicize it if the innovator of a
> drug with exclusivity declines a written request. The study reports,
> which are particularly those funded with public funds in response to
> written requests, are published in the FDA dockets. The FDA reviews of
> the study reports and recommended label changes are published in the
> dockets in the Federal Register. In particular, it is the clinical and
> pharmacology sections which will be abstracted and made public.
>
> There is a dispute-resolution mechanism. If the FDA recommends label
> changes and the supplier does not accept recommendations, then they
> are referred to the Pediatric Subcommittee of Infectious
> Disease\--that is Dr. Chesney\'s committee\--for advice. If the
> committee recommends label changes and the supplier declines, then the
> FDA may, at that point, designate the product to be misbranded.
>
> So, in summary, the Pediatric Rule of 1998 is still in effect. It is a
> rule, an initiative, that is being monitored closely. The Incentive
> Program, which was initially described in the FDAMA of 1997, has been
> modified and embodied now in the Best Pharmaceuticals for Children
> Act.
>
> Prior to the Best Pharmaceuticals for Children Act, we actually had
> established a Pediatric Subcommittee of the Oncology Drugs Advisory
> Committee and had a series of four meetings. These were in September,
> 2000. It was September 11, actually, 2000, when we had a joint meeting
> initially with our colleagues from the Pediatric Subcommittee of the
> Antiinfectives Advisory Committee where we discussed common themes
> with trial design and cooperative groups and then we had an
> oncology-only discussion where we approached methods that could be
> used to describe and link tumor types.
>
> The theme throughout these meetings was how can we apply and interpret
> the Pediatric Rule with regard to pediatric oncology. So the outcome
> of the first meeting was discussion on various principles and
> techniques that could be used to link tumor types with the
> understanding that whatever techniques would be used must be supported
> by quality science and must be accepted by the investigators in the
> field.
>
> We had a second meeting, then, in April, 2001 where we focused on
> hematologic tumors and asked a question, and Dr. Poplack was one of
> our keynote speakers at that meeting, which of the many kinds of
> leukemias and lymphomas\--and there is a comment that
> hematopathologists often make that there are three things that you can
> count on in life; death, taxes and the classification system
> changing\--which, under current classifications or under other
> classifications could we consider to have linkages.
>
> We followed that by meeting in June, 2001 where we looked at solid
> tumors and central-nervous-system malignancies with, again, the same
> principles involved. Dr. Pat Reynolds, who was a member of the
> committee at that time, made a very interesting discussion on
> potential linkages between neuroblastomas and some adult tumors which
> was, I think, insightful for its allowing us to focus on issues that
> may come in the future in terms of how to rethink our paradigms on
> tumor classification.
>
> Then, in November, 2001, we had a discussion on study designs and
> extrapolation. This theme, which was carried out in oncology, has been
> extended through the Office of Pediatrics and under the guidance of
> Dr. Bill Rodriguez who is our Director of Science. A group of us have
> been meeting for a year now to look if we can systematically examine
> extrapolation.
>
> We have identified four areas as potentially providing key evidence.
> This was a retrospective study but we would like to turn it into a
> prospective examination of how one can systematically and
> scientifically look at extrapolation. So the key areas that we
> identified were nonclinical data, pathophysiology, natural history and
> response to therapy.
>
> I see one of my colleagues in the audience here, Dr. Debbie Birnbaum,
> who is a medical team leader in that office who has been particularly
> interested in the extrapolation to the neonatal population and has
> been a contributor to many of our pediatric initiatives as the voice
> for, as she puts it, the orphans of the orphans.
>
> We have also been busy trying to adapt Subpart D of the Common Rule.
> For those who are not familiar with the Common Rule, it came in the
> 1970s as the first national effort in any country to look at human
> subject protection in research studies. We have had a series of
> meetings with our Pediatric Ethics Committee in conjunction with the
> Pediatric Subcommittee of Antiinfective Disease to look at ethical
> issues.
>
> One of our mandates was to adapt the Subpart Rule D of the common rule
> which applies to children but it applied only to children in federally
> funded studies to studies which are now regulated by the FDA. This
> rule has been issued in draft form. Comments have been received and it
> is now in final preparation.
>
> So I would like to conclude with another document that many people in
> this room have contributed to. This is the International Conference on
> Harmonization, Efficacy Topic 11 which is this first international
> document which addressed pediatric drug development and pediatric
> clinical research.
>
> The principles that are stated in this document are that pediatric
> patients should be given medicines that have been properly evaluated
> for their use in the intended population, that product development
> programs should include pediatric studies when pediatric use is
> anticipated. Pediatric development should not delay adult studies nor
> adult availability and shared responsibility among companies,
> regulatory authorities, health professionals and society as a whole,
> and this shared responsibility, I think, is what brings us together
> here on this workshop.
>
> So all of us responsible people will proceed and hope that we have a
> productive and informative workshop.
>
> Thank you.
>
> Dr. Poplack?
>
> Dr. POPLACK: You mentioned the Pediatric ODAC. With all the changes
> you described, what is the status of that committee and where is that
> going?
>
> DR. HIRSCHFELD: One of the goals of this workshop is to help us define
> that question so that is an excellent question, Dr. Poplack. I think,
> following this workshop, we will be able to further refine the Best
> Pharmaceuticals for Children Act, explicitly describe some of the
> composition and some of the mandates of that committee. The FDA has
> been studying that act to be sure that the FDA is in compliance with
> all those aspects.
>
> I wanted to ask Dr. Murphy if there are any comments you would like to
> make because we are all fallible, any adjustments of any comments that
> I might have made.
>
> DR. MURPHY: No, Steve.
>
> DR. HIRSCHFELD: Thank you.
>
> Dr. Rackoff.
>
> DR. RACKOFF: We were talking about this last night and I wondered if
> you could comment on it now, the issue of whether or not and how the
> current rule and exclusivity provisions operate in order to require,
> or whether they operate and allow the FDA to require, pediatric
> studies.
>
> In other words, under what conditions can the agency require a sponsor
> to do studies and are there any conditions under which they can?
>
> DR. HIRSCHFELD: In effect, and correct me if I am misphrasing what
> your question is, what triggers the Pediatric Rule. I think that there
> has evolved some cohesion in the approach to the Pediatric Rule. I
> will give the general answer which is one has to first have this
> extrapolation or this linkage between the adult and the pediatric
> condition.
>
> Once that linkage is made, then one of two other conditions must be
> met, either the meaningful-therapeutic benefit condition or the
> substantial-use benefit. In other words, there is no intent on the
> part of the rule and no intent on the part of any of us as individuals
> to categorically apply the rule.
>
> It is intended to address public-health needs and to provide children
> and the people who take care of children with the best available
> information because the pediatric use will be anticipated.
>
> Dr. Murphy?
>
> DR. MURPHY: I think that is a really important question because what
> Steven gave you is how we do the assessment. But what is important to
> know is that every product that comes in, if that
> indication\--basically every product that comes in, the division needs
> to make an assessment, does it meet those criteria, because they are
> going to have to say that this application should have studies
> completed in children. We are not quite sure yet do these studies need
> to be done sequentially or that this product and this indication
> don\'t apply to children.
>
> That is what Steven was getting into. But I think that it is important
> to know that that assessment is really done on every application that
> comes in because we know, since the rule went into effect, that we
> have had over 400\--in drugs, this is\--400 applications come in and
> we know that we have had completed studies in 94 of those.
>
> We have looked at what role did the rule and what role did exclusivity
> play and we can tell you that you can\'t say it was due directly to
> the rule. What you can say is what else played. We know that about a
> third of those, exclusivity was involved. So we can say that we think,
> and we have always said this, that the combination of the rule and
> exclusivity work together.
>
> We think it is important because it makes all of us think about how
> might this drug be used in children. That is why we think it is an
> important player in the field.
>
> DR. HIRSCHFELD: Thank you for that clarification and amplification,
> Dr. Murphy. I will just underscore that I think we will move on to the
> first panel, that the position we would like to take is no matter what
> other strategy or question is being addressed, the question of can
> this, ought this, to be used and how, in children, is always there.
>
> I would like to call the comoderators of the first panel forward.
> Panelists, please take your positions.
>
> **Panel 1:**
>
> **Early Development of New Therapies for**
>
> **Pediatric Oncology**
>
> DR. SHAPIRO: Good morning. I am Alla Shapiro. It is my pleasure to be
> on this panel this morning and share moderator responsibilities with
> Dr. Rackoff.
>
> Our today\'s goal is not to solve any problems or come up with
> conclusions on some important issues. As Steven mentioned earlier, our
> goal is to identify the problem and develop topics for the discussion
> at future meetings of the Pediatric Oncology Subcommittee of the
> Oncology Drugs Advisory Committee.
>
> After the presentations, we will open the discussion followed by a
> public-comment session.
>
> I would like to take a few minutes to explain how the audience
> participation will work. We have planned fifteen minutes at the end of
> each panel discussion to give members of the audience an opportunity
> to give us their point of view. We look forward to hearing from you
> and will make all efforts to incorporate your comments and
> suggestions.
>
> In order to make everybody\'s voice to be heard, we have several
> microphones place around the room. If you are interested in any
> commenting, please raise your hand and I will call each speaker to the
> microphone. Please state your name and whom are you representing. To
> be fair, we would like to ask everybody to speak for five minutes. At
> four minutes, I will raise my hand and let you know that, in one
> minute, you have to wrap up your comments.
>
> Please remain at the microphone after your comments so you can answer
> questions from the panel. Thank you.
>
> Now I would like to turn the podium to our presentes.
>
> **Presentation**
>
> DR. SMITH: It is a privilege to be able to speak here this morning on
> the general topic of how potential new therapies for childhood cancer
> are identified and to set the framework for some of the discussions
> that will follow in the panel.
>
> I will be focusing on the role of pediatric preclinical testing and
> really be forward-looking in my comments and talk about the kinds of
> systems that we need for the future to identify potential new
> therapies for children with cancer.
>
> The first question; do we really need new treatments, new agents, new
> treatments for children with cancer? Of course, the answer is obvious;
> yes, we do. We need them because there are many children for whom our
> current therapy is not adequate.
>
> It is not adequate because of insufficient efficacy and we still have
> over 2,000 children and adolescents who die of their cancer each year.
> It is inadequate because of excessive toxicity and, for some of our
> standard therapies, the majority of children experience acute
> life-threatening toxicities. For some children, there are chronic
> persisting toxicities that diminish their long-term quality of life.
>
> So we need new treatments. We need new agents. But we don\'t need just
> any new agent. We need to prioritize the new agents that we will
> evaluate for children with cancer.
>
> There are dozens of new agents and hundreds of combinations of agents
> that are potentially applicable to the treatment of children cancers.
> That is illustrated here on this slide. This is somewhat dated but it
> illustrates the point, the CTEP pipeline of agents, over a dozen
> angiogenesis inhibitors, cytokines, multiple cytokines, multiple
> agents that affect DNA methylation or histone deacetylation, multiple
> antibodies, multiple signal-transduction inhibitors.
>
> Only a small subset of these agents can be evaluated in phase I
> studies in children and an even smaller subset in phase II and phase
> II studies. To illustrate the magnitude of the challenge, for children
> with neuroblastoma in the United States, we can probably definitively
> study a couple of agents every four or five years in definitive phase
> III trials.
>
> How do we make sure that we are picking the very best one or two
> agents to study to improve therapy for children with neuroblastoma. So
> how do we make those prioritizations? The points that I will be making
> will focus on the potential utility of a systematic approach to
> pediatric preclinical testing.
>
> This is based on a couple of hypotheses. The first is that the rate of
> discovery of more effective therapies for children with cancer will be
> increased by selecting active agents for phase I and phase II
> evaluation. The converse of this hypothesis makes the point obvious
> that if we only pick agents that are inactive to study in children, we
> are not going to make much progress.
>
> So if, from that universe of potential agents, we are picking the
> agents that are active, our chances of improving outcome increase.
>
> The second part of the hypotheses in support of a preclinical testing
> program is that a systematic approach to pediatric preclinical testing
> will increase the percentage of active agents studied in clinical
> trials in children with cancer potentially leading to improved
> therapies for children with cancer.
>
> Why do we think this might work? We have some glimmers of hope that a
> pediatric preclinical testing program might provide us good guidance
> on which agents to study. The work of Dr. Peter Houghton from St. Jude
> has shown a strong correlation between the activity of agents against
> rhabdomyosarcoma xenografts and the clinical activity of the same
> agents.
>
> So, for example, the drug melphalan was first identified as an active
> agent in xenograft models, rhabdomyosarcoma xenograft models, in mice
> and then shown to be an active agent in newly diagnosed children with
> rhabdomyosarcoma.
>
> The topoisomerase 1 inhibitors, topotecan and irenotecan, were first
> identified as quite active agents against rhabdomyosarcoma and
> neuroblastoma xenograft models, again primarily the work from Dr.
> Houghton\'s laboratory. These were then shown to be active agents for
> children with both rhabdomyosarcoma and children with neuroblastoma.
>
> Then the work of Dr. Reynolds who is here today showing that
> neuroblastoma cell lines that are established at different points of
> therapy acquire the same drug resistance phenotype that mirrors the
> clinical resistance pattern of patients as they progress from
> diagnosis and through the intensive chemotherapy and bone-marrow
> transplant that many of these children receive.
>
> So there is reason to think that preclinical testing would provide us
> reasonable guidance. Whenever I talk about preclinical testing, a
> question often comes up and so I will ask it myself; what about adult
> studies showing a lack of predictive value for preclinical models? A
> very important paper from the Developmental Therapeutics Program at
> the NCI published last year in the British Journal of Cancer makes
> points about the limitations of the models that they have used over
> the past decade.
>
> They demonstrated a general lack of tumor-specific predictive power
> for preclinical models. If an agent were active in multiple
> preclinical models and multiple different xenografts, then it was
> likely that it was going to be active in one or more adult cancers.
> But just because an agent were active in a breast-cancer model didn\'t
> predict for clinical activity in breast cancer.
>
> One point to emphasize, though, is that the predictive utility of
> adult preclinical models is limited, in part, by their inability to
> consider differences in pharmacokinetics between humans and mice. So
> when the preclinical models are being used for adults predictions,
> this is before the agents entered the clinic.
>
> We don\'t know if there are differences between how mice and humans
> handle the agent. This is important. It is very important because mice
> are not humans. Mice may tolerate much higher systemic exposures of
> some drugs compared to humans or they may tolerate much lower systemic
> exposures of some drugs to humans. This can have an enormous impact on
> whether a drug is read out as active or inactive in a mouse model.
>
> We have the advantage in pediatrics that when we will be using these
> preclinical data, we will have access not only to the mouse data but
> also to the initial human phase I experience and so we will know
> whether there are differences in human and mouse drug metabolism that
> may explain the activity of pattern of observed in the mice.
>
> So any pediatric preclinical testing program must evaluate preclinical
> pharmacology of tested agents in order to account for differences in
> human and mice PK.
>
> This is a schema for what a systematic pediatric preclinical testing
> program might look like. It grew out of a meeting of the CTEP and the
> Children\'s Oncology Group Phase I Consortium sponsored approximately
> a year ago. In this model, there are a panel of tumors. This might be
> a panel of neuroblastoma xenografts, a panel of osteosarcoma
> xenografts. There are some transgenic models of mice genetically
> engineered to have deficits or differences in specific genes.
>
> An agent entering the program, the first question would be is the
> target of the agent identified. If is a known agent and there is a
> transgenic model, then the initial screen of the agent would be done
> across the xenografts and with the relevant transgenic model. If not,
> the initial screening would only be done in the xenografts.
>
> If the agent showed no activity at the maximum tolerated dose in the
> mice, that is enough. The results would go to the steering committee
> as a \"no activity\" in these models. If it is active in one or more
> models, the activity is more fully evaluated. Is the activity observed
> at lower doses than the MTD? What is the range of activity? And are
> there other more resource-intensive models that can be evaluated to
> better understand the preclinical activity of the agent? Again, the
> results of the level of activity in the different tumor types are
> reported to a steering committee.
>
> There are a number of issues that have to be addressed before there
> could be a systematic preclinical program, a preclinical testing
> program. One is what I call the \"field of dreams\" question. If you
> build it, will they come? If we develop a preclinical testing program,
> will we, in fact, have access to agents that are in an appropriate
> stage of their development through pharmaceutical sponsors?
>
> There are a number of issues; intellectual-property issues,
> data-sharing issues, who the data can be shared with, at what times it
> can be shared, and other factors as well that would affect timing of
> access to new agents.
>
> CTEP sponsored a meeting on May 29 with pharmaceutical and academic
> lawyers and with NIH technology transfer staff. We made significant
> progress at that meeting towards developing a model MTA that would
> facilitate access of a pediatric preclinical program to new agents. I
> think there was a general sense of optimism among participants at the
> meeting that, for many companies, the issues that might affect access
> could, in fact, be addressed.
>
> Another key issue is the issue of identifying molecular targets and
> pathways. A substantial proportion of the new agents under development
> by pharmaceutical sponsors now have defined molecular targets. This
> percent will only increase in the future. It is essential to determine
> the expression of these targets in pediatric tumors.
>
> Towards this end, the NCI is collaborating with the Children\'s
> Oncology Group Phase I and Pilot Consortium to develop tissue arrays
> and protein arrays and to develop gene-expression profiles for
> pediatric cell lines and for xenografts that might be used for
> preclinical testing. So, if there is an agent with a known target, we
> can say, well, we have these cell lines. We know they express the
> target. These don\'t. These xenografts express the target. These
> don\'t.
>
> So these tissue arrays, protein arrays, will be a resource to the
> pediatric research community as well as, potentially, to the
> pharmaceutical sponsors.
>
> So the picture, perhaps, five years from now, perhaps a decade from
> now, is that when we talk about how potential new therapies for
> children cancer are identified, we start with the biology. We start
> with the biology of the signalling pathways involved in cell survival
> and tumor-cell growth.
>
> That lets us identify targets that might be therapeutically targeted.
> This information is available to a preclinical drug-testing
> consortium. These are targets that may be important for neuroblastoma
> or osteosarcoma or another childhood cancer. The preclinical
> consortium can then go to pharmaceutical sponsors, to the NCI, to
> academic investigators collaborating with the NCI through the Rate
> Program to say, are there agents in your portfolio that modulate this
> target, contest those agents.
>
> If they look promising, these can be evaluated through the various
> mechanisms that Dr. Reaman will describe further, COG Phase I
> Consortium, the Pediatric Brain Tumor Consortium, the new approaches
> to Neuroblastoma Therapeutic Consortium. Given, if the agents are
> tolerable and are promising to phase II and pilot studies and then the
> best agents proceeding to phase III studies.
>
> So, in closing, the main point I would emphasize is that predictive,
> preclinical models of childhood cancers may increase the rate of
> discovery of more effective therapies for children with cancer. In
> order to know this, to validate this, a systematic application of
> these preclinical models is need in order to validate the utility of
> the preclinical models and an assessment of the feasibility of
> establishing a pediatric preclinical testing program is ongoing at the
> NCI, and that this is one of the key features in terms of how, in the
> future, we think potential new therapies for childhood cancer can be
> identified.
>
> Do we have questions now or wait until later?
>
> DR. SHAPIRO: I think we will wait for the discussion part. Thank you,
> Dr. Smith.
>
> Our next presenter is Dr. Reaman.
>
> **Presentation**
>
> DR. REAMAN: Thank you very much. I am going go really focus my
> comments on the earliest stages of drug testing in the pediatric
> population. But, before doing so, I just wanted to address one of the
> other questions that the panel was to discuss and that is what
> diseases are being targeted.
>
> Basically, all pediatric cancers are targeted in a program of drug
> development for pediatric oncology. There are, however, a number of
> diseases that we would consider very high risk. At the present time,
> only 77 percent of children with cancer are expected to be alive, free
> of disease five years from diagnosis and presumably cured.
>
> There are a number of patients with specific diseases for which that
> percentage is much lower. They include relapsed acute lymphoblastic
> leukemia, acute myeloid leukemia, certain biological and clinically
> unfavorable classes of neuroblastoma, metastatic sarcomas of tissue
> and bone and high-grade and brain-stem gliomas.
>
> The Children\'s Oncology Group is a recently formed consortium, North
> American based, clinical-trials group which currently is constituted
> by 238 institutions throughout all of North America, all of Australia
> and New Zealand and a few institutions in Europe.
>
> There are currently 212 institutions in the United States in every
> state of the United States with the exception of Alaska, Wyoming and
> Montana and in every Canadian province, another fifteen institutions.
> Part of the mission of the Children\'s Oncology Group in its overall
> mission of curing and preventing childhood cancer is to identify new
> effective agents for pediatric malignancies.
>
> This is done basically through a consortium of institutions who are
> members of the COG to which Dr. Smith alluded. The mission is to
> identify and develop effective new agents for children and adolescents
> with cancer through scientific rational and efficient clinical and
> laboratory research.
>
> There are a number of challenges in pediatric drug development.
> Fortunately, we have limited patient numbers due to the success of
> front-line therapy so, to some extent, we are victims of our own
> success.
>
> Another challenge is the ability to integrate new agents into standard
> curative but presumably toxic regimens. Another is the eventual
> application of molecularly-targeted drugs to childhood cancer. Dr.
> Smith has gone over mechanisms that we will be using to identify
> potential targets and, ultimately, to validate those targets in
> pediatric cancer.
>
> The Children\'s Oncology Group has been organized in a number of
> committees, disease-specific committees, which include all of the
> common pediatric cancers. It is a multidisciplinary group so there
> are, in addition to pediatric oncologists, surgeons, radiation
> oncologists, laboratory-based scientists and a number of scientific
> committees dealing with issues related to childhood cancer,
> epidemiology, late effects and, obviously, one of the most important,
> developmental therapeutics which is chaired by Dr. Peter Adamson and
> Dr. Susan Blaney is the Vice Chair. They would actually be giving this
> presentation.
>
> The Developmental Therapeutics Committee is responsible for bringing
> new promising agents through in initial phase I testing, the
> definition or identification of toxicities, the identification of
> dose-limiting toxicities, the identification of maximum-tolerated or
> optimum-biologic dose in pediatric pharmacokinetics, to phase II
> studies where efficacy of a specific agent and a specific disease is
> assessed, to phase III studies where the efficacy is compared to
> standard regimens.
>
> All of the phase I testing of new drugs in the Children\'s Oncology
> Group is done within the context of the COG Phase I and Pilot
> Consortium. Over the past five or six years, there have been close to
> 1,000 children entered on phase I studies of the Children\'s Oncology
> Group or its legacy groups both in leukemia and solid tumors. There
> are currently some 200 patients on studies.
>
> There are 17 open studies and 29 completed studies. Some of these
> recently completed studies are for known cytotoxics that are listed
> here for modulating agents, the signal transduction agent, STI571 or
> Glivac, and a number of biologics, 9-cis-retinoic acid and monoclonal
> antibodies, specifically fusion protein with IL2 for use in
> neuroblastoma.
>
> Because of the problem with numbers of patients and because of the
> exquisite detail and care with which these early studies identifying
> toxicities in pediatric patients require, a consortium of
> institutions, of highly qualified institutions, is a necessary
> mechanism and, really, the optimal mechanism for accruing sufficient
> numbers of patients.
>
> This was done through a competitive process in order to build the
> consortium, also to develop an organizational structure or
> infrastructure that allowed for efficient operations and data
> management in a statistical approach and then opportunities for
> correlative biology.
>
> There was an application in review. The members of the consortium that
> are members of the Children\'s Oncology Group are listed here some of
> the larger children\'s hospital in North America in major university
> pediatric programs.
>
> In the past, these institutions have accrued around 100 patients per
> year on phase I studies and our proposal, or plans, are to expand that
> to about 120 patients per year during the initial year of the grant
> cycle. This consortium is actually supported by a separate UO1 grant
> mechanism from the NCI.
>
> There is specific expertise within the COG Phase I Consortium in
> Pharmacology in the identification and investigation of biologic
> correlates in phase I and II trial design as well as performance,
> working with colleagues at the FDA and the NCI in regulatory
> oversight, in investigational new drug requirements as well as working
> with our industry sponsor colleagues for requirements in industry, for
> monitoring studies, specifically toxicity as well as reporting
> response for the important consideration of specimen acquisition for
> pharmacokinetic and pharmacodynamic studies as well as for correlative
> biology studies in a number of highly qualified laboratories that are
> part of this consortium.
>
> The organization is listed here, as I mentioned. The leadership is
> provided by Drs. Adamson and Blaney and utilizes the operation center
> of the Children\'s Oncology Group and its statistics and data center,
> primarily the resources and the expertise of Dr. Richard Sposto.
>
> I don\'t think we have to spend a great deal of time on organization
> and management but just a minute on study coordination and monitoring
> which is managed by the research and data coordinators. There has to
> be a very tight control over treatment slot allocation, three patients
> usually to a specific dose level. This is done through an electronic
> data-management system, a remote data-entry system in which each of
> these institutions participates.
>
> Part of this also includes monitoring and validating these data to
> make sure that there are no errors or delinquencies. And there is a
> scheduled formal review at specific landmark times that are so stated
> in the protocol. There is also coordination of specimen submission and
> image submission when that is required.
>
> There are weekly reviews of reports of accrual in toxicity. This is
> done in a weekly developmental therapeutics leadership call and at key
> decision points regarding escalation or deescalation or expansion of a
> cohort, there are decisions and discussions with this leadership
> group. Again, this can be done fairly rapidly through the group\'s
> remote data-entry system.
>
> This also creates comprehensive study databases and provides the
> opportunity for concurrent and retrospective data screening with
> electronic feedback. There is quality control and quality assurance
> which is built into the databases for these phase I studies through
> both the operation center and the statistics data center staff and
> operations.
>
> Careful design of data-collection screens are the responsibility of
> the statistics and data center. The remote data-entry system is
> evaluated for concurrent and retrospective errors. There is a formal
> study review by the study committees and audits of all of these
> studies is performed externally by Theradex.
>
> As far as the design of Phase I studies, I am not going to go into
> this because I think that really will be a subject of the subsequent
> panel. But the current status of the consortium is that a number of
> phase I studies and pilot studies are opened. A number of additional
> studies are in development and there are plans for the development
> within the next year of an imaging center that will be utilized as an
> opportunity for evaluating surrogate endpoints from radiographic
> studies.
>
> Recently opened and approved studies are listed here, some
> signal-transduction inhibitors specific for the EGF receptor, an
> oligonucleotide Genasense for BLC2 and the farnesyl transferase
> inhibitor.
>
> Cytotoxics, proteasome inhibitor, depsipeptide and flavopiridol, again
> biologics, radiolabeled monoclonal antibodies against CD20 and the
> human chimeric antibody against GD2 with the IL2 fusion protein in
> neuroblastoma and a number of modulating agents as well.
>
> The pilot trials that will be done as part of this consortium will
> really be to look at agents that have been identified through the
> phase I consortium and have demonstrated efficacy in phase II studies,
> and then integrate them with current therapy regimens as well as
> looking at combinations of new agents and combinations of modulating
> agents with cytotoxics and looking at both escalation of doses or
> refinement of doses with these novel regimens and also looking through
> pharmacokinetic evaluations at the targeted drug exposures.
>
> Some of these pilot trials are listed here as planned, not yet opened.
>
> With respect to some of the correlative science that will be part of
> this consortium, it is centered around pharmacology, biology and that
> biology, obviously, leads to some of the prioritization that Dr. Smith
> has already mentioned.
>
> With respect to clinical pharmacology, in the phase I studies, the
> relationship between pharmacokinetics, pharmacodynamics and now, most
> importantly, pharmacogenetics will be evaluated as well. Scaling
> adults doses based solely on differences in body-surface area in
> pediatrics ignores a number of physiological developmental changes
> that occur related to volume of distribution and drug clearance and
> metabolism and therefore detailed pharmacokinetic studies are required
> in pediatrics.
>
> This can certainly play a role in altering both tolerance and
> efficacy. So the role is to define drug disposition, to correlate
> pharmacokinetic parameters with outcomes as well as demographics and
> to do this using limited sample methodology and phenotyping for
> pharmacogenetic studies since drug responses are determined by
> multiple factors which are related not only to metabolism and
> transport and interaction with molecular targets. There are a number
> of molecular methodologies that will be evaluated within the
> consortium.
>
> The prioritization, in addition to the preclinical data that Dr. Smith
> mentioned, obviously, there are many more agents that will be
> available than we will be able to evaluate in pediatrics so we will
> have to look at safety and activity data in adults.
>
> Prioritization really will primarily focus following completion of
> broad-based and disease-specific pediatric phase II testing. Malcolm
> has already showed the NCI pipeline but prioritizing is going to be
> the major future goal of the consortium through improved understanding
> of tumor biology and molecular mechanisms of drug action.
>
> The development of novel agents by the consortium will clearly form
> the foundation for future advances in the care of children with cancer
> by providing not only more effective and more targeted therapy but
> eventually less toxic therapy as well.
>
> Thank you.
>
> DR. SHAPIRO: Thank you, Dr. Reaman.
>
> Our panel is open for discussion as well as for questions to the
> presenters.
>
> DR. RACKOFF: Go ahead, Susan.
>
> DR. WEINER: I have several questions but let me start with a question
> for Dr. Reaman, and that has to do with the last description of the
> Phase I Consortium and what the linkage is between the studies that
> are required for labeling since the focus today is on labeling in
> pediatric-oncology drugs, or the possibility of pediatric-oncology
> drugs, standards that are required by the FDA and the studies that are
> being done in the phase I consortium for starters.
>
> DR. REAMAN: I think the linkage would really relate to the
> identification of toxicities, dose-limiting toxicities, and toxicities
> that may be specific to the pediatric population as well as the
> identification of maximum tolerated dose.
>
> I think as far as labeling, with respect to efficacy and indication,
> that is not something that really is at all related immediately, at
> least, to the Phase I Consortium but would only come following studies
> of efficacy of new or novel agents in specific pediatric cancers.
>
> DR. WEINER: So that the standards that would be required by the FDA or
> for companies to submit their compounds to the FDA for pediatric
> approval, those standards and data properties are the same as being
> considered in the COG phase II and phase III trials?
>
> DR. REAMAN: Yes; and there will be data elements from the Phase I
> studies that industry sponsors will, I am certain, find necessary or
> useful as parts of their FDA submissions with respect to toxicity and
> with respect to pharmacokinetic data that is available as well.
>
> DR. RACKOFF: I had a number of questions and I know there are a couple
> of issues on which we are supposed to alight. They are not directed at
> anyone specifically, but I think that Greg hit on one of the major
> issues in this area. I think I have said this before in other meetings
> we have had on this subject, is that there are an increasing number of
> compounds coming into development and there is not, luckily, an
> equivalent increase in the number of patients available for study.
>
> We have talked about how we would select patients that would be
> candidates for study. Malcolm talked about that. But how do we
> reconcile what has been discussed by folks from the agency that every
> application is going to be reviewed and requests will be considered
> for every compound that comes through and the fact that there is no
> way we can test every compound that comes through in pediatrics in
> real time?
>
> How will those decisions be made between two promising compounds in
> the same disease?
>
> DR. WEINER: I think that touches on the larger question, Wayne, of the
> overall strategies for prioritization because there are so many
> factors that will determine what drugs go into a finite set of
> patients because there are decisions with respect to the rule, there
> are decisions that companies make about whether or not they will allow
> their compounds to be tested in phase I, there are decisions of the
> pediatric oncologists within phase I as to which compounds they would
> prefer, their preclinical data.
>
> I think that, with respect to Point 2 on the discussion issues,
> Malcolm\'s strategy about having a preclinical network is a deliberate
> attempt to have a pathway towards prioritization, but I think that the
> only way that the prioritization question can be addressed is through
> the pediatric ODAC and through, essentially, consensus among the
> pediatric-oncology community as to what are the best scientific
> opportunities because that is really what families are depending on
> will govern those decisions.
>
> DR. SMITH: Someone from the FDA would need to address how the
> Pediatric Rule would be applied. I won\'t presume to address that for
> them. I think the issue isn\'t only with the FDA in how it applies the
> Pediatric Rule but it is also about pediatric exclusivity.
>
> Just as an example, there may be a whole batch of drugs for
> non-small-cell lung cancer and it may be a fairly large market and
> they may just not have what appears to be a lot of utility for
> childhood cancers. Even though there may be a desire for pediatric
> exclusivity for studying one or more of these agents, the
> prioritization process for \"is this the right drug to study in
> children\" may differ.
>
> The same issue with exclusivity applies for the third or fourth drug
> in a class and how many particular growth-factor inhibitors, specific
> growth-factor inhibitors, do we need to study in children.
>
> Certainly, in many cases, we will want to study at least one. Maybe we
> will want to study two. But when we have three or four or five in the
> same class, there needs to be a good reason for why all of those
> warrant prioritization because, if that warrants prioritization, that
> is probably knocking something else off the list and that some else
> could be of greater priority.
>
> DR. REAMAN: I think another issue that is important in prioritization
> of specific agents is this relative guarantee or confidence of the
> continued development of the agent to be tested so that we, given the
> fact that our patient population is small, don\'t want to begin
> evaluating agents for which there is no commitment on the part of
> industry to continue to develop.
>
> The other consideration also relates to the specific disease in the
> population of patients and whether or not there are adequate numbers
> of patients and what the overall scientific agenda is in looking at
> new ways to approach specific diseases.
>
> DR. HO: Greg, just a follow-up on that, your point and Malcolm\'s,
> with respect to multiple agents, let\'s say, of a similar class or
> similar mechanism target. It is difficult because, I think in industry
> there tends to be, perhaps, an overemphasis on being first on class to
> the point that if one is not first in class, sometimes, their
> physicians may not continue which may not be the most appropriate.
>
> We certainly know from history that many compound classes that are
> novel, it is not the first-in-class agent that makes it through and is
> the best one. So when you get into specific examples, let\'s say EGFR
> receptors where you have several small molecules out there, they are
> probably more similar than not in terms of the preclinical profiling.
> It is only in the clinic that they might differentiate themselves if
> they do.
>
> So, sure; you can test the first one, maybe test the second one. But
> when it comes to the third and fourth, you simply say, okay, it\'s not
> worth it, we are going to move on to another class of agents and
> forego that completely. If that is the case, how does that affect the
> implementation of the Pediatric Rule and FDA guidances?
>
> DR. REAMAN: That is why, Susan, when you suggest that the onus can be
> on the agency, it is difficult to conceive of how that would work even
> as an ODAC because there is an inherent conflict of interest between
> applying the rule and allowing exclusivity and setting priorities.
>
> That is what I was trying to explore is what questions can we ask
> about what other mechanisms there are that can look at\--and
> EGF-receptor inhibitors are a good example. Not only are there
> multiple small molecules but there are also multiple large molecules
> that target the same receptor.
>
> That is one thing. The other thing that is interesting, Greg, that you
> mentioned and you might want to respond to again is that the person
> sitting to your left is a strong advocate of getting drugs into the
> clinic in children early in the development cycle.
>
> If one waits until there is some greater or higher probability of
> further development, then you are going to get drugs later in the
> development cycle because those decisions are not made until later in
> the development cycle. So I don\'t know how you can reconcile those
> two things.
>
> DR. HO: The person sitting to my left shares my enthusiasm, or I share
> her enthusiasm or conviction, that we need earlier access to drugs for
> investigation in pediatrics than later. Again, not so early that we
> can\'t rationally prioritize what studies need to be done, when and
> how and in what groups of patients.
>
> But I am not sure that there is necessarily the inherent conflict
> which I think you might be implying. I think, if there is the early
> availability of agents for testing in pediatric preclinical models and
> early evidence of toxicity or lack of toxicity of agents in adults,
> then I don\'t understand why there should be a problem with early
> availability or earlier availability of those agents for pediatric
> trials.
>
> DR. SMITH: I would say that, in general, we think there is value to at
> least having a fairly good adult phase I experience before we bring
> something into children. There are just too many examples of drugs
> that don\'t make it through the adult phase I experience or have
> toxicities that we are just uncomfortable with bringing immediately
> into children and it gives us a good starting dose so that when we do
> a phase I trial in children, we are using a dose\--we are really
> pretty close to what will be phase II dose, a dose that we would
> actually be using subsequently to look for efficacy.
>
> So I think there are many benefits for at least having that adult
> phase I experience and that it does help us pick from the universe of
> potential agents the ones that, in fact, are most likely to be
> successful in children, is one of the factors, one of several factors,
> that helps us do that.
>
> DR. REAMAN: I certainly included that as part of early access in
> contrast to what our experience has been in the past where we do phase
> I studies after drugs are licensed in the adult population.
>
> DR. POPLACK: I just wanted to ask Malcolm what mechanism do you see
> for performing the prioritization within the preclinical group in the
> screening system. It strikes me we are in a very ironic situation in
> pediatric oncology because, given all that is going on in biology,
> there are going to be so many more potential agents coming down the
> pike given the fact that, with the gene-expression data that you will
> be generating, there will be many agents, many more agents, specific
> for each particular downstream gene in the process that people will be
> excited about.
>
> Where and when and who, in particular, will be doing the
> prioritization at the preclinical stages? You mentioned a steering
> committee? Is Pediatric ODAC a part of this? What do you envision
> happenin?
>
> DR. SMITH: I would envision something like a steering committee made
> of persons with preclinical expertise and biologists as well as
> clinicians who know what the major problems are that we need new
> agents for.
>
> I am less sanguine that we are going to have hundreds of new drugs
> each year that will be specifically relevant for pediatric cancers. I
> think if we had a system that we are able to look at twelve to fifteen
> new agents each year, that we would likely be hitting those agents
> that would be\--we would hit most of the agents that would have likely
> applicability in the pediatric setting.
>
> So that is what we would probably target is a structure able to do
> that number of agents or combination of agents per year.
>
> Peter, you are involved in this. What do you think?
>
> DR. HO: When I saw the slides up about the recent experience with
> phase I studies, 120 patients or so, that is probably only five to
> eight studies a year of first phase I in children. So, in terms of the
> prioritization\--and I think is probably a reasonable estimate to say
> that probably about twelve or fifteen, or so, in that range of new
> agents that may be appropriate for pediatrics may be coming in for
> evaluation once the systems are set up.
>
> But the capacity is about half of what you are going to be evaluating,
> it looks like. So what happens to the other half?
>
> DR. SMITH: Presumably some of them will, in fact, not show much
> activity if, indeed, the testing program\--there will presumably be
> some that won\'t show much activity.
>
> The other factor is that, as we know more about biology, the kind of
> broad phase I studies escalating to MTD may become less important. So
> we may have an agent and a target for rhabdomyosarcoma and, depending
> on the adult experience, the classic phase I study may not be
> appropriate and we may be able to move more directly to testing in a
> relevant population.
>
> DR. HO: Just one thing to add to that which may be interesting is that
> the conventional paradigm of taking a large fairly unscreened
> population for a phase I study and doing dose escalation and so forth,
> that we have become quite comfortable with in oncology.
>
> This is, of course, quite a bit different from what is done in other
> therapeutic areas. As we get into some of our novel agents now that
> are not conventional cytotoxics in which this biologically affective
> dose or however you want to term it becomes more important than
> finding an MTD for dose in phase II and III.
>
> What we are finding in our own experience in working with these agents
> is, in fact, dose selection is even more problematic and requires,
> let\'s say, randomized phase IIs of different doses to really take
> something to phase III. So, in fact, you may end up needing more
> patient experience to come up with a dose for these types of agents.
>
> DR. REAMAN: We have talked about the preclinical models and looking at
> gene expression and tissue microarrays of some of those cell lines,
> but what about even earlier collaboration in the design of small
> molecules that might be specific for targets in specific pediatric
> tumors? Where do you see any potential role for industry collaboration
> in those kinds of investigations?
>
> DR. RACKOFF: That is actually something we have discussed at a number
> of these sessions is what\--the compounds we don\'t know about and how
> to find them. I think it is a very difficult question. I think there
> are two answers that I have. One is that I think that most of the
> targets that we are looking at today are common to all the companies
> treatment are looking at them. There are very few\--well, I don\'t
> know about them, I guess, but, as you look at AACR abstract books, we
> are all looking at many of the same targets.
>
> I guess it is the question, really, for the biologists to discover and
> understand if there are targets that are exclusively ones toward which
> we should direct drug development in pediatrics. I don\'t know that we
> know the answer to that. AKT is important. ARAS is important. Flit 3
> is important. Are they really going to be exclusive molecules,
> molecules that are exclusive to pediatric cancers? I don\'t know the
> answer to that.
>
> So that is a very difficult question. To get back to Malcolm\'s
> preclinical testing paradigm, how would we identify drugs that might
> go into that that we thought weren\'t hits in our other targets? How
> do we define that universe of Drug X\'s I think is a very important
> question for future ODACs.
>
> DR. SMITH: I would say that the universe of Drug X\'s, as we have
> envisioned it, has been restricted to those that are ready to enter
> the clinic. So it is not the whole universe of stepping back two steps
> and candidates that never made it or that are still only long-distance
> candidates.
>
> But it is a very good question. We are also considering ways that we
> might develop pediatric-specific, encourage the development of
> pediatric-specific molecules.
>
> DR. RACKOFF: We haven\'t really addressed that issue yet.
>
> DR. WEINER: It is not clear to me that it is really relevant for this
> forum since we really are only talking about drugs presumably that are
> in pathway towards adult development.
>
> DR. RACKOFF: David, did you have a comment?
>
> DR. POPLACK: I wanted to ask Malcolm whether or not\--at what stage
> the preclinical testing will kick in, if there is an agent that seems
> to be of interest, are you going to be waiting until the adult study
> is done before the preclinical testing is done since you have a lot of
> studies and will, paradoxically or ironically, this end up retarding
> the introduction of a drug into the clinic in children?
>
> DR. SMITH: We have discussed the preclinical testing at that cusp
> between it is as drug that is going into the clinic and it is not yet
> in the clinic and if there is a clear commitment to the clinic that
> those would be the types of agents that we would like to be able to
> test in the testing program.
>
> So, at the same time that the adult phase I data are being generated,
> the pediatric preclinical data could also be generated so that, in
> fact, there wasn\'t a delay. That is the goal. The other side of that
> is it is possible that, given a large number of compounds up front,
> that the system might require that, for certain agents, they go
> through the adult study first, you understand the toxicities and then
> move it into that preclinical screening system because you may not be
> able to deal with all the compounds you have interest in.
>
> DR. SMITH: I think that the preclinical data could be useful even if a
> drug is entered\--even if it is late for some drugs and this is such a
> high priority, for other reasons, it is going to enter pediatric
> evaluation, that those data could still be very important in that
> transition from phase I to phase II and what tumor types are really
> relevant for phase II evaluation.
>
> So there clearly could be situations in which the drug enters
> pediatric phase I evaluation without the preclinical data but then the
> preclinical data help inform the decision of what tumors are studied
> in phase II or in pilot studies.
>
> DR. RACKOFF: I want to take a few minutes to address the other issue,
> the other bullet here, because it often gets ignored. Let me just, if
> I can, and Alla, if you have any other, summarize because it was the
> goal of meeting, the questions I wrote down; how will choices be made
> by the NCI and COG; how will the choices made by NCI and COG be
> accounted for in agency deliberations and requests. I think it is an
> important issue we need to address is the interface between the two.
>
> How will the universe of Drug X\'s be defined? We have talked about
> that in several different ways. I think a related question is how will
> the prior probabilities that we have from adult studies be factored in
> to your scheme?
>
> The MTA issue, we have had a separate forum on and it is going to be a
> very important issue to solve. I think, like Malcolm said, having a
> master material transfer agreement that at least all of the people on
> the preclinical testing site can agree to. If a company doesn\'t agree
> to it, well, they may be in trouble but at least they won\'t have to
> negotiate ten different contracts to get the drug tested.
>
> Any other questions? Does that summarize well, without taking into
> account any public comments, what questions we need to address in more
> detail in the future?
>
> Susan?
>
> DR. WEINER: I just have one summary comment.
>
> DR. RACKOFF: Because I do want to move on to formulation. I think it
> is an important issue.
>
> DR. WEINER: My summary comment is this, and this is what keeps me up
> at night and this is what drives me to work on this issue every day.
> The basic reason is trust. The patients and families trust that the
> FDA, that the NCI, that the COG, that the AAP and that the advocacy
> community have a single goal which is the rational introduction, the
> coordinated introduction, of the best science into children to cure
> their cancers with minimal side effects.
>
> It strikes me, after having thought about this problem and worried
> about this problem in the middle of the night many times, that we look
> for repeated demonstration of what gets called collaboration of that
> coordination, really, from all of you all the time. It is vital that
> there be national, rational strategies for the introduction of these
> drugs so that companies are not introducing drugs into kids and
> essentially diminishing sample sizes for reasons other than what is
> likely to be good for them so that the FDA is not concerned about
> extrapolation issues that may have to do with products where what the
> pediatric oncology doctor is saying is that they believe this is a
> good treatment for children, et cetera, et cetera.
>
> I would hope that, coming out of this meeting, we would have some
> statement, some summary, some commitment that would move that forward.
>
> DR. RACKOFF: On that note, I will move on to cherry flavoring because
> I think it is an important issue. Just an illustrative point is we
> have a compound that is in development in cooperation with Peds
> Oncology Branch and actually the COG. They have the compound fairly
> early in development. They are doing a study that involves infants.
>
> When I finally got on board and was reading the protocol, I noticed
> that there is an instruction in the protocol to crush the tablet for
> infants. There were no data to support that. It had just been done in
> some other studies and was, therefore, brought into this protocol.
>
> It actually has taken us almost a year, I hesitate to say, to develop
> the powder form and package it in a way that is suitable for\--that
> meets all regulations and is suitable for study. I think it gets to
> the issue of it is not going to be very fruitful to develop all these
> new agents and oral outpatient chemotherapy if we can\'t give it to
> our youngest patients.
>
> As we look at the patients you are talking about, neuroblastoma
> patients who tend to be young high-grade glioma patients often have
> feeding tubes. We need to consider these seriously.
>
> I.V. concentrations and excipients can often be important.
> Palatability, solubility, stability are not easy issues and can add
> years to the drug development cycle of pediatrics. There is a
> famous\--I don\'t know if it is famous, but there is a well-known
> example of a drug that is useful in pediatric oncology. It was
> developed by a company that is headquartered overseas and they put it
> in the traditional lemon-lime flavoring where it had about a
> three-second stable life.
>
> So these are issues that we really haven\'t addressed in the
> discussions we have had so far. I think that, as there are more oral
> agents coming into development, it might be very informative to have a
> session in the ODAC where we have experts on this. They are very
> technical issues, and really get a handle on the time frames around
> developing pediatric formulations because I think it is not a
> quick-and-dirty task even for companies like ours who have multiple
> drugs, over-the-counter drugs, in kids.
>
> It takes years to develop really acceptable formulations. So I will
> just put that out there to say that I think that ought to be an issue
> for detailed discussion at one of these sessions in terms of how and
> when those issues come into play.
>
> Malcolm?
>
> DR. SMITH: It is relevant to our earlier discussion that if there are
> three or four small-molecule inhibitors, the company that can say,
> \"We have a pediatric formulation that is a suspension or solution
> that is palatable,\" that is the one that should be studied in
> neuroblastoma bacteria it really is the safest way to administer the
> drug.
>
> So it is an issue in terms of the prioritization as well as does this
> drug have a formulation that is pediatric-friendly.
>
> DR. HO: I would just add in terms of time lines and so forth and what
> I think I am hearing, which I think has been espoused in the past, is
> that basically we really consider bringing a compound into phase I in
> pediatrics after the adult phase I is over with and we want to take a
> look at that safety data. That is probably about a year or so after
> introduction of the drug into the clinic as a whole.
>
> But the way that industry frequently makes decisions with respect to
> risk management is such that let\'s see the data and then make a
> decision and go forward. For oral agents, having to, then, go forward
> into producing a formulation that is suitable for children, I think
> that is really what Wayne was getting to before, at least, in our
> organization, takes anywhere from six to twelve months.
>
> There isn\'t always the support for producing formulations that may
> never get used until after you get your headline data that suggests,
> okay, let\'s do this. So that is certainly something that would add a
> lot of time into getting the introduction of a promising compound into
> children when you need that.
>
> So one thing that, perhaps, as we go forward might be helpful for this
> and the Pediatric ODAC Committee as a whole is to, perhaps, convene
> experts who have the experience in developing pediatric oral
> formulations because that doesn\'t always exist in every single
> pharma.
>
> DR. REAMAN: I am concerned that we are automatically assuming that
> oral formulations are, number one, safer and, number two, better.
> There are, as Wayne mentioned, many technical considerations but there
> are a lot of low-tech considerations as it relates to administering
> drugs to children with or without feeding tubes.
>
> Sixty capsules of fenretinide a day, although it is an oral
> formulation, certainly isn\'t, I wouldn\'t say, pediatric-friendly. So
> I don\'t think we should necessarily leap to the conclusion that there
> really needs to be an oral formulation. I think there needs to be a
> formulation that can be used in pediatrics.
>
> Even in some of the oral formulations, we have had difficulties
> administering those agents through feeding tubes because of adherence
> of the compound to the plastic tube. So it is not always the solution
> to the pediatric problem.
>
> DR. RACKOFF: That is why I suggest that there might be common ways,
> really, to approach this so that if it is an oral agent, rather than
> develop a full-fledged pediatric formulation, and I think the COG
> should build these into their thinking, is, when we do the phase I,
> should we include crushed-tablet PK once we reach MTD, do three
> patients or five patients, six patients, with crushed-tablet PK or
> mixing with chocolate syrup or chocolate pudding.
>
> Those are things that tend to get put aside until later for us in the
> development cycle. They are much easier to do, I would suggest, as an
> added cohort in a phase I than for us to do as a complete food-effect
> study that we have got to submit to the agency.
>
> I don\'t know if Peter would agree with that. I just think that we
> don\'t think enough about these kinds of issues and probably half the
> agents you had up there on your eighteen unlicensed agents that are
> under study list are oral agents.
>
> DR. POPLACK: Wayne, I just think that the last thing we need is to
> increase the patient requirements on phase I studies. We have such
> limited patients. I am not sure that doing that within the phase I
> context is the appropriate way.
>
> In the grand scheme of things, whereas in individual drugs like
> fenretinide and others, there are some examples where formulation is
> really critically important. By and large, we are looking for more
> effective agents. By and large, we give most of our drugs
> intravenously and would that eventually we would be able to have many
> oral agents, et cetera.
>
> There is a lot of work in terms of bioavailability et cetera that will
> have to be done. I think it is a topic of interest and importance but
> if I were to prioritize, I would put it a little bit lower perhaps in
> the first issues that were raised in this session.
>
> DR. RACKOFF: I don\'t disagree with you. I think you are right. But
> the point is to think about when we would do it and how we would do
> it, so at what point and in what populations would you need it.
>
> My question is when and how, not really that we do it in every phase I
> but it may be that, in an agent that is highly active in adults and
> determined that it is clearly is similar in children, that you would
> consider it early whereas in an agent where there may not be any phase
> I activity, you would do it in phase II if it were going to go into an
> infant population.
>
> So I wouldn\'t suggest that you would do it in every case but that you
> would think about it as part of your drug development plan in Sue and
> Peter Adamson\'s committee. Is there a possibility that this drug
> could go into a population where it couldn\'t be given in the form it
> is being provided?
>
> If so, what studies would we need to do and, if we need to do them,
> when would we do them? That\'s all. We tend not to think about them
> until after a study is already open which happened to us. That is what
> I would like to see us try and avoid.
>
> DR. SMITH: Wayne, the other thing I would add is that I think it is
> more of a challenge now than it was. If you are giving
> cyclophosphamide over a day or ifosphamide over five days or etoposide
> over three or five days, I.V. works great. But, for a number of the
> new agents, they are administered continuously or three weeks out of
> four. So, for those, it really, for feasibility, the oral formulations
> are being developed.
>
> So, for those drugs which we are seeing more and more like that, the
> issue of an appropriated pediatric oral formulation is important
> because of the prolonged continuous administration.
>
> DR. RACKOFF: I don\'t know about pipelines of others in the room and
> we are not here to comment on that but I would say that there is a
> significant proportion of drugs in discovery and development in other
> companies as well as ours that are oral that may not ever be able to
> be formulated in I.V. and that proportion is probably going to
> increase, not decrease.
>
> Is that a fair statement?
>
> DR. HO: Yes; I absolutely agree with you on that. I mean, the history
> of medicinal chemistry suggests that all the more soluble compounds
> have been discovered early on and now we are just dealing with a bunch
> of rocks.
>
> DR. WEINER: I guess my only comment about this is that whatever
> formulations are used, if they are evaluated in phase I, that they not
> add to the burden of the child\'s condition. Phase I patients
> typically are dying children. For kids with gliomas of one sort or
> another, or even if they don\'t have gliomas and have other kinds of
> brain tumors, for example, vomiting can be a very serious issue and
> disrupt scheduling in important ways to say nothing of issues about
> motor control and swallowing, et cetera.
>
> So I would hope that that would always be a consideration.
>
> DR. SHAPIRO: If there are no other comments from panelists, we are
> exactly on time to open the public comment session.
>
> **Public Comment**
>
> DR. SHAPIRO: I would like to call on Dr. Finkelstein to the
> microphone.
>
> DR. FINKELSTEIN: A couple of things. one is my pediatric hat applauds
> Dr. Murphy. I would encourage your agency to continue to evaluate
> every drug to see if it has an application for the child. I realize
> there was a comment here from the oncology panel, but, from a
> pediatric point of view, we applaud you an we applaud your agency.
>
> I would like to comment on the fact that all of us are here. It really
> follows up Dr. Weiner\'s comment. All of us are here in pediatrics. We
> talk to each other so we have the scientific community. We have COG.
> We have the NCI. We have the FDA, the community and we do talk to each
> other.
>
> Susan is correct. There are a number of challenges that were posed by
> your group today that, if we don\'t solve here, we should at least
> indicate to ourselves we are going to solve in the future.
>
> One of them is prioritization. I firmly believe that when it comes to
> the clinic it belongs to the clinician. So, Greg, I think it belongs
> to COG. That is my view. I don\'t think there is any question about
> it. The pediatric oncologists have to do the prioritization and I
> don\'t think we should give it up.
>
> The next thing has to do with availability from industry. This
> obviously concerns me because I realize there are intellectual rights.
> But if, indeed, in this group where we have industry, pediatric
> oncologists in industry, with COG and the NCI, if we can\'t solve that
> here, we won\'t solve it for the nation.
>
> So I am certain we can\'t solve it in the morning of Thursday, the
> 18th of July. But I am sure in another session we can solve it and I
> would hope that your subcommittee would make that as a recommendation
> for another session.
>
> Last, but not least, we do not want children at the end of the food
> chain. So I recognize that everyone has all these prescreening
> suggestions and, Malcolm, they are delightful but I don\'t know if
> they are operational. So we need things that are really operational.
> Until that happens, Greg, I think it is up to COG to identify the
> agents with the NCI, with industry, prioritize to get the ball rolling
> as quickly as possible.
>
> DR. REYNOLDS: Pat Reynolds, Children\'s Hospital, Los Angeles. I would
> just like to comment on the formulation issue and thank Wayne for
> bringing that up. Greg mentioned fenretinide one that a number of us
> working on it had a struggle with as a formulation issue.
>
> Obviously, there are a lot of other agents that are similar in which
> we are going to see micromolar levels that need to be delivered and,
> as Malcolm mentions, need to be delivered over a period of time, not
> like a standard cytotoxic. In particular, for example, with
> neuroblastoma, we are looking at these agents in a fashion where we
> want to deliver them after completion of cytotoxic therapy when we are
> not going to necessarily have a central line in to deliver I.V.
>
> So oral agents are a major component. One of the problems that we have
> found, at least in working with fenretinide, is that the expertise
> just does not exist there. The publications in the literature just do
> not exist there on how to optimally develop formulations for the
> pediatric population, whether this is intravenous or oral.
>
> I think we need to put some emphasis on that from both the FDA
> standpoint as well as the NCI standpoint bringing forward the science
> on developing pediatric formulations.
>
> DR. RACKOFF: Let me just respond. I don\'t know who these guys are but
> I know we have got some scientists in our company who are real
> experts, and Peter does, because we have got some products, and other
> companies as well, that are out there. Soft-Chew Tylenol took twenty
> years to develop. It doesn\'t happen overnight.
>
> So I agree with you that bringing these folks together and not just
> pediatric\--I don\'t know how to do this. It might be just an
> educational experience for us to hear about how it is done, even to
> the extent\--and I have heard about this, of how they do focus groups
> with kids in terms of picking pediatric formulations.
>
> It would be an educational experience and it may be something I will
> try and organize at COG at our group that meets there because it is
> something that there is not a lot of understanding about, as you found
> out with fenretinide.
>
> DR. REYNOLDS: I think developing some science on what is on the GRAS
> list, what could be used for this that could be palatable, what
> things\--we are finding there are lot of problems with what is on the
> GRAS list that maybe stabilize certain compounds in suspension
> formulations.
>
> So I think that all of that science is very understudied and if it
> could be brought forward at some point, it would really help all of us
> out.
>
> DR. ALLAND: Good morning. My name is Leila Alland. I am working at
> Schering Plough in clinical research. Until fairly recently, I was a
> practicing pediatric hematologist-oncologist. My question is really to
> Dr. Reaman. In my training, I worked both at some very large
> children\'s hospitals and then, in practice, at a smaller institution
> that was also part of the Children\'s Oncology Group.
>
> Access for the patients to the phase I studies depended, as you
> alluded to, to what institution these children were being treated at
> so I was wondering how much room there is for expansion of the phase I
> pilot consortium to other institutions within COG.
>
> DR. REAMAN: The plan was to start with about twenty institutions and
> potentially expand. The limiting factors are resources, financial
> resources, related primarily to the external auditing that is involved
> plus the level of expertise.
>
> The hope was that these institutions would be spread out
> geographically and that patients could, in fact, be sent to phase I
> centers. I know from personal experience that that is much easier said
> than done. At that particular point in a child\'s disease course
> isn\'t the best time to change caretakers and institutions of care.
>
> But, unfortunately, just given the resource constraints, the number of
> institutions, at least in the beginning was limited. As Dr. Smith
> mentioned, the way phase I studies may be done in the future without
> the need for pharmacokinetics and, when we are not looking
> specifically at defining dose-limiting toxicities may allow us earlier
> to expand the consortium.
>
> I just want to respond, if it is okay to respond, to Dr. Finkelstein
> that the COG has no intention of giving up any role in the
> prioritization. It has a role. It doesn\'t have the only role. It is
> really a shared role and we will be certainly and equal participant
> with the FDA and the NCI and industry and with patients and advocacy
> groups in making those decisions.
>
> DR. RACKOFF: Malcolm
>
> DR. SMITH: I would, to Dr. Finkelstein, second that that we, in our
> efforts, are attempting to collaborate with the Children\'s Oncology
> Group and with this phase I consortium to set up valid means of
> prioritization
>
> To the question of access, this is a very important question. The
> point I would emphasize is that phase I studies are not a very good
> means of getting access of patients to drugs. You have three patients
> that enter on a cohort. Accrual stops and then you have to wait a
> month or two for data to come in to expand accrual.
>
> Pediatric phase I studies may only enter fifteen to twenty patients. I
> think the key to the access issue is to have as efficient a mechanism
> as possible for developing the phase I study, getting it done quickly
> and efficiently and then, if it really looks like a promising agent,
> to have it open COG-wide as a phase II study in which case, the study
> is not stopping unless there is reason to stop for toxicity or for
> lack of efficacy.
>
> That is a much broader way and assured way of getting access to the
> new agents.
>
> DR. HO: In support of Malcolm and Greg\'s statements, we should just
> recognize that limited access, if that is the right term, in phase I
> is, of course, not an issue exclusive to pediatrics. I know when we
> are doing our adult phase I studies, we place them in quite a small
> subpopulation of all the cancer centers and institutions out there
> because of the need for a high level of expertise to conduct these
> trials.
>
> DR. REAMAN: I think it is really a very important educational issue
> that we need the help of parents and patients in communicating that
> message to families because, although, clearly, access isn\'t a
> consideration or shouldn\'t be a consideration for phase I when
> families read the lay press, unfortunately, they immediately think
> otherwise.
>
> But I think if we could, together, work on educating patients and
> families, that would be very, very helpful.
>
> DR. WEINER: I think that, and perhaps this will be discussed later on,
> but the notion that phase I trials in pediatrics are, indeed, given
> for therapeutic benefit if they have been through phase I in adults.
> If that is the prevailing view, then that is really what needs to be
> communicated because, otherwise, it is very scary from a family\'s
> perspective to consider that one is giving up one\'s child for
> experimental purposes, in effect.
>
> So it is one thing that really\--so, as a community value and as a
> community belief from the physicians and scientists, I think that, if
> that is true, then that really should be communicated as well, even if
> the probability is low, that there will be therapeutic benefit.
>
> DR. PAZDUR: I have a question. This is Richard Pazdur from the FDA. I
> wanted some consensus. To follow up on Wayne\'s response to Greg\'s
> comment, I had the same kind of conflict when you were talking about a
> need for a commitment from the company to continue the development of
> the drug and then the other comments that were made wanting a phase I
> adult dose, perhaps.
>
> When should drugs go into phase I studies in children? I have heard
> different comments from the pediatric academic community, one being we
> want these drugs the same time they go into adults or do you want that
> commitment? That commitment, really, whether we like it or not, comes
> from the company when they see activity in those adult studies. That
> is when they are going to be putting the moolah, so to speak, behind a
> drug and that commitment to that drug.
>
> So should the adult studies be completed? We have a dose. It saves a
> number of children, obviously, that goes on a trial. One does not have
> to go through fifteen dose-escalation steps. But there is an
> alternative, or a negative to that. Are we simply going to screening
> drugs then that have activity in adult disease and may miss basically
> drugs that may have activity in those unique pediatric diseases.
>
> Remember, you guys have a lot more success than we do in treating
> adult tumors. There might be different biologies here and there
> probably are different biologies. Are we going to be selecting drugs
> here that are only active in adult diseases and potentially miss drugs
> that are active or potentially active in pediatric diseases?
>
> DR. REAMAN: My point about the commitment, that there would be
> continued development, wasn\'t necessarily intended as a condition for
> doing a phase I study but as a way of prioritizing if there are a
> number of agents of the same class or even different classes.
>
> So I don\'t think we need a commitment that is dependent upon whether
> or not there is activity in adult cancers. I do think, as Malcolm
> mentioned earlier, that waiting until at least the completion of phase
> I studies in adults is absolutely essential.
>
> We depend very much on the MTD determined from adult phase I studies
> and we are already limited with the number of patients and the number
> of agents that we will be able to test. If we were to start without
> that information, we would be able to evaluate far fewer drugs. So no
> reason as far as I am concerned to start any sooner than that
>
> DR. SMITH: Richard, to use Steve\'s language, our guidance on when to
> start pediatric phase I trials is not a regulation and there could be
> extenuating circumstances that would change that but would be that we
> have the adult phase I experience and we understand the toxicities and
> the doses and so on.
>
> With regards to your other point of missing a pediatric agent, I think
> it is an important point. I don\'t think we are going to find it in a
> phase I trial just by doing the phase I trial. I think if we do have a
> preclinical testing program, potentially that would be picked up in
> the preclinical testing program and would be another argument in favor
> of such a program.
>
> DR. WEINER: The case that was brought up by Wayne from the IP meeting
> a couple of weeks ago is the problematic situation where a drug has
> been through adult phase I testing. It is entered into the pediatric
> screen. It shows activity and interest in the pediatric screen, and
> the drug gets jettisoned by the company.
>
> Supply is obviously a question. Then, if there is really interest,
> pediatric interest, in the compound, whose responsibility is it to
> take over that drug-development pathway for kids alone?
>
> DR. RACKOFF: I don\'t think we answered that question at that meeting,
> tough
>
> DR. SMITH: My sense was that the company could not be held responsible
> for developing, that, if there was a public need and it wasn\'t in the
> company\'s interest, that, somehow, the public need would have to be
> addressed in another way. But we should be lucky and that situation
> won\'t arise, but it could.
>
> DR. RACKOFF: We will see if there are any last comments. I want to
> retract one comment I made because I know people in New Jersey will
> watch this tape and it probably didn\'t take twenty years to develop
> Soft-Chew Tylenol. I don\'t know how long it took. That is my point.
> It may have been a week. Who knows? But my point was that these things
> don\'t happen overnight.
>
> Are there any other final comments from the panel, then? Thank you.
>
> **Panel 2**
>
> **Designing Clinical Oncology Studies for Children**
>
> DR. GOOTENBERG: In the interest of time, we are going to move ahead. I
> am Joe Gootenberg. This is the second panel. The first thing I would
> like to do is have the panel members each introduce themselves and
> tell the audience what sectors they represent. Susan, let\'s start
> with you as the comoderator.
>
> DR. BLANEY: I am Susan Blaney. I am the Vice Chair of Developmental
> Therapeutics for the Children\'s Oncology Group. I am from Texas
> Children\'s, Baylor College of Medicine.
>
> DR. SPOSTO: I am Richard Sposto. I am a statistician with the
> Children\'s Oncology Group for the Developmental Therapeutics. I am
> from the University of Southern California.
>
> DR. SHURIN: Susan Shurin. I\'m Chair of the Bioethics Committee for
> the Children\'s Oncology Group. I am at Case Western Reserve
> University in Cleveland.
>
> MS. TRAYNOR: I am Diane Traynor, Co-Chair of the Alliance for
> Childhood Cancer and also with the Pediatric Brain Tumor Foundation.
>
> MR. HURLEY: I am Mike Hurley with Abbott Laboratories in the Global
> Oncology Development Group.
>
> DR. HAGEY: I am Anne Hagey, Abbott Laboratories, Global Oncology
> Development Group and Pediatric Hematology Oncology.
>
> DR. GOOTENBERG: I am going to add that Wayne Rackoff, who was on the
> last panel, is being kidnapped to be on this panel, too, as soon as he
> walks in the door because we felt we really wanted to make sure we had
> a lot of industry representation. The questions that we ask will have
> a lot of relevance to industry and so I wanted to make sure that we
> have Wayne up here.
>
> While we are waiting for Wayne, let me introduce myself. I am Joe
> Gootenberg. I am a medical officer in Biologics at the Food and Drug
> Administration. Just because I have the floor, I am going to take the
> time to say that the Center for Biologics and Biologics Oncology is
> where we study the cutting-edge investigative products.
>
> We do the monoclonal antibodies, cytokines. We do the interferons, the
> immunoregulatory drugs. We also do cellular therapies. We are doing
> the cancer vaccines. Genetic therapies. In the future, events willing,
> we will be regulating stem-cell therapies.
>
> Karen Weiss is the Director of our division. Did I miss anything there
> Karen? Okay.
>
> Wayne, we would like you to introduce yourself again and tell us where
> you come from just for the record.
>
> DR. RACKOFF: I am Wayne Rackoff. I am a pediatric oncologist in
> clinical development at Johnson & Johnson.
>
> DR. GOOTENBERG: Now I am going to take a few seconds to give you an
> overview of how this panel will approach its mission. First, we are
> going to have a series of educational components to bring us all onto
> the same level, let\'s say, here. That is going to include a
> presentation from Susan Blaney and one from Rich. They are going to be
> discussing not only the designs of pediatric trials and the unique
> aspects of those designs but I think, as importantly or more
> importantly, how pediatric clinical trials are developed.
>
> Do they fall out of the sky? Do you open up a book and there they are?
> What mechanisms and what paths to clinical trials take on the way to
> being developed and then executed.
>
> Susan Shurin is going to give a short presentation on ethics
> associated with clinical trials. This is going to get aimed, I hope,
> into one of the questions for discussion which has been added on as a
> very specific question to raise questions about which is the
> requirements for tissue biopsy in studies, early studies, having to do
> with molecularly targeted therapies.
>
> After we have our educational component, we are going to have the
> discussion issues and I am going to structure this that we introduce
> each discussion issue, and the panel will discuss each discussion
> issue to some extent, before we open up to general panel discussion.
> That way, I think we will be able to touch upon that in more detail.
>
> Then we hope to have some good intra-panel discussion followed by the
> open public discussion which we have seen already and I hope that we
> will have even more input from the members of the public here. The
> public includes, of course, people on FDA who aren\'t on the panel,
> academics who aren\'t on the panel, industry that isn\'t on the panel,
> other members of the public and advocacy groups who are not on the
> panel. It is everybody who is not on the panel.
>
> Having said that, Susan will give the first presentation.
>
> **Presentation**
>
> DR. BLANEY: Good morning. As Dr. Gootenberg mentioned, Dr. Sposto and
> I are going to give an overview of some of the issues involved in
> designing clinical-oncology studies for children.
>
> I think, as evidenced by some of the issues raised during the first
> panel, this is becoming an increasingly complex paradigm.
>
> Just in the way of background, historically, as Dr. Reaman mentioned
> earlier today, there has been tremendous progress in the overall
> survival for children with cancer. On the left is plotted the
> five-year survival. On the X axis is time in years. Overall, for all
> pediatric cancers, that survival now approaches 70 to 80 percent.
>
> Tremendous success, as you all know, has been made in diseases such as
> acute lymphoblastic leukemia and Wilm\'s tumor, more modest success in
> tumors such as neuroblastomas. However, there are challenges that we
> face. Just as an example, the acute nonlymphocytic leukemias and some
> of the CNS tumors.
>
> However, even in those tumors where we have had acute success, there
> are high-risk populations. Here you can see the probability of overall
> survival for children with high-risk neuroblastoma during this time
> interval and we have only achieved a modest gain in improvement in
> survival.
>
> Although we have achieved success, as I have demonstrated on the first
> slide, that success does not come without a price. On this slide, what
> you can see is from a frontline myosarcoma treatment protocol, the
> worst degree of toxicity that was experienced by patients at any time
> during their therapy.
>
> These are coded using the NCI common toxicity criteria. As you can
> see, at some time during their therapy, more than 80 percent of
> children experienced a severe life-threatening or fatal toxicity. This
> is treatment that we deliver every day to children with cancer.
>
> In addition to acute toxicities, there is risk for long-term
> toxicities. Adriamycin, a drug that we use commonly in the treatment
> of leukemias, lymphomas and other solid tumors, has a long-term risk
> of cardiac toxicity. This is just one example of long-term toxicities
> that our patients might be faced with.
>
> Here you can see the risk of developing congestive heart failure that
> increases with cumulative anthracycline dose but, importantly, even
> five or ten years after completion of therapy, there is not a plateau.
> So children who receive treatment for childhood cancer have to be
> followed for the rest of their life and that is an important thing
> that we must consider when we are developing clinical trials.
>
> I am just going to step back and give you an overview of the drug
> development process in pediatric oncology. This is an organized
> national clinical-trials effort. It has been supported by the National
> Cancer Institute since the 1950s. As Dr. Reaman mentioned, it is
> required because children cancer is relatively rare and it has been
> highly successful and efficient. More than two-thirds of pediatric
> patients are enrolled in clinical trials and that is unlike our adult
> oncology patients where only a minority are enrolled in clinical
> trials.
>
> These clinical trials have, in large part, been due to the success
> that we have been able to achieve.
>
> Dr. Reaman showed you this overview, a simple schematic of the
> Children\'s Oncology Group. I am just going to approach it from a
> focus a little bit differently. When we are developing new agents, we
> have to take into consideration the disease committees that we are
> working with. There is representation from all of the major childhood
> oncology diseases as well as from rare tumors. So, in developing
> drugs, there is a lot of communication that needs to go on between
> these disease committees, the discipline committees.
>
> Pediatric oncology doesn\'t just require pediatric oncologists. It
> requires a team approach involving statisticians, surgeons,
> pathologists, radiologists and all of the other support that you see
> here. So these people are critical to incorporating important
> questions such as correlative studies or issues to address, for
> example, neuropsychologic questions in patients undergoing treatment
> for CNS tumors.
>
> Then there is the scientific committees for developmental therapeutics
> falls into. Developmental therapeutics is involved in drug development
> from phase I through Phase III. However, the primary effort is focused
> in this initial phase I pilot consortium.
>
> In the past, we would develop drugs basically as we had access to
> them, as they came down the line, and would worry about prioritization
> later after we had conducted our broad-based phase II studies. But
> that paradigm is switching and now we are having increasing
> communication very early on in the preclinical stages and before
> initiation of the phase I studies with our colleagues in the disease
> committees to know is there going to be a place\--if we develop this
> drug, is there going to be a place to incorporate into these important
> phase II and phase III studies that are going to answer the ultimate
> question; that is, what is the impact of this agent in the treatment
> of childhood cancer.
>
> So pediatric-oncology clinical-trial activities are conducted through
> a variety of venues. The primary national effort and international
> effort is through the Children\'s Oncology Group. Where does the
> Children\'s Oncology Group get access to drugs?
>
> Most of the agents that we study are sponsored through the NCI,
> through cooperative research agreements that the NCI has with
> industry. However, there are occasions when there is a drug that we
> think it is very important to study and, for a variety of reasons, the
> NCI might not have an agreement with that industry sponsor. So we also
> work directly with industry in developing new agents.
>
> In addition, there are other consortia that Dr. Reaman mentioned, the
> Pediatric Brain Tumor Consortium which is focused on the early
> development of new and innovative therapies for children with CNS
> tumors. Again, access to those drugs is primarily through those same
> two mechanisms; likewise, the Neuroblastoma Consortium, which is
> funded through a PO1 grant and sponsored by the NCI.
>
> In addition to these mechanisms, however, there are other mechanisms
> for developing new agents. There are international consortia. There
> are institutional trials that may be single institution trials or
> limited institution trials. Again, access to drugs for these
> institutional trials often come directly from industry. They may be
> investigator initiated or NCI-sponsored through a variety of grant
> mechanisms including R21s, PO1s or RO1s.
>
> Why conduct separate pediatric trials? I think that has been addressed
> in many different forums and there is not time to elaborate on each of
> these points in any detail, but just to say that there are many
> diseases that are different. There are many examples of times when the
> pharmacokinetics or the pharmacodynamics of the agent under study may
> be different. And the prior therapy and the tolerance that the
> patients have to the therapy may be different.
>
> In many cases, children will tolerate more of an agent but, in some
> cases, our front-line treatments are much more intensive. In the phase
> I setting, they may tolerate less and, as a result, we may need to do
> further dose refinement in the phase II setting.
>
> What are the current challenges that we face in pediatric oncology
> drug development in our design of clinical trials? Dr. Smith talked
> about preclinical prioritization so I won\'t discuss that further. I
> think the biggest challenge that we face is our limited patient
> numbers and, in addition, the rational development of a molecularly
> targeted agent.
>
> Obviously, there are other challenges that we face but these are the
> major ones that we need to address when we are designing clinical
> trials.
>
> So what are the implications of limited patient numbers in the design
> of clinical trials? For the most part, this means that
> single-institution studies are not feasible. The largest children\'s
> cancer centers may be able to conduct a phase I study as a
> single-institution study but, in general, that is not feasible and
> that is why the Phase I Consortium was developed, to do this in a
> timely and expeditious fashion.
>
> Phase II studies can\'t be conducted in a single institution.
> Obviously, phase III can\'t. So, as a result, some single-institution
> studies aren\'t feasible. That means that the clinical-trial design
> process is a little bit more complicated. Obviously, there are more
> resources that are required to support this study and there is more
> coordination of data management and regulatory issues.
>
> Another implication of limited patient numbers is it slows our pace of
> drug development. We can evaluate fewer new drugs. There are fewer
> possible studies that can be done. It is more challenging to integrate
> new agents into what are currently curative but nonetheless toxic
> regimens, as I have demonstrated.
>
> This impact of limited patient numbers cuts across all phases of drug
> development from phase I through phase III.
>
> As a result of more effective standard therapies that have been
> developed, we have to have larger studies in the phase III setting to
> identify new and superior treatments. This increases the overall
> length of the drug-development process and it is virtually impossible
> to conduct a randomized study of an uncommon or rare pediatric tumor
> in a timely fashion. It takes many years, three to seven years. Three
> is being optimistic.
>
> This is just an example of a time line. As has been alluded to this
> morning, we don\'t have access to drugs in most instances until the
> phase I studies in adults have been completed and there is some
> indication that there may be an approvable indication for adults, or
> the promise of an approvable indication.
>
> All phases of drug development in pediatrics take longer than in
> adults. If you look at this overall time frame from the preclinical
> study to the completion of the phase III trial, and that doesn\'t
> include the time to analyze the data and see the impact of the new
> therapy compared to the therapy, it is, at best, a twelve to eighteen
> year period.
>
> Just as an example is topotecan, one of the topoisomerase inhibitors
> that entered pediatric development in the early \'90s. Accrual to the
> phase III study that is looking at this agent won\'t be completed
> until July of 2004 and then it will be several years after that until
> we know the ultimate impact of that trial.
>
> So small patient numbers mandate the development of preclinical
> predicted disease models, efficient use of resources, novel
> clinical-trial designs and refinement of the drug-selection process.
>
> I am just going to briefly talk about the rational development of
> molecularly targeted agent, another challenge that we are increasingly
> facing. As we integrate these new agents, we are going to have to
> address the standard process for evaluating a drug in the phase I
> study. Are we going to evaluate maximum tolerated dose or look at an
> optimum biologic dose.
>
> That is going to require us to develop new clinical-trial designs in
> the pediatric setting. It is just not unique to pediatrics. The same
> holds true in adult cancers as well. In the phase II and phase II
> setting, we are going to be challenged at evaluating, since some of
> these new agents are not cytotoxics\--challenged at looking at
> surrogate markers of response and how to do that, especially if there
> are not imaging modalities to do that, if it requires an invasive
> procedure, and look at new endpoints that we haven\'t classically
> evaluated in pediatrics; that is, time to progression.
>
> If we are looking at new endpoints and we require that patients
> express a specific target in order to be eligible for a study, we are
> going to decrease the number of patients, further decrease the number
> of patients, that are available for study.
>
> A challenge that is spaced across the development of these new agents
> in the oncology world is the validation of these surrogate markers and
> then, again, as I mentioned, obtaining tissues for correlative
> studies.
>
> Correlative studies, we consider in the Phase I Developmental
> Therapeutics Consortium to be those studies that don\'t have prospect
> of direct benefit of the patient. That means if we are doing a study
> of a new agent and the endpoint is achieving a certain drug exposure
> and it requires pharmacokinetics to assess whether or not you have
> achieved that exposure, then that, obviously, is a requirement.
>
> But if it is defining pharmacokinetics because it is a new agent and
> it is not going to impact any decision-making process for a particular
> patient, then that does not directly benefit that patient. We feel
> that it is coercive to mandate that type of study in order for the
> patient to receive therapy.
>
> Nevertheless, our success at being able to get these types of studies
> in the phase I setting and making these optional for patients is very,
> very high. I would say that more than 95 percent of patients will
> consent to them even with the knowledge that they are not going to
> obtain direct benefit.
>
> So, addressing the challenges that we face in designing trials, the
> preclinical prioritization is being addressed through the Preclinical
> Consortium that is in development. The limited patient numbers need to
> be addressed through novel trial designs and cooperative group trials.
>
> The rational development of molecularly targeted agents again requires
> input from the Preclinical Consortium, novel trial design and
> development and validation of noninvasive correlative studies to
> assess benefit.
>
> The biggest issue, I think, that we face in addition to the patient
> numbers and statistical design is communication and information
> exchange. This requires input from all arenas and the size of the box
> has no correlation with the importance of the input. It is just really
> important that this communication be effective and go in all
> directions.
>
> There are some formal mechanisms from communication but a lot of what
> goes on in the drug-development process right now is also informal. So
> we have to strive to ways to formalize this communication. People like
> Dr. Rackoff have been instrumental in trying to bring industry in a
> coordinated way. The efforts of Dr. Hirschfeld from the FDA have been
> instrumental in trying to also involve the NCI and the COG and all the
> other people in these arenas in doing things in a more formal and
> systematic way.
>
> But, without this, it is a challenge. Even with this communication, we
> face a lot of challenges in our clinical-trial designs.
>
> DR. GOOTENBERG: Thank you, Susan. That was a very good introduction to
> what we are going to be talking about. I do think you touched upon the
> unsaid issue of communication and sharing of clinical-trial designs as
> well as clinical-trial results.
>
> Now we will have Dr. Sposto.
>
> **Presentation**
>
> DR. SPOSTO: I would like to thank Dr. Gootenberg for inviting me to
> give this presentation. What I want to talk about is a little bit more
> maybe of the technical details of clinical-trials design especially
> the kinds of compromises that we have to make in pediatric oncology.
> Since this is a didactic presentation, I am going to be didactic and
> start out with a definition of a clinical trial which is any form of
> planned experiment which involves patients and is designed to
> elucidate the most appropriate treatment for future patients with a
> given medical condition. This is from Dr. Stuart Poplack\--that is
> misspelled\--in a 1983 book.
>
> Most aspects of clinical-trials design have been discussed extensively
> in the literature and, for the most part, adult and children\'s
> studies are very similar in the design aspects. But there are special
> challenges for pediatrics and I will describe some of these here.
>
> As has been said many times, many pediatric cancers are rare so that
> adequately sized or timely studies are not possible in single
> institutions or small consortia so we really must have large
> cooperative groups like the Children\'s Oncology Group and the several
> European cooperative groups that exist.
>
> Some cancers occur primarily in children. Medulloblastoma/PNET and
> neuroblastomas are two examples so that treatment efficacy data will
> not necessarily be available from adult studies where you might
> otherwise have those available.
>
> Maybe one of the most important things is that many childhood cancer
> cures are achieved in the majority of patients. Some examples have
> been given; acute lymphocytic leukemia, Hodgkins disease, B-cell
> non-Hodgkins disease, B-cell non-Hodgkins lymphoma, even average-risk
> medulloblastoma, the majority of patients are \"cured\" of their
> disease.
>
> But cure, in this sense, is really apparent eradication of the
> original neoplasm and doesn\'t really refer to the fact that the child
> has like he never had cancer before because these cures are achieved
> at a cost of sometimes significant acute and long-term morbidity
> including neurocogitive and quality-of-life sequelae, growth
> abnormalities, fertility, risk of second neoplasms.
>
> This is especially important to consider in children because cured
> children do have a long remaining lifetime who have experienced these
> outcomes of treatment. So, as treatments improve in pediatric
> oncology, the objectives of the clinical trials, especially phase III
> trials, and the whole effort shift toward reducing the morbidity of
> treatment while maintaining or improving efficacy of treatment.
>
> This has been done in Children\'s Oncology Group and by other groups.
> One way is by modifying current best therapies. I can give you some
> examples of studies that have been done in COG to eliminate field
> radiation therapy in Hodgkins disease or to attempt to do that, to
> reduce neuraxis radiation therapy in medulloblastoma and to reduce
> alkylating agents and PB16 in the treatment of B-non-Hodgkins
> lymphoma.
>
> But perhaps in the future, I think the approach will have to be that
> we will identify novel targeted agents that may not have the toxicity
> associated with them but are very effective agents. Maybe that would
> be the way to go, and should be the way to go.
>
> Let me talk very briefly about some of the technical aspects of
> clinical-trials design. We have heard about a lot of different trials.
> We think of them in generally three classes; phase I trials which are
> preliminary studies of toxicity to establish the maximum-tolerated
> dose, usually; phase II trials which are preliminary studies of
> efficacy and sometimes screening trials that include further studies
> of toxicity; and phase III trials which are reviewed as definitive
> studies of efficacy in usually newly diagnosed patients but also
> recurrent patients sometimes. They are usually randomized studies.
>
> As I said, phase I trials establish the maximum tolerated dose and
> also document the frequency and type of toxicities that occur and use
> a minimum number of patients. As Dr. Reaman, and I think others, have
> pointed out, these patients are enrolled in successive cohorts,
> treated over increasing doses of treatment until unacceptable rates of
> toxicity are observed.
>
> But the number of patients in these studies is small by design.
> Therefore, the estimate of the maximum tolerated dose will be somewhat
> imprecise. So investigations of toxicity will have to continue in
> subsequent studies.
>
> Let me just illustrate that by referring to the standard phase I
> design that we often do which is a three-patient cohort design where
> we treat up to six patients at each dose but three at a time and,
> depending on the outcome in those three patients, we either escalate
> or expand the cohort and, in the expanded cohort, maybe escalate again
> or de-escalate or stop the trial because we find that it is too toxic.
> Many people here are probably very familiar with that trial.
>
> What this shows is the imprecision in the maximum-tolerated-dose
> estimates. This is like 1000 replicates of a hypothetical trial of ten
> different dose levels of a drug. Each of those dose levels is
> associated with a true dose-limiting toxicity rate ranging here from
> about 1 percent at the lowest dose to 40 or 45 percent in the highest
> dose.
>
> What this shows is the outcome of about 1000 trials and what dose
> level would have been selected from that trial. You can see that, in
> the majority of cases, the standard design chooses MTDs that
> correspond with about 15 or 20 percent dose-limiting toxicity rate
> which implicitly, I guess we assume, is reasonable depending on the
> definition of dose-limiting toxicity.
>
> But the point I want to make here is that there is some dispersion
> here and there is not an insignificant chance that actually we would
> end up with dose-limiting-toxicity rates that are very small, but
> maybe at subtherapeutic doses and, also, very high, 35 or 40 percent
> and the trial would result in that.
>
> So this just points out the need to further investigate toxicity
> later. This is probably less of a concern in children than in adults
> because we do start at a starting dose that was dictated by the phase
> I studies conducted in adults so we are less likely to get too low
> doses.
>
> There are other types of designs, continual reassessment methods,
> accelerated designs, also designs that include pharmacokinetics and,
> as other people have commented, in the future we will be looking at
> designs where the toxicity isn\'t a primary concern but we want to
> look at surrogate measures of efficacy in finding optimal doses.
>
> COG generally uses a standard design at present because it is well
> understood but also because we do start at the 80 percent of the adult
> MDT, there is less advantage to these other designs. But we will use
> them when they are appropriate.
>
> Phase II studies are preliminary evidence of treatment efficacy. They
> are usually multistage. They also include multiple separate disease
> strata because, as opposed to in phase I trials where the issue is
> toxicity, on phase II trials, it is efficacy and we really want to
> evaluate that in an histology-specific way, a diagnosis-specific way.
>
> The endpoints, traditionally, are tumor response but, fewer cytostatic
> agents, for example, time to progression may be a more appropriate
> endpoint and also novel imaging mechanisms will allow us to look at
> treatment efficacy in different ways.
>
> Let me tell you about the sensitivity or the power of these trials
> because it talks to what we can do in pediatric cancer. This is an
> operating characteristic for a standard two-stage design. What is
> shown on the bottom here is the probability of tumor response ranging
> from about 20 percent to 70 percent.
>
> What this is is the chance that this standard two-stage design will
> result in the decision that the agent is effective. This is a
> screening trial. You can see, for king of a large study\--there are
> two large studies here. One has a maximum sample size of 72 patients,
> the other 53 patients. We can very easily distinguish between an
> ineffective agent, defined here as 20 percent, and one that has 35 or
> 40 percent response rate which you can detect that with a very high
> power so have a very precise answer.
>
> But rarely can we do phase II studies of this size in pediatric
> oncology. We usually do smaller trials. This one has a maximum sample
> size of 19. You can see that we are not really able to reliably to
> detect agents that are responsive only at 40 percent. But, perhaps, at
> 50 percent we can and, certainly, at 60 percent.
>
> If we did these trials all the time, we would limit the number of
> agents that we do. Maybe this isn\'t bad. Maybe we should only be
> interested in agents that clearly demonstrate high response rates
> before we continue on to further study.
>
> Some other speakers have mentioned randomized phase II trials that can
> be used to screen concurrently available treatments or investigate
> schedules. Dr. Simon at CTEP has written about selection designs to
> throw out ineffective agents early. But this is not always possible in
> pediatrics again because our patient numbers are limited. This is the
> third time you have seen this phrase, I think.
>
> Phase III trials are a large part of what we do. In phase III trials,
> we enroll large numbers of patients. These are usually newly diagnosed
> patients but not necessarily. They are assigned randomly to two or
> more treatments and, thereby, getting an unbiased answer, or what we
> think is an unbiased answer of treatment efficacy.
>
> You see long-term endpoints, event-free survival and survival. As
> treatment is improved and we are reducing therapies, these may also
> include and probably have to include the quality-of-life and
> neuropsych endpoints and other things like that.
>
> But we confront a dilemma in pediatric oncology because, even with
> large cooperative groups like the Children\'s Oncology Group, it may
> be impossible to design a trial that can be completed in a reasonable
> time. Here, a reasonable time, I mean under ten years between the
> start of the study and when the results are published, and have a
> trial that, perhaps, can detect the smallest difference of clinical
> interest with traditionally small type-1 and type-2 errors.
>
> People, in designing trials, will say 5 percent type-1 error, 20
> percent type 2 error, to find a 5 percent increase in cure rate. If we
> tried to do that trial in most pediatric cancers, it would take twenty
> years. It is just not a possible thing to do so we have to make
> compromises.
>
> One reason that pediatric oncology is different is that, as opposed
> to, let\'s say, breast cancer where you do a large thousand-patient
> trial and that is a small fraction of the incidence of breast cancer
> in the United States, our study cohort is not really a sample from a
> large population. It almost is the population. As Dr. Blaney
> mentioned, we enroll more than two-thirds of pediatric-oncology
> patients on the trial.
>
> So I think we have to think about this in a different way because if
> we make trials longer and if we make them bigger, we are making them
> longer and just increasing the time frame to study different drugs in
> combinations.
>
> So our only options may be the large and very long studies which we
> don\'t want to do because we can\'t, and small randomized studies
> which are unbiased but some people would say are underpowered and,
> therefore, not desirable. We can perform a single treatment,
> historical control study, which we can do in certain instances where
> the outcome is known to be grave, for example brain stem glioma, but
> in other diseases it is very difficult to justify a valid historical
> control study to get an unbiased answer.
>
> We can conclude that the question can never be answered, but that is
> not a very attractive option. One way, obviously, is to perform wider
> collaborations. Now, since COG is really a pan-North American group
> and partially international, if we are talking about wider
> collaborations we are talking about the international collaborations.
>
> We can try to shift the focus of some of our trials maybe to look at
> ways to retrieve patients better but that will compete a bit with
> developmental therapeutics efforts. Another way is to try to come up
> with very sensitive and specific markers that will predict failure
> early on. I don\'t know that we have ones that are as sensitive and
> specific as we need, but that would allow us to target the patients
> that we know will fail with current treatments and may improve the
> power of our studies.
>
> So, that is a compendium of the issues that we face. One future
> challenge that I want to bring up, that has been alluded to, is that
> since many of our treatments are so successful but so toxic and we
> hope to identify novel, much more effective and much less toxic
> agents, we are still confronted with the fact that we have small
> numbers of patients and these patients with standard therapies have
> very high cure rates.
>
> So, the question is going to be how can we design studies that
> actually will allow us to back down from these toxic therapies,
> because these types of randomized Phase III studies are so-called
> equivalence trials which traditionally require very, very large
> numbers of patients that we don\'t have and we are going to have to
> pay very close attention to the kinds of morbidity and toxicity we are
> attempting to reduce in these studies because the studies that we can
> do are not going to be as powerful as we would otherwise think we
> would need.
>
> I will leave it right there. Thanks very much.
>
> DR. GOOTENBERG: Thank you, Dr. Sposto. That was a very clear talk. Now
> Dr. Shurin is going to talk about the ethics, and this is very
> important because this is unique in some ways to pediatric oncology
> because children are, by definition, both ethical and legal
> definition, a vulnerable population and in whatever we do, we have to
> understand our obligation to protect them.
>
> While the slides are coming up, we may as well make use of the time to
> talk among the panel. We have had presentation about the designs of
> pediatric cancer trials and we have had some particulars about the
> compromises necessary. I am interested in knowing within industry how
> are clinical trials designed, by what mechanisms is a pediatric
> clinical trial designed, or are they designed at all? It could be that
> the answer is just no. I would throw that open to our three industry
> representatives.
>
> MR. HURLEY: In general, the design of clinical studies, whether they
> are for pediatrics or adults, by industry are started with a panel of
> outside experts, and we try to get an opinion from them and their
> various practices, and what type of patient population a particular
> drug that you have designed is most likely to be effective in; what is
> the chance that that patient population is going to be essentially
> clean, meaning that they have no other disease states that would
> interfere with a clear understanding of it. Then you sit down with
> them and start developing a protocol.
>
> After the protocol gets into sort of a draft stage, and often if it is
> a fairly innovative drug, you will take it to FDA and discuss with
> them some of the design, particularly because in some cases the
> particular endpoint you are using to demonstrate clinical efficacy may
> be unique, may not be a standard established one, and discuss with FDA
> whether or not the proposed standards or the criteria you are looking
> for to show a change as a benefit of the drug will be acceptable for
> registration purposes.
>
> So, it is really a two- or three-stage process. That can be short-cut
> if you are very familiar as a sponsor with that type of drug. For
> example, if you are dealing with a simple development of an antibiotic
> and you have developed a dozen of those, you have a pretty good idea
> of the criteria that FDA will accept. You have a pretty good idea of
> what the population is out there. You have been studying it and you
> can develop it essentially internally. So, I guess those are basically
> the two ways that they could be developed.
>
> DR. GUTENBERG: I would pose a further question. Maybe, Wayne, as a
> pediatric oncologist with some experience you might know this, are
> there, and what are the circumstances under which industry finds it
> necessary to go outside of the collaborative group in oncology\--I am
> only asking about oncology\--in order to find the patient population
> to test new drugs. Have you had any experience with that?
>
> DR. RACKOFF: Yes, the answer is yes, I have had some experience with
> that and I think that it really has come because of the collaboration
> between pediatric oncologists and industry and their friends and
> colleagues in academic medicine or in the cooperative groups. So, in
> the case with which I am familiar it was really being approached by
> folks who wanted to do the study outside of the cooperative group
> mechanism and facilitate that.
>
> I think that one mechanism that works well, and it is probably more
> useful, is to have the drug at CTEP under a creator because in that
> circumstance not only individual investigators but the cooperative
> groups have access to the drug but you have review of the protocols on
> the industry side.
>
> DR. GOOTENBERG: From the FDA perspective, and I may be getting into
> territory we shouldn\'t be treading on but I am only asking for
> questions to be defined from the FDA perspective, which has
> hypothesized that we invoke pediatric rule for a new biological, but
> that there are not sufficient numbers of appropriate candidates,
> subjects, within the collaborative group setting. Is that something
> that industry has a set remedy for?
>
> DR. RACKOFF: No, and that comes down to the whole issue of priorities,
> and there is another issue which I wanted to ask Rich about and I
> guess Susan as well as anybody else on the cooperative group side,
> there was an article a couple of years ago about relaxing the type-1
> error parameters in clinical studies in children. It didn\'t get very
> far but I wonder if it shouldn\'t get further than it has. It would
> come down to really the industry side, if I went to my regulatory
> group and said, well, the cooperative group is proposing doing a study
> with a type-1 error of ten percent instead of five percent in order to
> facilitate the study being done in a timely fashion and they think,
> given the activity of the drug, that is reasonable, then it would
> really involve a partnership. It would involve our regulatory group
> accepting that, and it would involve the agency accepting that for
> possible registration, and it would involve the cooperative group
> accepting that.
>
> I think the other thing that we should address along the way later on,
> after Susan gives her talk. You know, we had talked about the problem
> with success, and one of the problems is that you use typically a cure
> model in designing pediatric studies, and when we do studies in
> pancreatic cancer we look at immediate survival. Those are much
> shorter studies to do and I don\'t know how we can get around that.
> Having cured so many kids, I would rather have the situation that we
> cure more kids and have to take longer to do the studies, but if you
> want to quicken the pace of drug development we have to put our arms
> around that question and see if we can embrace some of the methods of
> doing the study.
>
> DR. GOOTENBERG: Thank you very much. We are looking forward to this,
> Susan, and we are going to go ahead with the presentation.
>
> **Presentation**
>
> DR. SHURIN: I was asked to focus on some of the ethical issues that
> are raised by performance of Phase I studies in children with cancer.
> I think one of the things that is most depressing is how little data
> there are about these kinds of issues in general as, not too terribly
> surprisingly, of course, much of it has been obtained in adults.
>
> I would like to start out with addressing a question that Susan Weiner
> raised earlier, which is what are the aims of these studies? The aims
> of the investigators are often different from the aims of the people
> who participate in the studies. What I would like to sort of raise as
> a straw man, or something like that, is that these differences in the
> motivations that people have for performing or participating in these
> studies may all be valid as long as they are recognized, and as long
> as we are really clear on where people are coming from and what the
> expectations are because that minimizes the difficulties with
> communication and coercion.
>
> First of all, why do investigators perform Phase I studies? I think a
> Phase I study is a toxicity study, a study to look at the way that a
> drug is handled in human subjects. Most of the Phase I studies that
> have been done in oncology are done traditionally to aim at getting
> the maximum tolerated dose because the usual paradigm in oncology is
> that more is better and you are going to give as much as you can
> possibly get away with.
>
> This is changing as we are getting into biologics and we are talking
> about the optimum biologic doses, and this actually goes into some of
> the issues about getting samples from patients because it is a lot
> different if you are looking at whether or not a targeted drug is
> reaching its target than you are whether you are taking a blood
> sample, which is certainly not a terribly invasive thing to do, to
> determine what the level is within the blood or within some other body
> fluid.
>
> So, why do investigators perform the studies? Well, first of all, to
> test scientific hypotheses. That is why they do any study. To develop
> new therapeutic agents so that they can improve therapies. There are
> some other things that come into this and I want to raise these
> because they are present, and not to tell you that they are bad
> because I think, in fact, that everybody is human and you respond well
> to rewards.
>
> There are issues of people\'s career advancement, recognition,
> acclaim, publication, promotion if that means anything in medical
> schools anymore. They are not the primary motivators but they may be
> some things that motivate people, maybe the things that motivate
> people to put in 18 hours a day instead of 8 hours of day, those kinds
> of things.
>
> Then, there are also economic rewards. These are occasionally,
> although in pediatric oncology almost never, related to personal
> finances but they certainly may be related to institutional issues in
> terms of program development. I think when you look at the issues of
> what does it take to be a Phase I institution, you have to put
> patients on studies and if you can\'t do the studies you can\'t be a
> Phase I institution. And, there are institutional reasons for the
> different institutions to participate, for which they may reward the
> investigator who is primarily responsible.
>
> Why do the industry sponsors, the corporations sponsor drug
> development? Well, they are in business. These are products for the
> marketplace. It is all part of the business place. It is not a bad
> thing. This is exactly what businesses are supposed to be doing. The
> scientific research arm of any industrial corporation depends on
> bringing drugs from the bench to the bedside. If you don\'t get it to
> the point where you can actually market it, it is not successful and
> you might as well not bother developing it in the first place.
>
> Then, the individual scientists who are working within industry have
> the same motivations as the clinical investigators, and I think one of
> the things that has come out fairly clearly is what a fluid sort of
> system this is in which people are involved in governmental aspects;
> people are involved in industry; people are involved in academics; and
> there is a significant amount of not only going back and forth but
> also knowing each other quite well.
>
> Why do patients participate in Phase I studies? This, when it has been
> studied, is actually fairly unequivocally answered I think, which is
> that the patients participate because they want therapeutic benefit.
>
> Now, in one study in which this was done, 85 percent of the patients
> said that they are participating because they are hoping for a
> therapeutic benefit. Eleven percent of those were participating on the
> advice of physicians and primarily were participating because they
> trusted the advice of the physician who recommended that they enroll
> in the study. This comes down to what it is we have that protects
> patients and probably the number one most effective is the integrity
> of the investigators who are involved in conducting research. About
> four percent participated because of family pressure\--we want you to
> continue doing something, keep doing something when they were ready to
> stop. This is an adult study.
>
> I think if you look at this issue in pediatrics you will find it is
> really very different for children who may not even have a feeling
> about this, but for adolescents, what I certainly see as a practicing
> pediatric oncologist is people participating because family members
> are not ready to give up and what the family members are after is
> therapeutic benefit.
>
> Now, this happens in spite of the fact that the consent form says that
> the aim of the study is to determine what the toxicity of the drug is
> and to look at how this drug is metabolized in people. Is the
> information conveyed? Yes, it is conveyed. That is what the goal of
> the study is, but that is not why patients enroll. Many of them can
> tell you that they are hoping to benefit future patients and those
> altruistic feelings may be present, but they are not the major
> motivations that get people enrolled in these studies.
>
> I am going to come back to some of the basic principles of human
> subject research ethics, and there are three big things here. One is
> respect for the autonomy of persons; beneficence and justice.
>
> In terms of autonomy, there should be a right of the subject to make a
> choice and to assume risks. This became a huge issue when the HIV AIDS
> advocacy groups started challenging the way that drugs were approved
> as the AIDS epidemic became widespread. People said, okay, you are
> being very paternalistic, you are telling us we can\'t assume these
> risks. We are ready to assume these risks. We have nothing to lose.
> This is not unlike the kind of thing you hear from the kinds of
> patients who are eligible to participate in Phase I oncology trials.
> We want to take these risks. We frequently hear this from our patients
> and parents as well. If there is nothing better, no matter what
> happens, I am ready to participate; I am willing to take the risks.
>
> We have to ensure that those risks are not excessive, that we are not
> subjecting people to risks that are not acceptable, but there really
> ought to be a right of people to make the decisions to accept these
> risks including, if our motivation is to answer the question of how
> the drug is distributed and their motivation is to hope for benefit,
> that is really okay. It is their right to make that decision.
>
> Beneficence, in terms of beneficence our big goal should be to
> maximize benefit and minimize harm. I would like you to keep that in
> mind as we talk about such things as getting tissue samples when we
> are looking at targeting drugs that are going to go specifically to
> certain targets within tumors, which may require somewhat greater
> risks than just drawing blood though a central venous access device
> which is not particularly painful, difficult or risky to the patient.
>
> Then there is the principle of justice, and that really states that
> there should be a fair distribution of the burdens and the benefits of
> research. This becomes a very key issue for children because children,
> as a class, are not going to be able to benefit from research if
> children, as a class, don\'t participate as research subjects. There
> are several reasons for this which have to do with the fact that the
> children are different and the diseases are different.
>
> I am going to go through some of these things, not in great detail but
> just skim over the surface to sort of get you thinking. In terms of
> autonomy, our subjects are particularly vulnerable. Oncology patients
> who are eligible for Phase I trials tend to be pretty vulnerable
> anyway, as the AIDS patients are vulnerable. These are patients who
> usually feel that they really don\'t have many choices.
>
> The biggest issue in terms of pediatrics is that the decision to
> participate is usually a proxy decision, that is to say, it is made by
> the parents. That really complicates the issues of autonomy because
> the child is not necessarily the one who needs to be aware of the
> choices made because that choice may, in fact, be made by a parent.
>
> The hope and optimism, which is often the primary motivation for
> participating in a Phase I study, is often not that of the child but
> of the family. Again, it is not necessarily a bad thing but it is a
> thing that compromises the extent to which the child, who is in fact
> the research subject, is able to exercise choice.
>
> Paternalism is certainly much more complicated because, as opposed to
> the paternalism that the HIV advocates were complaining about which
> was the issue of the government is protecting us from ourselves or the
> system is protecting us, paternalism and coercion may actually come
> from the parents rather than from the child. I am not saying, again,
> this is a bad thing but it is important to recognize that this is
> often what drives participation in these kinds of studies.
>
> The personal costs, particularly of such things as being away from
> home, not sleeping with your favorite dog, undergoing painful
> procedures and what-not, because of the fact that it is a proxy
> decision, are not borne by the person who is actually consenting to
> participate in the study.
>
> Informed consent in Phase I oncology trials has been studied. This is
> a study that was done in the University of Chicago and they taped the
> discussions and determined that, in fact, the primary study aim being
> that of toxicity and dose determination was, in fact, disclosed. So,
> it is not an issue of the fact that it isn\'t said but it is
> disclosed. The information is there. Ninety-three percent of the
> participants in this study that was done at the University of Chicago
> said that they understood most or all of the information that was
> provided, which included the information that this was a toxicity
> study. However, only a third of the patients could actually state that
> the purpose of the trial was dose-finding and toxicity. So, it
> represents how people process information much more than it represents
> what we say.
>
> The issues of autonomy and informed consent\--the autonomy, the
> protection of your right to choose freely depends very heavily on your
> being aware of what is being chosen. So, you really do, in fact, have
> to understand it. So, the issue of what is disclosed and what is
> understood then becomes a very critical issue in terms of not what
> their motivation is but in terms of what their cognitive understanding
> is of what has been said. The fact that hope is a major motivator may
> impact the autonomy much more than lack of disclosure by the
> investigators. Again, I think it is how things are heard much more
> than what is said.
>
> Again, keeping in mind that people ought to have the right to make
> personal decisions, which others may not agree with, I think it is
> important that we not get into situations in which we limit people\'s
> right to choose by saying we are going to protect them from
> themselves. That should be a lesson that came out loud and clear from
> the HIV experience and also from the experience of breast cancer
> advocates.
>
> Beneficence I think is an important concept here because if we don\'t
> get data on children we are not going to be able to help future
> children, and that is really very crucial. Minimizing the harm is
> especially important when the vulnerable subject is not anticipating
> it. Again, this comes down to the issues of toxicities of drugs, but
> also of what other kinds of procedures one may do in order to get
> information.
>
> In terms of distributing the benefits of research and the burdens of
> research we must have, the current incentives for enrolling children
> in clinical trials I think are extremely important. Kids are very
> different from adults in their drug metabolism and pharmacokinetics.
> Several of my colleagues here have mentioned this several times,
> pediatric tumors are different from adults. I think Rich just
> mentioned this as well, that the issues of what happens in small cell
> lung cancer isn\'t applicable to primitive ectodermal tumors and if we
> are going to pursue our goal of justice we have to be sure that
> patients are enrolled in these studies.
>
> Looking at the issues of tissue biopsies, one of the things I want to
> be sure everybody understands is that if we are looking at optimal
> biologic dose of a highly targeted therapy, then what the blood level
> is isn\'t what is really important at all. What is important is what
> has actually made it into the tumor, and has it made it to the part of
> the tumor that it needs to get to. This is then not a correlative
> study; this is actually a primary study aim.
>
> Dr. Blaney mentioned the issues of getting tissue as parts of
> correlative studies. If this is something that is an ancillary study
> and it is not the primary subject of the study, you may look at do we
> offer the drug without getting the tissue. But if the question can\'t
> be answered without getting that tissue, I think it becomes a very
> different ethical issue because then you are really compromising the
> ability to get the information that you need to be able to carry drug
> development further.
>
> Obviously, there are downsides to tissue biopsy. They are invasive.
> They are potentially painful. They always carry some risk to the
> patient. They offer no benefit to the patient. They increase cost of
> the study. There are lots of reasons not to do them.
>
> In terms of doing clinical trials, I think it is exquisitely important
> that we answer the question to validate the contributions of all
> participants in the study. If you have a number of patients who don\'t
> participate to the extent that the study question can be answered,
> then the contribution that is made by the patients who did participate
> fully and who did provide all of the information, their contribution
> is rendered useless. So, it is an unfair thing to do. It is an unjust
> thing to do. You want to protect future subjects and patients from
> unnecessary risk, toxicity and lack of benefit, and you need to
> preserve the integrity of the science. I don\'t think there is any
> situation in which anything that is bad science is ethically
> justifiable.
>
> So, I think the real issue in terms of obtaining tissue is going to be
> identifying whether this is an elective procedure which is for
> correlative or ancillary study, or is this a procedure which is
> targeted towards answering the primary study question. If you are
> leaving it out, if you are saying, okay, you don\'t have to
> participate in the biopsy even though this is the primary study
> question, then what you are doing is reinforcing, as an investigator,
> that the major goal of participation in the study is therapy.
>
> Now, it may be the patient\'s reason to participate, but we are saying
> that what we are doing is trying to answer questions about this drug.
> They have every right to participate because they want therapeutic
> benefit, but we are implying then that we are offering them this drug
> with the hope of a therapeutic benefit, and that is exactly what we
> told them that we weren\'t doing when we enrolled them on the Phase I
> trial in the first place. This is a confusing message; it is a mixed
> message and I think it is important that we not give it. Also, again,
> we are compromising the output of the study if we are not answering
> the questions and we are adding to the burdens of other patients.
>
> In terms of the imperatives for study designs, extremely stringent
> study design and conduct is important. That includes rapid turnaround,
> rapid reporting, all the kinds of things that Dr. Reaman has already
> mentioned. It is exquisitely important that we minimize risks and
> discomforts and maximize the benefit. We have to ensure truly informed
> consent, and I really loved Dr. Blaney\'s last slide which had
> communication at the middle. I think that is one of the huge issues
> and one of the things that we really need to work on, and we need to
> publish the results.
>
> **Discussion**
>
> DR. GOOTENBERG: Thank you, Dr. Shurin. That was comprehensive and, if
> I can misuse the word, a very well targeted presentation here.
>
> I want to give a charge to the panel and I want to make sure that we
> stick to this. What we have to remember is that you are not here to
> answer any of these questions. We are here to refine the questions; to
> clarify questions; to prioritize questions that might be brought to
> the ODAC subcommittee. Because of that, I would foresee that our
> discussion would be more in terms of, well, one question that I see
> that could be brought to ODAC which would be very important would be
> this\... There might have to be substantive discussion to explain why
> the questions are important or to clarify issues between us, but I do
> think that we should keep clearly in our vision that our goal here is
> to clarify and prioritize questions for the subcommittee and not to
> try to answer them here now.
>
> What I am going to do is go down through each of the bullets that we
> have here, which are the discussion issues that we have, and open a
> short discussion and then we will have a general discussion after
> that.
>
> Editorially, panel one did step over our territory here. The first
> discussion issue was do potential cancer therapies need to be
> developed\--and the ambiguity there is in that word \"developed\"\--in
> adults because it is really how far developed before being made
> available for testing in children.
>
> I would throw out as one question what about the case which might
> arise more and more in the future as targeted therapies come along and
> where mechanisms of tumorigenesis in children may prove very different
> for certain tumors than they are in adults, what about the case where
> we have a targeted therapy that looks like it would be useful for the
> childhood cancer and not for adult cancer? I am going to open this
> general question for general discussion of the questions and
> prioritization from the group.
>
> MR. HURLEY: Well, this first general question sort of has a lot of
> implied assumptions in it. We have to address the assumptions in order
> to parse out the question. One of the assumptions that seems to be in
> there is that there is a limited number of patients available for
> studies. Given that assumption, then you could ask this question. I
> think if you take that assumption away and look at the question on its
> face, you would say, no, you do not need to develop it in adults
> first. I think that is the only reason even in non-targeted therapies,
> that is, targeted for a specific childhood cancer, you would not need
> to do it in adults, but also in cancers where there may be some
> overlap between adults you would not need to do it, except for the
> fact that there is a small population.
>
> If I can take a personal opportunity here, I would like to get a
> clarification. There was a statement made that two-thirds of the
> pediatric patients are in clinical trials. Could I get clarificatioon,
> is that in the 238 COG sites, the two-thirds? Or, is that two-thirds
> of the 20,000 on prescriptions?
>
> DR. GOOTENBERG: Now on treatments.
>
> MR. HURLEY: Now on treatments. So, of the 20,000 now on treatment, are
> we saying two-thirds of those are currently in studies?
>
> DR. BLANEY: Two-thirds of patients that are newly diagnosed are
> enrolled in front-line studies through the children\'s oncology group.
>
> MR. HURLEY: You mean in the children\'s oncology group of
> institutions, two-thirds of those in those institutions are on?
>
> DR. REAMAN: Right, which is about 90-plus percent. Of those,
> two-thirds are on clinical trials. It is only two-thirds because of
> eligibility criteria. So, basically about 95 percent of children that
> are eligible are on. Under the age of 15 is crucial.
>
> MR. HURLEY: Under the age of 15. Thank you. So, I would say then if
> the assumption is that there is a lack of available patients for
> studies, then using the adult is the next nearest species, if you
> will, that you could test a drug in and get more information before
> you screen.
>
> One thing that you asked during the break when they were putting up
> the new computer, you had asked about whether or not consortia in
> cancer are used by the pharmaceutical industry in developing drugs. I
> can say from my experience in adult cancers, generally not, or only as
> an adjunct and not as the primary source for developing the drug. In
> pediatric cancer trials, and we are involved in I think three of them
> right now, they are all individual investigator IND trials, not
> involved with a collaborative group.
>
> DR. HAGEY: I think an appropriate question for ODAC might be what
> phase would be most appropriate, what phase of adult development would
> be most appropriate in terms of knowing when to start in children.
> Given that there is a smaller number, I can see some benefits to
> starting drug development in children after the drug has gone through
> Phase II in adults, given that by that time the dose finding has been
> maximized. In addition, the dose schedule has been refined.
>
> There is also an interest in the adult world in looking into
> metronomic dosing which may be translatable to children. And, if you
> didn\'t wait until Phase II you might not be able to use the benefits
> of that knowledge when designing the Phase I pediatric trials. You
> will have more toxicity data because more patients will have received
> the drug, and further animal studies are typically undertaken during
> Phase II.
>
> MS. TRAYNOR: I would like to address this from the viewpoint that if
> we do what you were talking about now, that would certainly prolong
> getting these new treatments into the children, which is a concern I
> think for the advocates in that we would like to be sure that there is
> no toxicity for the children, but I think with some of these new
> treatments that you are looking at that is not going to be as much of
> an issue, dose toxicity would not be as much of an issue. So, I think
> that in relationship to putting the treatments into children sooner,
> if there is a toxic agent that could be harmful to the children, then
> we would want to see it go through a Phase I trial.
>
> I think something for ODAC to look at in relationship to these new
> treatments is, is that an issue in choosing whether or not it would go
> into treatment in children sooner than having it go through Phase I in
> adults. DR. BLANEY: One of the things we need to do is to avoid making
> generalizations that become guidances that people then follow as the
> rule, and we have to address each of the agents in the potential
> population for which it is going to be developed on a case by case
> basis because if we are looking at developing new drugs that would
> ultimately be incorporated into the ALL setting, they may be very
> different than a new drug that is targeted at a brain stem glioma
> population, if we are that fortunate to have drugs that are that
> targeted.
>
> DR. GOOTENBERG: Then it is really much the same. We have questions
> that would refine and clarify the question, just off the hat, can
> adult and pediatric plans be coordinated to improve access,
> investigator access to the most promising new cancer therapies during
> the drug development cycle?
>
> What ancillary questions would clarify that kind of question? We need
> to have specifics, specific questions regarding that, sub questions
> that will allow us to approach answers.
>
> DR. RACKOFF: I think timing right now of those studies may very well
> be driven by when requests are made. So, one of the questions for ODAC
> should be when should the agency consider issuing requests. Should it
> be at IND stage? Should it be at the end of Phase I and Phase II
> meetings or that interface? So, I think that is a reasonable question
> because I think a lot of what is going on is being driven by the
> requests.
>
> DR. BLANEY: I think one of the things we need to address is the
> potential negative impacts on that, especially, as you say, industry
> is looking at similar targets so as they get analogs, additional
> analogs and then the next generation analogs, we have finite patient
> numbers that are, at best, suboptimal. So, when is it appropriate to
> initiate them because there are limited patient numbers?
>
> DR. GOOTENBERG: Just to try and clarify what you are talking about
> there, the industry, let\'s just make believe, consists of fifty, soon
> to be five, companies\--
>
> \[Laughter\]
>
> \--who may each have a small molecule that is targeted to the same
> target, and one of them got there first by two weeks, and one is two
> weeks behind them, and one is six months behind them. So, that is a
> prioritization question because of the limited number of subjects we
> have to test them on. Is that the kind of thing you are talking about?
>
> DR. BLANEY: That is the kind of thing I am talking about. Then, if we
> have developed a cooperative group mechanism in order to, hopefully,
> expedite and make the drug development process efficient, if industry
> has a new analog, we cannot foreseeably do that and then go to outside
> investigators to do that and those patients potentially become
> ineligible for studies that are being done in the cooperative group
> setting under theoretically a national or international drug develop
> plan for those patients.
>
> DR. GOOTENBERG: Right, but I mean if we get fundamentally down to it
> and this is the question that can be raised, can we expect\--and I
> think the answer is no\--industry to follow entirely the COG
> prioritization for what you are calling an analog\--
>
> DR. BLANEY: Right.
>
> DR. GOOTENBERG: \--drugs which are like other drugs, not the first in
> a class or something like that. Is that a question that ODAC would
> face?
>
> MR. HURLEY: Actually, I was going to wait to propose this rather
> outrageous approach, but let me first answer or address the question
> that we are talking about and that will put in light what I was about
> to say what might be one end of the spectrum that something could be
> done but it would be rather radical.
>
> We, as an industry and others can comment if they feel differently,
> tend to go after those indications, those disease states where there
> is a sufficiently large population that we can produce it at a price
> and have a sufficient population to buy it so that it does return an
> amount of money to our investors. As you have been hearing today, the
> pediatric population is very small. They define orphan drug status
> which already gets kind of special attention from FDA, and those are
> drugs which are not likely to be developed by industry either because
> there are just not enough patients to warrant the full development
> program and the amount of money that you could get back from the
> patients in exchange for that. It is just not enough to do it. So, we
> have to then rely on public institutions to handle those kind of
> things.
>
> There is a requirement for 200,000 patients a year. If it is less than
> that, we couldn\'t qualify. Here we are talking about 20,000 patients
> a year. So, it is very small. What is possible is if you can piggyback
> onto the development of a drug for a cancer that is or a sufficiently
> large size, let\'s say prostate cancer or breast cancer where the
> primary indication will handle the burden of the cost of the
> development, and in those cases then the company wants to participate
> as a responsible entity within the community and will do what it can
> to provide that drug for investigation in these other small areas.
>
> I think I mentioned that we have two or three drugs right now where
> individual investigators feel that over a year or two they may be able
> to get 20, 30 patients and they want to study our particular drug in
> those patients and we provide them.
>
> Again, because of the cost considerations, we are focusing on the
> major cancers and they happen to be in adults. We use a process called
> investigator IND, that is, we will provide the drug to the
> investigator. The investigator takes full responsibility for
> developing the protocol. However, before we sign an agreement with
> them to provide them the drug necessary to implement that protocol we
> certainly want to look at it and we give them our advice and counsel
> but basically it is their design, and they are the ones that are the
> driving force behind testing that particular drug, our drug, in this
> disease state or this juvenile cancer.
>
> So, I think that happens in a number of other pharmaceutical
> companies. What you are saying is that because this is a special
> population, if we are dealing with 20,000 cancer patients a year that
> represents a public policy opportunity. In other words, if we decide
> as parents and as grandparents that in the United States we would like
> to have even very rare diseases, that is childhood cancers, addressed
> in an aggressive fashion, there are certain opportunities perhaps
> through the medium of FDA\--and I hate to put you on the spot, but FDA
> is the entity that issues INDs, investigational new drug applications.
> Under the guidance of the law that empowered them to do this, they
> allow whether or not a drug can be studied, and also whether or not it
> is appropriate to be studied in this particular indication and we
> submit in advance our protocols for that.
>
> If FDA decided that because of public policy no INDs will be accepted,
> except those that will meet the criteria of a consortium-designed
> paradigm for studying, that might be a route. So, I offer that for
> consideration.
>
> DR. GOOTENBERG: So, if I can restate your question as a question, the
> question would be for the committee should FDA, let\'s say, play down
> sponsor investigator protocols which would not yield scientifically
> valid information for drug development and licensure and push it
> towards consortia?
>
> MR. HURLEY: Well, you have sort of implied that it might not be
> scientifically valid. I am sure that our studies, given all the
> counsel and advice we get, are scientifically valid. The way I would
> rephrase that is should FDA consider, in its approval of INDs that are
> addressing studies involved in childhood cancers, the public policy
> implications of authorizing that particular study, whether that study
> is under an IND sponsored by an investigator, whether it is sponsored
> by a pharmaceutical company or whether it is sponsored by a
> consortium.
>
> DR. GOOTENBERG: So, now we have a question and as an FDA person I
> understand a lot of the implications there. I would ask the question
> where is the money going to come from to run the studies in the first
> place? That is a question we could pose. That is not an FDA question.
>
> MR. HURLEY: No.
>
> DR. GOOTENBERG: No. Any other discussion regarding the coordination of
> development, adult development, pediatric development?
>
> \[No response\]
>
> Our next question here would be to clarify what are the constraints to
> obtaining reliable answers in pediatric cancer trials and how can they
> be overcome?
>
> Limited numbers is a constraint to obtaining reliable answers. What
> other constraints do we want to bring before the committee?
>
> DR. RACKOFF: Rich and Susan never got a chance to respond to my
> question and it was just that issue.
>
> DR. SPOSTO: I guess one thing that you pointed out that was a good
> point, and I think you cited pancreatic cancer, is that the majority
> of patients fail and the fact is that the statistical techniques that
> we use, the sensitivity of those is directly proportional to the
> number of patients that fail and not the number of patients that are
> on the study. In children and diseases where there is a high fraction
> of cure it is not really the patients that are on the study but the
> patients that fail, and that is a small number. So, that is just
> limited. In an adult cancer, if you put a certain number on and then
> follow them for longer, you will see more failures and that, you know,
> helps you get more power. In children\'s cancer after a couple of
> years there are no more failures. So, the only way to get more power
> is to put more patients on the study. That is just a fact of life.
>
> The paper that Wayne was referring to is one that was related to
> something that I said before, which is that in adult cancers it is a
> little bit different than in childhood cancer. In adult cancer, and I
> will cite breast cancer again, if you do a randomized study in a
> thousand breast cancers you want to be very sure that you get a very
> precise answer, and that means low type-1 error; low false-positive
> rate; very high sensitivity for the result because once you get the
> result you have to be sure of it because whatever your decision is, it
> is going to be amplified in the entire population of patients with
> breast cancer. A recent example I guess is the Women\'s Health
> Initiative. You have obviously heard the result of that massive trial
> which is very precise and has very large implications for all women
> taking hormone replacement therapy.
>
> In childhood cancer it is a bit different because the population that
> we are making the inference to is the population that we are studying
> and, in order to get large trials, we can do very, very large trials
> to be very precise about the answer but what that is going to do is
> just prolong the time until we get the answer. So, then we have a real
> trade-off of a very certain 20-year long trial that is not going to
> succeed because nobody is going to stay around for 20 years to do it
> and, given the pace of progress in medical technology, whether those
> results are actually going to be relevant in 20 years is another
> question. Or, we just do smaller trials that we think are very well
> designed and give us unbiased answers but they don\'t have the kind of
> precision that we may be used to in adult cancer.
>
> One way to make those compromises, as Wayne suggested, is to increase
> the type-1 error where, if we see a result that is significant at p
> less than 0.08 which doesn\'t hit the magic p less than 0.05, does
> that necessarily mean that we conclude that, therefore, there is zero
> effect of this new intervention that we tried? I think that is the
> wrong conclusion. I think there is still some evidence that if we are
> seeing a difference, even though it doesn\'t meet usual criteria for
> significance, maybe we should look harder at that and consider whether
> we want to go forward on that pathway because we could be missing
> something that actually is very good.
>
> Now, the only way really to look at it that I can think of is in the
> context of the entire research program of pediatric oncology and if we
> do long trials we study less things; if we do short trials we study
> more things and that is the basic trade-off. But I don\'t know what
> the right answer is. I think our little study about that changed our
> opinion about how justifiable smaller trials are, and we concluded we
> are sort of doing the right thing in not doing very, very long trials.
>
> DR. GOOTENBERG: So, that is one of the constraints and that is a big
> constraint and what we have is a question of whether by relaxing the
> type-1 error, would this be a benefit to research into childhood
> cancer? We are running out of time so the last question\--
>
> MR. HURLEY: I would like to add to that.
>
> DR. GOOTENBERG: Yes?
>
> MR. HURLEY: Type-1 error is one way of adjusting the trial protocol
> and design in order to relax the standards used when you do have a
> much larger population. I would ask FDA to look at other trial designs
> such as the continuous reassessment method and Bayesian statistics to
> see if there are designs they can allow in this special population,
> because it is so small, and to use different criteria than what they
> would use if you had cancers that affect 200,000 people as opposed to
> affecting 200 or 300 people. So, I would ask them to seriously
> consider having almost staged criteria, and the smaller the patient
> population, the more flexible the design and the less precision is
> required.
>
> DR. GOOTENBERG: That would be a proposed question to take to the
> pediatric ODAC subcommittee.
>
> DR. SPOSTO: This is kind of related to how to make these studies more
> informative, but rather than waiting for disease progression, we could
> come up with surrogate measures that are very highly sensitive and
> specific that could tell us, for example, at the end of chemotherapy
> that there is a very, very high probability that there is no neoplasm
> left, or that there is and further treatment is necessary. That may be
> a way to actually get more information out of trials and actually do
> them more quickly because you wouldn\'t have to wait sometimes for
> long-term outcomes.
>
> DR. RACKOFF: If you look at day 15 marrow, it is a very good
> predictor. There haven\'t been many remission induction trials in
> which you could test whether you could use that as an early way to
> sort patients, but they certainly exist even without looking at the
> molecular level and I think we have some of those things.
>
> DR. GOOTENBERG: I am going to throw out discussion about what
> questions are the right questions to bring to the committee about the
> aspects\--although we have had some very good discussion already\--for
> tissue biopsy thinking about targeted therapies.
>
> DR. RACKOFF: I want to ask Susan Shurin a different question, which
> is, we and a number of companies, I know because it was presented at
> AACR, are doing microarray work and we typically say that you don\'t
> have to participate in the microarray work to participate in the trial
> because people are sensitive about having their DNA used. But, given
> what you said, I wonder if that is the right approach. I mean, there
> is no risk involved in terms of pain or discomfort because it is
> usually coming from the same sample, especially in hematologic
> malignancies, that is being obtained for diagnostic purposes. I know
> that in some countries in the EU there are much different opinions on
> this than in the U.S., but I don\'t know if you have any insight as to
> the current state of the use of DNA, and is it so special that we
> can\'t require that as part of the study.
>
> DR. SHURIN: I think it sort of comes down to a matter of opinion. My
> personal feeling is that if it is dissociated from any identifier it
> can\'t possibly have any risk at all, and I don\'t even see why it has
> to be brought out as a separate part of the consent form. It relates
> to a high level of sensitivity which, as I read what people say,
> reflects a very high level of distrust, and I think maybe the most
> important thing is that we need to behave in ways that make people
> feel that they can, in fact, trust us. I think it is ridiculous,
> frankly.
>
> DR. GOOTENBERG: But as a potential question to the committee, the
> question is whether this is a correlative study or whether this is a
> primary objective of the studies you are talking about, you know, to
> differentiate that, for the committee to clarify correlative or
> primary objective, use of microarrrays, genomic, endpoints and the
> modulation of targets. I am looking for a way to pose that question so
> we can take it to the committee.
>
> DR. SHURIN: Yes, because that really does come down to what is the
> function of how this is being looked at in this context because if you
> are looking at it from a microarray standpoint, this is what
> distinguishes an alveolar rhabdomyosarcoma from an embryonal
> rhabdomyosarcoma. That should be something that is so totally
> separated from all of the outcome data that it shouldn\'t be an issue
> in terms of actually looking at it. If you are going to correlate with
> outcome, then you actually have to have that outcome data and people
> have to consent to it.
>
> It is important information and I think it is something that we need
> to identify, how the information is going to be used, because the
> problem in terms of getting consent is that if it is sort of, well, we
> are going to use it somehow but we are not quite sure how. That is a
> problem and that really comes down to how we are going to use it.
>
> DR. GOOTENBERG: And if I was going to take this to an extreme, I would
> say I can foresee the days when this kind of data will be an inclusion
> criterion.
>
> DR. BLANEY: I think that is a separate issue. I think of that as an
> issue of a study looking at if the drug is getting to the target. That
> is a whole different issue, and if there is not a prospect of a direct
> benefit and obtaining samples of something that has greater than
> minimal risk, the question of whether or not the parent has the right
> to make that decision on behalf of the child\--I mean, my
> understanding is that for some of those issues the IRB doesn\'t have
> the authority to make that decision and it has to go to the Secretary
> of HHS.
>
> DR. SHURIN: I think that is true. I think the real question is whether
> in that setting you actually provide a drug which also has a very low
> probability. The statistics say that somewhere between four and six
> percent of people who participate in a Phase I trial even have a
> response, and that is not necessarily a benefit. So, the question then
> is do you provide the drug if you have to get the tissue in order to
> answer the primary study question. That is what I would think would be
> a difficult thing to justify as opposed to a correlative study in
> which that is not primary.
>
> DR. GOOTENBERG: One of the points of this panel is not to get down
> into the answers that you are heading towards, but I think we have
> clearly identified that this is a hard question.
>
> DR. SHURIN: Yes, but I do think it is important that you identify what
> the information is. It is sort of the same thing as providing a Phase
> I drug if you are not going to do the pharmacokinetics because then
> you are not answering the question.
>
> DR. BLANEY: No, you are answering the question. The question is what
> is the maximum tolerated dose or optimal biologic dose. We are not
> doing that for pharmacokinetics. The pharmacokinetics are done not
> necessarily real time, and those are analyzed separately from what the
> optimal dose is. We feel that it is coercion to require families to
> say we are to get this drug that has potential benefit, and benefit
> isn\'t necessarily measured just as response. It can be stabilization
> of disease. That is coercive.
>
> DR. SHURIN: But that does come down to the question of what the
> purpose is. What you are saying implies benefit. It comes down to
> Susan Weiner\'s point that, in general, the way these studies are
> designed and the way that the primary study question is phrased from
> the scientific standpoint is that it is designed to answer the
> scientific question of the maximum tolerated dose.
>
> DR. GOOTENBERG: I am going to take the prerogative of cutting this off
> and ask the panel members if they could try to phrase this into a
> question that could be posed, the questions that, in a parallel way,
> would get some yield from the ODAC committee. Is there any more
> discussion, because we are really running out of time and I really
> want to get to the open public comments? Is there any more discussion?
>
> DR. HAGEY: I think one question might be to see if there are
> mechanisms that can be set up so one can be assured that when you do
> find the optimum biologic does, by microarray or by target
> identification or what-have-you, that that dose translates into
> greater efficacy because that is not always going to be the case. Just
> finding that in and of itself might not be useful.
>
> DR. GOOTENBERG: All right. Then, we are going to open this panel to
> the public comment. As everyone knows, we really desire to have public
> comment. I don\'t want anybody to feel at all inhibited. Please come
> up and talk. The microphones are around the room. Iris has microphones
> if you need an extra microphone. What I would like to do, again, would
> be that you indicate that you wish to make a comment. If we have a lot
> of people, we will have you come up and sit up here. You must, for the
> record, state your name and state whom you are representing, and we
> will try to be fair and so try to keep your comments to no longer than
> four or five minutes. I will give you an indication beforehand that
> your time is nearly up. Once again, if you will stay at the microphone
> to allow time for questions from the panel. I just want to take a
> survey now. How many people feel that they have a desire for public
> comment right now? Five? So, let\'s start off.
>
> **Public Comment**
>
> MS. WEINER: I will be brief. My comment really is a follow-up to Mr.
> Hurley\'s point about FDA\'s requiring as part of an IND the agreement
> to a consortium that is strategizing a way to maximize the resources
> in pediatric oncology to get the best answers.
>
> I believe that that could be one purpose of the pediatric ODAC, and I
> believe was intended to be the purpose of the redefined pediatric ODAC
> in Best Pharmaceuticals Act for Children. I think that it would be a
> way that would make sure that all the constituencies that are
> represented here today would be involved in that decision, and would
> also maximize the 12,400 newly diagnosed in the 20,000 total. Thank
> you.
>
> DR. GOOTENBERG: Dr. Forman, did you want to speak?
>
> DR. FORMAN: We are supposed to identify ourselves, correct?
>
> DR. GOOTENBERG: Yes.
>
> DR. FORMAN: I am Ed Forman. I am an member of the Alliance for
> Childhood Cancer, a member of the Children\'s Oncology Group, a member
> of the Academy of Pediatrics but, perhaps most importantly, a
> practicing pediatric oncologist.
>
> I wonder if this is a good question, should adults always be tested
> before children? Can that policy be made clear to the public? I wonder
> if it is clear to the public. The overall goal is to increase cures
> with acceptable toxicity as fast as possible, coupled with a respect
> for persons. That is, in ethical terms, not using a human solely as a
> means to an end. So, imagine we have an agent that in preclinical
> testing shows desirability and it has a target in common with prostate
> cancer and breast cancer. So, should men be treated first? Well, that
> seems totally unfair by a principle of distributive justice, equal
> access.
>
> How about adults versus children? We are not talking about
> non-therapeutic research where the child has absolutely nothing to
> gain. Imagine yourself in this instance as a parent who looks at the
> time line whose child is failing therapy and looks at the time-line
> for the development of new drugs. There is very little hope to be
> offered there.
>
> We have to look at the balance of toxicity and benefit, like in a
> Phase I where there is a scientific interest but there is benefit,
> hope seen on the part of the parent. With the new targeted therapies,
> it is conceivable that that toxicity risk is going to be less. So, are
> we acting, to use Susan\'s term, overly paternalistically towards
> children and denying them immediate access along with adults to
> certain new therapies?
>
> A comment was made, you know, adults and children are very different
> and there have certainly been terrible track records of drugs that
> were safe in adults and having toxicities in children. Actually, some
> of the best examples were that they were toxic in infants and not
> children. So, there are multiple subpopulations here, and by looking
> just at adult toxicity, as has been mentioned, we might miss drugs
> that are useful for children and have no use at all in adults. So, are
> the arguments sufficient to always test adults before children?
>
> DR. BLANEY: There are examples of drugs and pediatric oncology where
> they have been tested in children before adults when there is a
> specific rationale or a specific target, for example, monoclonal
> antibodies in the case of neuroblastoma or some of the intrathecal
> agents. So, I don\'t think there is a rule that something has to be
> tested in adults before children. The advantage to that in many
> situations is that we avoid putting patients on suboptimal dose
> levels. If there are ten escalations in the adult setting that would
> be 30 patients and that would be two trials for us and two to four
> years. So, there is the advantage of waiting that one year before we
> start a trial for something that is non-specific.
>
> DR. FORMAN: I think those are wonderful points, but children often
> have less toxicity to drugs. Even if you begin with the adult, there
> is still an escalation that has to go on in children as well.
>
> DR. BLANEY: Correct, but presumably we are at a dose if the drug has
> activity, anti-tumor activity if it is a traditional cytotoxic.
>
> MS. HOFFMAN: Ruth Hoffman. I am director of Candle Lighters Childhood
> Cancer Foundation, and I am a member of the Alliance for Childhood
> Cancer and also a parent of a 15-year survivor of AML who is doing
> really well, actually.
>
> I guess one of the players that hasn\'t been discussed is the IRB.
> They are a participant in the development of the adult trial going to
> the pediatric trial. I guess as an IRB member, I am not sure who to
> address this to, whether to COG or ODAC and whether they would take
> this on, but we look, obviously, at study design but we also look at
> toxicities and specifically at case reports.
>
> As an IRB committee member, my frustration is in interpreting those
> case study reports. We are given the numerator but we are not given a
> denominator of the adult study. So, we get, you know, 20 reports each
> month, or whatever, GI bleeds in an adult study on a drug, and I
> don\'t know if those 20 bleeds are correlating to 200 adults on trial,
> 2000 adults on trial or 20,000 adults on trial and, therefore, I
> can\'t then extrapolate that to what the toxicity would be in a child
> and then go further and say, yes, I think that is an acceptable risk,
> as an IRB member, for that to then become a pediatric study.
>
> So, I don\'t know if that is something ODAC could address in
> redesigning or refining those case report studies or whether it is
> COG. It is just a very hard thing to do.
>
> DR. RACKOFF: Well, I think there are some regulatory issues involved
> there too in terms of what is required for reporting, and what level
> of concern there is. I don\'t know, under the current regulations, how
> you could change that kind of reporting.
>
> DR. SCHER: Hi. I am Nancy Scher. I am an adult medical oncologist. I
> am in the Division of Oncology Drug Products and I was an IRB
> chairperson in my previous life for about ten years. I just wanted to
> address that. It seems to me that you have the right to request
> additional information. That happened to us several times when we kept
> on getting reports of the same toxicity again and again. We did ask
> our investigators to contact the company and get more information, and
> so we did get some answers. Very often there is an independent data
> monitoring committee which is able to address some of those concerns.
>
> DR. SMITH: Malcolm Smith, from the Cancer Therapy Evaluation Program.
> I just wanted to reiterate a point that Susan was making, and that is
> that in the COG Phase I consortium, the policy there is one that we do
> support, that non-therapeutic studies, studies that don\'t provide a
> direct benefit to the patient, those do need to have no greater than a
> minor increase over minimal risk. Were they to be more than that,
> whether or not there was a primary study endpoint or not, unless they
> were being used to direct therapy of that patient and, hence, could be
> justified as having a therapeutic intent, we would not approve such a
> study. We would have to seek approval from HHS for that.
>
> For Phase I studies, although the primary objective is to determine
> dose-limiting toxicity, that is not inconsistent with there being a
> prospect of benefit. So, we do do these Phase I studies as having a
> prospect of benefit and, of course, realize that that prospect is
> limited.
>
> DR. GOOTENBERG: Thank you. Dr. Smith, it has been mentioned here a
> couple of times that you can carry out trials where the risk is more
> than minimal in children if you get the permission of the Department
> of HHS. We shouldn\'t exclude that as a question that might go to the
> board. Should that be sought under these circumstances? Now, Dr.
> Pazdur, you wanted to make some remarks?
>
> DR. PAZDUR: I have several questions and comments, and these are
> lessons learned from adult medical oncologist. Most of our
> applications that are coming for adult indications are large trials.
> What they assume is an internationalization of trials where we have
> many trials having representation of U.S., Western Europe, former
> Soviet Union, Eastern Europe, China, etc. I just wonder what is going
> on in pediatrics regarding internationalization of trials.
>
> Again, most of the trials that are being done and are being submitted
> for adult indications are company-sponsored trials, and what we are
> taking a look at here in pediatrics is basically government-sponsored
> trials or under the auspices of an NCI mechanism. Could we somehow
> look at more of an internationalization of trials? These are common
> diseases. I don\'t know what is going on in Europe, but could there be
> some flexibility as far as increasing numbers of patients in this
> regard because this has been dealt with, with the agency. We have
> accepted international data. We do not discriminate trials that have
> an international component to them, and in fact we welcome them. Any
> comments?
>
> DR. BLANEY: I can comment and I am sure Dr. Reaman can add to my
> comments. We have regular communication with the European oncologists
> that Dr. Smith and colleagues set up at meetings, such as ASCO or
> other meetings, so that we can try to make sure at least that we are
> not duplicating efforts and using our precious resource, which is
> patients, to answer the same questions. Obviously, adding
> international sites becomes a tremendous resources issue, especially
> with monitoring and I think that is the biggest obstacle.
>
> DR. PAZDUR: But here again, you know, this is not insurmountable
> obviously.
>
> DR. BLANEY: It is not insurmountable.
>
> DR. GOOTENBERG: Remember, we are looking at questions to ask and the
> question would be something along the way of would this be desirable.
>
> DR. REAMAN: I think the question should be how could we enable the
> internationalization or international harmonization of trials in
> pediatric anti-cancer drug development. As Dr. Blaney mentioned, our
> major interest there is in making sure we are not duplicating efforts
> so that we and our European colleagues aren\'t studying the same drug.
> Unfortunately, we require our foreign investigators or our
> international investigators to abide by a number of regulations that
> are imposed by our federal government, which they find so onerous that
> they are unwilling to abide by those and it makes such international
> trials really very difficult. We are looking at ways to accomplish
> that in Phase III trials and that could certainly include Phase I and
> Phase II also, I would think.
>
> DR. RACKOFF: But COG, just as a comment, includes sites from other
> countries right now.
>
> DR. REAMAN: I mean, it is an international group but there are many
> other international groups, and there are many, many international
> institutions that are not part of our group.
>
> DR. GOOTENBERG: Dr. Pazdur?
>
> DR. PAZDUR: Yes, the other comment that I had was relaxing type-1
> error which obviously has the possibility or probability of
> introducing falsely positive drugs into clinical trials. This is a
> double-edged sword obviously, and it gets back to the comment that was
> on many of the slides, being a victim of your own success.
>
> As somebody who has treated GI cancer for my whole professional life,
> I would be more than willing to relax those when it comes to
> pancreatic carcinoma where there are no therapies, but in a situation
> where you have potentially curative therapies, identifying a falsely
> positive therapy and then carrying that therapy into a situation and
> examining it in a potentially curative situation would have tremendous
> repercussions and negative aspects to it. Do you want to comment on
> this? I understand the effort to identify new agents is at this
> equipoise between effective therapies and curative therapies versus
> the need to identify new agents.
>
> DR. GOOTENBERG: Dr. Pazdur, since we are trying to develop questions,
> I don\'t think we will comment on that.
>
> DR. PAZDUR: Okay, but that could be a question.
>
> DR. GOOTENBERG: I wrote it down.
>
> DR. RACKOFF: Just to complete the question, the question really was
> since you are studying populations and not samples, and type-1 error
> is based on sampling theory, are there allowances that can be made
> given that situation? I don\'t know.
>
> DR. GOOTENBERG: I think that is a very deep fundamental statistical
> question that Dr. Pazdur brought up. We are saying the population, so
> we would have to go back to the fundamental statistics on that one.
> Other public open comment? Dr. Reaman?
>
> DR. REAMAN: Just to go back to the issue of international trials, I
> think in addition to expanding sample size, there is also the
> increased opportunity to look at the role of genetic and epigenetic
> phenomena and polymorphisms also. So, I think there really are
> multiple reasons why we should look at ways of expanding.
>
> DR. GOOTENBERG: If there is no further public comment, I am going to
> take the prerogative as a panel co-moderator to recess this workshop
> for lunch, and suggest that everybody be back here at 1:35 by that
> clock, and we will start panel three right on time. Thank you.
>
> \[Whereupon, at 1:15 p.m., the Workshop was recessed for lunch, to
> reconvene at 1:50 p.m.\]
>
> [A F T E R N O O N P R O C E E D I N G S]{.underline}
>
> **Panel 3**
>
> **Access to New Therapies for Childhood Cancer**
>
> DR. FORMAN: Let me welcome you to panel 3. To be sure you are in the
> right place, this is access to new treatments to childhood cancer,
> with an emphasis on access. I am one of the co-moderators, Ed Forman,
> from the Alliance of Childhood Cancer.
>
> DR. DAGHER: Ramzi Dagher, medical officer in the Division of Oncology
> Drug Products, FDA.
>
> DR. FORMAN: The pattern we are going to use this afternoon is
> identical to that of this morning. We are going to have an educational
> or didactic component which will address two questions, how do
> children with cancer currently gain access to investigational studies?
> And, what are the considerations in providing pediatric information in
> a product package insert, that is, labeling? In other words, what is
> the current situation?
>
> The discussion issues are really what we think ought to be the
> situation, what mechanisms are or should be used in treating children
> with cancer off protocol. What is or what should be the role of
> product labeling in pediatric oncology.
>
> Of course, our effort, as has been said in the last panel, is to
> develop good questions for the pediatric subcommittee of ODAC. So, I
> would like to ask the panelists to introduce themselves and then,
> discussants, when you introduce yourself you might mention that you
> are a discussant and possibly the topic of your discussion.
>
> DR. HUNTLEY: My name is Carl Huntley. I am a pharmacist at the
> Pharmaceutical Management Branch\--actually, I guess I am wearing two
> hats at this point. Since the branch chief retired, I am acting branch
> chief but I am also head of a section, the Clinical Trials Research
> Pharmacy Section, and deal with special requests or special exception
> requests for agents for patients who can\'t otherwise normally get
> onto a clinical trial. That includes pediatric patients as well.
>
> DR. FINKELSTEIN: I am Jerry Finkelstein. I am here representing the
> American Academy of Pediatrics, but I am a pediatric oncologist,
> active in COG, and I am on the faculty of UCLA.
>
> DR. SHOEMAKER: I am Dale Shoemaker, from the regulatory affairs branch
> in the Cancer Therapy Evaluation Program of NCI. I am here to speak
> about how NCI handles early access, expanded access.
>
> DR. WILLIAMS: I am Grant Williams, deputy director, Division of
> Oncology Drug Products. I am going to give some regulatory background
> on treatment use of cancer drugs in adults.
>
> MR. HURLEY: Mike Hurley, with the Abbott Laboratories, in the global
> oncology development group, and I am filling in for Judith Ochs who
> was unable to be here, and I am filling in as a representative of the
> industry.
>
> DR. MEADOWS: I am Anna Meadows, a pediatric oncologist at the
> Children\'s Hospital of Philadelphia. I am a member of COG and
> professor at the University of Pennsylvania School of Medicine.
>
> MS. HOFFMAN: I am Ruth Hoffman, director of Candle Lighters Childhood
> Cancer Foundation. I am a member of the Alliance for Childhood Cancer
> and patient advocate.
>
> DR. DAGHER: I think we will go ahead with the didactic presentations,
> starting with Dr. Grant Williams, deputy director, Division of
> Oncology Drug Products.
>
> **Presentation**
>
> DR. WILLIAMS: I wanted to thank Joe especially for the large sandwich
> and the five minutes to eat it in.
>
> \[Laughter\]
>
> I was going to measure it but I couldn\'t find a ruler large enough
> for both dimensions so I used the RECIST criteria and it was okay.
>
> Today I am going to present a discussion of treatment use of
> investigational drugs in adults to prepare us sort of for our
> discussion of the same topic in pediatric patients. First I will give
> you a brief overview of treatment use in adults, and then I will give
> you some background of issues discussed at the December, 2000 and 2001
> ODAC meetings where we discussed the same issue.
>
> At these meetings we had input from industry, from ethicists, from
> patient advocates and from ODAC members. The focus of these ODAC
> discussions was to obtain advice on when it is appropriate for FDA to
> allow experimental drugs to be used for individual cancer patients.
>
> It was quite clear that another important aspect that was outside of
> FDA\'s authority was defining when companies should provide access. I
> think one of the outcomes of these meetings was the feeling that there
> really needed to be some kind of a consensus conference sometime to
> discuss these issues, that is, when should industry or sponsors
> provide access to experimental drugs. As I mentioned, what really
> drove these ODAC sessions for us was the fact that we were having to
> make decisions when, as FDA, to allow drugs to be given, but a more
> fundamental question is when would industry ask FDA to provide.
>
> Here are the definitions. I think seeing this audience, I need not
> define here what an IND is; what a sponsor is; what a drug
> manufacturer and investigator are. They are all very key players in
> this process.
>
> Of course, the usual purpose of an IND is to allow for investigations
> to determine whether a drug is safe and effective. If the findings of
> those studies are favorable, all the data are then submitted to the
> FDA. However, there are times when it may be appropriate to make an
> investigational drug available primarily for treatment rather than for
> the usual purpose of investigating the drug\'s safety and
> effectiveness.
>
> The terminology around treatment use of experimental drugs can be
> confusing. In fact, I was just discussing with Dale a minute ago these
> terms, and I am not sure that people ever use the same terminology in
> this setting. But these two terms are frequently used, single-patient
> treatment use and expanded access treatment use.
>
> Basically, expanded access just refers to treating multiple patients
> under a single protocol, and single-patient use deals with individual
> protocols or treatments that are drawn up for each patient by the
> individual investigator.
>
> Historically, there have been several different methods for expanded
> access. Since the 1970\'s NCI has worked with FDA to provide
> investigational use under a mechanism called Group C. This mechanism
> was only for drugs provided by NCI. Dale Shoemaker will discuss this
> further in a few moments. In 1987 FDA developed an official program
> called treatment IND. This program was written into the regulations.
> Both of these different mechanisms, Group C and treatment IND are
> formal mechanisms for drugs that are usually very advanced in their
> development, usually within months of being marketed. Over the years
> expanded access protocols have also been approved for promising drugs
> provided by industry, and some of these protocols were just submitted
> as protocols, not as specific treatment INDs.
>
> FDA has also approved many applications for just treating single
> patients. There are two mechanisms that we have used for handling
> single-patient use. For the first mechanism, called the single-patient
> IND, a new sponsor files a separate IND, and for the second mechanism,
> called the single-patient exception, there is already an existing IND,
> an existing sponsor and then an investigational protocol.
>
> With the single-patient exception mechanism, a patient who is
> ineligible for an investigational protocol is treated under a plan
> that is usually a slight modification of the existing protocol. The
> same IND and the same sponsor are used. This is a more efficient
> mechanism for single-patient treatment.
>
> The legal requirements are basically the same as they are for any IND.
> There must be a drug manufacturer that will supply the drug. There
> must be a sponsor that reports to the FDA. There must be an adequately
> trained investigator. There must be informed consent and IRB approval.
> And, there must be concurrence by FDA that there is sufficient
> evidence supporting the drug\'s safety and efficacy.
>
> The following are the items the FDA usually considers in evaluating
> treatment use of experimental drugs; evidence of drug activity and
> toxicity; other treatments that are available for the patient\'s
> cancer treatment; whether the sponsor is conducting clinical trials
> that are needed for marketing of the drug; and whether the proposed
> protocol is likely to interfere with clinical studies needed to prove
> whether the drug is safe and effective.
>
> In this slide I would like to expand on these initial two points. The
> first important question is what evidence do we have that the drug is
> effective in humans? One aspect of this question is to consider the
> stage of drug development. Do we have data from Phase I, Phase II or
> Phase III studies? Then, what do the data show? For instance, what is
> the response rate and what are the toxicities?
>
> The second, is there effective standard therapy for the patient\'s
> cancer? If so, how effective is that therapy? For diseases where there
> is no standard therapy or a standard therapy is not satisfactory, FDA
> has usually permitted single-patient treatment if data suggests that
> the experimental treatment is relatively safe.
>
> During discussions with ODAC on these points, FDA received a variety
> of opinions. In general, however, the committee stated that there
> should be a reasonable level of anti-tumor activity, and there should
> be a reasonable amount of study of toxicity.
>
> Here are some of the concerns expressed by ODAC discussants, primarily
> industry discussants. First, there may be a limited drug supply early
> in drug development, especially with some kinds of drugs when batches
> for early studies are small. Drugs from these batches are scarce and
> very expensive. Before a company converts to a commercial stage
> procedure, it may be unreasonably for the oncology community to expect
> them to provide large amounts of drug for treatment use.
>
> Next, there is the concern over competition between expanded access
> programs and the regulatory programs that would lead to drug approval.
> Competition can be either for patients entering trials or for internal
> company resources. Most expanded access protocols exclude patients who
> are eligible for Phase III regulatory trials to minimize this.
>
> Another worry raised by industry is that use in a less controlled
> setting of treatment use would lead to more reports of severe adverse
> reactions, potentially raising safety concerns that might delay drug
> approval. This was discussed by FDA and basically we didn\'t believe
> that that was a realistic concern, not one that we had ever observed.
> Lastly, historically we have learned very little about a drug from
> treatment use programs.
>
> There was also discussion of when expanded access programs were likely
> to be sought, not necessarily when they should be done but when they
> are likely to be sought by the community. First, when early studies in
> humans show promising results, this often calls for expanded access;
> and common tumors where patients regularly run out of treatment
> options. Then finally, realistically, in the circumstances where one
> expects many requests for treatment use, such as when a drug is widely
> discussed in the media.
>
> There were recommendations from industry representatives who had
> recent experience with expanded access protocols. A single informed
> consent form facilitates the widespread use of a drug under expanded
> access protocol. An important feature is that there should be firm
> rules about entry, with no exception made based on persistence or
> political position of the person calling. In order to prevent
> interference in the process of getting the drug to market, patients
> are usually excluded who are eligible for clinical trials that would
> support FDA approval. Finally, data collection requirements should be
> discussed with the FDA, and there is a certain possibility that the
> data reporting will not be\--I wouldn\'t say as onerous, but as
> intense as usual.
>
> There are limitations regarding the data from expanded access
> protocols. Because of this, it is certainly important to collect data
> on adverse events that are serious and unexpected, but it is not clear
> that other data is always helpful. The other data is often
> questionable in this setting because they are single-arm studies
> often. The conditions widely vary from patient to patient; they are
> not a defined population, and physicians are often less experienced at
> collecting data and may not have the same support staff for assuring
> high quality data.
>
> As we move towards discussions in pediatrics, one question we may
> consider is whether pediatric data from treatment use might be more
> useful than are data from treatment use in adults since we generally
> have less experience in most investigational drugs in children than in
> adults.
>
> Thank you for your attention. I will now turn the podium over to Dale
> Shoemaker, from the NCI.
>
> **Presentation**
>
> DR. SHOEMAKER: Thank you, Grant. As I said, I am from the regulatory
> affairs branch in the Cancer Therapy Evaluation Program of NCI. What I
> want to talk to you about today is CTEP\'s mechanisms for access to
> investigational agents for patients who are unable to participate in
> clinical trials. What I should tell you is that what I am going to say
> here applies to both adult patients and pediatric patients. So, this
> is the policy across the board for all patients.
>
> The real purpose is to make available to individual cancer patients
> and their physicians investigational agents that have what we consider
> notable clinical activity against specific malignancies or cancer
> types.
>
> We have three mechanisms for the early access. It could be called
> either early access of expanded access but they are called special
> exemption protocols, Group C treatment IND protocols, and treatment
> referral center protocols. I want to go in a little detail about each
> of these.
>
> But before I do that, there are several issues we need to consider for
> any of these mechanisms that are asked when a request is made, and
> these are the following: Is the patient ineligible or unable to be
> treated on a regular research protocol? Have all standard therapies
> been exhausted? Is there objective evidence that the investigational
> agent is active in treating the malignancy for which the request is
> being made? And, is the investigational agent likely to benefit the
> patient while keeping in mind the risks that are involved?
>
> For the special exception protocols, this is functionally equivalent
> to, I would say, a single-patient IND; you could call it an emergency
> IND. The request that we get can be made for all investigational
> agents that we sponsor at CTEP, but it is generally not granted for
> agents in Phase I clinical development. This is particularly so
> because the agents must have demonstrated efficacy in a disease state
> for the request. So, naturally, this is going to be more Phase
> II/Phase III clinical development studies. The approval depends on
> meeting the criteria outlined above, and also, as Grant spoke about,
> the availability of the agent in question. All the requests that come
> in are reviewed and approved by physician staff in CTEP.
>
> I should tell you that we looked back for calendar year 2001 for
> special exception requests. We received about 1000 requests. Of those,
> 45 percent were granted and the investigational agent was provided; 35
> percent of the requests were referred to clinical studies that were
> ongoing across the country; and 20 percent were denied. Out of that 45
> percent that were granted, 13 percent of those were for pediatric
> patients.
>
> The Group C protocol that Grant already alluded to is a process that
> was initiated in the mid 1970\'s. In the mid 1970\'s NCI divided up
> their investigational agents into lettered agents. Group A were Phase
> I; Group B were Phase II/Phase III; and Group C were for agents that
> had demonstrated activity on a particular tumor type for which we were
> hoping there was going to be an NDA or BLA submitted shortly or was in
> the works so the agent would become commercially available. This was
> to be seen as an interim between those periods, where we knew it had
> activity but it was not yet on the market so it could be made
> available to patients.
>
> For this process, a request is made to FDA for the investigational
> agent which, as I just said, had demonstrated reproducible efficacy in
> one or more specific types of tumor and we felt the agent was likely
> to alter the treatment of a tumor type and could safely be
> administered by a properly trained healthcare provider. The key thing
> here was without specialized supportive care facilities. So, this
> meant it could be done in individual private offices.
>
> The FDA approval was sought for investigational agents, as I said, for
> which an NDA or BLA was already submitted or would be submitted in the
> relatively near future. To date, we have sponsored more than 20 Group
> C protocols. There is at the present time one active Group C protocol.
> The last Group C protocols that we had that accrued a lot of patients
> were back in the early \'90\'s. In 1990 we had an agent for colorectal
> cancer that accrued about 4600 patients or about 4600 patients were
> accrued to the Group C protocols. There was also a leukemia agent. It
> was the same thing, about 4600 patients were accrued before the NDA or
> BLA was approved.
>
> We also have a mechanism we call the treatment referral center
> protocols. These protocols are used for highly promising agents for
> diseases such as breast, prostate, lung and ovarian cancer. These
> protocols are similar to a simple multicenter clinical trial, a large
> one-arm study, with relatively open eligibility and very simple
> objectives. These protocols are used to ensure the equitable
> distribution of the agents with limited availability. This has worked
> particularly well. As you will see in this bottom point here, the TRC
> protocols are initially offered to all NCI designated clinical and
> comprehensive cancer centers. So, that means a pretty equal geographic
> distribution across the country.
>
> Typically, we do collect safety and efficacy data from these treatment
> referral center protocols. These protocols, and also all the others I
> have spoken about here, are managed by what we call our treatment
> referral center. It is located in the Pharmaceutical Management Branch
> of CTEP. This is the group that receives the initial requests that
> come in from the outside, be they from patients or investigators. They
> provide the information to the community oncologists and other
> healthcare professionals about the therapeutic options for cancer
> patients.
>
> So, the first priority is always to find out what clinical trials are
> ongoing across the country to try to get these patients, if they meet
> the eligibility criteria, into those clinical trials. If a patient is
> unable to participate in these trials, then we try to see what early
> access or expanded access mechanism might be considered for that
> patient. And, here is a listing of the contacts for the treatment
> referral center.
>
> For the Group C and treatment referral center protocols, there are set
> criteria to determine whether a patient is eligible for the criteria,
> or for the special exceptions, these are addressed on each individual
> request.
>
> For all of these, to properly evaluate the request we ask for the
> following information about the patient. It includes age, sex,
> diagnosis, previous therapy, current clinical status, the doses and
> schedule of the agent you intend to use, the concomitant therapy and
> any pertinent laboratory data.
>
> Each request is reviewed and assessed on the basis of established
> guidelines developed by the staff oncologists in the CTEP, and the
> response is provided as quickly as possible, usually within the same
> day as the request.
>
> Our requirements for investigators for all of the early access,
> expanded access include having a written protocol, signed by the
> investigator; the FDA 1572 form to show us the investigator\'s
> credentials; IRB approval; and written informed consent. Then, we do
> get back a final patient report. It provides a summary of efficacy and
> any adverse events that occurred. We do ask that agent accountability
> be kept so we know exactly how much drug we shipped and how much drug
> was used for the patient.
>
> That is it. I would be happy to answer any questions you might have.
>
> **Presentation**
>
> DR. DAGHER: I will be speaking today about some considerations for
> pediatric labeling for oncology, and I will start with some comments
> regarding labeling in general and then will switch gears to some
> specifics about pediatrics and oncology.
>
> The role of labeling can be summarized as follows: The label provides
> some important information on dosing, safety and efficacy, but can
> also provide some specific information relevant to special populations
> such as the elderly or children. Another key role that the labeling
> can play is as a source of marketing information, and that is
> something we should keep in mind as well.
>
> Switching gears to some comments on pediatrics and pediatric oncology
> specifically, both Steve Hirschfeld and Diane Murphy earlier today
> emphasized that it is really quite early to assess the full impact of
> the regulatory initiatives that were outlined earlier today, the
> pediatric rule and the incentive program. However, we can say that 28
> written requests have been issued in the Division of Oncology Drug
> Products specifically, and we hope that these initiatives will result
> in the conduct and completion of studies in pediatric oncology.
>
> Ultimately, these activities, hopefully, will result in the submission
> of pediatric oncology submissions specifically, and there are some
> potential outcomes for these submissions. First, studies could result
> in data supporting a new indication. Another possibility is that
> studies will provide pediatric dosing and safety information without a
> new indication being sought or supported by the data where the current
> indication is for an adult disease.
>
> In the situation where a new indication in pediatric patients is being
> sought, the evidence could be provided by new clinical trials or by
> extrapolation of data from adult efficacy studies. In either case,
> adequate information on dosing and safety would be expected to be
> included in the submission and ultimately in the labeling.
>
> In the situation where dosing and safety supplement is provided and a
> new indication is not being sought, a number of points should be
> considered and certain information should be provided in the label, or
> at least be contemplated. First of all, with regard to the study or
> studies, descriptive data about the population and study design would
> be desirable and information on drug exposure would also be considered
> for inclusion in the labeling.
>
> Obviously, we are all interested in information on the
> pharmacokinetics and pharmacodynamics in children. With respect to
> pediatric dosing, in some situations it may be appropriate to have an
> approach based on body surface area, and in other situations a
> weight-based approach may be more appropriate. Finally, safety
> information would also be desirable.
>
> The question that was put to the panel is as follows: what is the role
> of product labeling for pediatric oncology? As the other moderators
> have emphasized earlier today, our role here is really to generate
> hypotheses and questions to put forward in future forums. So, I would
> like the panel and the audience to contemplate a couple of different
> aspects of this question. One is when is it appropriate to provide the
> information, and the other would be what kind of information should be
> provided? Again, I urge the panel to generate questions as you see
> fit. Thanks you.
>
> DR. FORMAN: This might be a bit out of order, but the first question
> you posed, when is it appropriate to provide information, do you want
> to say something about the risks and benefits of providing
> information?
>
> DR. DAGHER: Again, what we are hoping to do during the panel
> discussion is generate some questions. So, you have just pointed out a
> potential question, which would be what are the risks and benefits of
> providing information in different situations? One situation might be
> where all you have is the dosing and PK data. Obviously, some of the
> answers to that question of risk/benefit may be different when you
> have that versus when you have a submission which includes also
> significant efficacy data.
>
> DR. FORMAN: Thanks, Ramzi. Let me review the discussion questions, and
> we plan to hear from the panel first and then open it up for public
> questions and comments.
>
> What mechanisms ought to be used for children with cancer off
> protocol? And, what should be the role of product labeling for
> pediatric oncology? Is there anyone on the panel who wishes to
> comment?
>
> DR. MEADOWS: I just wanted to ask a general question of Dr. Williams.
> You said when should the industry provide access to drugs. I am
> wondering why wouldn\'t the industry want to always be in a situation
> of providing access to drugs if, obviously, safety is assured. I mean,
> it is just a general question.
>
> DR. WILLIAMS: Obviously, our first motive really for asking the
> question from the committee was to help us make decisions for when we
> would allow it. It implies that sometimes we wouldn\'t allow it.
>
> DR. MEADOWS: Wouldn\'t allow access to drugs?
>
> DR. WILLIAMS: There are some times when we don\'t think that it is in
> the patient\'s interest for them to be treated with untested drugs.
>
> DR. MEADOWS: A single patient?
>
> DR. WILLIAMS: Right. Yes, that is what we were talking about at that
> time. But there are circumstances when it is clearly in the patient\'s
> interest to have access to drugs, and I think when you look at a
> treatment INDs or the big protocols that NCI offers, those are clearly
> those circumstances. But we have to find that line when we might say
> no. For instance, a patient who has a curative option and wants to use
> some nutritional therapy that is under an IND, we have to make those
> decisions. We were grappling with that.
>
> But then, step back from that and industry is grappling with the fact
> that they have a finite amount of drug and finite resources and when
> should they offer the treatment, at what point in development might
> this be an option? So, I think there is probably agreement that there
> are some places where various parties would not and good conscience
> would not offer access, and some cases where they would.
>
> DR. MEADOWS: I guess I didn\'t understand the context in which you
> said that. I think industry would never want to restrict access,
> expanded access to drugs because that is the whole idea, to figure out
> if it is worth anything so that they can make more and more money. But
> there are two very separate questions, expanded access and individual
> access, and they are not at all the same. We want expanded access and
> many of us would agree with you about individual access.
>
> DR. WILLIAMS: Well, ultimately our job is to provide expanded
> access\--
>
> DR. MEADOWS: Right.
>
> DR. WILLIAMS: \--by marketing a drug and the question is at what
> point, short of marketing, should industry offer it, and then at what
> point should FDA say yes or no.
>
> DR. MEADOWS: I just wanted to clear up that point.
>
> DR. WILLIAMS: I guess I would like to ask a question to focus us, what
> are the unique problems with children with regard to offering access,
> because I don\'t think I understand those, and I guess we could have
> some discussion, but also is there a question that you would like to
> have asked with more study before another body either a workshop or
> pediatric subgroup of ODAC?
>
> DR. MEADOWS: Well, the children don\'t ask for the drugs; it is the
> parents. That is one of the big differences. I don\'t know, I think if
> you are not a patient yourself looking for a drug\--there has to be a
> difference between a parent looking for a drug for a child, not
> experiencing any of the effects of the disease of the treatment. I am
> just sort of grappling with that.
>
> DR. FINKELSTEIN: If I can answer with a question, and I will paint a
> scenario but I don\'t know if it really applies to STI571, but I can
> see the scenario where here was a drug that was very exciting for
> Philadelphia chromosome leukemia, and it was obvious that somewhere
> down the line ALL Philadelphia chromosome positive leukemia patients
> should be offered this agent, true, as an investigational agent
> because we don\'t know if it will be active but it was quite obvious
> that it was going to come down the line. If I can move the clock back,
> I could see where all this publicity for this drug, for CGL
> Philadelphia chromosome positive leukemia was there and a
> sophisticated parent would say, hey, my child is ALL Philadelphia
> chromosome positive; I want the drug now. Do we have a mechanism to do
> that? That is the question.
>
> DR. MEADOWS: Not now but before\--
>
> DR. FINKELSTEIN: Well, I am using a scenario that I think actually
> occurred historically to answer your question.
>
> DR. MEADOWS: Well, the main problem with that occurring on an
> individual basis is that you don\'t get a whole lot of information
> from the patients who use that drug with that off-label indication. I
> think that is a shame because I don\'t think children should be
> experimented upon unless you can get something out of it.
>
> DR. FINKELSTEIN: Well, I can answer that too because pediatric
> oncology\--you know all this; I am not lecturing you. Pediatric
> oncology is a protocol-driven discipline. We are probably more
> protocol driven than any other discipline in medicine in these United
> States. That is what we are, protocol driven. Therefore, with very
> rare exceptions every one of us is attuned to the fact that the
> patient could be on some kind of protocol. Create the data because if
> you don\'t create the data in your everyday activities you have your
> hands rapped. So, creating the data and sending it back to some source
> I don\'t think is something that is foreign to the pediatric
> oncologist. Medical oncology is not a protocol-driven discipline.
>
> DR. MEADOWS: So, we would like more opportunities to be able to have
> access\--
>
> DR. FINKELSTEIN: Earlier on.
>
> DR. MEADOWS: \--to protocols and trials that someone can learn from
> and that our patients can benefit from.
>
> DR. FORMAN: I would like to pick up on Jerry Finkelstein\'s question.
> I have a question that I think follows directly from that. These
> special mechanisms for access all use a common terminology. They
> exclude patients eligible for registration on research studies, and I
> emphasize \"research\" meaning unproven studies. So, Jerry raises a
> question where there is a protocol. It is a toxic protocol. There is
> already evidence that is not going to do a lot. Along comes a new
> agent which is relatively non-toxic and an intelligent parent says can
> I have access to that drug? And, if you say no, then it seems to me,
> if you want to generalize, you are putting the interests of research,
> the interests of advancing knowledge, the interests of society above
> the interests of the individual or personal autonomy.
>
> If a new agent came along which looked very promising and it was
> relatively non-toxic\--I take back \"promising\" since we have no idea
> how it would work in PH positive ALL, but should we hold to the
> regulations that people must march onto the next available protocol,
> research protocol?
>
> DR. WILLIAMS: Of course, those aren\'t actually regulations; they are
> the internal regulations I guess of the company or whoever is giving
> the drug. There are no rules that we have. Now, we have to make our
> own decision of yes or no from the FDA standpoint, but if a company or
> NCI has a set of criteria, that is where these rules actually have
> come from. They are from the company or NCI. Whether we think they are
> reasonable or not, I think they sound reasonable to me but I think you
> could get a debate about that sort of ethical situation.
>
> MR. HURLEY: If I could follow-up on that a bit, my understanding is
> that if we have a drug that we are developing, and as I mentioned
> earlier, we tend to develop drugs for larger cancers which are in
> adults so they may have application in pediatric cancers. When we are
> conducting a trial we have to file an IND with the FDA in order to
> conduct that trial, and that indicates that we will be studying it in
> adults. If we were to start a pediatric study we would have to file a
> separate IND for the pediatric patients. That may or may not be true
> but that is my current understanding. I see someone shaking his head,
> no.
>
> Let\'s assume for argument that that is true, that there would be a
> separate one filed, if there is not one filed and a parent comes along
> and says that angiogenesis inhibitor I read about, I happen to be a
> biochemist myself, etc. and blah, blah, blah, I would like to try that
> with my child who has been through one treatment standard regimen
> which doesn\'t seem to be working. My child has agreed and would like
> to try that as well. If the company, one, had the compound available
> in a dose that would be suitable, there has been in the past a
> response that, well, we would first have to have a pediatric protocol;
> we don\'t have one currently and we would be looking to perhaps
> develop that after we have gone further on the adult side. So, that
> parent essentially would not have an opportunity.
>
> If it is possible under the IND for adult cancer and a pediatric
> patient representative, such as a father comes along and says we would
> like to try it, and they talk with their treating physician and the
> physician agrees this might be appropriate in the situation, if that
> is acceptable, then there have been in the past some of these
> individual compassionate use approaches and you would then be able to
> provide the drug to the patient.
>
> If that would be acceptable, then that is exactly the opposite of what
> I proposed this morning, and that is for every adult cancer treatment
> that has an IND, have it open for pediatric use through compassionate
> basis for those that want to seek and try these new indications based
> upon the physician, based upon the parent, and based upon the child.
>
> So, we are supposed to make questions. We should say to FDA or should
> we say to ODAC should you consider allowing compassionate use on an
> individual patient basis for drugs that are currently under an IND for
> adult cancers? Should you allow consideration for compassionate use
> for children on a one-off basis?
>
> DR. WILLIAMS: That is a great question. I think it is basically
> semantics whether you call it a new IND or special exception under an
> IND you already have.
>
> MR. HURLEY: Our regulatory departments live on those small
> differences.
>
> DR. WILLIAMS: Yes, but at the oncologist level I think the decision
> would be the same, is there sufficient evidence to allow selection of
> a dose? Is there sufficient probability of some effect so that it is
> basically ethical to do?
>
> So, I would take your question and turn it around to say what are the
> situations? What amount of adult data? Do you have to have pediatric
> efficacy or not? Do you have to have a demonstrated dose pediatric
> Phase I or not? Those sorts of questions, before you would allow, say,
> special exception for pediatrics.
>
> MS. HOFFMAN: From a parent\'s perspective, I think communication of
> seeing a response\--I mean, most of these situations are compassionate
> basis. Kids have exhausted treatment, as mentioned earlier. They are
> dying. Also as mentioned earlier, 85 percent of these parents, you
> know, believe that there is a curative possibility with this
> treatment. In fact, a very small percentage will have the response
> rate and, as far as I know, to date no cure was found in most of these
> Phase I trials. I think that is not something that is commonly known
> by a family and that is key in communicating. My guess, dealing with
> families, is they push, and they push, and they push one more thing
> and one more thing, and they really, truly believe that the magic
> bullet is there. I mean, I have seen cases\--you know, putting a child
> into another Phase I trial is cruel, and the child often, in cases I
> have dealt with, does not want to continue treatment. It is often the
> mom who pushes, and pushes, and pushes, and the child dies a horrible
> death.
>
> So, I think there needs to be a balance. There needs to be
> communication. You know, what is the probability of efficacy? Probably
> very low, if at all, and I think that that has to be definitely
> factored into it. Am I saying kids should not go into Phase I trials?
> No, I am not saying that. I believe in Phase I trials. I believe in
> the science. I believe in altruism and I think that that is a big
> factor, but I also believe in balance and do we need a third party
> acting on behalf of this child? That is something else that I think
> needs to be considered in some of these cases. I am not sure that the
> parent always is the person that is acting in the best interests of
> the child.
>
> DR. MEADOWS: In fact, if there is some suggestion that the drug would
> be useful in a pediatric patient, then it would be important to
> develop a protocol so that it could be tested in a number of product
> patients with similar diseases. If you agree with the things that you
> said, that there is some chance that it would be effective and, as you
> said, if the safety and doses are known, then why not just go ahead
> and do a protocol and get more patients on it, and not waste drug in
> the other way? I mean, it sounds kind of cruel but I don\'t think it
> is cruel.
>
> DR. FINKELSTEIN: The answer is you are right, we should get a
> protocol.
>
> DR. MEADOWS: Right.
>
> DR. FINKELSTEIN: On the other hand, if you have a single parent, and
> we all know we should develop a protocol and it is going to take six
> to twelve months to develop the protocol, and their child is sitting,
> needing that drug, we need a mechanism for that patient.
>
> DR. MEADOWS: Well, you said that child needs that drug\--
>
> DR. FINKELSTEIN: Hold on. From the parent\'s point of view the child
> needs the drug\--
>
> DR. MEADOWS: Well, yes, and they need\--
>
> DR. FINKELSTEIN: With due respect to comments far at the end, I have
> to tell you when I entered this field the question at that time was
> how in the world could you even treat children with cancer. Forget
> Phase I, Phase II, we didn\'t even use those phrases. How in the world
> could you treat children with cancer because they are all dying? So,
> we put on our blinkers and we plowed ahead, and now we have a 75-80
> percent cure rate.
>
> DR. MEADOWS: But it was not by individual patients getting individual
> drugs.
>
> DR. FINKELSTEIN: But the timing of the question was if you have a
> parent or you have a child with a single need, sure, you need the
> protocol for STI571. We now have them, but a year and a half ago we
> didn\'t have the protocol but we had a drug out there.
>
> DR. MEADOWS: And you are too soft! You can\'t say no!
>
> \[Laughter\]
>
> DR. DAGHER: In terms of redirecting to generating questions, it sounds
> like really sort of two questions on different sides of the coin, if
> you will, have been generated. A point that Dr. Meadows makes that in
> some ways, depending on how you do it, allowing \"expanded access\"
> for children might be detrimental in one situation where there are
> very small numbers of patients and the data generated could compromise
> the generation of a protocol. On the other side of the coin, the
> question you are asking is should there be situations where access is
> granted since there is no alternative therapy?
>
> But what I want to encourage the panel to do is generate some other
> questions, maybe not so much about whether access should be granted or
> not but, again, given the presentations outlining the current
> mechanisms that we have available, can you generate questions
> regarding these mechanisms? Would you have a separate or alternative
> set of criteria to some of the ones that have been outlined? Would you
> consider an entirely new mechanism? Aside from whether or not access
> should be granted, what other concerns could there be about the
> different mechanisms that exist, and how could those be refined? Do
> people have any questions they want to put forward regarding those
> issues?
>
> MS. HOFFMAN: One frustration for parents who are desperately looking
> at that stage is that it takes them so much time. They are calling
> industry; they are calling NCI; they are calling their doctor. There
> is no central repository or database for institutional studies, like
> MD Anderson and Sloan-Kettering have some institutional studies;
> industry studies that have not gone into COG yet; COG studies that are
> done under consortium. Something that would be really handy is a
> mechanism, a common database where they can go and say this drug is
> available on a compassionate basis or it is not available on a
> compassionate basis or these are the criteria so, you know, they could
> save so much time and be able to answer for themselves my child had
> this; he is eliminated. It would help a whole lot if there was a
> mechanism or a common location to find that information. It would save
> me hours too.
>
> MR. HURLEY: There is that mechanism. Sometimes it is called the
> newspaper. We get calls from physicians and sometimes patients
> themselves saying, gee, I want to get this. Unfortunately, sometimes
> we get congressional inquiries and that forces us to tweak the system
> even more to try to help the patient. That is what we are here for, to
> help the patient.
>
> But unless there is proven data concerning efficacy and safety, that
> balance, we have to deny that special request, unfortunately. But you
> have to base it on something. You don\'t want to kill the patient.
> After all, these things are poisons that we give these people. Poisons
> for the cancer but, unfortunately, poisons for the patient. So, that
> mechanism that you mentioned earlier may be communications. Remember,
> there is some statistic out there, I don\'t know whether it is three
> percent or five percent of all patients that actually have cancer
> actually get on a clinical trial.
>
> DR. FINKELSTEIN: Not in pediatrics.
>
> MR. HURLEY: I don\'t know what that is in pediatrics, but just in
> general.
>
> DR. FINKELSTEIN: I have a question for you. First of all, it is not in
> pediatrics and we discussed that this morning. Ninety percent of all
> children under the age of 15 have access to a center. Now, maybe only
> two-thirds of them go on a clinical trial. Over the age of 15 it is a
> real problem because you have the adolescent.
>
> My question to those of you who control the drugs here, in Washington,
> I agree that a child is not an adult. On the other hand, when you have
> a 12-year old, 80 kg child who weighs more than me, are you going to
> be looking for dosing? I mean, what are you going to use as your
> criteria for a child? Are you going to use age or size in terms of
> determining that there really isn\'t a dosage available?
>
> DR. FORMAN: That is a good question. I wanted to go back to the
> comment that you need sort of minimally decent efficacy and toxicity
> data, and what constitutes sufficient efficacy and toxicity data or
> acceptable risk data? Who makes that decision? And, will the criteria
> be absolutely transparent to the public? Of course, when they get a
> \"no\" they want to know if it was done fairly.
>
> DR. WILLIAMS: This is actually determined by the FDA when they review
> the request. If the question is to the company who is offering it,
> they will have to make that determination on their own. But, I guess,
> the question that you are offering would be specifically for children,
> what are those criteria. That is the kind of discussion we had before
> ODAC for adults, and there was quite a spectrum, and it is not defined
> in the law. It is a judgment that there is sufficient evidence of
> safety and efficacy to proceed. So, it is really left to the judgment
> of the FDA for that decision, and we could change the specific
> question to how does that pan out in pediatrics when you have a
> different disease, for instance, and there is efficacy data in this
> disease, and then we have this pediatric disease and they have
> evidence of safety at this dose in adults, but how much evidence do we
> have for the dose in pediatrics?
>
> DR. FORMAN: I want to just emphasize that judging whether the risk is
> worth taking shouldn\'t\--it depends on who the FDA is, and this is
> where the subcommittee can play a role. I would think it would include
> parents on that committee, advocates, and not just scientists making a
> judgment about what risk is acceptable.
>
> DR. MEADOWS: To substitute a word, you said evidence of efficacy but
> maybe it should be evidence of promise\--promise rather than efficacy
> because, obviously, when drugs are begun to be used in adults it is
> just a promise rather than any evidence. So, you could just as well
> say, well, there is a promise that this will work in relapse ALL
> because it is so sensitive. All is so sensitive anyway. So, why go
> through the adult phase when you don\'t have a whole lot of ALL in
> adults? Start it in children.
>
> DR. DAGHER: Dale, you mentioned in your presentation that you wanted
> to emphasize that these mechanisms are available to both children and
> adults. Another panelist brought up the question of when you do get a
> request for a child, whether it is a young child or an adolescent, and
> maybe Carl could also address this, are there considerations about the
> age, the dosing, the extrapolation to the adult setting? Are there
> judgments there that are made, or how does that process work?
>
> DR. SHOEMAKER: I think there are all those things, and they also
> consider what is the disease you are talking about; what stage of
> disease; what standard treatments are available; what the patient has
> been treated with already. You go into all of those issues to try to
> decide.
>
> I did want to follow-up on one thing that you brought up about a
> compound like STI, where we have some of the newer compounds which are
> molecularly based, you have an idea of what diseases they might be
> effective against, or at least you hope you might know what they are
> going to be effective against. I think it is incumbent upon us to try
> to anticipate in some cases what studies we should be looking towards
> and try to get protocols in the process earlier, written and activated
> quicker. I think in the case of STI, that might have occurred to some
> extent but not as fast as it could have.
>
> DR. DAGHER: If there aren\'t any other comments about this question or
> other questions to be put forward with respect to the access question,
> we can turn to the labeling but, again, if there are any other
> comments on the access question or other questions that you feel
> should be put forward?
>
> MR. HURLEY: I would just like to comment on the last comment. I think
> that would be an excellent idea. We should ask ODAC if they feel it is
> appropriate at the time, let\'s say, after you get your Phase I data
> in adults for cancer, to anticipate that there may be use for this
> drug somewhere down the line in pediatric patients. Perhaps through
> some mechanism, and I don\'t know whether this is the company doing it
> themselves or through COG, ODAC or whatever, that protocols be made
> where we could have somewhat stock protocols for the different types
> of pediatric cancers so that they could be easily modified for the
> particular drug, and turn that immediately into an initiation, even
> though that was not on the immediate horizon; it might have been on
> the horizon for the company for five years until it got through, but
> if they get a request for 25 patients and five of those fit into this
> protocol and seven fit into here, that we put them in there and allow
> for individual compassionate use but, yet, anticipate that this is the
> kind of data that we would collect should we go forward and we would
> have that data available.
>
> DR. WILLIAMS: I guess what you are saying is that we should consider
> whether in pediatrics you actually have the structure to collect
> better data in this sort of a system. Maybe it wouldn\'t be as good as
> the normal Phase II protocol, but at least collect much better data in
> sort of Phase II format by some kind of a mechanism such as that.
>
> DR. HUNTLEY: That is important, to make it a protocol rather than a
> mechanism of expanded access through, say, the NCI because, as was
> mentioned earlier, it is limited data that we collect. Well, why not
> have a protocol and get the data, and then treat more patients?
>
> DR. DAGHER: Do you want to go forward and consider the labeling
> question at this point?
>
> DR. FINKELSTEIN: I will tackle it with a question to the FDA. In
> pediatric oncology we have obviously carried on our discipline
> regardless of whether a product is labeled or not. Certainly, in
> pediatrics you need labeling, in general pediatrics. In pediatric
> oncology, because we are protocol driven, we have been driven by the
> protocols.
>
> Now, there are a number of drugs that we use every day. doxorubicin is
> not labeled for pediatrics. Am I right? How about doxorubicin? Is it
> labeled for pediatrics? How about VT 16? Pick any. What I am getting
> at is we really use these drugs. VM I think is. So, let\'s use that.
> It doesn\'t really matter. I am not picking on industry, I am really
> trying to use an example, drug XY&Z we may use eery day and have used
> it every day for the last five years. We will continue to use it. We
> really know the drug. I don\'t see how anyone is going to put energy
> in to meet the FDA requirements for labeling.
>
> On the other hand, should there be some kind of labeling mechanism,
> whatever that means, for pediatric oncology where it is indicated that
> it is definitely used in research protocols, something that modifies
> your general labeling criteria?
>
> DR. DAGHER: Well, as I pointed out, there are different kinds of
> information that could be put into the label. So, I guess just to try
> to paraphrase to generate a question, what you are asking is could
> there be very different kinds of information that could be provided in
> a label based on what we are looking at, whether it is a new
> indication or a situation where there is a drug that is out there,
> approved in adults and being used in a number of settings in
> pediatrics.
>
> DR. WILLIAMS: I think what you are talking about is just a subset of
> the problem we have with all cancer drugs, not just pediatric. We have
> taken several different initiatives over the last few years to try to
> get labeling improved but, you know, where people are already widely
> using it, especially when drugs are off patent, there is not a great
> incentive to get the data in. We have looked at trying to do that but
> I must say that there has not been a great deal of success, and we
> have thought about, you know, could we go to the literature and get
> data and if there is a reasonable amount of data in the literature, we
> would do that. I would just say that there hasn\'t been a great deal
> of success.
>
> So, I am not sure what we would discuss before ODAC that would push it
> forward. Maybe later somebody can have other ideas for how we could
> take this forward. But we ought to take it forward as a question, is
> there some way that we can improve the pediatric labeling based on
> drugs that have a widespread experience and look back at the
> literature. Perhaps pediatric ODAC could help to examine that. I am
> not sure.
>
> DR. FORMAN: To clarify at least for me, what difference would it make
> if an agent has labeling to industry, to the public, to a physician?
>
> MS. HOFFMAN: How do you then take into consideration the large teen
> population that are not on protocol, that are not being seen in COG
> centers, who are being treated at the local hospital by some doctor
> who says, hey, I can do this; I can handle this with no sort of dosage
> guidelines?
>
> DR. FINKELSTEIN: I can tell you what our initiative is. The initiative
> is very simple, and it is a very difficult problem. The initiative at
> the American Academy of Pediatrics and pediatric oncology community
> have taken it, to try to educate our medical oncologists that these
> patients are falling between the cracks. The adolescents, we have been
> able to show, who are treated off protocol do not do as well as those
> treated by one of our centers. We will use every media possible. So,
> if there is anybody out there from the media, we will be delighted to
> meet with you, and if you want to put the video on, live.com.nation,
> we would like them all to hear this.
>
> MS. HOFFMAN: I will be the devil\'s advocate here. I think it is more
> than just educating the medical practitioners or the medical
> oncologists. I think it is a teen thing, mostly because teens want to
> be independent. They want to be in control of their life. I am
> thinking of a call that came into the office last week, non-Hodgkin\'s
> lymphoma being treated at a local hospital; the kid does not want to
> go to a COG center because he wants to be close to home so he can
> still do his thing.
>
> I think you still have an issue of dosing because, yes, I agree that
> that is the ideal goal, let\'s get them into a COG center, but I am
> not sure that is the reality and I think it is education of the teens
> as well and I am not sure that that is going to be heard and adhered
> to. So, you still have the dosing issue. So, being the devil\'s
> advocate here, how can you handle that?
>
> DR. DAGHER: You actually brought up two different questions, and I
> think some of the other members from COG will address the question of
> how do you get to the teens. You linked it to the labeling, and the
> comment I will make there is that, again, in the label in general we
> have a section for special populations. We went over that briefly.
> Also, if there are compelling reasons in a specific situation for
> including some dosing information relevant to a specific age group,
> certainly that can be contemplated. I don\'t know if that is what you
> were getting at or, if you feel that is an important question, that
> can be raised as a question, are there situations where dosing,
> whether it is for adolescents or infants or whatever, should be
> included in the label.
>
> DR. MEADOWS: It is more than dose; it is regimen. It is how you put
> the drugs together to make the result that Jerry is talking about that
> we get when patient with a Ewing\'s tumor is treated at a pediatric
> institution compared to \"St. Elsewhere\'s.\" They may use the same
> drugs, and they may mix them up and they use the right dose, but they
> don\'t know that we have determined that there are better ways and not
> so good ways to do the whole sequence.
>
> Many years ago, before there were so many places that treated children
> with cancer, we made it a practice to try to get everybody within a
> hundred mile radius to come to us so that we could plan their therapy,
> and then we sent them out to the community to continue treatment. So,
> your adolescent with Hodgkin\'s or non-Hodgkin\'s lymphoma doesn\'t
> have to have all this treatment in the COG center. He can have it
> locally provided there is a local oncologist who agrees to abide by
> the protocol that the center prescribes.
>
> It sounds so self-serving but it is really not. I mean, we are really
> trying to do the best for these teenagers. Many places have developed
> specialized areas in which teenagers can be treated within the COG
> center. They also don\'t like to hear babies cry in the next bed or
> even in the next room. That is a big thing. So, I think we have a lot
> of work to do in trying to get the adolescents under our wing, but it
> is not a question of labeling.
>
> DR. HUNTLEY: Just to add to that, with established protocols, CTEP or
> at least the Pharmaceutical Management Branch within CTEP, is working
> on mechanisms to help the patient get treated at what we consider a
> local physician. We have mechanisms currently in place to take care of
> those patients. So, the next step is just to get the information out
> there for the patients, as was brought up earlier, to get on
> protocols.
>
> DR. FORMAN: Any other questions from the panel? It is open to the
> audience for comment and questions. I have a question for Susan. Does
> a child need an advocate every time you offer a protocol, other than
> the parent? And, is that even legal?
>
> DR. SHURIN: I guess you can put that onto your list for questions. I
> don\'t think anybody has an answer. There are people who have
> advocated doing that, and there are people who have done it in certain
> circumstances.
>
> DR. DAGHER: Wayne, you had a comment?
>
> DR. RACKOFF: Yes, a comment rather than a question. You know, the
> label for folks in industry is really the license. We often get caught
> up in looking at the label as a complete compendium of information. To
> me, the importance of a label in pediatrics is that it is the license
> that gives you the hook to enforce pediatric exclusivity. We realize
> the content of the label is important, but I think the real importance
> of it in the pediatric setting is that by requiring labeling you can
> enforce exclusivity. You know, it might be nice for one question to be
> asked, should there be a special section of the label that announces
> in the PDR or in the compendium that this drug is in compliance with
> peds rule, or has fulfilled the obligations of peds exclusivity. That
> may be an additional incentive, PR incentive to the industry.
>
> DR. HIRSCHFELD: Steven Hirschfeld, FDA. I have a proposed question
> that could be brought forward, and it is a nomenclature question. That
> is, maybe the panel wants to consider a change in calling what has
> been termed compassionate use to something else because sometimes the
> compassionate thing is not to allow a patient access at that point,
> and it implies that if you don\'t do it you lack compassion; if you do
> do it, you are compassionate. Yet, that can be contradictory. So, that
> is a question I would like to move forward and look for some
> nomenclature.
>
> Before Dr. Pazdur gets a chance to ask his question, I wanted to
> introduce Rita Bergman, who is an adolescent, who is a childhood
> cancer survivor and would make a comment, I think, on some of the
> topics you have just been discussing. Rita, please.
>
> **Public Comment**
>
> MS. BERGMAN: Thank you. Yes, as he said, I am a childhood cancer
> survivor. I was treated when I was ten. I am 18 now and am working for
> Dr. Hirschfeld.
>
> Addressing all of the issues about accessing adolescents, I thought a
> lot about what would happen if I relapsed and generally it is a
> nightmare situation where I think I would not seek out any treatment
> at all. The first thing I think of is running away from all possible
> drugs and trying to live peacefully. I think where that is coming
> from, and I also have several friends who are in treatment currently
> and their parents want them to go forth with it and they are ready to
> stop. They have been years with it. I think it is a totally natural
> desire, of course, to just want to try to have some control of your
> life and to feel normal. You were all adolescents; you remember that
> time.
>
> I guess I believe strongly in the idea that educating teens or
> children about what they are about to face\--unfortunately, I am a bit
> pessimistic about that as well because, certainly, with most of these
> treatments it is not going to be making your life better right away,
> and if you are at the point where you are seeking one of these trials,
> yes, things don\'t look so good. So, I guess education to try to get a
> good process in line\--I don\'t know, when you are a teen you are
> developing a social conscience and a sense of altruism and I see that
> as the biggest issue here from somebody who would be facing potential
> treatments. You would need to feel strongly that sense of wanting to
> give to other people because I don\'t think that therapeutic personal
> benefits are that strong when you are going on a treatment. Thanks.
>
> DR. FORMAN: Before you leave, could I ask you a question?
>
> MS. BERGMAN: Sure.
>
> DR. FORMAN: You said you were pessimistic, and I wasn\'t sure if you
> were pessimistic about the success of therapy or about adolescent
> decision making.
>
> MS. BERGMAN: A little bit for both. I think I am a little bit
> pessimistic about the ideas of some of the Phase I trials and how
> beneficial they will be for patients, but also the adolescent
> decision-making process because it is hard to weigh all the factors,
> the influences of parents and the medical community, feeling scared by
> what is happening and wanting to have control. I hope that answers it.
> Thanks.
>
> DR. FORMAN: Thank you. On the other hand, you have demonstrated a lot
> of wisdom.
>
> MS. BERGMAN: Thank you.
>
> DR. PAZDUR: There are several points I wanted to bring up. One is what
> does the product label mean, and I think it has a lot of different
> meanings to different people and this is one of the big problems that
> we have. Is it patient information? Is it physician information? Is it
> a licensing agreement? Is it something that advertisement can be taken
> from? We spend an inordinate amount of time at the FDA on the exact
> working of a label because we see it not only as a licensing agreement
> but also something that basically advertising information can be taken
> from directly. So, we are very careful on the exact wording; what p
> values can and cannot be put in; the exact wording.
>
> In pediatric oncology where you do not probably have a very
> competitive market as far as drugs in a sense, that may not be
> important but in adult oncology it is very, very important because one
> company can make a claim over another company.
>
> So, exactly what the product label means and what we want it to mean
> has different meanings to different people. We are always grappling
> with what should go in the label and we have been looking at should we
> include supplemental information from the literature. But, then we get
> into a situation where we have different evidentiary levels of proof
> of different claims that could be made. For example, the initial IND
> or NDA which may be the main part of the label would have two
> well-controlled studies which we have gone over methodically, looked
> at all of the x-rays, did all of the survival curves over again.
> Should we then contaminate that label with something from the
> literature that we have never seen the primary data on, but just so
> physicians could have an understanding of perhaps another usage of the
> drug?
>
> That would be fine if you consider the product label a physician
> education device or an avenue for physician education or patient
> education. However, to encourage companies to do well conducted
> trials, to get supplemental NDAs in, over time it would be an
> unmitigated disaster because people would consider why do a
> supplemental NDA? All I could do is publish it in the literature and
> the FDA could just put it in the label and people could use it as they
> would.
>
> So, I think people have to be very cognizant when we talk about
> labeling of what we want it to be. There are many avenues, many, many
> avenues for physician education. This organization or this avenue that
> we have with the product label is a very unique aspect. Here, again,
> once you start putting in different levels of evidence that we
> haven\'t reviewed, that may not be quite up to snuff, I think we could
> get into a rapid downhill situation.
>
> The other issue that I wanted to bring up that we are facing now with
> the introduction of the pediatric rule is the addition of pediatric
> dosing information into the product label and potential de facto
> claims that can be made. For example, if we put in based on a Phase I
> study, a pediatric dose, what does that mean? When should it be used?
> Are we giving this company kind of a blanket indication for pediatric
> use of this drug?
>
> For example, another situation might be inadequate information that
> may go into the product label. You know, five patients or ten patients
> with neuroblastoma were studied and there was one response. Does that
> constitute evidence that that drug works in that disease? And, if we
> put that information into the product label with the dosing
> information, are we in fact giving a de facto indication to that
> sponsor? Therefore, over time that would mitigate them going on doing
> really well conducted trials.
>
> I think these are some of the points that we have run into recently
> that we really have to be aware of when we talk about the pediatric
> rule. Obviously, everybody wants information to be put in there, but
> what is the eventual implication of that information? We have to be
> very careful because these can represent de facto claims and,
> therefore, actually over time prevent the adequate trials being done.
> So, I really caution people. I think we have a great deal of
> enthusiasm to improve the product label. We have product labeling
> initiatives to make it more user-friendly, and this may create some
> schizophrenia on the part of the agency, what do we want out of the
> product label? Is it a patient information avenue? Is it a physician
> information avenue, or is it a licensing agreement? Is it an
> advertising agreement? All of these multiple aspects are sometimes
> compatible but may be sometimes incompatible with each other.
>
> DR. WILLIAMS: Ramzi, I wonder if that latter point could be wrapped
> into a potential question? It has come up with us. I know Steve has
> mentioned that the pediatric group in general has been grappling with
> it. That is, when we put information in, what amount of information
> can we put in under circumstances, for instance, where we don\'t have
> a corresponding indication in adults?
>
> DR. REYNOLDS: Pat Reynolds, Children\'s Hospital, Los Angeles. I
> wanted to address a comment that Ruth made in two contexts, first the
> labeling issue. The comment is basically that parents are different
> than, I think, adult patients seeking therapy. Parents expect their
> child to live beyond them and they become very desperate when their
> child is not going to live beyond them. Whereas, an adult cancer
> patient can many times come to grips with the fact that, well, you are
> eventually going to die and this is it. So, it is a very different
> perspective.
>
> I think within the context of that, there are two issues that I want
> to bring up. One is that I think that the FDA does an outstanding job
> of being obsessive-compulsive about labeling. What I would like to ask
> is whether or not the FDA could consider taking a role in what is
> presented to parents in the context of doing clinical trials by
> investigational institutions doing IND agents. They are taking IND
> agents, sometimes made by themselves, mixing them in with other
> therapies and then presenting data bout their efficacy to parents, and
> there is no oversight of this because it is not done in the context of
> the cooperative group.
>
> So, I think there is a definite role for the FDA to look at labeling,
> if you will, of clinical trials. This is a topic that Dr. Shurin and I
> had considerable discussions about the ethics of, and I think it
> would\--
>
> PARTICIPANT: It is informed consent.
>
> DR. REYNOLDS: Well, it is not informed consent. It is about what data
> you can receive to parents. In other words, what data is acceptable.
> For example, if you are presenting progression-free survival, but
> forgetting the fact that you have 20 percent of AML patients there as
> secondary leukemias and not telling the parents. There is a lot of
> this going on that needs to be really addressed, and I think that the
> agency is the only one to address it. That is my personal opinion.
>
> The second issue is expanded access. I think that a role that was not
> discussed and I would like to propose should be considered, I think
> one that Jerry was alluding to, is the fact that we are now seeing,
> and I think we are all very happy about that, agents that are not
> additionally cytotoxic, agents that don\'t cause the same toxicities
> that we are used to seeing in oncology. These agents have various
> efficacy but quite often they are going to be cytostatic, meaning that
> they are going to take a long time before you actually get a labeled
> indication for them because you are going to have to measure
> progression-free survival to define them. As those are in this window
> of being studied, we have fairly non-toxic, fairly non-risky agents
> and, yet, we have these parents that you have heard from Ruth about
> that have those children that are truly at the end of life, and every
> physician taking care of them knows they are the end of life.
>
> Why should that child go on a cytotoxic Phase I trial and spend the
> last month of his life in the hospital? If they could access to some
> of these relatively non-toxic agents, what you are giving those
> children\--those children should be on trials. As you have heard from
> a parent who has dealt with this and dealt with it with other parents,
> at a certain point of their career, if you will, as oncology patients
> you come to a point where you have to say enough is enough.
>
> Yet, those parents need hope. We must give them some hope, and by
> giving them an expanded access agent that doesn\'t cause much toxicity
> you provide that hope. If that can be done better in a context where
> we can learn something, something that Anna has brought up, and I
> think we have seen too much of that; we have seen this expanded access
> where we never learn anything, we would really I think see an
> improvement and I would like to see perhaps the panel address some of
> that as well.
>
> DR. DAGHER: With regard to the first point you made, I think a lot of
> the issues you raised are related not just to the consent form but to
> the consent process. Now, in terms of FDA\'s rule, when protocols are
> submitted to FDA under a variety of mechanisms, we do review the
> consent forms that are provided there to make sure that information
> that is provided is balanced in terms of presenting the known data on
> toxicity or any hope of benefit, etc.
>
> But, as I think others would comment on, the consent process is a
> process and it is not just the consent form. It is not just the IRB.
> That is another organization that plays a role in defining what is
> presented to patients on a specific protocol where they are going to
> be getting a specific drug. Again, since it is a process, I don\'t
> think that one entity controls what is presented to patients in that
> regard. I think there is a number of players that have a stake in
> that.
>
> DR. REYNOLDS: But the question I guess I am addressing more
> specifically is you are reviewing the consent form, but are you
> reviewing the web sites for the institutions and the data they are
> presenting on those web sites to recruit patients onto studies? I
> don\'t believe that you are and I think you need to be.
>
> DR. ALLAND: Leila Alland from Schering-Plough. I wanted to bring up
> another aspect of labeling which mostly applies to adult oncology,
> which is that it is important for reimbursements and this is much less
> of an issue for pediatrics because, as everyone knows, they are
> enrolled in clinical trials so that is usually enough of an
> endorsement that there will be reimbursement for that patient.
>
> But I could foresee in the future with some of the newer agents where
> there may be equivalent efficacy but a better safety profile that it
> would be important to have that information specifically for
> pediatrics in the label in order for it to be used.
>
> DR. WEINER: I am Susan Weiner, from the Children\'s Cause. I have two
> questions for the panel. One has to do with a request. I am trying to
> phrase this as a question. The point is that to try to resolve FDA\'s
> schizophrenic stance, in Dr. Pazdur\'s words, about labeling, one
> would want to make sure that the rule and the incentive are applied in
> ways that are going to maximize the chances that the treatments are
> going to be effective for kids in the context of the clinical trial
> system as it currently exists, rather than having a focus on
> laboratory itself since we all agree it will never be a marketing
> issue in kids. So, I think it is important to keep our eyes for that,
> and I would hope that the strategies that the committee will address
> for how to do that would be up front.
>
> The second point really has to do with the question of single-patient
> use. Here I refer to a comment that Dr. Reaman made to me perhaps a
> year ago in anticipation of the meetings that Dr. Williams spoke of.
> Here is really the challenge again for this collective, and that is,
> how would it be possible to create sufficient Phase I trials with
> promising drugs, including those that have relatively little toxicity,
> so that families are not clamoring after individual access but,
> rather, have other options in Phase I trials that look promising to
> them?
>
> DR. DAGHER: Any other public comments?
>
> DR. HAGEY: Ann Hagey, Abbott Laboratories. This is a question to pose
> to ODAC regarding access. Might it be beneficial to have a mechanism
> in place to track the number of pediatric applicants for a particular
> drug or indication beyond which\--the magic number might be ten which
> would trigger some sort of letter to the company, or ten reasonable
> requests would mandate a protocol be put into place?
>
> DR. FORMAN: Let\'s not call it compassionate access but non-research
> access, it is commonly stated that nothing can be learned from those.
> On the other hand, if Dr. Finkelstein\'s hypothetical case went into
> immediate remission with the use of that agent, I hope that wouldn\'t
> be buried. But could there be requirements\--maybe there are
> requirements that when a drug is released through this kind of access
> that the therapist be, in a sense, an investigator and there be an
> initial assessment of quality of life on a form, and be required to
> report back whatever happened. The accumulation of such cases might
> provide some information. So, it wouldn\'t be totally non-research.
>
> DR. DAGHER: I think there are currently some mechanisms to track some
> of this data, and maybe the folks from NCI could provide their
> experience.
>
> DR. SHOEMAKER: Yes, we have actually had some of the treatment
> referral center protocols. There have been forms derived so you could
> collect data on efficacy and safety, and it has been useful I think in
> some of the applications then made to the agency as far as safety
> especially.
>
> DR. FORMAN: It is 3:15. I think this panel will wrap up and turn it
> over for the summary discussion. Drs. Keegan and Pazdur, the floor is
> yours.
>
> **Summary Discussion**
>
> DR. PAZDUR: I guess we could reintroduce ourselves. I am Richard
> Pazdur, from the Division of Oncology Drug Products, from CBER.
>
> DR. KEEGAN: Pat Keegan, from the Center for Biologics, Clinical Trials
> Group.
>
> DR. BLANEY: Susan Blaney, Developmental Therapeutics, Children\'s
> Oncology Group.
>
> DR. RACKOFF: Wayne Rackoff, Johnson & Johnson.
>
> DR. SHAPIRO: Alla Shapiro, FDA.
>
> DR. DAGHER: Ramzi Dagher, FDA.
>
> DR. FORMAN: Ed Forman, Alliance for Childhood Cancer and also Brown
> University.
>
> DR. GOOTENBERG: This is Joe Gootenberg, from biologics cancer, FDA.
>
> DR. PAZDUR: The purpose of this workshop was basically to identify
> issues that we would like to carry forward in future pediatric ODAC
> subcommittees. So, that has been the focus of both the morning and the
> afternoon sessions.
>
> What I thought we could do is have each of the panelists go through
> their panels and describe what are the essential aspects that they
> think need to be carried forward into future meetings. I know Susan
> has to leave for a plane, so we will probably start with her first.
>
> DR. BLANEY: Just to summarize, our panel discussed some of the
> clinical design issues for pediatric oncology and the mechanisms by
> which clinical trials are designed in the Phase I through the Phase
> III setting, and then how this information is shared or disseminated
> amongst all the various players in the drug development process.
>
> So, some of the questions or issues for discussion, based on the
> presentations that we heard and the questions that arose, are, first,
> when or under what circumstances would it be acceptable for new agents
> to enter clinical trials prior to or concurrent with the initiation of
> adult trials.
>
> A second question, or one of the second issues for our discussion was
> how can adult and pediatric development plans be coordinated to
> improve access for investigators to the most promising new cancer
> therapies during the drug development process.
>
> Under that issue were raised some of the potential trial designs. So,
> our question for the FDA would be how could we employ, or would you
> accept some of the Bayesian or continual reassessment methods in
> clinical trial designs in the Phase I and Phase II setting? Could
> there be some relaxation of the traditional rules and look at
> historical controls and time to progression as endpoints that would
> achieve labeling for these studies?
>
> Another question that we would like to ask to the FDA is\--a lot of
> the discussion focused around prioritization. So, one of the questions
> is, is it within the FDA jurisdiction to be involved in the
> prioritization process? Could the FDA consider public policy and
> review of IND applications, or could it be required that IND
> submissions meet criteria for consortium study, and can that be a way
> to maximize the benefit of ODAC?
>
> Another question that we wanted to ask was is it desirable or possible
> for the FDA to be involved in fostering international cooperation? If
> so, what would be the rule of the FDA in doing that? Joe, did you have
> anything?
>
> DR. GOOTENBERG: I am going over right now the things that we discussed
> together, Susan, and I think the only part that I thought was
> generalizable beyond what you talked about, because that was very
> comprehensive, was in our last discussion bullet where we started
> discussing tissue biopsies, a target modulation. That is really
> generalizable, and the question that would go to ODAC submission about
> that would be for them to hold a discussion of the ethical concerns
> regarding clinical trial requirements for samples that involve greater
> than minimal risk, or samples that were in some way sensitive in
> clinical trials. Examples of that would be tissue biopsy to study
> target modulation in Phase I and II trials of targeted therapies, and
> as was also brought up, the sensitive one would be the collection of
> DNA or RNA samples for microarray analysis. I am sure there are plenty
> more sensitive ones but that is all that is necessary for the
> examples. So, I think that is the end of the report from our panel.
>
> DR. PAZDUR: Thanks. Wayne and Alla, do you want to go next?
>
> DR. RACKOFF: Just to summarize what methods are available to set
> priorities for emerging agents, there were descriptions how COG and
> the NCI might set priorities for input into studies or into the
> preclinical consortium studies. What we thought was the overriding
> question is how should those decisions be coordinated with the
> agency\'s decisions regarding grants of exclusivity or requests for
> exclusivity. You know, what mechanism could be used to coordinate the
> agency\'s decisions with those of the clinical trialists at the NCI
> and the COG? What forum can be used? What legal requirements need to
> be met?
>
> Then, just from the industry perspective, how should or can the agency
> deal with a sponsor\'s proposal for exclusivity when NCI and COG have
> decided that the compound is not a priority for investigation?
>
> Finally, with formulation, I think I have realized that it is
> something that we don\'t understand well in terms of what goes on in
> that area, and the real question is when and how should the agency
> request\--when in the process is it reasonable to request plans for
> pediatric formulation. I guess that is really the overriding question.
> I don\'t know, Alla, if I covered all what we talked about.
>
> DR. SHAPIRO: Yes, I think all the emphasis was put in and I just want
> to emphasize again that as of today, for the prioritization process
> all the pieces for successful prioritization are there from industry
> and from NCI as to how to make joint efforts most successful.
>
> DR. PAZDUR: Ramzi and Dr. Forman?
>
> DR. DAGHER: For our panel there were two issues that we discussed. One
> was access to investigational agents and the other was labeling. With
> respect to access to investigational agents, a number of potential
> questions arose.
>
> One of the questions that was identified early on actually approaches
> two sides of the same coin. There was a suggestion that because
> investigators in oncology who treat children with cancer are attuned
> to the requirements for reporting of safety and benefit information,
> because of the large number of children being treated in the
> cooperative groups, potentially data provided from an expanded access
> program in children might be more useful than that provided from
> similar programs that have been available for adults. So, one question
> is could data from expanded access programs in children be more useful
> than those that we have seen in adults?
>
> On the other side of the coin, there was a concern raised that that
> strategy could be detrimental because we already have very a limited
> number of patients for studies, and one downside to the approach that
> was identified was that we could actually be limiting the possibility
> of studying a drug in an organized fashion.
>
> So, the next part of the question is sort of the other side of the
> coin, would such an expanded access program in children actually be
> detrimental for a number of reasons? So, there are two questions sort
> of on different sides of the question.
>
> Another question that was identified was whether patients have to
> exhaust all research clinical trials possibilities before having
> access in an off-protocol setting.
>
> Another question really concerns the criteria that are used for
> deciding when a patient is eligible to receive a drug in an
> off-protocol setting, and the question is how and who decides what is
> \"sufficient\" activity and acceptable risk for access to an
> investigational agent. The question that was raised along with that is
> could there be mechanisms to provide those criteria in a transparent
> fashion to the public so that there is a perception, or at least it
> would help to provide information and allow a fair consideration of
> eligibility to access programs.
>
> With respect to the labeling, one general question that was brought up
> and was sort of a recurring theme throughout the discussion was what
> difference would it make if an agent has labeling, and what difference
> that would make to the industry, to the public or to practicing
> physicians.
>
> Another question that was brought up, although it was brought up in
> the context of labeling probably has implications for other areas,
> which is whether the criteria that are used for considering
> information to be included in the label, whether those criteria could
> be modified.
>
> Another question regarding labeling that was raised from the industry
> side was whether there could be some kind of statement in the label
> regarding compliance with a written request. I think those were the
> main issues that were raised.
>
> DR. PAZDUR: I guess there is one question, and that is where do we go
> from here. We have gotten a lot of information. I want to emphasize
> the commitment, not only of the Division but also CBER and the entire
> FDA, to continue the pediatric ODAC meetings. This is a firm
> commitment. We will take these questions, obviously, there is a lot of
> information here; digest this information. With many of you, I think
> we will be in telephone contact regarding the planning of the future
> meeting.
>
> My plans for this would be to continue, as perhaps schedules would
> allow in the next quarter, to have a meeting in the fall, early or
> late fall, to conduct the next pediatric ODAC meeting after we have
> had time to digest this material.
>
> Obviously, there are many players here, and we really appreciate
> everybody\'s participation and continued participation throughout
> really the pediatric issues and addressing pediatric issues as far as
> drug development, and they include COT, the advocacy groups, industry,
> NCI and the FDA working together as partners.
>
> I think one of the major things that an advisory committee gives us is
> the aspect of transparency. I think it is especially important now,
> having discussed this with many people at the breaks, that we try to
> make this whole process of who we issue written requests to; how these
> written requests are conducted in a timely fashion, if they are
> conducted at all; who is complying with pediatric rule, who is not;
> who is conducting studies per the exclusivity aspects, and have a
> really transparent approach to this. Really the pediatric ODAC
> committee does give us this mechanism.
>
> In addition to discussing rather thematic issues, as we have, and
> questions, perhaps even product specific discussions can take place at
> subsequent pediatric ODAC meetings, discussing who we issue written
> requests to, etc.
>
> Again, I think that this was kind of a reevaluation of where we have
> gone with the previous four pediatric ODAC meetings, and really
> represents an excellent kind of launch off to starting a new
> commitment to pediatrics, especially with the more recent pediatric
> legislation.
>
> I would like to thank all of the people that were involved with the
> conduct of the meeting, as well as the participation at the meeting. A
> special thank you to Elaine Holland-Binding, from the American Academy
> of Pediatrics, who really kind of fostered this meeting and really put
> a lot of time and effort in this. We really appreciate also the
> advocacy community coming out and really expressing their opinions of
> where, in their opinion, we should go with this, as well as the
> academic physicians and practicing physicians, and other people from
> government.
>
> So, without any further comments, I wish you a happy summer, and we
> will be in contact with you in the early fall for future meetings.
> Thanks.
>
> \[Whereupon, at 3:40 p.m., the proceedings were adjourned.\]
>
> \- - -