ATDEPARTMENT OF HEALTH AND HUMAN SERVICES

> FOOD AND DRUG ADMINISTRATION
>
> CENTER FOR DRUG EVALUATION AND RESEARCH
>
> **PEDIATRIC SUBCOMMITTEE**
>
> **OF THE ONCOLOGIC DRUGS ADVISORY COMMITTEE**
>
> Thursday, October 17, 2002
>
> 8:25 a.m.
>
> Advisors and Consultants Staff Conference Room
>
> 5630 Fishers Lane
>
> Rockville, Maryland
>
> PARTICIPANTS
>
> Victor M. Santana, M.D., Chair
>
> Thomas H. Perez, M.P.H. Executive Secretary
>
> ODAC MEMBERS
>
> Jody L. Pelusi, F.N.P., Ph.D.
>
> Donna Przepiorka, M.D., Ph.D.
>
> Gregory H. Reaman, M.D.
>
> CONSULTANTS (VOTING)
>
> Peter Adamson, M.D.
>
> Alice Ettinger, R.N.
>
> Jerry Finklestein, M.D.
>
> Ruth Hoffman
>
> Robert Nelson, M.D., Ph.D.
>
> Patrick C. Reynolds, M.D.
>
> Victor Santana, M.D.
>
> Susan Weiner, Ph.D.
>
> GUEST SPEAKERS (NON-VOTING)
>
> Barry Anderson, M.D., Ph.D.
>
> Susan Blaney, M.D.
>
> Joachim Boos, M.D.
>
> Peter Houghton, M.D.
>
> Eric Kodish, M.D.
>
> Bruce Morland, M.D.
>
> Dave Poplack, M.D.
>
> Edward Sausville, M.D.
>
> Malcolm Smith, M.D.
>
> INDUSTRY GUESTS (NON-VOTING)
>
> David Emanuel, M.D.
>
> Anne Hagey, M.D.
>
> Judith Ochs, M.D.
>
> Wayne Rackoff, M.D. (by telephone)
>
> Steven Weitman, M.D.
>
> FDA
>
> Joseph Gootenberg, M.D.
>
> Steven Hirschfeld, M.D., Ph.D.
>
> Richard Pazdur, M.D.
>
> [C O N T E N T S]{.underline}
>
> [PAGE]{.underline}
>
> Call to Order and Introductions:
>
> Victor Santana, M.D. 5
>
> Welcome:
>
> Richard Pazdur, M.D. 8
>
> Conflict of Interest:
>
> Thomas H. Perez, M.P.H. 10
>
> Charge to the Committee:
>
> Steven Hirschfeld, M.D., Ph.D. 13
>
> Preclinical Models: What Can They Tell Us?
>
> Peter Houghton, Ph.D. 21
>
> Applying Preclinical Data to Clinical Studies:
>
> Edward Sausville, M.D. 38
>
> Applying Preclinical Data to Clinical Studies:
>
> Patrick C. Reynolds, M.D. 53
>
> Committee Discussion 64
>
> **Current Practice**
>
> Children\'s Oncology Group Perspective:
>
> Peter Adamson, M.D. 79
>
> Industry Perspective:
>
> Steve Weitman, M.D. 92
>
> European Perspective:
>
> Bruce Morland, M.D. 104
>
> European Perspective:
>
> Joachim Boos, M.D. 116
>
> Committee Discussion 130
>
> **Identifying and Overcoming Barriers**
>
> Children\'s Oncology Group Perspective:
>
> Gregory Reaman, M.D. 153
>
> National Cancer Institute Perspective:
>
> Barry Anderson, M.D., Ph.D. 163
>
> Children\'s Hospital and Specialty Group Perspective:
>
> Susan Blaney, M.D. 176
>
> [C O N T E N T S]{.underline} (Continued)
>
> [PAGE]{.underline}
>
> Open Public Hearing:
>
> Terry Rugg, M.D. 196
>
> **Identifying and Overcoming Barriers**
>
> **(Continued)**
>
> Industry Perspective:
>
> David Emanuel, M.D. 199
>
> Industry Perspective:
>
> Wayne Rackoff, M.D. 206
>
> Patient and Family Perspective:
>
> Ruth Hoffman 208
>
> Committee Discussion 219
>
> Questions to the Panel 245
>
> [P]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
> [E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
> [N]{.underline} [G]{.underline} [S]{.underline}
>
> **Call to Order and Introductions**
>
> DR. SANTANA: Good morning and welcome. This is one of a series of
> meetings that the Pediatric Oncology Subcommittee of the Oncology
> Drugs Advisory Committee for the FDA has had. We began our work, I
> believe in September of 2000 and have had a number of meetings
> advising the
>
> agency of issues related to pediatric oncology.
>
> Dr. Hirschfeld later on in the morning will actually describe for us
> the charge that we have before us today.
>
> With that, we will get the meeting started. I do want everybody to
> introduce themselves. Please use the microphone as there are minutes
> that are generated from this discussion, so please state your name,
> your affiliation.
>
> You have to hit the little talk button on the righthand side of your
> speaker. If it is turning red, you are being recorded, so be careful
> what you say among yourself. It will be there for posterity.
>
> Can we start with Joachim over here in corner, please.
>
> DR. BOOS: My name is Joachim Boos. I am coming from Germany, from the
> University of Münster and from the German Pediatric Oncology Society.
>
> DR. BLANEY: I am Susan Blaney from Texas Children\'s Cancer Center,
> Baylor College of Medicine.
>
> DR. HOUGHTON: Peter Houghton, St. Jude Children\'s Research Hospital.
>
> DR. POPLACK: David Poplack, Texas Children\'s Cancer Center, Baylor
> College of Medicine.
>
> DR. MORLAND: Bruce Morland, pediatric oncologist from Birmingham
> Children\'s Hospital in the UK, representing the United Kingdom
> Children\'s Cancer Study Group, New Agents.
>
> MS. HOFFMAN: Ruth Hoffman, Candlelighters Children\'s Cancer
> Foundation.
>
> DR. NELSON: Robert Nelson, Children\'s Hospital, Philadelphia.
>
> DR. REYNOLDS: Pat Reynolds, Children\'s Hospital, Los Angeles.
>
> DR. FINKLESTEIN: Jerry Finklestein, UCLA, Long Beach, and the American
> Academy of Pediatrics.
>
> MS. ETTINGER: Alice Ettinger, St. Peters University Hospital and the
> Association of Pediatric Oncology Nurses.
>
> DR. ADAMSON: Peter Adamson, Children\'s Hospital of Philadelphia,
> representing the Children\'s Oncology Group Developmental Therapeutics
> Program.
>
> MR. PEREZ: Tom Perez, Executive Secretary to this meeting.
>
> DR. SANTANA: Victor Santana from St. Jude Children\'s Research
> Hospital in Memphis.
>
> DR. PELUSI: Jody Pelusi, oncology nurse practitioner, and I am sitting
> as the consumer rep.
>
> DR. PRZEPIORKA: Donna Przepiorka, University of Tennessee Cancer
> Institute from ODAC.
>
> DR. REAMAN: Greg Reaman, Chairman of the Children\'s Oncology Group in
> Children\'s Hospital and George Washington University here in D.C.
>
> DR. WEINER: I am Susan Weiner. I am from the Children\'s Cause, and I
> am a patient rep.
>
> DR, HIRSCHFELD: Steven Hirschfeld, U.S. Public Health Service, Food
> and Drug Administration, the Division of Oncology Drug Products and
> the Division of Pediatrics.
>
> DR. GOOTENBERG: Joe Gootenberg, U.S. Food and Drug Administration,
> Center for Biologics, Oncology.
>
> DR. PAZDUR: Richard Pazdur, Division of Oncology Drug Products, Food
> and Drug Administration.
>
> DR. SMITH: Malcolm Smith, Cancer Therapy Evaluation Program, National
> Cancer Institute.
>
> DR. SAUSVILLE: Ed Sausville, Developmental Therapeutics Program,
> National Cancer Institute.
>
> DR. ANDERSON: Barry Anderson, Cancer Therapy Evaluation Program,
> National Cancer Institute.
>
> DR. OCHS: Judith Ochs, AstraZeneca Pharmaceuticals.
>
> DR. HAGEY: Anne Hagey, Abbott Pharmaceuticals.
>
> DR. WEITMAN: Steve Weitman, Ilex Oncology.
>
> DR. SANTANA: Anybody on the phone that wants to introduce themselves?
>
> DR. RACKOFF: This is Wayne Rackoff with Johnson & Johnson.
>
> DR. SANTANA: Thank you, Wayne.
>
> I am going to pass on the microphone to Richard Pazdur, the Director
> of the Oncology Drugs Program for a brief welcome.
>
> **Welcome**
>
> DR. PAZDUR: I would just like to thank you on behalf of the Center for
> Drug Evaluation and Research and the FDA for your attendance at this
> meeting.
>
> It also gives me great pleasure to introduce one of our new members
> basically to the Center for Drug Evaluation, and that is Dr. Shirley
> Murphy, who assumed the position of Director of the Division of
> Pre-Pediatric Drug Development, whose mandate is basically to
> implement the Best Pharmaceuticals in Children\'s Act.
>
> Dr. Murphy has had a long academic career. She was Chair of the
> Department of Pediatrics at the University of New Mexico, is a
> renowned pediatric immunologist and pulmonologist, and before joining
> the FDA spent four years in industry.
>
> Shirley, do you have any words?
>
> DR. MURPHY: I am just very happy to be here. Actually, Jerry
> Finklestein was my mentor. He was the faculty person when I was a
> resident, and this is the first time I have seen him in 20 years, and
> he looks\--or I think it is more than 20, Jerry\--but he looks better
> than ever.
>
> When I was a resident, I took care of his oncology patients when he
> would go on vacation, so it is very happy to come full circle and be
> part of the children\'s oncology community. I look forward, through
> the legislation that we have together, we are really mandated to bring
> oncology medications forward for children and to make sure children
> aren\'t left out of the loop.
>
> So, I look forward to working with all of you.
>
> DR. PAZDUR: Thank you, Shirley, and we honestly look forward within
> the center and also within this committee to work with you. Thanks.
>
> DR. SANTANA: Thanks to both of you, and we also do welcome your
> involvement and helping us figure all these issues out.
>
> I think we have an administrative issue, which is the conflict of
> interest, so I will have Mr. Perez read that document, please.
>
> **Conflict of Interest**
>
> MR. PEREZ: Thank you.
>
> The following announcement addresses the issue of conflict of interest
> with respect to this meeting and is made a part of the record to
> preclude even the appearance of such at this meeting.
>
> The topics of today\'s meeting are issues of broad applicability.
> Unlike issues before our committee in which a particular product is
> discussed, issues of broader applicability involve many industrial
> sponsors and academic institutions.
>
> All special government employees and federal guests have been screened
> for their financial interests as they may apply to the general topics
> at hand.
>
> Because they have reported interests in pharmaceutical companies, the
> Food and Drug Administration has granted general matters waivers to
> the following special government employees which permits them to
> participate in today\'s discussions: Dr. Peter Adamson, Dr. Jerry
> Finklestein, Dr. Robert Nelson, Dr. Jody Pelusi, Dr. Donna Przepiorka,
> Dr. Greg Reaman, Dr. Victor Santana, Dr. Susan Weiner, and Ms. Alice
> Ettinger.
>
> A copy of the waiver statements may be obtained by submitting a
> written request to the Agency\'s Freedom of Information Office, Room
> 12A-30 of the Parklawn Building.
>
> Because general topics impact so many institutions, it is not prudent
> to recite all potential conflicts of interest as they apply to each
> member, consultant, and guest.
>
> FDA acknowledges that there may be potential conflicts of interest,
> but because of the general nature of the discussion before this
> subcommittee, these potential conflicts are mitigated.
>
> We would also like to note that Dr. Anne Hagey, Dr. David Emanuel, Dr.
> Judith Ochs, Dr. Wayne Rackoff, and Dr. Steven Weitman are
> participating in today\'s meeting as non-voting industry guests. As
> such, they have not been screened for conflicts of interest.
>
> In the event that the discussions involve any other products or firms
> not already on the agenda for which FDA participants have a financial
> interest, the participants\' involvement and their exclusion will be
> noted for the record.
>
> With respect to all other participants, we ask in the interest of
> fairness that they address any current or previous financial
> involvement with any firm whose product they may wish to comment upon.
>
> That concludes the conflict of interest statement.
>
> I would like to acknowledge that on the phone we have one guest
> participant, Dr. Wayne Rackoff from Johnson & Johnson. Also, on the
> phone, if not now, maybe later, are representatives of the European
> Medicinal Evaluation Agency. They have a number of individuals that
> will be listening in, not participating, in today\'s meeting.
>
> The EMEA has been intimately involved with the FDA in the development
> of guidances on many topics, areas that are of mutual interest to both
> agencies. Today\'s topic is one of these areas and therefore they have
> been invited to listen in to the meeting\'s discussions.
>
> Thank you.
>
> DR. SANTANA: Thanks, Tom.
>
> Does anybody have any conflicts of interest that they wish to further
> disclose?
>
> \[No response.\]
>
> DR. SANTANA: Thank you.
>
> I am going to now invite Steve Hirschfeld from the Division of
> Oncology Products to give the charge to the committee and overview of
> the issue at hand today.
>
> Steve.
>
> **Charge to Committee**
>
> DR. HIRSCHFELD: Good morning, everyone, and welcome to this meeting of
> the Pediatric Subcommittee of the Oncologic Drugs Advisory Committee.
> This is our first meeting under the new mandate from the Best
> Pharmaceuticals for Children Act, and this committee has been written
> into law, which I think is a recognition of the importance of the work
> of this committee.
>
> I would like to thank some people. To begin with, I want to thank
> Captain Thomas Perez of the U.S. Public Health Service for picking up
> the administrative responsibilities for this committee, which have
> been complex and diverse, and for coordinating the many, many tasks
> which were required to put this meeting together. I think he has done
> it not only successfully, but in an exemplary way, so thank you,
> Captain Perez.
>
> I want to thank also Dr. Richard Pazdur, who has been involved from
> the inception of this committee and has been not only supportive, but
> a participant in every one of the meetings.
>
> There are some other people, too many in fact to recite by name, but I
> wanted to note that we have on our panel today two people who have at
> great inconvenience, but nevertheless with overwhelming enthusiasm,
> come great distances to be here.
>
> That is Professor Joachim Boos from the University of Münster and
> Professor Bruce Morland from Birmingham Children\'s Hospital, so thank
> you both for making that long transatlantic trip and coming here.
>
> I also want to acknowledge the participation of our colleagues from
> the EMEA and then a special acknowledgment because so many people, not
> only in this room, but on this very panel, have been under the
> tutelage over the years of one of the guiding lights I find of
> pediatric oncology, who has been not only a supporter but a
> participant and a contributor to the deliberations of this committee,
> and that is Dr. David Poplack, so thank you for your participation,
> too.
>
> \[Slide.\]
>
> This committee first met in September 2000 with a charge of attempting
> to put a framework on an interpretation of the Pediatric Rule. The
> Pediatric Rule stated that if a product was under review for an
> indication that was found in adults, that there was a mandate to
> develop that product for children.
>
> In oncology, this is particularly challenging because depending upon
> how one looks at classifications, there are over 150 cancers, and we,
> as pediatric oncologists, have been always telling the world that
> children are different and pediatric tumors are different, but as we
> have increased our understanding of the biology of tumors, we see that
> it was, to paraphrase Walter Pater in his Essays on the Renaissance,
> it was only the limitations of the eye which made us think that some
> things were the same or some things were different.
>
> As new techniques have evolved, we have attempted to incorporate that
> thinking into our deliberations. So, in September 2000, we had a
> meeting of the discussion of methods that may be used to describe and
> link tumor types.
>
> Then, in April 2001, we focused that discussion on hematologic tumors,
> and in June 2001, we discussed solid tumors and central nervous system
> malignancies.
>
> These discussions led to recommendations on how one might approach,
> both in general principles and with some specific examples, of linking
> various tumors on a variety of bases. One of the maxims that my
> pathologist colleagues always tell me is that there are three things
> that are certain in life - taxes, death, and classification systems
> will change.
>
> So, we wanted to have a flexible approach that would allow us to
> continue to interpret the classification system, so that we could be
> sure that if it was possible within our scope to enhance product
> development for children with cancer, we would have that opportunity.
>
> We had tried to apply some of these at a meeting in November 2001
> where we discussed study designs and the general principles involved
> in how we might extrapolate information or borrow data as the case may
> be, and that will be one of the themes which we will talk about today
> in our meeting October 2002, what data may we borrow, what data should
> we look at in terms of making determinations of when pediatric studies
> should be initiated in children with cancer in a drug development
> program.
>
> \[Slide.\]
>
> There is a formal statement regarding pediatric clinical studies which
> was promulgated from\--and several people in this room and on the
> telephone have worked on it\--an efficacy topic called E-11 from the
> International Conference on Harmonization.
>
> The premises of that 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, that pediatric
> development should not delay adult studies nor adult availability, and
> lastly, and I think importantly, that shared responsibility among
> companies, regulatory authorities, health professionals, and society
> as a whole.
>
> This committee represents all of those constituencies, and we will
> together share that responsibility and hope that we could make
> progress.
>
> \[Slide.\]
>
> The document addresses when pediatric clinical studies should be
> initiated in two sections. One section is addressing when diseases
> predominantly or exclusively affecting pediatric patients are under
> study, and the recommendation is that the entire development program
> will be conducted in the pediatric population except for initial
> safety and tolerability data, which will usually be obtained in
> adults.
>
> The \"usually be\" is an interpretive phase which perhaps we can
> discuss during the course of this conference.
>
> \[Slide.\]
>
> The other circumstance, which may be more applicable to the pediatric
> malignancies that we are focused on, is when serious or
> life-threatening diseases, which occur in both adults and pediatric
> patients, for which there are currently no or limited therapeutic
> options.
>
> Then, the medicinal product development should begin early in the
> pediatric population, following assessment of initial safety data and
> reasonable evidence of potential benefit.
>
> These recommendations were reached by international consensus among
> the Japanese, the Europeans, and the Americans, and although several
> people in this room and others have worked on this, we all recognize
> that these were in effect interim statements.
>
> They were worded in such a way that they could be interpreted in the
> various regions and at various times, give us a great deal of
> flexibility.
>
> \[Slide.\]
>
> What we would like to do today is ask the question: What information
> is necessary to consider exposing children with cancer to an
> investigational agent, or to paraphrase, what should the evidence
> burden be?
>
> There is a fairly well known routine from a review called Beyond the
> Fringe, that the late Peter Cook and the late Dudley Moore did where
> they interviewed, in their impersonations, Bertrand Russell.
>
> They were asking him whether he wanted apples, and there were many
> permutations on trying to get an answer out. Included in those was
> \"could\" or \"should\" or \"must,\" so in order to clarify, I think
> we consider all these possibilities, but the encompassing phrase that
> I would want to recommend in the accompanied principle is what should
> be necessary to consider exposing children with cancer to an
> investigational agent.
>
> So, best of luck and we will eagerly await your deliberations.
>
> Thank you.
>
> DR. SANTANA: Thanks, Steve.
>
> I think we are going to have a session after the initial presentations
> for comments and discussion, so if anybody has any comments or further
> questions to Steve, we could come back to him then.
>
> I want to start the official presentations by inviting Dr. Peter
> Houghton to give us the initial talk that hopefully will lead to a
> discussion of how we can use preclinical models to help us, guide us
> more appropriately in trying to deal with some of these issues.
>
> DR. HIRSCHFELD: While we are working on the audiovisual adjustments, I
> did want to also have a special acknowledgment for the outstanding job
> that Victor Santana has done as chair of this committee. He has had
> multiple responsibilities, and yet has always found time to put, not
> only full effort in preparing for these meetings, but has sometimes
> done double duty as a presenter and a discussant and a chair, and has
> managed to have our meetings run exceptionally well and concluding all
> time.
>
> So, thank you, Victor.
>
> DR. SANTANA: Thanks, Steve. In spite of all that, I still have a job
> at St. Jude.
>
> **Preclinical Models: What Can They Tell Us?**
>
> **Peter Houghton, Ph.D.**
>
> DR. HOUGHTON: It is particularly a pleasure to be here this morning as
> I am playing hooky from the Study Section in another part of
> Washington.
>
> \[Slide.\]
>
> Victor has asked me to talk about preclinical models and what they can
> tell us, in particular, how can we develop drugs in a rational way for
> treatment of children with cancer even in the absence of some adult
> data.
>
> I am going to show you some of the work we have done over the years
> that suggest that there are preclinical models that may be quite
> predictive of therapeutic utility of some drugs.
>
> Obviously, no model is perfect, but I think if we use these models
> reasonably intelligently, they can be quite informative and guide us
> in both identification of drugs that might be useful in children and
> how perhaps to best use them in the clinical situation.
>
> \[Slide.\]
>
> About 20-plus years ago, we started to think about drug development
> and how drug development for childhood cancers has to be somewhat
> different because of the limitations and restrictions that are imposed
> upon developing drugs for children in relatively rare diseases.
>
> It is clear that virtually no drugs are being developed specifically
> to treat childhood cancers and particularly solid tumors, so our aim
> was to develop and validate tumor models to potentially identify
> important new drugs.
>
> Then, in terms of Phase I testing, how do the Phase I trials really
> help us to prioritize drugs for Phase II evaluation, and again to
> develop models that might help develop a process allowing a more
> rational prioritization.
>
> If we look at the Phase II component of pediatric clinical trials, we
> can ask whether those trials really reveal any insight as to whether a
> drug succeeds or fails, and to try and develop models that might help
> us to understand the success or failure of clinical trials.
>
> \[Slide.\]
>
> So, the models that we started developing in the early \'70s and then
> with respect to pediatric cancers, when I went to St. Jude in the late
> \'70s, human cancers grown in immune-deficient animals,
> immune-deprived or congenitally athymic or SCID mice.
>
> These models have been developed by many groups around the world,
> essentially, now I think we have encompassed most of the models of
> various childhood cancers, solid tumors, and also there are groups
> that have models now of acute lymphocytic leukemia from childhood both
> at the diagnosis and relapse stage.
>
> \[Slide.\]
>
> When we look at these types of models, we have to think about how to
> validate them, and in the premolecular characterization era, one of
> the ways of doing this was to ask whether the models respond
> qualitatively and quantitatively to drugs known to be active in the
> respective clinical disease.
>
> So, we can ask if a diagnosis model of rhabdomyosarcoma, for example,
> whether it is highly sensitive to the drugs that are active in the
> clinic, and clearly, that is the case.
>
> We can ask whether tumors developed from children that relapse from
> therapy are significantly less responsive to those drugs in the mouse,
> and that clearly is the case, and that tells us that it is not just a
> consequence of transplanting a human tumor into a mouse that dictates
> the response.
>
> Then, we can ask whether the models prospectively identify effective
> agents. We started to look at this in the mid-\'80s with Mark Horowitz
> and Andy Green at St. Jude, and demonstrated that these models could
> be quite useful in a prospective mode.
>
> So, we look at retrospective data where we look at the drugs that are
> shown to be active in the clinics, vincristine, cytoxan, dactinomycin,
> adriamycin, the first three being sort of standard therapy for
> rhabdomyosarcomas, we can see that in the panel of xenografts, we get
> a fairly high response rate to vincristine, the lowest response rate
> to dactinomycin.
>
> On the right side of the presentation, you see the reported clinical
> response rates to single agents, so this is pretty historic data, and
> may not be currently applicable to the way these drugs are given at
> the present time, but at least there is an interesting correlation
> between the activity in the model systems, and the model systems
> clearly show activity of drugs that are known to be active if you use
> the criteria in the model system that is used in the clinic.
>
> We are not particularly interested in growth inhibition, we are
> interested in tumor regressions and complete regressions as being
> objective responses in the mouse.
>
> If we look at the model systems in a prospective mode, in the
> mid-\'80s, we identified melphalan, as I mentioned, with Mark Horowitz
> and Andy Green, and showed that in the model systems, melphalan, a
> bifunctional alkylating agent, is extremely active in these models,
> and clinically, at St. Jude, it was shown to be effective in around 80
> percent of children at diagnosis with Stage 4 rhabdomyosarcomas in an
> upfront window trial.
>
> More recently we have looked at topotecan. The response rate in the
> xenografts is around 70 percent, and has clear activity in clinical
> rhabdomyosarcoma, interestingly, with a higher response rate in the
> alveolar subtype rhabdomyosarcomas, which is the predominant model
> that we use in the preclinical setting.
>
> \[Slide.\]
>
> Turning to another model which we have developed quite recently is
> models of Wilms\' tumor. We are trying to develop a model of diffuse
> anaplastic Wilms\' tumor, which is very rare, but is chemo-refractory
> and has a poor prognosis, but to do this, we have to establish a very
> large number of Wilms\' tumors, and most of them have been of
> favorable histology shown from WT1 through WT10.
>
> These tumors are exquisitely sensitive to vincristine. The 6+ on these
> graphs is complete regression without growth during a 12-week period
> of observation. Similarly, most of these tumors show objective
> responses either in PRs or CRs to cytoxan in the model system, again
> very consistent with the activity of these drugs in Wilms\' tumor of
> favorable histology.
>
> In the bottom line SKNEP, which is a diffuse anaplastic, is much less
> sensitive to vincristine although it retains sensitivity to cytoxan.
> So, we produced this model to see if we can identify prospectively
> drugs that might be of value in relapsed Wilms\' tumor and the
> camptothecin agent, topoisomerase I, topotecan, they are exquisitely
> sensitive to this agent, and this has been the subject of a Phase I
> trial with Jeff Dome at St. Jude, and will subsequently be put into a
> national trial based on some rather promising results even in the
> Phase I trials.
>
> \[Slide.\]
>
> So, the other aspect is the more modern characterization of these
> tumors, and that is to look at them in terms of gene expression and
> proteomics, and the Wilms\' tumors have a very high level of
> expression in certain kinesians, much higher than any other tumor that
> has been identified by the Glaxo/Smith/Kline group.
>
> Consequently, we are working with GSK now to see if a particular
> inhibitor will have significant activity against Wilms\' tumors,
> perhaps moving us into more of the molecular realm of drug
> development.
>
> \[Slide.\]
>
> So, where do xenograft models fit? We believe they can be useful for
> identification of novel agents, both classical cytotoxic agents and
> those that work through defined molecular targets.
>
> We believe we can identify drugs that have very broad spectrum
> activity both in a wide range of pediatric tumor types when grown in
> animals. We can identify drugs that show a lack of cross-resistance
> with currently available therapy.
>
> We believe that the model systems may be helpful in optimizing
> schedules of administration and will allow us to develop relationships
> between tumor response and the systemic exposure of these drugs, and I
> am going to deal with these last two points in a little bit more
> detail.
>
> \[Slide.\]
>
> These are examples of tumor growth and the schedule dependency of the
> camptothecin agent irinotecan CPT level. Shown on the left panel is
> the growth of individual tumors in mice, in SCID mice, without
> treatment.
>
> In the center panel, we are looking at the effect of CPT-11 given for
> five days with cycles repeated every 21 days over the first eight
> weeks.
>
> In the right panel, the drug is given over 10 days.
>
> What is important to note is the total dose per week and total dose
> over the entire course of therapy between the two groups is identical,
> so lower doses for a longer period of time are clearly more effective
> than are short, more intense courses. This applies to all the
> camptothecin agents we have looked at so far.
>
> \[Slide.\]
>
> At least initial preliminary data largely from Phase I trials suggest
> that there may be some benefit in going to longer dosing schedules. At
> the top is shown available clinical data for topotecan, and at the
> bottom is shown irinotecan data.
>
> One can see that with a daily times 5, we are seeing even in Phase I
> some activity around 8 percent, but the two trials that have looked at
> the protracted schedules of 5 days times 2 are showing considerably
> higher response rates.
>
> Similarly, if we look at the bottom panel, the two studies that are
> published using daily times 5 times 2 schedule are clearly giving
> response rates that are higher than this obtained for the daily times
> 5.
>
> This is Phase I data, and obviously, it would be nice to do a
> randomized study in Phase II, but I think the animal data is very
> compelling. The protracted scheduling of these drugs, which are after
> all very specific cell cycle dependent killing agents that work only
> in S-phase during DNA replication, that a protracted schedule of
> administration makes a lot of sense based on the mechanism of action
> of this class of agent.
>
> \[Slide.\]
>
> So, we have, rather than using mouse maximum tolerated doses, we have
> tried to develop relationships between response and drug systemic
> exposure.
>
> \[Slide.\]
>
> So, we have taken tumors from children, grown them in a variety of
> mice, and then we can look at questions of dosing, schedules of
> administration, and relate this to the pattern, pharmacokinetic
> pattern in terms of systemic exposure and AUC.
>
> Then, we have taken this information and have designed clinical trials
> that as closely as possible paralleled the results we have obtained in
> the animals, perhaps to give optimal dosing of these drugs.
>
> So, this allows us to make a comparison of the systemic exposure, the
> AUC, at a maximum tolerated dose in patients, with the AUC causing
> tumor regressions in the model systems.
>
> \[Slide.\]
>
> Retrospectively, we can look at data that we have generated over the
> last, say, 10 years, and look at a group of drugs that really have not
> had any activity in the clinic, yet, have had activity in the model
> systems, or alternatively, have had activity in model systems and have
> activity in the clinical situation.
>
> What I have done here is to show you the relative tolerance of the
> mouse relative to human, AUC, the systemic exposure of a drug at a
> maximum tolerated dose in the mouse divided by AUC at the MTD in the
> human.
>
> You can see for DMP-840, there is about a 15- to 20-fold greater
> tolerance in the mouse than there is in patients. For carzelesin, it
> is around 80-fold difference.
>
> On the other hand, on the right column, if we look at the effective
> dose range, so if we are looking for objective responses as a function
> of decrease from the MTD, the maximum tolerated dose in the mouse, we
> see that most of these drugs have a very limited range with effective
> dosage, so carzelesin, for example, we achieve 80 times greater
> systemic exposure in the mouse than human, and yet, the effective dose
> range from the MTD in the mouse is less than 2, so if we divide the
> dose from the MTD by half, we still lose any objective regressions in
> model systems.
>
> On the other hand, we take a drug such as melphalan, where there is a
> positive activity in the clinic and in the model systems, we see that
> the AUCs are essentially identical in mouse and human, the dose
> effective range is 3- to 4-fold, and we see activity in the clinic.
>
> For a drug such as irinotecan, which is really a very exceptional
> drug, we see that the mouse is about 16-fold more tolerant to the
> active metabolite SN-38. The dose effective range of this drug is
> around 100, the reason for that, we have at this point no idea.
>
> \[Slide.\]
>
> On the other hand, we can take a drug that is currently in Phase I and
> potentially could go into Phase II, MGI-114, and we see that the
> maximum tolerated dose, we see dramatic activity in 14 out of the 16
> tumors. Anything that is a 4+ on this table is an objective regression
> 50 percent, 5+ is a complete response, 6+ is complete response without
> regrowth during a 12-week period of observation.
>
> One can see dramatic activity at the MTD in the mouse, but if we
> reduce that dose by 4- to 5-fold, we see that, in reality, there is
> only one objective response out of 14 tumors that have been evaluated.
>
> The problem is even at this dose, we are still 10-fold above the
> systemic exposure that can be achieved in children. So, this would be
> a drug that we would say would have a low priority to go forward in a
> Phase II trial.
>
> \[Slide.\]
>
> So, with respect to neuroblastoma, we have made one preclinical
> prediction. Using the topotecan scheduling of daily times 5 times 2,
> so it is Monday through Friday, Monday through Friday in the animals
> because we don\'t treat them at the weekends.
>
> Preclinically, we saw activity, objective responses in 4 out of 6
> tumors at a systemic exposure of 100 ng.hr/ml topotecan lactone, which
> is the active form.
>
> So, we conducted a targeted Phase II trial under the leadership of
> Victor Santana at St. Jude to target the exposure to 100 ng.hr/ml plus
> or minus 20 percent. In clinical Stage IV Neuroblastoma, the responses
> of that trial are 16 out of 28 partial responses or around 57 percent,
> suggesting that if we translate accurately will be doing the animals,
> then, there is a good correlation with clinical activity.
>
> \[Slide.\]
>
> So, where do xenograft models fit in drug development for childhood
> cancer? It really would be nice to include pediatric tumor models in
> the early stages in NCI screening or industry or academia, but having
> tried that for about 20 years, it seems fairly unlikely to happen.
>
> We believe that the models will be able to prospectively identify
> active agents. We believe that the models can be used for optimizing
> administration schedules and perhaps putting the appropriate schedule
> into the clinic at an earlier time.
>
> We believe that the models may be useful for prioritizing agents that
> go into Phase I as there are many agents out there with little basis
> for anticipation that they will have activity in pediatric tumors, and
> we believe that the system may allow rational decisions to advance or
> stop development from the Phase I to the Phase II step, because Phase
> II trials in pediatrics, especially single institution Phase II trials
> can take several years and consume considerable resources.
>
> I think the data from the animal models will certainly help us to
> focus Phase II trials where appropriate.
>
> \[Slide.\]
>
> So, in conclusion, valid models of childhood cancers do exist if they
> are used intelligently. Models reflect clinical drug sensitivity.
>
> Species differences in drug disposition, metabolism, and tolerance are
> the major problems in accurately translating results.
>
> The models accurately identify clinically active agents when systemic
> exposure is normalized between species.
>
> \[Slide.\]
>
> In terms of practical considerations, what do we need? We need access
> to drugs at an early stage. We need to establish a national consortium
> to encompass virtually all of the frequently occurring pediatric
> tumors.
>
> We need to develop predictive pharmacokinetic models to translate data
> from the animals to the clinic.
>
> We need to characterize available models through genomic or proteomic
> screens to identify molecular targets that are expressed in the
> pediatric tumors that may be the subject of drug development for adult
> malignancies.
>
> We need to develop a funding mechanism to support experimentalists
> involved in preclinical to clinical translational studies.
>
> In terms of characterization of current models using molecular
> techniques, this is an initiative developed through CTEP at the NCI
> through Malcolm Smith and Barry Anderson, and similarly, the idea of
> establishing a national consortium is also being led by the same two
> individuals and Peter Adamson, COG.
>
> \[Slide.\]
>
> So, this is the proposed schema for developing a national consortium
> with Tumor A through E, panels of different pediatric childhood
> cancers that will be evaluating drugs in various sites around the U.S.
> and perhaps abroad, but the idea is to bring in a drug, drug X from a
> pharmaceutical company, then, to screen according to the wiring
> diagram shown here.
>
> The idea is to identify drugs that have a specific activity against a
> particular tumor at the MTD in mice, but then if so, to do a full
> dose-response curve pharmacokinetic work-up and, where appropriate, to
> use transgenic or orthotopic models as secondary screens after
> subcutaneous xenograft evaluation, and then to take this data and,
> through central analysis, refer it back to the Developmental
> Therapeutics Committee of the Children\'s Oncology Group to allow and
> hope some prioritization of drugs going into pediatric trials.
>
> What this clearly needs is a buy-in from the pharmaceutical industry
> where they will allow early access to drugs that are in early clinical
> trials to be put through the screening model with the hope of
> identifying drugs that will be helpful to pediatrics.
>
> Thank you.
>
> DR. SANTANA: Thanks, Peter. I am going to hold questions and comments
> because we do have a brief period after the three presentations, and
> these three presentations kind of carry the same theme.
>
> I want to thank Peter again and then I am going to invite Ed to go
> ahead and give us his perspective.
>
> **Applying Preclinical Data to Clinical Studies**
>
> **Edward Sausville, M.D.**
>
> DR. SAUSVILLE: Thank you very much. I am happy to have this
> opportunity to present a perspective from the Developmental
> Therapeutics Program at NCI on these important issues.
>
> I would like to, first of all, have a bit of a disclaimer. I am not a
> pediatrician, so the perspectives that I have been asked to address
> would be of general relevance as we apply them to adults, but as you
> will see, I think they raise a number of issues that will come up in
> the course of the day.
>
> \[Slide.\]
>
> The goals of preclinical drug studies proceed at least from a
> regulatory framework from the standpoint of deriving the data to
> support an Investigational New Drug application. This is approval by
> the FDA to conduct human studies, and the main criteria is safety and
> likely reversible toxicity to allow the start of Phase I trials.
>
> There are a number of special issues that one could imagine coming up
> in the development of pediatric Phase I oncology drugs. There are
> relatively few things we compare to the adult population of patients,
> however, there are many agents, and therefore the question comes up of
> how we can best match the patients to drugs that are available that
> hopefully would ultimately benefit them.
>
> There is clearly an unmet medical need with respect to the patients in
> the pediatric population that come to the point of being candidates
> for this, however, there are ethical concerns in that whereas in
> adult, there is the capacity to make an informed consent and
> oftentimes in the populations that are selected for study, not the
> need for urgent response, this clearly is not the case in the
> pediatric population.
>
> These patients in the pediatric age group frequently have seen much
> prior treatment, are on a number of concomitant medications, and
> therefore, how these might influence the experience of an initial
> first in human drug as applied to the pediatric population is a
> concern.
>
> Lastly, as we have heard many times, pediatric patients have a unique
> biology both in the tumor and the host, and therefore the value of
> adult data in study design, I think is of issue and will be considered
> in this meeting.
>
> \[Slide.\]
>
> Now, the classical NCI recommendations that have governed the entry of
> new drugs\--and this is from a paper from Sylvia Marsoni and
> colleagues, she is now back in Milan, which emanates from her time at
> the NCI\--is to begin studies in pediatric patients with solid tumors
> and leukemias at 80 percent of the maximal tolerated dose observed in
> adults with solid tumors. So, in essence, there would be prior adult
> data prior to beginning the pediatric studies.
>
> To enter solid tumor and leukemia patients at each level, and escalate
> in fixed, 20 percent increments, distinguishing myelosuppressive
> toxicity that might be actually desirable in the leukemia population
> versus non-myeloid toxicity.
>
> In the absence of non-myeloid toxicity, to escalate beyond the solid
> tumor MTD in leukemia patients, in children.
>
> \[Slide.\]
>
> However, there are a number of issues that have come to the fore that
> question this basis and urge every consideration of this classical
> practice.
>
> First of all, from the standpoint of biology, pediatric tumors may
> have, and indeed have been demonstrated to have, targets that are
> intrinsically different from adults, and therefore adult data will
> never actually be available for drugs directed to these targets.
>
> From the standpoint of pharmacology, past practice is weighted toward
> cytotoxics. The question of the relevance of these practices to
> so-called \"targeted\" agents that might not have cytotoxic endpoints
> could be questioned.
>
> Then, in terms of timing, there are many new agents. There has been an
> explosion of interest in the pharmaceutical industry and academia over
> the past 10 years, and therefore a delay in completing adult studies
> before application in pediatric neoplasms may therefore actually
> exacerbate the unmet medical need.
>
> \[Slide.\]
>
> Now, just to focus and clarify the components of an IND, and this is
> primarily for didactics, but in addition to the definition of the
> substance and the actual clinical plan, the critical issues in putting
> together the IND is the pharmacology and toxicology information and
> prior human experience that go into this.
>
> \[Slide.\]
>
> So, how are Phase I dose and schedule fixed in adults? Animals,
> usually mouse studies in models, define likely active schedules\--and
> Peter did a great job in illustrating some of the ways that these can
> be used\--bearing human-derived tumors.
>
> The likelihood of human activity is essentially stochastic, the more
> models with activity, the greater likelihood of human activity.
> Limitations, as Peter stated, are the difference between animal and
> human pharmacology and metabolism.
>
> Drug concentrations or the effect on the target, as Peter illustrated,
> and particularly with respect to pharmacology, can provide very
> important ancillary information.
>
> Toxicology is conducted according to a series of protocols developed
> by the NCI in the 1970s and which address the requirements of the FDA.
>
> The starting dose is a fraction of a dose causing no or minimal
> reversible toxic effects, and escalation of dose steps occurs in a way
> that would likely capture a reversible toxic effect.
>
> \[Slide.\]
>
> So, what are the problems with so-called maximum tolerated dose driven
> endpoints?
>
> Drugs regulating pathways important in oncogenesis or tumor biology
> are effective by combining with high affinity binding sites,
> therefore, one must distinguish between targeted in comparison to
> non-targeted toxicity in relation to these binding sites.
>
> Clearly, if the tumor or organism does not reliably express a basis
> for a targeted effect, there could be a misprediction of the potential
> value of the agent.
>
> Whether dosing beyond the effect on the desired target buys additional
> therapeutic value is not clear. Therefore, an additional interest is
> to define, in preclinical studies, a biologically effective dose, as
> well as the maximum tolerated dose.
>
> One could imagine, therefore, using a biologic rather than toxic
> endpoints in Phase I.
>
> This issue is as important in the agents that are under development
> for adults as with children.
>
> \[Slide.\]
>
> Now regulatory considerations for preclinical development of
> anticancer drugs\--again, this is an area that has been written about
> and discussed by many colleagues at the FDA\--and in this recent
> article from DeGeorge and colleagues, the types of preclinical studies
> expected for support of clinical trials has to consider the intended
> use of the drug, as well as the population of patients being studied.
>
> In situations where potential benefits are greatest, greater risks of
> treatment toxicity can be accepted provided that they are addressing
> these at-risk populations and therefore the required clinical testing
> can be relatively minimal.
>
> \[Slide.\]
>
> The application of this through the years has led to a relatively
> abbreviated toxicology for oncology drugs where, in the case of small
> molecule agents, two species, one rodent and one non-rodent, and in
> usual practice, this is usually rats and dogs, are studied on a
> clinical route and schedule that again follows NCI guidelines.
> Although pharmacokinetics is optional in a regulatory sense, it is
> strongly encouraged.
>
> Biologicals, in contrast, have a somewhat different approach where the
> focus is a most relevant species, and this is usually a non-human
> primate, again following the clinical route and schedule.
>
> \[Slide.\]
>
> The objectives in preclinical toxicology and safety studies are to
> determine in appropriate animal models, the maximum tolerated dose on
> the desired schedule and elicitation of dose-limiting toxicities, the
> definition of schedule-dependent toxicities, the documentation of the
> reversibility of adverse effects over the likely dose range to be
> studied with the goal of defining a safe starting dose.
>
> \[Slide.\]
>
> I list here the so-called standardized NCI protocols from a relatively
> earlier era where, in mice, dogs, and rodents, there is determination
> of lethal doses at various fractions of the dose range anticipated to
> be used in humans.
>
> \[Slide.\]
>
> Over the past decade, NCI toxicology philosophy has evolved somewhat,
> so that we now focus on so-called agent-directed studies that are
> importantly, pharmacologically guided and to integrate the safety
> studies with the preclinical efficacy data and the proposed clinical
> protocol.
>
> This would lead to a rational evaluation of the role of schedule
> dependence, pharmacokinetics, and metabolism in the development of
> toxicity, and relate plasma drug levels and area under the curve to
> the safety and occurrence of toxicity.
>
> Actually, as Peter illustrated, this would be an important opportunity
> to correlate with activity in the preclinical models.
>
> And, importantly, to extrapolate toxic effects across species.
>
> \[Slide.\]
>
> The goal of this is certainly a better scientific basis for
> development, greater flexibility in designing dose schedules, and
> allowing a data-rich IND submission to support Phase I and hopefully,
> in a variety of the ways listed here, optimize the Phase I experience.
>
> \[Slide.\]
>
> So, to illustrate this briefly, just so that everyone has a common
> viewpoint of how this proceeds, and all this data has been disclosed
> in various AACR and other presentations, Ishihara Sangyo Kaisha
> submitted a series of benzophenylureas, shown here, and using a series
> of pharmacology studies, it was possible to show that, in essence, the
> dimethyl was a prodrug for the other forms and that this was chosen to
> move forward.
>
> \[Slide.\]
>
> In a variety of tumor xenograft models, there was percent tumor over
> control, no worthy evidence of activity on a schedule that was
> intermittently either parenterally or by an oral regimen.
>
> \[Slide.\]
>
> This led to toxicology studies that exactly mirrored that schedule. In
> the rat, the MTD was 360 mg/M^2^, in the dog, somewhere between 150
> and 240, and therefore, this experience drove the determination of a
> starting dose, which as you can see was one-sixth to one-tenth of that
> maximum tolerated dose in the sensitive species. In both species,
> there was concordance of the toxic effects because at dose-limiting
> effects on marrow and GI tract were observed.
>
> \[Slide.\]
>
> In addition to this, in addition to the safety information, one
> determines what the efficacious drug levels in plasma are, correlates
> drug plasma levels and the area under the curve with toxicity and
> safety, and attempts to ameliorate toxicity by changing the route and
> schedule, and compare toxicity with accepted clinical agents when that
> is appropriate.
>
> \[Slide.\]
>
> Just to emphasize the point that Peter made, and there are important
> influences on schedule and route and the appearance of toxicity, some
> recent examples are listed here. If one looks at penclomedine, when
> given as a bolus, neurotoxicity is dominating, when orally given, bone
> marrow toxicity dominates. So, this information is very important and
> routinely acquired before going into human experience, or we go back
> and do it after the human experience suggests it.
>
> \[Slide.\]
>
> So, how predictive of human experience are these safety-testing
> algorithms? In NCI data that will be presented in detail at the
> upcoming NCI-URTC-AACR meeting in Frankfurt, the predictive power
> actually varies somewhat with the endpoint desired.
>
> If one wants to focus on a safe starting dose, if one uses 2 to 3
> species including rodents and non-rodents, there is a 97 percent
> ability to predict actually a safe starting dose. This drops somewhat
> if one uses the mouse only to about 83 percent.
>
> But if one focuses on a correct elicitation of the human maximum
> tolerated dose, there, no one species is actually completely
> predictive. Rodents in particular are actually very bad at predicting
> the maximum tolerated dose. It gets a little bit better in the dog.
>
> We are aware of no in vitro or in silico methodology that has yet
> emerged to predict human toxicity with the possible exception of
> efforts to use marrow cultures to distinguish between rodent and human
> sensitivities.
>
> \[Slide.\]
>
> This data actually mirrors the industry experience that was collated
> in a very useful publication whose reference is shown, where in data
> that was contributed by a number of companies, from a number of
> different therapeutic areas, if one looks at the concordance between
> occurrence of human toxicities that were observed in the clinic with
> what would have been predicted by the animals, 71 percent of the human
> toxicities were associated with some toxic experience in animals.
>
> This was best mirrored by the non-rodents and very poorly or at least
> less well captured only in rodents, however, and this is an important
> issue, approximately 30 percent of human toxicities were not predicted
> by the animal experience.
>
> Thus, if one considers a situation where there would be first in human
> experience in the pediatric population, one has to consider that one
> would be open, if one went forward with that, and using the current
> algorithms, to potentially experiencing new toxicities for the first
> time in the pediatric population, and that is something that this
> group I hope will consider.
>
> The conclusion of this body was that two species are best predictors.
> Again, single species, if one is going to use, the non-rodent tends to
> be better than the rodent.
>
> \[Slide.\]
>
> So, consideration in applying these data to the pediatric population
> lead us to a number of questions, and I would just list these.
>
> First, how closely do adult and pediatric maximum tolerated doses
> actually correspond? Is there a difference between cytotoxics and
> non-cytotoxics in this regard?
>
> Are the determination of classical maximum tolerated doses still
> relevant if one is going to apply this primarily to the pediatric
> population, or should the age, maturity, or the nature of the tox
> species that is used be reconsidered if adult human Phase I data is
> not actually to derive pediatric dosing?
>
> The importance of efficacy model pharmacokinetics and pharmacodynamics
> in guiding this, I think was well illustrated by Peter\'s talk and
> needs to be hopefully applied on a broader scale.
>
> Another issue that deserves consideration is the chronicity,
> reversibility, and age-relatedness of target-related toxicities. For
> example, it is well known that anti-VEGF receptor antagonists have
> effect on the bone growth plate and therefore could be qualitatively
> different in their implications for use in the pediatric population.
>
> The recently studied anti-EGF receptor antagonists likewise have a
> cutaneous toxicity that is relatively well tolerated by most adults.
> How it would extrapolate to growing skin and its implications is a
> matter that is certainly not clear in the literature.
>
> \[Slide.\]
>
> I would like to acknowledge the contributions of my colleagues who are
> listed here to my presentation, who have importantly put together this
> data.
>
> Thank you very much.
>
> DR. SANTANA: Thanks, Ed.
>
> We are going to continue moving forward and I will ask Pat Reynolds to
> get started with his presentation.
>
> **Applying Preclinical Data to Clinical Studies**
>
> **Patrick C. Reynolds, M.D.**
>
> DR. REYNOLDS: Thank you, Vic, and thank you for the invitation, Steve.
>
> What I want to address, you have heard about in vivo models, I want to
> address primarily in vitro models, but to also contrast a little bit
> about the kinds of things we might learn from in vitro models versus
> in vivo models in terms of preclinical drug testing in pediatric
> cancer.
>
> \[Slide.\]
>
> One of the models that led to successful clinical application of in
> vitro testing is shown here, which is studying retinoic acid.
> Initially, this work was done with transretinoic acid and then it was
> recognized that we probably couldn\'t obtain the levels we needed in
> patients with transretinoic acid, so it was in vitro modeling, that is
> shown on the righthand panel, using a dose schedule that we thought
> would be obtainable in patients of essentially two weeks exposure
> targeting 5 micromolar levels, which got significant responses in
> vitro, and led us to do a Phase I study, which documented we could get
> those levels in patients, and then went on within the Children\'s
> Cancer Group to do a randomized study in which completing cytotoxic
> therapy patients were randomized to get either 13-cis-retinoic acid or
> no further therapy.
>
> That showed a significant benefit for those patients randomized to get
> 13-cis-retinoic acid and has led to its incorporation within the
> treatment of high-risk neuroblastoma in most centers at this point.
>
> \[Slide.\]
>
> If one looks at in vitro testing of anti-neoplastic drugs, the assay
> systems that you use really need to have a wide dynamic range.
> Ideally, 3 to 4 logs of cell kill should be measured, yet, you need to
> still have a high throughput.
>
> The cell line panel that you employ needs to have multiple cell lines.
> These need to include those that are not only the ones at diagnosis
> that are going to be sensitive to normal drugs, but the ones that are
> going to be resistant to the standard drugs used to treat the patients
> as we see them today.
>
> Major mechanisms of resistance need to be identified and reflected in
> the cell line panel. Exposure to drugs should be done at clinically
> achievable levels and schedules.
>
> As hypoxia is known to antagonize a number of drugs in terms of their
> antitumor action, testing really needs to also be done under hypoxic
> conditions.
>
> \[Slide.\]
>
> Now, the limitations of in vitro testing are well known. One is the
> selection for cell cultures for their ability to grow in vitro, might
> not reflect the human condition.
>
> Artificially high drug exposure can occur in vitro, and one has to be
> careful to look into that when one is designing these types of
> studies.
>
> Cell culture oxygen conditions in standard incubators far exceed the
> physiological, and one needs to take that into consideration.
>
> Cell-to-cell contact, especially with normal cells, is not preserved.
>
> But if one designs the types of preclinical testing that one carries
> out to take into consideration these sorts of limitations, it may be
> possible, as we have seen at least with the one example I showed you,
> to use in vitro data to move forward a drug successfully into the
> clinic.
>
> \[Slide.\]
>
> Our approach is to use a very high throughput, high dynamic range
> system in which we have digital image microscopy that works with an
> inverted microscope to measure in 96 well plates, viable cell numbers,
> and shown on the righthand panel, you can see the dynamic range goes
> through 4 logs if one seeds the viable cells into a plate in the
> presence of excess dead cells.
>
> This relies upon fluorescein diacetate, which shows you the viable
> cells, and you can see here in one of these images from a microwell
> that you can easily recognize the viable cells as being brightly
> stained, and this is what the computer is essentially recognizing.
>
> Using this system, we have characterized a number of neuroblastoma
> cell lines, and this shows you the panel we selected, which
> encompasses those at diagnosis, shown on the lefthand side. In the
> middle are patient samples that were placed in the culture after
> progressive disease, during induction chemotherapy, many of which are
> matched to those from the diagnostic specimens.
>
> Then, those placed in the culture at time of recurrence after
> myeloablative therapy. As you see, the fold resistance to the drugs
> tested in this particular experiment, which was a carboplatinum,
> cisplatinum, melphalan, doxorubicin, etoposide, all commonly used
> against neuroblastoma, clearly goes up to some degree when one gets
> recurrence after induction chemotherapy, but clearly, there is a high
> degree of resistance occurring after transplant as one might expect,
> and this is sustained resistance.
>
> It is, in fact, those cell lines that we feel allow us to select new
> agents better because these are, in fact, the kinds of tumors that we
> are going to see if you are going into Phase I or II setting in the
> children since most children are now treated with myeloablative
> therapy before they recur.
>
> \[Slide.\]
>
> One of the types of agents we have worked up in vitro with that system
> is a glutathione depleter that we obtained from the NCI, buthionine
> sulfoximine or BSO, and this shows you the dose-response curve in red
> for melphalan, by itself in this cell line, adding melphalan plus 1
> micromolar BSO.
>
> Keep in mind the adult experience was that continuous state levels of
> 500 micromolar BSO were obtainable. That caused a significant
> sensitization. You go up to just 10 micromolar BSO, you get a really
> tremendous sensitization in this cell line.
>
> \[Slide.\]
>
> In fact, this is work by Clark Anderson at Children\'s Hospital, L.A.,
> and within the NAT consortium he had done a pilot study. This shows
> you one of the patients from his 30 percent response rate he saw in
> the pilot study in which recurrent neuroblastoma after multi-agent
> chemotherapy, saw a dramatic shrinkage of tumor treated with BSO
> melphalan.
>
> In this particular study, there were no stem cells support given, so
> we were limited in giving the melphalan to doses that were tolerable
> with the amount of product toxicity that was going to occur, and there
> is currently a Phase I study ongoing looking at dose escalating the
> melphalan in the presence of BSO, which we expect would achieve even a
> higher response rate.
>
> Again, this is another example of an agent moved into the clinic that
> has shown responses in the clinic all based upon in vitro testing, and
> not xenograft testing.
>
> \[Slide.\]
>
> Now, xenograft models for drug testing, which you have heard elegant
> work from Peter already, from the St. Jude\'s group, and of course
> others doing similar types of work, these provide another way of
> looking at drugs and one that certainly gives you kinds of information
> that you can\'t get in vitro.
>
> The kinds of models that you use there, I think you need to use, as
> Peter has shown, signs that are responsive and resistant to standard
> agents. Subcutaneous xenografts allow for easy measurement, but most
> pediatric tumors don\'t present as subcutaneous tumors, so one has to
> consider other types of models.
>
> There is a lot of work going on in a variety of laboratories looking
> at intravenous injection to mimic minimal residual disease in nude and
> SCID mouse models, and immunocytochemistry can detect that MRD and
> characterize it.
>
> The new rodent imaging models are methods that can be applied to these
> models, allow for assessment of response in organs, potentially in a
> variety of organs. To just show a sort of example from that, I am
> going to show you in a moment the kinds of things one can do with
> that.
>
> \[Slide.\]
>
> The limitations of rodent models for drug testing are as follows. One,
> as you have heard already, the pharmacokinetics in the mouse is
> certainly different from the humans, as applicable to testing the
> efficacy as it is the toxicity, as pointed out already by Edward.
>
> The adult mice, as well as adult dogs, I might add, are what is used
> for this testing. One cannot use the pediatric model in this setting,
> so that might be a limitation.
>
> Animal testing is clearly labor-intensive and expensive. The
> subcutaneous tumors may be quite different than the orthotopic
> setting, and transgenic animal models, while interesting, I think we
> need to keep in mind that if those are used for drug testing, they
> will be providing virgin tumors that have not yet developed resistance
> to currently employed drugs, and this has to be considered in applying
> data from those types of models to going into the Phase I and II
> setting.
>
> \[Slide.\]
>
> Just to show you an example of the types of imaging that is coming out
> now, and there is even more exciting stuff coming with the luciferase
> assays and the micro-PET scanners, but one can get high resolution
> radiographs now and pick up bone metastases in these mouse models,
> which can be confirmed, as you see in the center panel, by histology.
>
> There are even micro-CT scanners available, which although a little
> more labor-intensive than the plain films for doing this routinely,
> certainly confirm the results that you get with plain films or
> histology.
>
> \[Slide.\]
>
> So, for drug testing in pediatrics, what results should encourage
> pediatric clinical trials?
>
> I would suggest that multi-log killing of cell lines, multiple cell
> lines, including those established at relapse, and this obtained at
> clinically achievable drug levels, would certainly be one criteria
> that should encourage us.
>
> Activity against multi-drug resistant cell lines in hypoxia should be
> considered because the tumors that we see in these patients will not
> be presenting in 20 percent oxygen, so that has to be a component at
> least of in vitro testing. It is already a component of the in vivo
> testing that we see in xenografts.
>
> Responses in xenografts, ideally in those that are multi-drug
> resistant, and significant activity of drug combinations might
> encourage Phase I trials even if the single agents show only modest
> activity.
>
> So, I think that using the laboratory to work out combinations is
> something that has been under-explored and should be emphasized in
> this sort of work.
>
> \[Slide.\]
>
> What results should discourage pediatric clinical trials? I think poor
> activity, i.e., less than or equal to 1 log of cell killing at
> clinically achievable drug levels in multiple cell lines might want to
> make us think twice about whether or not to move forward.
>
> Obviously, poor activity in xenograft models known to be responsive to
> standard drugs would be another, although we need to be careful
> because if one is doing a xenograft model, and one can obtain much
> higher levels in the human than one can in the mouse, then that would
> not be used to discourage you if you know you can get in the human
> with the higher levels.
>
> Availability of agents with more promising activity for the same
> target population should factor into this, so one should take the sum
> total of the data together and apply it if one does not have a lot of
> agents in the pipeline that look interesting, one still may want to
> move forward an agent, whereas, if there are a lot of agents, one may
> want to think twice.
>
> In other words, the whole concept that we have all been discussing in
> the NCI consensus panels that Malcolm has put together has been one of
> prioritization, there is no black and white.
>
> \[Slide.\]
>
> In summary, preclinical drug testing may be a means of prioritizing
> new agents. There are a variety of models for doing that, and these
> need to be studied.
>
> Validation of the existing models should be undertaken both
> retrospectively, as well as prospectively, against the basis of
> clinical data we already have from the cooperative groups and
> individual institution trials on agent activity.
>
> Preclinical modeling of drug combinations may facilitate the design of
> Phase I and II studies, and those should be explored, as well.
>
> Thank you for your attention.
>
> **Committee Discussion**
>
> DR. SANTANA: Thanks, Pat.
>
> I think we are going to take a few minutes to have comments and
> discussion on the three presentations that we have visited regarding
> preclinical models.
>
> I want to start by asking Peter a question, and that is, do we have
> any sense based on all the data of xenograft models what the false
> negative rate is? That is, that there is a drug that we have tested in
> xenografts that we have said for X, Y reason, it is not active, we are
> not going to use it, but then ultimately, there has been experience
> clinically with that drug, and actually it has been found to be
> active.
>
> Do we have a sense of what that threshold of false negativity may be?
>
> DR. HOUGHTON: I don\'t think we do with respect to the pediatric
> models although we can look at the drug, such as etoposide, which is
> clearly very active, and that may be one example where the mouse model
> under-predicts activity, because in the mouse, etoposide is cleared
> very rapidly relative to that in children.
>
> So, that would probably be the best example of a false negative in the
> model systems, but I think if you use the models and you relate tumor
> response to pharmacokinetics, then, even if we had that data showing
> relative lack of activity, and some tumors do respond, but it\'s not
> dramatic, and we had the adult data showing the PK was maybe five, 10
> times higher, I think that would be a reason not to preclude that drug
> from pediatric trials.
>
> The whole ongoing process of model development is an experiment. I
> don\'t think I intended to indicate that if a drug didn\'t show
> activity in the sort of broad panel of models that we presented as a
> potential consortium, that that would preclude a drug going into the
> clinic.
>
> In fact, it would be very useful if those drugs did go into the
> clinic, because we need to do experiments that validate that
> preclinical models do have any role.
>
> DR. SANTANA: I have got one follow-up with a comment that you made,
> which is this issue of using preclinical models in the new era of
> biologics, because I think we are so used to these preclinical models
> helping as standard cytotoxics, but I want to hear more thoughts from
> you or from your group and how we can apply the models that we
> currently have to try to address these issues of the biologics, which
> may be completely different, and we are going to have to face in
> pediatric, too, because they are going to be used.
>
> DR. SAUSVILLE: I think you touch on what is also an emerging
> experience, and I wouldn\'t want to imply that there is substantial
> data to support one position or the other.
>
> What does seem to be emerging, and this is very much on the plate for
> oncology, drug development in adults, is that there is a disconnect
> between the science that develops the drug and then the clinical
> testing that goes on.
>
> In many cases, companies will launch fairly large Phase II and even
> Phase III trials with essentially no data as to the expression of the
> target in the population, whether the pharmacology that they are
> observing in the adults actually addresses the targets.
>
> So, I think there is a lot of concern, and we can point to recent,
> shall we say, less than optimal outcomes in terms of such experiences.
> An example would be the matrix metalloprotease situation where one has
> to consider whether not characterizing the effect of the drugs on the
> target as part of the clinical development scenario has really
> compromised the ability to make progress in these areas.
>
> What that means to me and to many of us at NCI is that we are strongly
> encouraging the grantees that we work with to develop protocols where
> the assessment of the molecular target addressed by the drug is built
> in, if possible, to some aspect of the drug\'s development process.
>
> We are very interested in supporting preclinical modeling efforts
> where in addition to the pharmacology information that relates to
> efficacy and toxic effects, pharmacology information related to the
> effect on the target could be very important to have available in
> decisionmaking.
>
> So, we can only stand in the bully pulpit, so to speak. I think this
> is going to require a bit of a behavior change on the part of people
> who do clinical trials, and also it is going to require an advance in
> diagnostic efforts, so that you can easily diagnose the presence of
> the target in these different populations.
>
> DR. SANTANA: I think a follow-up comment to that, I don\'t want to
> monopolize the discussion, but a follow-up to that is the whole issue,
> I was impressed by your one-third of the times that your model cannot
> predict the toxicities that will occur in humans.
>
> I have a suspicion, and I may be completely wrong, I have no evidence
> to have the suspicion except to say it may be much higher in biologics
> if the preclinical models cannot adequately assess the toxicity in
> those scenarios.
>
> Who was first? Go ahead.
>
> DR. GOOTENBERG: I am just speaking from the viewpoint of FDA
> biologics. We certainly take that into account in the ways that we
> would like to see the starting doses as a certain safety threshold
> below the NOAEL level, not below an MTD in preclinical models, and we
> also are very interested in assessing optimal biological doses, the
> same as you are saying, in many of these models where an MTD is really
> not a rational goal.
>
> DR. PRZEPIORKA: Two quick questions for Dr. Sausville.
>
> First, you indicated that the animal models do not accurately predict
> the human MTD, and cited NCI data as your reference. Was that based on
> mg/kg or actual drug exposure, and do you know if there is a
> difference between the predictability if you do this based on drug
> exposure rather than mg/kg?
>
> DR. SAUSVILLE: It was ultimately done on mg/kg or basically bioservice
> area issues. It has not been normalized with respect to pharmacology
> issues. You are quite correct that there might be a better refinement
> if one considers that.
>
> DR. PRZEPIORKA: You also raised the question about whether or not the
> adult and pediatric MTDs correspond. At a previous meeting, we had
> talked about they may not correspond and that there is data out there
> that can be looked at to see whether or not we should change the 80
> percent rule.
>
> Since that time, I was wondering had anybody gone back and looked at
> that data to see whether or not that rule is truly valid.
>
> DR. SAUSVILLE: On that, I would have to defer to my colleagues in the
> pediatric part of CTEP. I think one point that addresses\--again, I am
> speaking from data that is in the literature\--one does have the
> impression that with the passage of time, the ratio between the MTDs
> is changing, so that there is a better correspondence currently than
> there was in the past perhaps.
>
> Again, I think that is a cytotoxic-driven sort of experience, so while
> I believe that at one level, such an analysis that you described may
> be fruitful in refining the basis for that, I also think, as was
> pointed out a few minutes ago, really addressing concentration that
> addresses the target modulation is going to be real important, at
> least as equally important to me in making that consideration. Malcolm
> or Barry, you may want to comment.
>
> DR. ADAMSON: I think that everyone should start with an edge is on
> target that, because of the changing nature of the patient population
> that are studied, both adults as well as pediatrics, the differences,
> the divergent differences that we have seen (inside topics) are, I
> think, fewer at this point.
>
> For the biologics, we have had some experience of, in fact, there may
> be significant differences in tolerability and the 80 percent rule is
> probably not a relevant rule for some of the biologics because
> children, at least in certain situations, may be more sensitive to the
> biologic toxicities of some of these agents.
>
> So, we don\'t have a lot of preclinical data that can guide us on this
> front, and I think on an agent-by-agent basis we have to have
> discussions and considerations as far as where we ought to start.
>
> We are usually, however, not a log away from where we end up. We are
> not sort of held to the same limitations. Because we have the adult
> experience in front of us, we don\'t necessarily have to start at
> one-tenth of a mouse dose and have multiple escalations.
>
> What, in general, we are talking about is the addition of one or
> perhaps two additional dose levels if we have concerns about the
> tolerability in children.
>
> DR. BLANEY: I would just like to make a comment that sometimes the MTD
> that we define in the Phase I setting isn\'t ultimately the dose that
> patients in the front-line setting will tolerate. They will frequently
> tolerate more, at least with the cytotoxics, so the Phase I is only
> the first step and further dose refinement may need to occur earlier
> in front-line treatment protocols.
>
> DR. HIRSCHFELD: I had a question, which is a more general one, so any
> one of the panelists or anyone else with a thought in the area could
> respond.
>
> There was a distinction made between biologicals and cytotoxic drugs.
> What I would want to ask is, given our current knowledge of the
> various preclinical models, are there sensitivities which are driven
> by the type of agent, that is, is it the therapy which is determining
> the sensitivity and specificity of the model, or is it the tumor types
> that are in the model which are then more critical.
>
> I know the answer can be, well, a little of both, but I just wanted to
> raise the issue that maybe for some classes of drugs, if that is the
> case, then, certain models might be appropriate, or if it turns out
> that it is the tumor and it doesn\'t matter what you throw at it, that
> it is always going to be predictive, then, that would be another
> scenario.
>
> DR. HOUGHTON: I think if the latter is correct, then, we are in
> trouble, because we are developing molecularly targeted drugs for
> specific reasons, and if it doesn\'t matter if your target is there
> and the tumor responds, then, we are doing something wrong.
>
> I think what we would like to achieve, and, Malcolm, correct me if I
> am off base, is that with the pediatric models that are available, is
> to characterize them, so that we can identify potential targets that
> may also be the targets for drug development in the adult population.
>
> So, then if there is a specific kinase inhibitor that is being
> targeted for adult treatment, because that particular kinase is
> over-expressed in tumor X, then, we could at least focus the use of
> that drug against the models that express the target or over-express
> the target as a first attempt to see whether target inhibition relates
> to tumor response, and we can do this quite readily in the animals,
> much more readily than we can in the clinic.
>
> The second step would be to say does the drug have a wider application
> than just the tumors that have the over-expression of that target, and
> I think with that sort of data, we may well be able to answer the
> questions you raise, but I think at the moment, the data is not
> available to definitively answer the question.
>
> DR. SAUSVILLE: I would point out that of the data that exists, it is
> sending a mixed message. I mean if you look at the experience with
> STI571 and bcr/abl, there, there was an exact correspondence between
> the behavior of the regular old xenografts and the target in the
> regular old xenografts, and we all know the story.
>
> If you look at the history of the farnesyl transferase inhibitors,
> there, it has been very divergent, where the animals at one level or
> another greatly increased enthusiasm for agents that, at least in
> their initial iterations in the clinic, have been somewhat more
> problematic.
>
> DR. SANTANA: Any other further comments or response to Steve?
>
> DR. SMITH: I would just echo what both Peters said in two comments.
> One is we do have an ongoing project where we are attempting to
> collect a panel of pediatric cell lines and xenografts, so that those
> can be characterized molecularly, so that that can then inform both in
> terms of their gene expression profiles, but also tissue arrays and
> protein arrays, that can inform the issues of molecular targets for
> specific childhood cancers, and inform the preclinical testing
> process.
>
> The second point, to echo Peter Adamson\'s point or Susan\'s, that
> when we started, between 60 and 80 percent of the adult MTD, we are
> not logs off.
>
> You know, typically, we are either at the MTD, we are one or two dose
> levels below the MTD, or you have to drop back one dose level, so
> essentially, you know, it remains a very efficient way to introduce a
> drug with relative safety into the pediatric population, and then, you
> know, to determine a dose in this heavily pretreated population,
> recognizing that when we go forward, we may have to make additional
> modifications in less heavily pretreated patients.
>
> DR. WEITMAN: A comment and a question.
>
> We certainly did look at recently some of the changes in MTDs between
> adults and children, and there has been a trend with the cytotoxics at
> least for a decreasing margin or difference between the two.
>
> I think when we looked at it in more detail, it was due to the fact
> that certainly the kids that were going into Phase I studies were much
> more heavily pretreated, mostly transplant allogeneic, autologous
> transplants, radiation compared to a lot of the adults that were going
> on study are very minimally treated, in fact, sometimes no prior
> treatment at all, so I think that was affecting at least for
> cytotoxics. That is a comment.
>
> I guess as a question for either Pat or Peter, looking at the
> schematic, particularly that Peter showed, can you give us some idea I
> guess of the time frame to develop a gestalt for an agent, whether you
> think it is going to be active or not and warrant going into pediatric
> studies, particularly going through either that schematic or cell line
> studies, again, a time frame.
>
> DR. HOUGHTON: Ultimately, we would like to start by screening 15 drugs
> a year through this, and that is a study of in a sort of conservative
> way, so I would imagine a first cut to show any activity would be on
> the order of three months, and then if we showed activity, say, in
> neuroblastoma models, to run through the dose-response curves, would
> be another three to four months.
>
> So, we are talking about a six- to nine-month period of generating
> data, which is not a terrificly long period, I think.
>
> DR. WEITMAN: Would that be different for cytotoxic versus targeted
> therapy where you could potentially feel that there may be more
> molecular studies that would need to be done to validate the model?
>
> DR. HOUGHTON: I think we have to be very specific as to what the
> screening program is, because you could expand it to the point that it
> becomes so huge and all encompassing that you would never get anything
> done.
>
> I think the initial experiments will have to be to evaluate a drug in
> terms of its antitumor activity. A secondary component of that would
> be target validation in terms of target inhibition, but I think that
> has to be done outside this initial screen.
>
> It may be that particular labs would look at that outside the screen.
> I think the initial screen is set up to look for antitumor activity as
> the primary function. It may develop beyond that, but I think we have
> to be focused in the design of the experiment at the front end.
>
> DR. SANTANA: Pat, do you want to add onto that as it relates to the
> cell lines?
>
> DR. REYNOLDS: I think that the time frame that Peter is discussing can
> be compressed a little bit for cell lines, but then if one sees
> activity, one would probably expect to be going into xenografts, as
> well, so I think the time frame would be very consistent, and probably
> both could go on simultaneously and kind of cross-feed upon each other
> as far as making decisions.
>
> DR. SANTANA: Steve, I will give you one last prerogative.
>
> DR. HIRSCHFELD: I will try to be brief. Although my job description is
> to remain in equipoise, I wanted to point out that historically, the
> first targeted therapy was 6-mercaptopurine in 1952, and it is, as far
> as we know, quite targeted, and some of the agents that we are calling
> cytotoxics, such as the topoisomerase-1 inhibitors that were discussed
> this morning, are also quite targeted.
>
> I don\'t want us to be misled by putting a distinction which may be
> more semantic than biologic.
>
> DR. SAUSVILLE: So then my point is that that exactly illustrates the
> issue because you don\'t select patients based on any peculiarity of
> purine metabolism. You basically take all comers. So, I submit that
> that illustrates the issue.
>
> DR. HIRSCHFELD: Well, we could pursue that, but many of the therapies
> that have been considered targeted, in fact, you used STI571, in fact,
> have been shown to be relatively promiscuous in terms of their
> partners within the cell.
>
> DR. SAUSVILLE: Only if we were perfect.
>
> DR. SANTANA: Let\'s move on to the second set of sessions. If anybody
> needs to take a break, please feel free to do that on your own, but I
> think we need to move forward.
>
> I am going to invite Peter Adamson to give the Children\'s Oncology
> Group perspective on the current practice.
>
> **Current Practice**
>
> Children\'s Oncology Group Perspective
>
> Peter Adamson, M.D.
>
> DR. ADAMSON: Thank you, Victor, and thank you, Steve, for the
> invitation.
>
> First, I want to apologize, you don\'t have the slides in front of
> you. I finalized them on the plane home from the Middle East
> yesterday, and I use the term \"finalized\" loosely. Then, we
> transferred them over this morning from the MacIntosh to Windows, and
> knowing Microsoft\'s history as far as making software incompatible
> with itself, I have no idea what these are going to look like.
>
> \[Slide.\]
>
> Having said that, I wanted to step back before answering some of the
> questions that Steven has posed to convey a sense of urgency that we,
> in the Developmental Therapeutics Program at the Children\'s Oncology
> Group, feel about the importance of moving drugs into Phase I at an
> earlier stage and in a more efficient and scientifically rational
> manner.
>
> The downstream effects of every year that goes by while we discuss can
> we move them earlier have been profound, and our ability to really
> substantially change therapy for children with the introduction of new
> agents has been hampered by a number of factors, so this is a
> critically important issue for us.
>
> The reason it is important, I think we have to step back for a moment
> and look at what has happened in the treatment of childhood cancer
> from the 1960s to the current generation, 1990s, and overall, it is a
> remarkable success story when you look at it, and it is driven in part
> by acute lymphoblastic leukemia, such that today, approximately 75 to
> 80 percent of newly diagnosed children will be cured by current
> therapy.
>
> There are some clearly highly successful tumors including Wilms\' and
> select populations. Acute myeloid leukemias lag behind, but I think
> you have to look deeper than the overall success of the program to
> understand why we think this is such an urgent issue.
>
> \[Slide.\]
>
> Now, looking at the Children\'s Cancer Group studies of the high-risk
> neuroblastoma patients from two generations, the first 1978 to 1995,
> you can see that in that generation of studies, there were very few
> long-term survivors.
>
> Now, primarily through dose intensifications, as well as the
> introduction of a biologic agent, there has been an improvement, but
> nonetheless, and even I think the most recent study, there will be a
> step up, despite the great intensification of therapy, we have a long
> way to go, and neuroblastoma is just one example, but there are a
> number of pediatric malignancies that have been a great challenge for
> us including gliomas, brain stem gliomas, metastatic sarcomas, and the
> list will go on.
>
> Importantly, it is not that we have a select population of tumors
> where our cure rates are unacceptable, but it is the price that
> children are paying to achieve even the good cure rates.
>
> \[Slide.\]
>
> As shown here, are data from an intergroup rhabdomyosarcoma study of a
> 1,062 children and the number of patients that at any point during
> their therapy, experienced anywhere from mild to life-threatening
> fatal toxicity.
>
> As you can see, approximately 80 percent of children at some point
> during their therapy experience life-threatening or fatal toxicity.
> This is really the face of pediatric oncology today for many of our
> tumors.
>
> Moreover with pediatric patients, not only do we have the concerns
> about life-threatening and fatal acute toxicities, we have the issues
> of chronic toxicity.
>
> We all know the stories of anthracycline and the lifetime cumulative
> dose dependency, but what has clearly emerged over the last five to 10
> years is that the risk of cardiotoxicity doesn\'t go away, that these
> children, as they enter into their early adulthood years, are
> experiencing increased risk of cardiotoxicity.
>
> So, it is an urgent issue for us to try to move new agents forward in
> pediatric drug development.
>
> Now having said that, let me give you an idea of the paradigm I think
> we can move towards, and it has been mentioned here already, and that
> is the story of Gleevec. I illustrate it to show, in part, the ability
> of the Children\'s Oncology Group to capitalize on advances made in
> the laboratory and in adult studies.
>
> \[Slide.\]
>
> Now, we completed a pediatric Phase I trial of Gleevec in
> approximately a 12 month time. We determined the recommended dose, did
> pharmacokinetic studies, and we learned in this study that the
> pharmacokinetics in the children who were entered, and I believe all
> but one child had evaluable results, pharmacokinetics for this drug
> were, in fact, quite similar to the pharmacokinetics observed in
> adults, and finally, we examined responses.
>
> \[Slide.\]
>
> This trial was limited to children with Philadelphia
> chromosome-positive leukemias, and indeed, similar to adults, we
> observed responses both in Philadelphia chromosome-positive CML, as
> well as a small number of patients with ALL and AML.
>
> We had a recommended dose, and we are now moving it forward. For this
> drug, we recognized that there are a number of potential targets in
> addition to bcr/abl, and these include PDGF-R, as well as c-kit.
>
> What we can ask ourselves is, well, what is our base of knowledge for
> pediatric tumors for these targets, and it is somewhat limited, but
> not completely limited, and if one just looks at various types of data
> from functional data, as well as expression data, there are a number
> of tumors that this drug might be important to look at.
>
> We would certainly like to have additional preclinical data if
> impossible to narrow the field, but certain tumors obviously, we have
> the adult data to go on, but osteosarcomas, synovial cell, Ewing\'s,
> and desmoplastics, there is at least some evidence to suggest that
> these targets may, in fact, be relevant.
>
> We clearly need better preclinical data, but we are not looking right
> now at a broad-based testing of this.
>
> \[Slide.\]
>
> To get more to the questions at hand, what are the criteria we use for
> moving an agent forward in pediatric Phase I? I put the terms in
> quotes, because I can tell you historically where we have been, where
> we are now, but I think the future and what we have worked with Peter
> and CTEP on, is going to rapidly change the criteria that apply.
>
> The first one is availability of new agents for pediatric studies. I
> don\'t think I can emphasize enough that this has been the primary
> criteria that we have utilized. Any agent that we have had access to,
> in good part, we have moved forward, and the reason is we haven\'t had
> access to enough agents, so any agent that we could move forward into
> pediatric Phase I studies, we have.
>
> This is not an acceptable criteria. There are too many agents out
> there. We cannot be limited by the availability of new agents. We have
> to bring science into this. But I would be lying to this group if I
> said we have applied scientific principles over the last two decades
> when we have moved new agents forward.
>
> We have learned about these new agents, we have studied these new
> agents, but the criteria, the overriding criteria is has the agent
> been available for study in the pediatric population.
>
> We do look at the relevance of drug target in pediatric malignancies.
> Gleevec is certainly one example, but we are increasingly trying to
> apply this.
>
> Activity in preclinical model systems has been increasingly important,
> and Peter Houghton has demonstrated the potential impact of using
> preclinical models combining pharmacokinetic data in the models to
> pharmacokinetic data in humans.
>
> In pediatrics, we do have the advantage of when we decide to move an
> agent forward, that we, in fact, have some exposure and tolerability
> data in adults. The examples that he cited with MGI will indeed
> influence our decision to move an agent forward in drug development,
> but we are not just looking at a model system purely to screen a large
> panel of agents, we are looking at the model system in the context of
> human drug exposure and human malignancies.
>
> Finally, we do look at the experience in adult clinical trials, and
> certainly activity that is observed in adults will influence our
> ability to move that drug forward.
>
> \[Slide.\]
>
> So, if we can look graphically at the timeline of pediatric drug
> development in reference, in comparison to that with adult trials,
> there have been a number of agents that we have moved into pediatric
> Phase I following drug approval, when they have been on the market and
> in Phase IV.
>
> I would say the largest fraction have been when the adults are in
> Phase III. Phase II trials have been completed, pivotal Phase III
> trials are going on. We begin our Phase I studies in children.
>
> A smaller number, we have successfully moved into Phase I when the
> adults have been in Phase II, and I would have to think long and hard
> for the few examples when we have moved into Phase I when the adults
> were in Phase I.
>
> This situation, I think we will have to change, and I think we can
> safely change it. We can use data from adult studies, pharmacokinetic,
> pharmacodynamic, and in the future perhaps pharmacogenetic, to start
> Phase I testing in children certainly when it has completed Phase I in
> adults and entered Phase II, but, in fact, potentially, when it is
> still in Phase I in adults.
>
> \[Slide.\]
>
> What are the limitations of our current approach? Historically,
> patient numbers were the rate-limiting step for pediatric Phase I
> trials, not that the number of children with cancer has changed over
> the past decades, however, the current situation is that there are an
> insufficient number of new agents available for study in pediatric
> Phase I trials.
>
> There are a number of reasons for that, and they are certainly not all
> regulatory reasons. The impact of this, however, is that Phase I
> trials initiated following drug approval for adults results in use in
> children without any pharmacologic, safety, or efficacy data.
>
> When these drugs are available for adults, they are being utilized in
> children. We can spend a great deal of time discussing when we should
> get data, but once they are on the market, they are going to be
> utilized, and unfortunately, if we haven\'t even begun a Phase I
> trial, let alone complete it, we really have no basis for making a
> recommendation on how to safely use the agent in children, let alone
> to decide whether the agent has potential for efficacy.
>
> \[Slide.\]
>
> Now, the Children\'s Oncology Group during the merger of the four
> pediatric groups and the two pediatric cooperative experimental
> therapeutics groups has reorganized and currently, there are 21
> centers in the United States.
>
> Now, these centers weren\'t chosen for geographic reasons, but rather
> these are the most highly productive and committed centers to
> childhood drug development. The reason I point that out is to
> highlight the current commitment and efficiency in recent studies that
> have moved forward in Phase I in the Children\'s Oncology Group.
>
> \[Slide.\]
>
> Now, right now we are trial-limited, and again there are a number of
> reasons for that, but we have three agents under study in Phase I that
> have broad-based eligibility criteria as far as histologic diagnoses.
> We have one that is limited to neuroblastoma.
>
> We have a number of Phase I trials that truly are in select
> populations either for select CNS tumors or for hematologic
> malignancies also.
>
> Now, for the broad-based solid tumor studies, one of the big issues is
> that these studies of dose levels are literally filling in less than
> 15 minutes. When we have a study, as you know, we enroll three to six
> patients at a time, but they are truly cohorts of three, we open it up
> in Children\'s Oncology Group, the dose level is filled within
> minutes, and we have web-based systems to do that.
>
> In fact, because of the rapidity of this, we have had to develop
> waiting lists for these trials. Clearly, this is not acceptable. We
> need a significant number of more agents in Phase I if we are going to
> capitalize on the efficiency of our current systems.
>
> There are going to be another cohort of Phase I trials opening that
> will still leave us with insufficient numbers, and although we can\'t
> at this juncture say what is the optimal number of trials for
> available patients, it is likely to fall in the 8 to 12 Phase I trials
> that are open concurrently to fill the pipeline at an efficient rate.
>
> Needless to say, these would only be agents which we believe have
> potential relevancy for pediatric malignancies, and given the current
> explosion in new agents, I think we would be able to, with additional
> resources, looking preclinically, help prioritize among them.
>
> \[Slide.\]
>
> So, I will emphasize what Peter said earlier. We need to improve early
> access to new agents for preclinical studies. The consortium that is
> being set up under the leadership of Malcolm and Barry at CTEP, and
> with a great deal of industry input from a number of people in this
> room, we, at the Children\'s Oncology Group, I think can help us
> prioritize amongst the new agents, but access remains the critical
> issue.
>
> I believe we can safely initiate Phase I trials of select agents. This
> is not to imply we should study everything in the pipeline at this
> stage, but select agents, I think we can safely initiate once the
> initial cohorts of adult patients are evaluable in Phase I, when we
> have pharmacokinetics data, or when there is clear evidence of
> biologic activity.
>
> We cannot continue to wait for Phase III results in adults. We do have
> to strike a balance between the evidence in preclinical models, as
> well as data from adult, and trying to move the timeline forward.
>
> So, those, I believe were all the comments I had. I think you are
> going to probably wait for questions.
>
> DR. SANTANA: Yes, we are going to wait. Thanks, Peter.
>
> I am going to invite Steve Weitman.
>
> **Industry Perspective**
>
> **Steven Weitman, M.D.**
>
> DR. WEITMAN: I would also like to thank Victor and Steve Hirschfeld
> for the invitation today. I also apologize, as Peter did, for not
> having slides available. I wasn\'t quite as at a glamorous place as
> Peter was in the last three days, at a CLGB site visit, so I did my
> slides on the U.S. Air flight from Durham last night up to Washington.
> Again, I apologize if they are a little out of order.
>
> \[Slide.\]
>
> What I wanted to do is give a little bit of the industry perspective
> and company perspective. I do feel fortunate that I have a fairly
> extensive background in pediatric drug development, but now also at
> the industry side, to have a pretty good idea of sort of both
> perspectives and understanding the problems that both sides face in
> developing and answering the questions when drugs should be developed
> in children and what resources we like to have at hand before we make
> that decision to move forward.
>
> \[Slide.\]
>
> In an attempt to really get to this, I posed three different
> questions, and that is, again, in the development of a new oncolytic,
> when should pediatric studies be undertaken, what factors influence
> that decision, and lastly, maybe a little bit out of the line of this
> discussion, though I thought it was of interest to this group, should
> pediatric studies be performed only by cooperative groups.
>
> \[Slide.\]
>
> To really address the first question, again, when in the development
> of a new agent should pediatric studies be undertaken, I thought
> historically, just to get some background, I went back and looked at
> some of the drugs that have been approved within the last 10 years
> just to get some idea of when was the first adult study actually
> reported as compared to when was the first pediatric study actually
> reported.
>
> These are approximate times because as you go through the literature,
> you always find a little bit of data here and there in children, but
> really true studies, and as you can see here, over the last 10 years,
> the average time between an adult study being reported and a pediatric
> study being reported, was around five to seven years.
>
> Certainly, I think everyone would agree, based on what Peter just
> said, and from what we can see in the literature, that this is truly
> unacceptable.
>
> I get the sense looking at some of the more recent studies and
> interest, though, that this difference may actually be narrowing and
> becoming smaller, and again, whether this is due to the Pediatric
> Rule, FDAMA, the Best Pharmaceutical Act for Children, I think it is
> too early to really tell, but my sense is, looking at some of this
> early data, that this difference may actually be becoming smaller,
> which obviously is the focus of this meeting.
>
> \[Slide.\]
>
> One of the efforts that we did do, and I will put this as sort of
> interim results, I also posed these questions that I had in the slide
> to the ASPH/O group, which is again the American Society of Pediatric
> Hematology/Oncology, just when should pediatric studies be undertaken.
>
> So far we are up to now about 125 responders, and clearly I think the
> ASPH/O responders felt that these studies should actually be
> undertaken during the adult Phase I studies, maybe not a surprise to
> most of us here. Some felt, actually, about a third felt that they
> should actually be undertaken after the adult Phase I studies, and a
> few rare individuals felt they actually should be undertaken before
> adult Phase I studies.
>
> \[Slide.\]
>
> Question 2. What factors influence a decision whether or not pediatric
> studies are undertaken?
>
> \[Slide.\]
>
> Again, not necessarily copying Peter\'s slide, but historically, these
> are the factors that I came up with, which remarkably I think mirror
> exactly what Peter has shown - preclinical data, pediatric preclinical
> data. Drugs with new mechanisms or targets. Positive data from adult
> Phase I or Phase II studies, and then availability of drug for
> pediatric studies.
>
> Again, we asked the ASPH/O responders to rank these on a scale of 1 to
> 7 with 1 being the least influential and 7 being the most influential.
>
> \[Slide.\]
>
> To date, this is what we have seen so far, that clearly, the more
> common response, the strongest response was for the presence of some
> preclinical pediatric data as a major driving factor that would
> influence whether a compound goes forward into Phase I studies.
>
> As you can see here, there are a number of other areas, and
> surprisingly, just as Peter has alluded to, availability of drug
> continues to be one of the major factors to influence a decision
> whether a compound goes forward, not whether it is active in adult
> studies, not new mechanism, just can you actually get ahold of the
> drug.
>
> \[Slide.\]
>
> Lastly, Question 3: Should pharmaceutical companies conduct pediatric
> studies outside the cooperative groups?
>
> I think there was a pretty clear evidence that there is an opportunity
> there or an interest at least from ASPH/O members to conduct studies
> outside of the cooperative groups. Clearly, about half of the
> individual responders felt that this is the case.
>
> \[Slide.\]
>
> If you look at the reasons why we shouldn\'t do this, clearly, the
> most common answer was that this is just too small of a population, we
> are already at competition for patients for Phase I studies, and we
> really shouldn\'t have studies being conducted outside of the
> cooperative groups.
>
> There were a number of other comments that were shared including
> clearly no, it would be a terrible mistake to do, conflicts of
> interest, cooperative groups have been the cornerstone of success in
> pediatric studies, and all agents and studies should stay within that
> group, you know, the more convincing studies are done within the
> cooperative group setting, and then the cooperative group mechanism in
> concert with industry and NCI should be able to be the approach to
> take to meet all requirements both of industry and then FDA.
>
> \[Slide.\]
>
> When you look at the comments as far as why they should be conducted
> or that conducting studies outside the cooperative group is
> acceptable, clearly, I think the interest was speed, that the
> cooperative groups are congested, and that trying to do this outside
> of them, there may be an opportunity to help speed along the
> development of some of these compounds in this particular arena.
>
> Again, this was from the ASPH/O survey that we did that is still
> ongoing and may be updated as more information becomes available.
>
> \[Slide.\]
>
> Now, to get at maybe the question that Steve actually posed to me, and
> again, what is sort of the company perspective on this, I would say
> that each agent really needs to be considered separately and
> independently, that there isn\'t really any standard approach to say
> yes, all agents go into children as quickly as we can.
>
> I think there is a balancing, that we have to weigh a number of
> factors. What I would say, early pediatric studies, I would agree with
> Peter that I think getting them in during adult Phase I or Phase II
> studies is on the early side. Later pediatric studies would come when
> the adult Phase III or Phase IV studies have been either completed or
> at least ongoing.
>
> Now, what factors influence I think at an industry level whether a
> compound would go into an early pediatrics arena, and I would put down
> certainly medical, scientific perspectives if there is a similar
> disease process, such as leukemia.
>
> We have a drug that we are interested in, in looking at its use in
> leukemia. We feel that there is a similar disease process there, so
> that is a drug that I think warrants going into early pediatric
> studies.
>
> Also, if there is a similar target expression, such as Gleevec, I
> think that again sways us towards wanting to put this drug into early
> pediatric studies.
>
> I think there are a couple other factors that again are a little bit
> outside of what has been mentioned already, but I think do greatly
> influence industry decision on whether these compounds go forward.
>
> I put down, first of all, regulatory, that the Pediatric Rule I think
> has made industry at least think about these studies, and hopefully,
> that translates into early implementation of pediatric studies. Again,
> the Pediatric Rule is early, I think we will get a better handle on
> whether that has really made an impact as we go forward.
>
> I think when you look at the business development of these compounds,
> and looking at the potential impact of FDAMA and the Best
> Pharmaceuticals Act, exclusivity, I think again creates an environment
> within industry where they entertain the idea and think about these
> compounds going into a pediatric population much earlier than probably
> has ever been done in the past.
>
> I think those factors on your left certainly influence industry to
> think about implementing studies at an earlier stage in the
> development of a compound.
>
> Now, what factors could actually influence a later entry into
> pediatric studies? Again, not being in industry for quite a few years,
> a lot of this was a surprise to me, but things as simple as CMC,
> chemistry manufacturing, formulation.
>
> As we go into more and more oral agents, again, most of these agents
> are developed for adults. They capsule or tablet size, and most
> frequently, you will see capsules being developed before tablets being
> developed, and capsules are not obviously amenable to scoring and
> breaking into more pediatric-friendly dosage forms.
>
> This will greatly I think influence when a lot of these oral compounds
> can go into pediatric populations. Again, we don\'t typically plan, I
> think at the earlier stage for pediatric dose size.
>
> Stability, particularly for I.V. formulations. Most drugs, as they are
> first formulated, will go into vials, glass vials, which are
> single-entry vials. If you look at again the concentration of the drug
> in these vials, again, they are geared more towards the adult dosage
> form and adult dose.
>
> So, when you go into pediatrics, if you need 5 mg of a drug and the
> vial comes in 50 mg sizes, if you go into that for an I.V. dose to be
> given, you end up wasting 80, 90 percent of the drug, which again I
> think dissuades against early pediatric studies.
>
> Then, just simple drug supply. Again, something that has been brought
> up already, but something that I guess I didn\'t realize until really
> getting into industry, this is such a critical issue that is
> identified at a very early stage. It is not something that I would say
> is readily, or let\'s just make more drug.
>
> It is much more difficult to make drug, to get it on stability, to get
> and release the correct formulation when it has been approved for
> release, that this is decided at a very early stage in the development
> of a drug, and to identify studies early on, particularly an interest
> for pediatric, I think is so critical in the development of these
> compounds, which can influence when these compounds go into pediatric
> study.
>
> Lastly, I would say toxicology, unacceptable toxicities, clearly,
> industry is concerned with the development of compounds that may
> result in unacceptable toxicities. How that is perceived by the
> public, how it is perceived by investors, how it is perceived even by
> the regulatory group, I think is a concern to industry, and that
> frequently results in some hesitancy to go into pediatric studies.
>
> Then, unusual drug targets or unusual target organs, CNS, cardiac,
> renal, hepatic toxicities, I think all can be concerning enough to
> industry where it does shift some of the interest in early studies to
> develop those compounds more at a later stage.
>
> \[Slide.\]
>
> In summary, looking at more of a company perspective, I think there
> has clearly been shift towards really not if a drug should go into
> pediatric studies, but when it should go into pediatric studies.
>
> I think you will see that these compounds will become more available,
> that there is a shift towards pediatric studies more and more. I think
> most pediatric oncologists believe that studies should be done early
> versus late. Company involvement is okay, but there is some caveats to
> that.
>
> The perception at least is that conducting studies outside cooperative
> groups could speed up the process and that companies are showing
> increased interest in developing new agents in children.
>
> I think this is a reflection, again, of several new legislative
> actions including FDAMA and the Pediatric Rule, that most factors that
> influence a decision to conduct studies in children is that the
> industry views I think are fairly similar to pediatric oncology views
> and needs, but there are clear, obvious differences between the two
> groups.
>
> At that point, I guess I will stop and save questions and discussion
> for later.
>
> DR. SANTANA: Thanks, Steve. That was a very good perspective from the
> other side\--from the industry side, since I will be quoted in the
> minutes.
>
> \[Laughter.\]
>
> DR. SANTANA: I am going to invite Bruce to take his position at the
> podium and give us the European perspective of this issue, across the
> Atlantic now, right, the other, other side.
>
> **European Perspective**
>
> **Bruce Morland, M.D.**
>
> DR. MORLAND: Thank you very much. I would like to thank the committee
> for giving me the opportunity to give you a European perspective of
> issues relating to new drug development.
>
> What is already clear for me from the discussion and the talks is that
> the discussions that we are having in Europe are identical to the
> discussions that you are having today, and I could move this table to
> some committee room in Brussels, and we would be having exactly the
> same discussions.
>
> I think another important factor that needs to be taken into account
> is that the pediatric oncology population is a truly international
> collaboration. One only needs to look at the results, the stunning
> results that have been achieved with national/international
> collaboration in Phase III trials to give a lead to the whole issue
> about Phase I or Phase II clinical trials being a truly international
> field, not just one that nations individually have to sort out.
>
> So, I hope that this will just lead to further international
> collaboration and that we can help you along the way rather than us
> trying to do it alongside you or separately from you.
>
> \[Slide.\]
>
> We have a number of challenges to face within Europe, and it is
> uncanny how many of the things I am going to say, Peter Adamson has
> already said, probably far more eloquently, as well.
>
> But clearly, we, too, need to strive and are aiming to strive to
> access new drugs alongside and not after the adult Phase I/Phase II
> developments.
>
> We have some new challenge in Europe relating to legislation, and in a
> typically modest European way, we have better, not best, better
> medicines for children, and that legislation is expected in 2004. It
> is clearly very important, it has some challenges for all of us.
>
> A lot of our drug development has been in the area of academia, and
> there are some big challenges I think afoot to academic drug
> development programs certainly within the UK, and I think also
> throughout Europe, which means that a closer working relationship with
> the pharmaceutical industry is going to be essential.
>
> Those issues relate to Good Clinical Practice, Good Manufacturing
> Practice, which means that really even small biotech companies I think
> are going to find it challenging to actually manufacture drugs these
> days.
>
> In the UK, we have this strange thing called the Doctors and Dentists
> Exemption, which is monitored by the Medicines Control Agency, but
> this allowed doctors and dentists with really very little preclinical
> data to bring drugs into clinical trials.
>
> Now, I think with the new challenges that GCP are going to bring in,
> that exclusion is going to be really wiped out for us, and the
> academic drug development programs I think are potentially in
> jeopardy.
>
> \[Slide.\]
>
> Just a little geography lesson for you. The United Kingdom, this is a
> small island off the north coast of Europe. Some politicians would
> still like to maintain that island mentality, but we do actually have
> a tunnel that now joins the UK with mainland frogs, and I think
> certainly in the field of Phase I/Phase II drug developed for
> pediatrics, we have built very strong bridges across to mainland
> Europe, and I will explain some of those.
>
> The United Kingdom Children\'s Cancer Study Group, UKCCSG, is I guess
> analogous to COG within the United States. We have 22 major centers
> treating childhood cancer within the United Kingdom.
>
> \[Slide.\]
>
> The organization has been founded for some 25 years. We celebrated our
> 25th anniversary this year. We have a large number of members, which
> are both treating pediatric oncologists, allied professionals, a very
> active nurses\' group, et cetera, a number of overseas members, and
> unique I think in Europe is that we do have a centralized data office
> based in Leicester, which controls all of our trials activity.
>
> \[Slide.\]
>
> The New Agents Group of the UKCCSG was formed in \'87, and has been
> primarily involved in Phase I and Phase II trials. We also did run the
> Relapse Registry, which was aiming to monitor those patients who were
> relapsing in order to get a feel of what proportion of UK patients
> were being offered Phase I or Phase II clinical trials.
>
> In 1995, we established a very strong and now very robust link with
> the French group, SFOP, and their pharmacology group.
>
> \[Slide.\]
>
> I am just going to whiz through a couple of slides just to list the
> New Agent Group studies that have been performed since its inception,
> and really to highlight again a point that I think Peter raised very
> importantly is that none of the agents that have been tested are
> particularly novel, new, or exciting, they are pretty conventional
> drugs, and they have largely been developed on the back of experience
> in adult practice.
>
> \[Slide.\]
>
> We have importantly developed a code of conduct for managing our
> clinical trials, and here listed are some key components of that code
> of conduct. Again, we did worry when we moved out into Europe as to
> how easy it would be to get clinical trials working across different
> cultures.
>
> In fact, it has proved to be remarkably easy, and the barriers that
> are there are virtually nonexistent, and if they are there, they are
> extremely low barriers that you can hop over.
>
> \[Slide.\]
>
> There have been some issues about how long it does take us to open a
> study, and I think when the pharmaceutical industry come to us with
> new agents, the whole issue about, well, it is taking an age to
> actually get through all of these processes, and it is not
> particularly attractive to us, is a real issue, but these are some of
> the steps.
>
> I mean after some initial discussions in the group, we produce a
> protocol concept which goes to a wide UKCCSG meeting. In fact, what we
> used to then have to do is to take it to a second meeting to be
> finalized. As we only have two meetings a year, that automatically
> built in a six-month delay in initiating a study.
>
> As Steven witnessed earlier this year, I was able to negotiate that we
> could actually remove one of these steps so we have shortened it
> somewhat.
>
> We then had the ethical submissions, which in the UK now involves a
> national ethical submission, the so-called MREC for any studies
> involving more than five institutions. After the MREC submission has
> been approved, each individual hospital has to then submit also to its
> local ethical committee, and then you can open the study.
>
> I think that that process never takes less than a year, and is often
> taking two years.
>
> \[Slide.\]
>
> In terms of the code of conduct with specific regard to Phase I
> studies, again, there are some key components to what we think should
> be doing, and I have to say not all of the 22 centers within the UK
> conduct Phase I studies.
>
> We have restricted the number of Phase I centers, but clearly, the
> compromise is that we do reduce the number of eligible patients able
> to enter into our studies, but a lot of the issues relate to around
> staffing and particularly the need to have dedicated research nurse
> input.
>
> \[Slide.\]
>
> Similar code of conduct for Phase II studies, which again stresses the
> need for serious adverse event reporting and the importance of data
> monitoring and management.
>
> \[Slide.\]
>
> Just a few comments about the UK/French collaboration.
>
> \[Slide.\]
>
> We have now undertaken four joint studies with France, and that
> included a Phase II study of temozolomide, a study of an agent called
> PSC833, which is a cyclosporine analogue, which was being used to
> reverse multi-drug resistance, daunoxome, liposomal daunorubicin,
> Phase I, and irinotecan, CPT-11, Phase II study.
>
> \[Slide.\]
>
> I am just going to use that CPT-11 study as an example, and again put
> some timelines along the development of this study, very similar to
> again Peter\'s presentation.
>
> Here is the European development of CPT-11 in adult practice, which
> initiated Phase I studies in 1990 and went through to Phase II studies
> in 1992, U.S. licensing in 1996, and European approval was granted in
> 1997.
>
> Well, let\'s just look and see where the pediatric development fits in
> here. It wasn\'t until Phase II adult studies were started to be
> undertaken that the company really released a drug for us to be able
> to undertake some preclinical xenograft studies, so they started early
> in 1992, and they were predominantly carried out by Gilles Vassal in
> Institut Gustave Roussy.
>
> The French undertook a Phase I study, which recruited very quickly,
> but, in fact, the reason that this is quite a long study is, in fact,
> the MTD was defined at a very significantly high dose level than the
> adult study. This is a single infusion every three weeks, so Peter
> would tell me we are using completely the wrong schedule here.
>
> But the adult recommended dose is 350 mg, and the children\'s dose
> ended up being 600 mg/M^2^, so it was a very significant difference.
>
> The joint Phase II study followed on immediately after that, and was
> completed earlier this year. So, if we look at the facts, it took
> seven years from initiation of the adult Phase I study before the
> first pediatric Phase I study in Europe was undertaken. Our goal is to
> do this in 18 months.
>
> \[Slide.\]
>
> Since the collaboration, the UK-French collaboration, I think we have
> done a lot, and between the two groups, and jointly, we have
> undertaken a reasonable number of studies, however, we have been very
> dependent on access to drugs from the pharmaceutical industry. If you
> think you have got problems with accessing numbers of agents in the
> United States, it is even more of an issue for us in Europe.
>
> But I think the important factor to see here is that in a relatively
> short space of time, a significant number of patients, over 500
> patients have been entered into Phase I and Phase II studies, but of
> all of these agents, all of them for us have been initiated after
> approval in adults.
>
> \[Slide.\]
>
> I just want to do some horizon scanning for you and give you what we
> hope will be the future in Europe, which is what we are calling the
> ITCC Project, Innovative Therapies for Children with Cancer, which is
> a really Integrated Pan European Clinical Research Network, which is
> designed to conduct comprehensive drug development programs in
> pediatric cancers, so this is true translational research. It is
> promoting fundamental basic science, preclinical modeling, and conduct
> of clinical trials.
>
> \[Slide.\]
>
> To that end, we have formed a core group of partners within the
> project - Institut Gustave Roussy in France, Cancer Research-UK,
> UKCCSG, New Agents Group, and the French Pharmacology Group, the Dutch
> New Agents Group, and the Germans have joined us, too, and Joachim
> will give you some information about that very shortly, and the
> Italian group, as well, and the academic pharmaceutical input from the
> University of Newcastle.
>
> It is by no means comprehensive, we also have input from the
> pharmaceutical industry, the EMEA obviously close partners with us, as
> well.
>
> \[Slide.\]
>
> But what is envisaged is that we have a network throughout Europe
> which is guiding drug development for pediatric oncology and linking
> both the academic institutions together, the pharmaceutical industries
> together, the clinical network, and also the regulatory authorities.
>
> But as we all know, these networks are far from simple, there are very
> complex steps along the way, and once you actually start filling in
> all of these gaps, it becomes extraordinarily complex.
>
> But if a network works, and I hope this one will, and there is no
> reason why it shouldn\'t, it shouldn\'t matter where you start in this
> network, there should be a one-stop shop for anyone wanting to
> undertake pharmaceutical studies in Europe, which says you phone ITCC,
> and they can sort you out.
>
> \[Slide.\]
>
> So, let\'s just focus back on this timeline again. I think for us, the
> problems are way back here, and the issues are way back here, and one
> of my anxieties, and I don\'t know whether it is real because I have
> never been able to prove it, is what happens to the drug that is being
> developed usually by the pharmaceutical industry, that goes into a
> Phase I in adults, shows acceptable toxicity, then goes into adult
> Phase II data and because of lack of efficacy, the whole development
> program is halted.
>
> Those drugs will probably never have been tested in a preclinical
> model of pediatric tumors, and certainly won\'t have been investigated
> in a Phase I study in children, and who knows what the activity that
> drug might have had in pediatric oncology.
>
> Thank you.
>
> DR. SANTANA: Thanks, Bruce.
>
> Dr. Boos.
>
> **European Perspective**
>
> **Joachim Boos, M.D.**
>
> DR. SANTANA: Do we have a computer change?
>
> DR. BOOS: Yes, but I can use the time to tell you one additional
> conflict of interest I had. We have currently autumn vacations in
> Germany, and my family is going to London and asked me to come with
> them, but I told them no, this is such an important meeting in the
> societies that interested in this point of discussion that I will go
> to Washington, and therefore, I thank you very much for the invitation
> and try to give you a short illustration on how the things work only
> in Germany.
>
> \[Slide.\]
>
> What do you see here? Nothing.
>
> \[Slide.\]
>
> But now you see here some of the representative tumor types in
> pediatric oncology, and they all happen in Germany, too. It is
> interesting for us that in a list of the HHO where they summarize the
> chemotherapy-sensitive tumor types, most of them are pediatric tumor
> types, only very few are adult tumor types.
>
> If you look on the lists of what is labeled during the last years, all
> these yellow ones do not really, all these pediatric ones are not on
> the list. Labeling normally goes to indications which are not
> primarily sensitive or not common in pediatrics.
>
> This has two sides. First is immediately when they are on the market,
> and Peter Adamson told that they are used in pediatrics without any
> prevailing data, and the second is that in Germany, we currently are
> having very intense discussion in relation to the costs of the
> clinical treatment, and the health system is no longer willing to pay
> off-label for drugs.
>
> This brings the whole pediatric oncology into a disaster, and it is
> therefore our major interest to come to more labeling for pediatric
> drugs, and not to increase the costs by academic ideas, but to speed
> up the process to make it as cheap as possible and as safe as
> necessary.
>
> \[Slide.\]
>
> In Germany, we have a cancer registry for childhood, and this
> registered all patients up to the age of 15, and we have roughly 1,800
> new patients per year in the age under 15, and if we include the
> adolescent up to 18 or 20 years, we come up to roughly 2,400, 2,500
> new patients a year.
>
> All these patients are treated in cooperative treatment clinical
> trials, and you see here the indications and you see the trial groups,
> and it is the standard that there is one trial for the initial therapy
> and a second one for the relapse therapy, and with the second relapse,
> they are off study and on individual experimental therapy situations.
>
> \[Slide.\]
>
> These study groups have perhaps a bit Germany-specific role because
> there is a study committee and one coordinating center, and these
> centers are distributed all over Germany. In this map, I found Münster
> was not included, therefore, I added it for you. Münster is the green
> point. It is a bit bigger. This means not that it is more important,
> but we have the osteosarcoma trial, the Ewing\'s sarcoma trial, and
> the myeloid leukemia trial to organize for Germany.
>
> Other centers have other tumor types. The centers are the principal
> investigators, not only responsible for the quality of the protocol
> for protocol writing, adverse event monitoring system, things like
> this, is, in addition, responsible for organizing the quality control,
> which means central pathology refuse, central radiology refuse,
> central surgical planning, or things like this, and this is different
> than in many other countries, I think. There is an individual clinical
> consulting.
>
> This means if any participating center has difficulties with an
> individual patient because of toxicity, because of unusual location of
> the tumor in question to the surgery, in all these situations, they
> phone to the center, and this is the experienced center for everything
> happening in this entity, and therefore, is sometimes in conflict
> between protocol compliance and patient\'s interests, and normally,
> then, you might expect, the patient\'s interests is the leading for
> the decisions.
>
> Those protocols then are offered to the patients in roughly 80 to 100
> centers, and in indications where the adolescents are included, up to
> 250. So, we have currently up to 250, but the core pediatric
> facilities are 80 to 100, and they treat between 10 and 120, 130
> patients per year.
>
> So, they need the experience of the center in individual situations.
> The aim is that patients do not have to drive too far to the hospital
> to where they are treated, but get the qualified and standard therapy
> everywhere in Germany.
>
> This means that if they come into a situation where they want to be
> part of the Phase I or II trial, we have to organize it that way, that
> they can still stay at home as long as possible, and they are not
> willing\--or they are willing to go any center in the world or even on
> the moon, but if you have a new drug and cannot give them really a
> cure chance, then, we have the priority that the patients should be
> treated in the hospital that they are familiar with.
>
> \[Slide.\]
>
> The enrollment in the clinical trial system increased rapidly in the
> last years, and today, I think we are in the situation that more than
> 95 percent of the patients in Germany are really treated in these
> clinical trial organization, and this means from a statistical point
> of view, that this is not a subgroup with statistical probability. For
> Germany, at the end, the results of the trials describe the reality
> for the time the trial run.
>
> \[Slide.\]
>
> The results increased we saw in comparable presentation some time ago,
> increased from close to zero up to in the mean 70 percent, five years
> survival, and when the physicians began with that, they were not
> enthusiastic that the drugs really could work. They only saw patients
> dying.
>
> Now we know that these tumor entities have an interesting biology,
> have different biology, and are sensitive to chemotherapy, and I think
> we should continue with some enthusiasm and should try that the
> pharmaceutical industry shares this enthusiasm a bit more.
>
> \[Slide.\]
>
> So, if we have 2,000, 2,500 patients a year and 70 percent survivor,
> up to 700, 800 patients come into a situation where we can no longer
> offer them cure rates, they are palliative, and this is up to 50
> percent leukemia, lymphoma, and to 50 percent solid tumors.
>
> If we look only on specific tumor indications, like Ewing\'s sarcoma,
> for example, these numbers reduce significantly down to 20, sometimes
> 10 per indication per year in Germany, and this means we have to
> discuss when initiating a trial, is this really tumor-specific or is
> it more unspecific, is it really necessary to test a new drug in an
> indication like Ewing\'s sarcoma, or would it be much more feasible
> just to focus on safety and look in solid pediatric tumors or
> embryoblastic pediatric tumors.
>
> \[Slide.\]
>
> This gives you a short impression on the strategy of the current
> Ewing\'s sarcoma protocol, and is one of the few situations where we
> could define therapeutic windows, and this is in the high risk group
> where we now define the therapeutic window, and in cooperation with
> the group Bruce Morland just mentioned, this therapeutic window, we
> are now filled with therapeutic or Phase II trials, which are
> discussed in the ITCC project on in the French, British, and in
> between European cooperative Phase I/II group.
>
> \[Slide.\]
>
> Then, this group can take access to an organization, which is
> European-wide, and I took the Ewing\'s sarcoma trial to show this to
> you. It is the adverse event monitoring strategy, reporting strategy
> in the Ewing\'s sarcoma trial, which is European-wide.
>
> You see that the UK treats according to this protocol, France,
> Switzerland, Austria, Germany, The Netherlands. All these countries
> contribute to this trial and have the regional or national committees,
> and the specific departments or clinicians report to the national
> committee, and the committee reports to the database in Leicester and
> to the database of the EORTC in Brussels.
>
> Then, in Leicester and Brussels, all these data are summarized, and
> the information flows back, and the committees give it to the regional
> authorities and ethical committees, and what else.
>
> This works fantastic and includes I think roughly 300 departments, I
> do not know exactly the number.
>
> \[Slide.\]
>
> But then we have to organize the trials in this way, that every
> department can be part of the trial, and in specific situations,
> especially when labeling is the aim of the process, we need some more
> GCP conformity and some more audits in specific centers, and things
> like this.
>
> To provide a structural basis for such drugs, the German Ministry of
> Research and Technology some years ago initiated a program to sponsor
> coordinating centers for clinical trials, and those were seven centers
> for the first four years, and now again I think six or seven were
> added, so that we up to now have roughly 13 centers in the
> universities in Germany, and 7 of those have specific coordinating
> centers for clinical trials in children, and this compares a little
> bit to the PPIUs in the U.S. and I think looked closely over the ocean
> when designing this application.
>
> The coordinating center of clinical trials in Münster now is
> responsible for organizing everything with pediatric oncology drug
> development for the society and for the KKS network.
>
> \[Slide.\]
>
> Before we define a specific tool I want to introduce to you, and this
> is in kind of roundtable, where we try to organize that everything is
> transparent to everybody and that we can catalyze the decisionmaking
> between the different social groups which are interested or not
> interested in drug development for children.
>
> Therefore, our own society is at the table, the adult study groups are
> invited sometimes here, although generally, the pharmaceutical
> industry is invited to discuss with us, and then the regional
> authorities who have to check whether or not we work according to GOP
> and other things.
>
> Then, we have the ethical committees involved, one or two lawyers, and
> representatives of the patient groups, and discuss then the value of
> the preclinical data. This is normally an interesting, but not very
> helpful discussion.
>
> Then, we discuss the priority of the drugs. This would be a fine
> situation, but normally does not happen because we do not have enough
> drugs for 700 or 800 patients who really ask us to be part of
> experimental treatment.
>
> Then, we discuss whether or not it is necessary to develop a pediatric
> formulation, and in cooperation with our pharmaceutical technology, we
> have I think really a lot of experience to discuss this point, and
> sometimes it would be very helpful if, in the early discussions on
> pharmaceutical preparations, the companies would ask more to
> pediatricians or pediatric pharmacists because the choice of
> solubilizers or other necessary stuff could make things easier for us
> later on if you avoid benzyl alcohol or DMA or things like this.
>
> This, we discuss trials, the financial aspects, the ethical problems,
> the GCP compromises, because compromises are always necessary in
> pediatric multicenter trials, and then we discuss what this KKS can be
> supportive for the trial, writing protocols or something like this,
> everything we can do that the interested investigator has less work,
> then speeds up the process.
>
> So, this is a kind of catalyzer between industry, authorities, and
> investigators to enhance quality and to enhance the time frame,
> because the question of the patients is to hurry up, they are waiting
> for these drugs.
>
> Then, we define the network of 15 pediatric oncology centers
> cooperating with KKS, and these 15 represent roughly half of the
> patient numbers in Germany, so those are the bigger centers with more
> than 50 patients per year. They have contracts that they follow the
> SOPs and the GCP guidelines, and things like this.
>
> \[Slide.\]
>
> This all is more prospectively enthusiastic than we could fill it in
> the past with data, so a Phase I has never been done. I only remember
> one in Germany. This was on MTGD-1 some years ago, the only one I
> remember.
>
> There are several Phase II-like trials in the Clinical Trial Groups,
> but this is offering more less experimental therapy in first or second
> relapse.
>
> We currently, by the system of KKS, initiated some trials which is IV
> busulfan, two trials with gencitabine, one with asparaginase, and one
> with topotecan/carboplatinum. Those are only drugs which are long
> known on the market, and there is no trial with a complete sponsoring
> by the industry.
>
> We are interested in changing this. We are not primarily interested in
> running Phase I trials. If there is capacity and much more experienced
> groups, there is no necessity for us to spend time on Phase I trials,
> but we are now in the situation that we can contribute to Phase I
> trials if other groups need patients to speed up the result
> generation.
>
> \[Slide.\]
>
> The questions are always the same in these roundtables between
> industry and others, what is the preclinical marker indicating
> priority, okay, we discussed that. What is realistically an
> indication, what do we look for. This is a very important issue from
> my point of view.
>
> What are the realistic endpoints in second or third relapse? Response,
> probably not. What is a realistic level of significance if you focus
> on Ewing\'s sarcoma and have only 20 patients a year, can you really
> expect 0.5, is it really necessary, and what is the power you need?
>
> Every compromise here is much better than standard off-label use
> worldwide.
>
> \[Slide.\]
>
> Some very short words on preclinical screening because we just
> organized this pattern of roughly 15 cell lines representing all the
> pediatric tumor types, and there is no necessity to go on this in
> detail.
>
> We first tested in four Ewing\'s sarcoma cells lines, gemcitabine, an
> old drug we were rather interested in, and it is on the market since
> five or six years, and never been systematically investigated in
> children, and could expand the indication in the adult area year by
> year, so we were interested in this and saw very good preclinical data
> in these MTTSAs.
>
> \[Slide.\]
>
> We compared it to a very new drug mentioned here sometimes today,
> which is Gleevec, Ewing\'s sarcoma express c-kit and PDGF, and all
> these cell lines did it, but they were non-responsive in this in vitro
> testing, and therefore this was the first time we had decided to
> continue with gemcitabine, not with Gleevec, and a little bit in doubt
> whether this is really a sound basis for such a decision, but if I
> were a patient, I would prefer gemcitabine, not Gleevec after such
> results.
>
> Thank you very much.
>
> **Committee Discussion**
>
> DR. SANTANA: Thank you, Dr. Boos.
>
> One thing that occurred to me as I was listening to these
> presentations from the European perspective and the industry
> perspective that I think hopefully\--Malcolm may want to comment on
> this\--will be addressed in this national U.S. effort to establish
> preclinical models is the issue of standardization, and clearly are
> characterizing these models, so that when they are tested against
> different drugs, we are really looking at the same thing, and we are
> not trying to make judgments on potential activity when different
> groups are using different models that have not been adequately
> standardized.
>
> So, that is just an editorial comment, but it occurred to me as I was
> listening to some of these presentations that if industry is going to
> use different models than we are going to use in the consortium, that
> the NCI may use, we are going to set ourselves into a big problem, we
> are not really going to be able to use these models very effectively.
>
> Do you want to comment on that, Malcolm?
>
> DR. SMITH: I will just say as background our efforts in this area were
> really given a boost by a meeting that we sponsored in June of last
> year, getting a group of experts in preclinical testing together to
> talk about this challenge.
>
> Out of that meeting there was a sense of enthusiasm for proceeding
> with an effort in this area. The schema that Peter Houghton showed
> actually came out of that meeting.
>
> As that schema indicates, what we envision is a panel of xenografts
> that are well characterized in terms of their biological
> characteristics and that are used repetitively to test each of the
> agents that come through the preclinical system, so that we do get an
> experience with the same group of tumors and can then make both the
> retrospective correlation, then, the prospective correlations between
> the preclinical patterns of activity and the clinical patterns of
> activity.
>
> So, we are actively pursuing ways to support such an activity.
>
> DR. ADAMSON: I have actually a number of comments that I will try to
> tie together under one theme and to try to address at least one
> question that I think is an important question that Steve proposed.
>
> The theme of my response is going to be the importance of
> communication, and that is communication both nationally,
> internationally between academia, industry, and the cooperative
> groups.
>
> As far as whether should the cooperative group be the only venue for
> pediatric cancer drug development at least in Phase I, my answer is
> no, it should not be the only venue. Having said that, let me expand
> upon why I think it is a critically important and productive venue.
>
> The new COG Phase I consortium actually just started receiving funding
> in July of this year, so it is truly a new entity. Susan Blaney and I
> co-chaired that committee and we have also had the experience of
> working directly with industry on a number of non-oncologic pediatric
> drug development and have a very good sense of what industry timelines
> really are versus what academic timelines are and cooperative group
> timelines are.
>
> Although we have a productive cooperative group, we do not believe our
> timelines yet are where they should be. They are simply not at the
> level of efficiency that we are demanding of them, and certainly not
> at the level of efficiency that industry would demand of them.
>
> We have put in place a number of standard operating procedures and are
> actively addressing where we think the inefficiencies are. Our goal,
> and I think it is a realistic goal, is that our cooperative group will
> be the most productive, efficient venue for industry when developing
> new cancer drugs for children.
>
> With that in mind, what we can give to industry is it is really a
> remarkable resource with an infrastructure already in place with the
> pediatric expertise at major centers in place, but monopolies, in my
> opinion, are never good, be it Microsoft or be it other monopolies.
>
> I certainly think that there are centers in the United States that
> have demonstrated the ability to carry out these trials. St. Jude is
> an excellent example, the Pediatric Oncology Branch at the NCI is an
> example, and there are likely to be other examples.
>
> So, I don\'t think industry has to come to the cooperative group in
> order to develop the trial, but what is critical is that we
> communicate, because doing the Phase I trial, quite honestly, is easy.
>
> What is harder is the development plan for the agent, and that
> development plan ultimately should be looking towards Phase III. At
> Phase III, one has to utilize the cooperative group in pediatrics.
>
> So, to set out to do a Phase I without ever communicating with the
> cooperative group, I think is counterproductive. That is not a good
> utilization of resources.
>
> I don\'t think we should be the only place to do Phase I\'s, but we
> ought to know about Phase I\'s that are occurring, and discussions
> ought to take place with, well, how will we develop this beyond Phase
> I.
>
> If those discussions do not take place because industry is operating
> outside the cooperative group with certain institutions, then, I think
> we are doing a disservice to overall drug development in children.
>
> Industry, I think has an important role to play, and certainly
> bringing resources to the drug development process can always improve
> the efficiency upon systems, so the cooperative group mechanisms,
> which has resources, does not have sufficient resources to leap the
> gap that occurs when doing a fully industry-funded trial from one that
> is funded only by the NCI.
>
> The key point, however, is we need to communicate about this. We do
> not want to find ourselves in the situation that especially when it
> comes to analogues or me-too drugs that trials are being done only
> with pediatric exclusivity in mind, and not with long-term development
> plans.
>
> DR. SANTANA: Dave.
>
> DR. POPLACK: I just want to follow up on two points made by the
> speakers. The first is in response to Joachim\'s figure of the child
> and the denotation of the need for us to hurry up, but basically to
> emphasize the point that Peter Adamson made regarding.
>
> We are in a doubly ironic situation, because we have been so
> successful, we have fewer patients available for Phase I studies, and
> yet also we are at a time when we have so many more agents potentially
> available, but we can\'t get access to those agents.
>
> I really think, and hopefully, the advocates in the room will hear
> this clearly, that we are at a crisis point, we really have to do
> something in some way to influence government policy to make certain
> that access to these agents is provided to institutions and groups
> involved in studying these agents.
>
> I don\'t think it is very helpful, frankly, to come in and listen to
> comments, and not to single you out, Steve, but from the other side,
> that use issues such as formulation problems as being the mitigating
> circumstance that delays development in pediatrics. It is a bogus
> issue.
>
> I think the other issues that are out there are economic issues, and
> those are the ones that have to be dealt with in the spirit of
> cooperation. I know that the representatives in this room from
> industry, many of whom are pediatric oncologists and feel equally
> deeply as we do, the need to move the system along.
>
> We have to I think look to changes in policy and perhaps incentives
> first to make it easy for companies and advantageous for them to
> provide us access to these agents.
>
> The other point I want to emphasize was alluded to by Peter, and that
> is, it is important to allow single institutions or groups perhaps
> other than the COG to be able to do Phase I studies, but the big
> caveat is, is that things need to be organized and prioritized because
> we can\'t allow pediatric oncology to persist in repeating the history
> of our past, which has been somewhat checkered in terms of doing
> analogue studies in which individual institutions fall prey to
> economic pressures to do a study of an agent that is an analogue
> study, because those patients then get truly lost to studies that
> could be much more important, of drugs with new mechanisms of action,
> for example.
>
> DR. SANTANA: Jerry.
>
> DR. FINKLESTEIN: I do not want to preempt the next series of speakers,
> but I would like to give a quick historical basis.
>
> In February 2000, that is over two years ago, I had the opportunity to
> co-chair a meeting, some of the people in this room were there,
> representatives of FDA, NCI, the cooperative groups, the public, the
> American Academy of Pediatrics, and industry, and our topic was, as
> Peter pointed out, drug availability for children with cancer.
>
> I congratulated the FDA at that time, and I congratulate them now,
> because Mack Lumpkin, who really came up after a little meeting in a
> side room with a process that actually ended up with the institution
> of this committee. So, the FDA has taken a tremendous lead.
>
> Drug availability in February 2000 has yet to be solved, and we are
> already in October 2000, we have made very little progress. I would
> like to reemphasize what David just said.
>
> What we need from everyone is a change in behavior, and thus far, and
> I apologize, I was called out for part of your talk, thus far, I have
> not seen or heard in the last two and a half years any significant
> change in behavior by all individuals who address the problem of
> pediatric cancer and drug availability.
>
> So, I look forward to the next series of speakers whose topics are
> supposed to be identifying and overcoming barriers, and if we don\'t
> have the answers then, then, I believe it is the role of this
> committee to sit down and just drag out the issues, one by one, and
> create an algorithm which will change behavior.
>
> DR. OCHS: Hi. Judy Ochs from AstraZeneca.
>
> I was 20 years an pediatric oncologist, and I might add that in my
> company, on the Iressa or ZD1839 program, we have a token medical
> oncologist. The four lead physicians are pediatric oncologists. So,
> you already have a voice in many of the companies, you really do.
>
> There are several things that occurred to me listening to this
> presentation. The whole first part of your presentation focused on
> classic cytotoxic drug development.
>
> If you look at what is currently in the pipeline in most companies,
> all of the drugs, I saw a recent pie diagram, 15 percent are
> cytotoxics, and the other 85 percent are Other, whether they are novel
> agents, monoclonal antibodies, et cetera, so you have to be geared up
> to test these other agents, too.
>
> The other thing is that when you look at Phase I agents, a lot of
> these novel drugs are going to have novel targets. Iressa or ZD1839,
> we do have three pediatric trials, and they were started, and they
> were started rapidly, and a large part of the reason was Peter
> Houghton, because Peter not only had the xenograft model, but he also
> had data to show that the target was present in certain pediatric
> tumors, so we were able to go and do that very quickly and start
> discussions.
>
> In fact, we started discussions with both St. Jude and the cooperative
> groups while we were still doing the Phase I in adults. I would also
> say if you want to do Phase I trials in children, at the very end of
> Phase I of trials in adults or at the same time, then, you are going
> to have to be committed to work very closely with the company because
> the company\'s key priority is safety, and they are particularly
> anxious about safety in children, as other people are on the outside
> of pediatric oncology.
>
> When we ran the Phase I program with Iressa, which preclinically, our
> toxicology showed was an extremely safe agent, we had weekly telecons
> with all the investigators. So, again, it is a certain level of
> commitment on the cooperative group part.
>
> I would also state that I think that the major of the trials should be
> done in the cooperative groups, and of the three pediatric trials we
> have, one is with the cooperative group, one is with the Pediatric
> Brain Tumor Consortium, and one is with St. Jude, and that also
> reflects the fact that there are certain needs that companies may have
> for certain drugs that can\'t be done in a cooperative group
> mechanism.
>
> Part of the reason we went to St. Jude was Peter Houghton and his
> data. The other reason was it was a single institution, and at that
> time we were concerned about eye toxicity. We had a single institution
> which could perform serial studies. So, a lot of these targeted agents
> are going to have very specific needs that not all the time a
> cooperative group can take care of.
>
> Lastly, there is the time factor. I think right now you have a
> tremendous carrot. You have a tremendous carrot, which is the
> pediatric exclusivity, and most of the companies want to work with
> you, but again, if you are going to be looking at some of these newer
> agents, you need to rethink some of the things you are doing.
>
> We are grappling with how to do good clinical trial designs in these
> agents as it is, and it is a bit tougher in pediatrics in some ways,
> but again, you have a tremendous carrot. The companies are more than
> willing, but if you have a novel agent, you have to show us that you
> have the target present.
>
> I would agree also that I don\'t like the term \"targeted.\" I think
> it is biologically based as we are trying to figure out what the exact
> target is in some of these things.
>
> DR. PRZEPIORKA: A question for Dr. Hirschfeld or Dr. Pazdur. I was
> surprised not to see someone from the FDA speaking on the list this
> morning. The reason I say that is because we have heard a lot today
> about the access to barrier to drug, and that is clearly true if you
> were getting your drug from a pharmaceutical company.
>
> We have heard in the past a lot about the development plan and the
> pathway to registration, but many of the pediatric malignancies are
> truly orphan diseases, and if you really want to get to the point of a
> randomized trial, it may take decades, and yet there may be some drugs
> out there which someone wishes to study.
>
> They could get the drug by making it themselves nowadays now that
> academics have their own GMP facilities.
>
> How will you view individuals who come to you with INDs to do studies
> with no clear pathway for registration, and obviously, in a population
> so small that no company wants to take it up because of economic
> problems?
>
> DR. HIRSCHFELD: I was counting on the legacy of our previous meetings
> to make some of the points, and didn\'t want to take up time reviewing
> things which we have done before, but weave it into the conversation.
>
> So, I will take this opportunity to point out that we have issued
> about 30 written requests, and about half of them are for approved
> drugs, so anyone that does the math realizes that the rest are for
> investigational agents, and there is enormous interest in activity in
> pursuing programs.
>
> With regard to having a requirement that someone have a complete
> development plan, we don\'t have the mandate to do that, but we always
> ask that question, and our pediatric written requests just to discuss
> one aspect of our programs, not the entire aspect, begin with an
> introductory paragraph which emphasizes the need, first, for an entire
> development plan, and, second, for a pediatric development plan.
>
> So, we have put this in the fabric of our interactions with sponsors
> whether they are industry or otherwise for about at least two years,
> as Dr. Finklestein pointed out, and I am going to defer to Dr. Pazdur
> just to discuss our mention, our interest and emphasis on having an
> overall development plan.
>
> DR. PAZDUR: I think, number one, drug development is a stepwise basis,
> and when somebody comes in to us with their first Phase I drug study,
> they are not going to have a complete development plan because for
> traditional agents, more or less, they have been looking at hints of
> activity.
>
> We could talk all we want about targeted therapies, but many times
> people are looking at what are the initial glimmers of activity and if
> that tumor has activity or one sees activity in that tumor, then, that
> sometimes guides the pathway.
>
> We are asking sponsors to really concentrate on more of a development
> plan rather than just coming to us with individual protocols. That is
> part of our end of Phase II meeting to discuss with them where they
> are going.
>
> With our development of accelerated approval, for example, where many
> of our drugs are getting their initial approval, we want to have in
> place a development plan of where they are going to show clinical
> benefit even before we approve some of these drugs. That has to be in
> place.
>
> So, the development plan is something that evolves. Initially, we are
> not going to have it, especially at the time where many of you people
> want to have these drugs going into pediatric drug development, it is
> simply not there.
>
> There is a lot of talk about barriers to drug development and how
> tumors are selected\--or not tumors, but the selection of a
> development plan, and I still think no matter how sophisticated our
> models may be, the biggest encouragement for companies to invest in a
> drug is to see that initial glimmer of activity in a Phase I study.
>
> That is far more important than any alleged theoretical mechanism of
> action here, and that will basically dictate a lot of where they are
> willing to put their money as far as developing a drug in pediatrics
> because you have to understand that it is a financial expenditure that
> they are making here. That is what guides many of this.
>
> We have very little regulatory authority over that, nevertheless.
>
> DR. WEITMAN: I just want to comment on a couple of things, and I will
> echo a little bit what Judy said. Again, I don\'t want to be, you
> know, this side at least of the room be viewed as adversaries.
>
> DR. SANTANA: I completely retract that comment.
>
> DR. WEITMAN: We are all pediatric focused and have an interest,
> otherwise, we wouldn\'t be here today.
>
> Clearly, I share a lot of the frustrations with availability of drug
> having been in the shoes of Peter and others here, begging for drugs.
> I remember working with Charley Pratt trying to get gemcitabine, and
> that was such a frustrating experience. I think we all realize that
> availability is important.
>
> I do want to echo a couple of statements. I think certainly
> communication is important. I think once the drugs from what I can see
> get into adult Phase I, and there is that glimmer of hope in Phase I,
> where there is a commitment all of a sudden on the company to take
> that compound forward into multiple Phase II studies, at that point,
> the clinical development plans begin to be set.
>
> With that, that sets the number of studies based on how much drug has
> already been made or will be made. It does set the study populations.
> It does set to a certain extent the formulation, and again I am not
> implying that formulation prevents studies, but it clearly helps
> determine what capsule sizes are made, and so forth.
>
> I would echo the need for communication, and I would say when it comes
> to the end of Phase I, the start of Phase II, when those clinical
> development plans are being set, that is from what I can see the best
> time for this communication to start. I wouldn\'t say not at IND time,
> but once there is a commitment to go ahead with the Phase II because
> there is activity, enough in the Phase I to want to see that compound
> developed, that is when prior to really formulating the budgets around
> the clinical development plan, the numbers of studies which dictates
> how much drug is made, that is when really the communication within
> the pediatric community really needs to be undertaken.
>
> DR. SANTANA: Steve, let me just comment on that briefly. I think the
> issue of access in part has focused a little bit on the clinical
> access to the studies, but there is another side to that coin.
>
> It is the access of the drug much earlier, so that individuals who
> have an interest in testing it in models can have very early access to
> the drug, so we can determine very early on whether we have an
> interest even before we even get to the issue of discussing Phase I
> and II trials.
>
> DR. WEITMAN: I don\'t think that really should be any barrier there at
> all.
>
> DR. SANTANA: It is an issue.
>
> DR. WEITMAN: It is an issue, but I would agree, I don\'t think it
> should be and particularly if non-GLP material is required, for most
> of these studies it is not, and it shouldn\'t be an issue. Maybe
> that\'s at pre-IND state when that can be discussed.
>
> DR. ADAMSON: Just to pick up on that last point, Steve, I think, and
> Peter can probably comment on this better than I, it has been a
> critically limiting issue for preclinical development, trying to get
> these agents into preclinical studies, and what we are looking towards
> as far as our screening consortium is that when strong consideration
> is being made to move a drug into Phase I in adults, adult Phase I\'s,
> certainly no later than what it already is in adult Phase I\'s, that
> is when we want the agent to come into our consortium, so that by the
> time it is nearing the end of adult Phase I, we actually have some
> data to tell us is there a pediatric rationale to move this forward.
>
> Now, to come back a little bit to what Judy was saying, Iressa, in
> fact, I think was a good example, but it was a rare example, and I
> also think that the carrot, we have yet to see if this carrot of
> pediatric exclusivity is going to truly be relevant for early cancer
> drug development.
>
> Much of industry gets interested toward the end of the life cycle as
> far as what the true value of exclusivity is, and a lot of times
> exclusivity is not even being discussed when a drug is just entering
> Phase I.
>
> So, there may, in fact, need to be, as Jerry and Dave have pointed
> out, a change in behavior, a change in outlook. Perhaps an incentive
> of the preclinical studies is not only the positive data that may
> emerge saying yes, we want to move it into pediatrics, but there may
> be value to negative data saying that this is not an agent that is, in
> fact, we believe relevant based on the knowledge we have to move
> forward, and a company could hopefully use that information to say,
> okay, this was our, you know, attempt if we wanted to move it forward
> in pediatric, to meet our obligations, not exclusivity, but just to
> meet the pediatric drug development plan, however, there is sufficient
> evidence here that it is not relevant to this disease entity.
>
> Lastly, coming back to the point about cooperative groups, our Phase I
> consortium is flexible and that we recognize that it is not always
> appropriate or necessary to study a drug in 21 institutions, and when
> there is a rational reason not to do so, we have the flexibility not
> to do that and to study in a smaller number.
>
> We also have the flexibility to bring in other institutions that, in
> fact, bring expertise that we don\'t have.
>
> Having said all that, I still stand by my earlier statement that there
> are going to be occasions that, in fact, it is better and more
> efficient to do it outside the cooperative group.
>
> I envision that those will be fewer and less common as we move
> forward, but they will always be there, and the key is communicating
> with the cooperative group as far as what is in early development.
>
> DR. REYNOLDS: I just want to echo the comments by Vic and Peter that
> the access of these drugs for preclinical testing is an absolute
> disaster, to use a strong term for those of us that are trying to do
> this.
>
> We are averaging two years to try and get an MTA through to get this,
> and that sometimes it takes as much as two or three years just to get
> them to send an MTA from the company. I have one case\--I won\'t
> mention the drug and company\--in which there were 17 e-mails over a
> two-year span, and the only way I was able to get an MTA is thanks to
> Malcolm\'s people stepping in from the NCI and finally getting an MTA
> through.
>
> So, I bring this also up in the context of your earlier question,
> Steve, as to what the timing would be in terms of generating
> preclinical data.
>
> I can tell you that the timing is mostly not impacted by the time it
> takes to do the experiments, but 10 times as long as it has taken in
> trying to deal with the lawyers, and we have to come to grips with
> that and come up with a way where industry can work hopefully through
> the NCI, as Malcolm has been trying to do, over the standard MTA, that
> all the academic institutions participating in this can sign off on
> and that one MTA, they don\'t have to re-read it again, because it is
> standard, and if we can get through that point, that will be a major
> accomplishment and will really help this forward.
>
> DR. WEITMAN: One quick comment. I think at the time of IND submission
> really I think would be a critical time to look at some mechanism at
> that point when drug can be made available for these studies, because
> again I think that is early enough to give the pediatric community,
> the research community, the chance to get the drug to do their studies
> that they need, so by the time the adult Phase I studies are nearing
> completion, you know, or even before that, the results would be
> available from those studies.
>
> I know there may not be any regulatory way of doing that, but I think
> that, to me, would be an ideal time point and when to trigger
> providing drug for studies.
>
> DR. SANTANA: We are going to have time to follow up on this discussion
> because a lot of the session that we had planned for this morning was
> actually going to try to address some of these issues.
>
> For the sake of time, I am going to ask that we take about a
> five-minute break and then we are going to try to come back and finish
> the next three presentations, and then we will do our lunch break.
>
> \[Recess.\]
>
> **Identifying and Overcoming Barriers**
>
> **Children\'s Oncology Group Perspective**
>
> **Gregory Reaman, M.D.**
>
> DR. SANTANA: First, is a discussion of identifying barriers and how we
> could overcome those. We are going to have Dr. Reaman from the
> Children\'s Oncology Group give the first presentation.
>
> Greg, please.
>
> DR. REAMAN: Thanks very much, Victor. It is a pleasure to be here and
> it is a particular pleasure to be representing the monolith in this
> whole spectrum of pediatric oncology drug development.
>
> As I heard that word, which obviously I find a little bit difficult, I
> am reminded that I have always had the association of cooperative
> groups being monolithic, but since we have merged and become a single
> pediatric cooperative group, I can\'t even imagine the perception that
> people must, incorrectly of course, have of us out there.
>
> Although we are not a monolith, I think we do have some operational
> inefficiencies. I am not sure that they are really inefficiencies. I
> think we have some operational disasters. Many of them are, in fact,
> because of the fact that we are severely resource limited, we
> recognize those operational problems, we are dealing with them as
> rapidly as we can, and I think the pediatric cooperative group is the
> best place to do new drug testing in pediatric cancer.
>
> We, too, like industry, are very concerned about safety, safety in
> children. We basically exist or have existed for the last 45 years
> trying to prevent children from dying from cancer, so safety is a big
> concern of ours, as well. It basically drives all of the clinical
> trials that we do.
>
> \[Slide.\]
>
> The barriers. There are just a few and a lot of this will be
> repetitive, so I am going to move through it pretty rapidly.
>
> What we see as a cooperative group as barriers to new drug development
> are basically 3-fold - the market forces and economic forces that make
> drugs available for pediatric cancer, the current testing of new drugs
> in children, and the shifting paradigm, and it continues to shift and
> has been shifting for the last 10 years.
>
> The legislation and regulations which impact or influence drug testing
> in pediatric cancer, all of which initially began as a way of
> protecting the interests of children and guaranteeing their safety,
> and are they really a help or are they a hindrance, the difficulties
> with interpretation and the difference in perception among various
> interest group create problems for us, as well.
>
> The solution is really very simple, and it basically boils down to
> communication, which has already been raised, and communication and
> early communication, and it is hard to imagine, Jerry, that the
> meeting that we had with the FDA and the American Academy of
> Pediatrics was only two years ago. I thought it was four or five years
> ago, but time flies when you are having a good time.
>
> But I think that communication will certainly result in coordination
> which we really need.
>
> \[Slide.\]
>
> As far as market forces, cancer is not a common disease in the
> pediatric age group, and has been touted to only be 3 percent of the
> cancer problem.
>
> Patent exclusivity is also not the carrot that one would imagine that
> it could be, and the whole drive to label drugs with indications in
> pediatric cancer is not a particular carrot for practicing oncologists
> who are very used to using approved drugs off-label as either single
> agents or in combinations for the treatment of pediatric cancer and
> for the clinical trials in pediatric cancer.
>
> The problem is further complicated by the fact that pretty much the
> standard of care in pediatric cancer management is done within the
> context of academic centers and in large part within the context of
> participation in clinical trials.
>
> The provider audience for the pharmaceutical industry is relatively
> limited and confined, as well.
>
> \[Slide.\]
>
> As far as other barriers, there are certainly limited subjects for
> clinical trials, and we are happy about that to some extent. We are
> victims of our own success.
>
> Although we may have limited subjects for the development of new drugs
> for new indications for new diseases that are refractory to current
> therapies, we certainly have an equal obligation to find less toxic
> and safer drugs that are just as effective as currently available
> therapies.
>
> There is a requirement for the most part for multicenter studies with
> the exception of a handful of programs. In this country, most new drug
> testing requires the participation of multiple institutions working
> together.
>
> Another barrier includes the correlative studies which are required in
> pediatric new drug testing including pharmacokinetics,
> pharmacodynamics, and an increasing desire to do pharmacogenic
> studies, as well, and obviously ethical considerations in testing new
> drugs, new agents in children, the first ensuring that there is human
> proof of principle, are we testing new drugs in children for a
> potential therapeutic benefit in that child or are we evaluating
> maximum tolerated dose, potential pediatric dose-limiting toxicities.
>
> And then, of course, the issue of assent for participation in clinical
> trials in general, but specifically in new agent testing in minors.
>
> \[Slide.\]
>
> As far as the shifting paradigm, the timing of pediatric studies
> relative to adult trials is very critical, and I would certainly agree
> with Peter\'s statement that the only thing that drove pediatric Phase
> I studies in the past was the availability of a new agent.
>
> I would soften that a little bit in that we didn\'t always move those
> new agents forward only because of their availability, and we were
> also burned on many occasions testing drugs in the Phase I setting,
> and being very excited about them, only to find out that since the
> drug was inactive in breast or colon cancer, it wasn\'t going to be
> developed any further by the industry.
>
> Early adult toxicity data, I think is critical, early adult efficacy
> data, less critical, and the whole issue of how we now assess
> responses and particularly assess responses in clinical trials
> involving agents with novel mechanisms of action.
>
> \[Slide.\]
>
> We also have to look at how we proceed from Phase I and PK studies in
> the pediatric age group - do we automatically go to broad-based Phase
> II studies looking at efficacy in all of pediatric cancer, or do we do
> this in targeted disease groups, is refractory disease the only place
> to evaluate new agents in children, or is there a role for early
> evaluation in Phase II settings in particular patient populations.
>
> Obviously, the concern, as in most cancers, we don\'t treat with
> single agents, the role of combination studies.
>
> \[Slide.\]
>
> As far as molecularly targeted therapy, validation of suspect targets
> in pediatric tumors, we see as a potential barrier and one that is
> rapidly being overcome. We look forward to the fact that many of these
> agents, which are biologically or molecularly targeted, have
> relatively favorable toxicity profiles.
>
> We would like to assure that pediatric studies are in the agent\'s
> development timeline, so the early validation of suspect targets and
> the early inclusion of consideration of pediatric cancer is important
> in the development plan.
>
> Response assessment, we see as potentially difficult in the pediatric
> age group as we look at new trial designs looking at surrogate
> endpoints utilizing perhaps imaging as a technique, sometimes
> including tissue responses requiring repeated biopsies, and is that
> something that is actually going to be feasible in the pediatric age
> group.
>
> As far as legislation and regulations, we have the fear that we are
> coming to a feast or famine situation, and it is actually from a
> famine to feast situation, and that in the past, despite our pleas, it
> took five to seven to 10 years to gain access to an agent, and now we
> may have too many agents to test.
>
> This really needs to be carefully evaluated with incentivization
> plans, and how is that going to really fit with disease-specific drug
> development plans, and particularly when mandated pediatric testing
> looms on the horizon, and how is that testing actually going to fit
> into disease-specific, pediatric cancer-specific treatment strategies.
>
> I would again plead that there has to be early communication and
> coordination with the pediatric cooperative group if not solely on the
> basis of new agent testing, but where is that new agent going to fit
> in the scientific agenda of a particular disease treatment plan.
>
> I look to this subcommittee to really help in the definition of
> indication and substantial benefit in pediatric patients.
>
> \[Slide.\]
>
> Obviously, communication is important, coordination, so that rational
> prioritization can proceed is vitally important. The timing of adult
> and pediatric studies, should they be sequential, can they be
> simultaneous, do we have to have adult MTDs, do we have to have
> evidence of biologic effect.
>
> We need to have some evidence, and I think that evidence needs to be
> agent-specific, and we probably don\'t need a hard and fast rule.
>
> We do need to increase our efforts at validating potential molecular
> targets in pediatric tumors and work closely with the preclinical
> assessment and the consortium that has been already discussed.
>
> Translating those findings to clinical trials will be vitally
> important, and obviously making sure that consistent drug source and
> supply is going to be there for the pediatric population.
>
> \[Slide.\]
>
> Again, the therapy plans and even for targeted therapy plans really
> need to be disease specific.
>
> The other place where I think we need to definitely communicate and
> coordinate and collaborate is globally and internationally. Given the
> very limited patient population resource that we have, we can\'t
> duplicate studies of the same agent or analogues of agents in patient
> populations.
>
> We really can\'t do that, and I think we can have greatly enhanced
> opportunities for targeted Phase II studies in combination trials by
> working together internationally.
>
> Thanks.
>
> DR. SANTANA: Thanks. We will have opportunities for questions and
> comments later on.
>
> I am going to invite Barry Anderson from the NCI to give comments
> related to the NCI perspective.
>
> **National Cancer Institute Perspective**
>
> **Barry Anderson, M.D., Ph.D.**
>
> DR. ANDERSON: I want to thank Steven and Victor and give some points
> from the NCI about issues that we see as being important to be
> maintained and other barriers and challenges to be overcome, to foster
> a Phase I approach to pediatric oncology drug development in North
> America and the U.S.
>
> \[Slide.\]
>
> The first would be a point of infrastructure for actually being able
> to perform these studies, and as Peter Adamson has mentioned already,
> the COG Phase I pilot consortia, which now consists of 21
> institutions, was reconstituted with the fusion of CCG and in COG
> institutions together, and they currently have a host of Phase I
> trials open and a number of new agent studies that should be opening
> soon.
>
> Another consortium that I think someone else has mentioned today is
> the Pediatric Brain Tumor Consortium, and this was initiated in 1999.
> It consists of 10 institutions now.
>
> It has a number of Phase I institutions and studying therapies that
> are focused on not just new drugs, but new surgical approaches and
> radiation therapy strategies for children with CNS tumors.
>
> \[Slide.\]
>
> Outside of these larger groups, Peter Houghton has his PO1 grant at
> St. Jude Children\'s Research Hospital for the study of new agents in
> solid tumors, and as Pat Reynolds has mentioned, there is a program
> project grant that is held by Robert Seiger \[ph\] at Children\'s
> Hospital of L.A. for new approaches to neuroblastoma treatment or the
> NANT.
>
> This is I believe 12 institutions that is working together to look at
> new therapies focused on high-risk neuroblastoma, and they currently
> have four, Phase I trials and some Phase II trials open.
>
> Again, there is also the Intramural Program at the NCI Pediatric
> Oncology Branch, which can do Phase I studies independently, but also
> cooperates with the COG Phase I institutions.
>
> \[Slide.\]
>
> People have talked about prioritization of agents because of the
> plethora of new agents that we all read about and that we all hear
> about being studied in the adult clinics. We always will have a
> limited and shrinking number of patients available. We realize that
> many agents will never be studied and we have to make choices, so
> future progress in drug development in pediatrics is going to depend
> on trying to pick the right agents.
>
> \[Slide.\]
>
> This dated list of anti-VEGF agents shows you that if we can only pick
> one or two, because that\'s how many patients we have available, we
> have to be smarter about how we do that.
>
> \[Slide.\]
>
> So, the pediatric preclinical testing program that Peter Houghton has
> spoken about earlier has been something that we at NCI have been
> working on for the past year and a half.
>
> The goal would be to help prioritize among the available new agents.
> We are hopeful, with the information that Dr. Houghton has provided,
> that these models can be predictive, and efforts are underway right
> now to establish, one, a coordinated structure; two, that what testing
> procedures will be important to have is sort of a standard system to
> bring new agents through.
>
> We recently had a meeting between sponsors and investigators to talk
> about the legal agreements that will be necessary both on the
> institutional level, as well as on the pharmaceutical sponsor level
> and the NCI level, and for what Pat Reynolds had brought up.
>
> We are working on a model MTA that was presented during this meeting,
> discussed with lawyers that came from the pharmaceutical sponsors, NCI
> lawyers, lawyers from tech transfer groups within the institutions,
> and we now have gotten comments on that from a number of the
> institutions and the pharmaceutical companies, will send out sort of
> the next iteration of that and then kind of go on a broader scale, so
> we are hopeful that that will be a means to bring drugs that are
> actually early on in the pipeline at pharmaceutical companies to
> preclinical testing.
>
> \[Slide.\]
>
> Next, the topic of access to new agents. There is two components to
> that. In terms of access from the sponsors, we all know about the
> financial disincentives that there is to a sponsor to actually study a
> new agent in the small population of pediatric oncology and that often
> pediatrics is outside the drug development plan.
>
> I think the changes that have been made at the FDA, as well as the
> push from the patient advocates and from the COG has helped to
> influence these components somewhat. The limited drug supply remains a
> factor.
>
> We hear about that at CTEP when we have an agent that we are trying to
> help a drug company to develop. Oftentimes, because CTEP has a series
> of studies it wants to do, we have to advocate for setting some drug
> aside for pediatrics, as well, and often until there is some greater
> impetus behind that in terms of activity found, we still have to wait
> even with drugs that we see coming we think that CTEP has access to.
>
> Perceived risks of doing studies will always be there I think from the
> pharmaceutical industry point of view, and the question of how much
> need to demonstrate activity in adult patients before you go into
> pediatrics is something that has been discussed.
>
> Another component of that is need for correlative study information in
> targeted or biologically-based agent development, and that is
> something that we will mention in a second.
>
> \[Slide.\]
>
> Another part of access to agents is from the patients\' perspective.
> There has been some discussion as the number of institutions within
> the Phase I consortium has changed, about how do we get access to
> everybody because everybody needs to get access to Phase I studies.
>
> Well, we don\'t really think that Phase I trials are the way to get
> access to agents necessarily for all the patients who might want
> those. By the sheer nature of a Phase I study, there is frequent study
> closures, there is just a few patients that are ever going to be
> enrolled, and as Peter mentioned, the waiting list lotteries that are
> on hand whenever a particularly hot drug hits the media and
> everybody\'s attention.
>
> We feel it is actually better to speed up or facilitate the Phase I
> component of drug development, so that you have a better access
> through Phase II trials and pilot studies that can be open nationwide,
> and don\'t require quite the special attention that you have for Phase
> I studies.
>
> Also, in very special situations, the special exception programs can
> be activated either through the NCI or by industry until a study is
> available.
>
> \[Slide.\]
>
> Now, in terms of the appropriate timing of Phase I study initiative in
> pediatrics, when the endpoint is MTD, so that would apply mostly to
> cytotoxic agents as people have mentioned, we feel that upon
> determination of the adult recommended Phase II dose, that is when you
> should be able to open the Phase I study for pediatrics.
>
> That means that the study has already been proposed, it has already
> been perhaps approved maybe without the dose level that you are going
> to start out on, but that you should have that much information from
> adults beforehand, pragmatic reasons, again, because of the limited
> number of patients we have in pediatrics, but also to avoid those
> agents that would fail early phase adult trials.
>
> I can tell you that a number of groups, people have called us. They
> have done in vitro studies, they have done preclinical studies, and
> the drug disappears as it is going into the Phase II in adults, and
> everybody is like, but what about my five years of research. You know,
> there is nothing we can do about that, and I think that is just a
> reality that we need to deal with, and it is a danger of moving too
> far up into whenever things start with Phase I in adults.
>
> Ethical reasons are that you are again trying to optimize the
> potential benefit for your patients and trying to minimize the risks
> of toxicities.
>
> \[Slide.\]
>
> For targeted agents or biologically-based agents, we would say that
> you would want to start in pediatrics perhaps upon the detection of
> targeted biologic activity in the Phase I studies.
>
> This has to do with some of the same pragmatic reasons in terms of
> limited number of patients and drugs that are going to disappear, but
> also one component, and we will talk about this more, is that with the
> new biologically-based studies, they are often asking for correlative
> studies that can require invasive procedures in children, so there is
> an additional ethical reason beyond the benefit and risk ratio, but
> also talking about the regulatory limits on invasive research
> procedures of greater than minimal risk in children.
>
> I think that this is a pediatric reality, that regulatory and ethical
> differences between adult and pediatric Phase I study conduct is an
> issue and a challenge to pediatric drug development.
>
> \[Slide.\]
>
> So, the last point about special challenges and innovative approaches
> within the development of agents for targeted therapies, the pediatric
> reality is that children may receive an experimental treatment posing
> potentially greater than minimal risk if there is the potential for
> direct benefit. That is what can allow us to do a Phase I study in a
> child and give them an experimental drug.
>
> Children may only participate in research with no prospect of direct
> benefit to the child, such an invasive tissue collection that is done
> only for research purposes provided the risk represents a minor
> increase over minimal risk.
>
> That last quotation, \"provided the risk represents a minor increase
> over minimal risk,\" has caused a lot of meetings to be had, a lot of
> definitions to be promulgated, and I don\'t think there is a clear
> answer on that topic quite yet, but this is a pediatric reality.
>
> \[Slide.\]
>
> Now, when you have these two components in the same Phase I study, I
> am going to give you a new drug, we are going to try to monitor what
> is happening in your tumor, the IRBs that are approving these have to
> consider what the whole experiment is.
>
> The potential benefit that comes with the experimental agent, the drug
> that you are giving the child, doesn\'t give that experimental
> procedure that you are necessarily going to do, an invasive biopsy of
> liver, let\'s say, any benefit if there is not a clinical decision
> that is being made based on the biopsy results, if all you are doing
> is getting research information, and the family and the clinic never
> finds out about that, that does not necessarily flow one to the other.
>
> So, the risk-benefit analysis is considered separately for these two
> research components within that same Phase I study.
>
> \[Slide.\]
>
> We think that in pediatric oncology, a major challenge then in this
> time of biologically-based and targeted agent development, is to
> develop pediatric alternatives if an invasive biopsy is what is
> thought to be needed during the adult studies.
>
> Minimally invasive surrogate tissue sampling is something that should
> be looked into. In our studies that have been proposed and are
> underway, they are usually buccal mucosa, sampling peripheral blood
> cell studies that are done, such as in a PS341 study where they are
> looking at the proteosome levels in peripheral bloods cells as a way
> of monitoring the effect of the drug, and bone marrow cells are
> another relatively less invasive surrogate tissue.
>
> Tumor cell isolation from accessible tissues, such as peripheral blood
> or bone marrow is another approach, the non-invasive imaging
> modalities that Dr. Reaman mentioned, and also the idea of correlating
> through PK in children, drug levels that have been associated with
> antitumor activity and/or target modulation in either the preclinical
> models that we would hopefully see in studies done from the
> preclinical testing program or actually in adults during the Phase I
> studies that were preceding the pediatric studies.
>
> \[Slide.\]
>
> Another component or another issue that has been a challenge I think,
> and it just reflects all our discussions today, all the drugs that we
> have been talking about or all the issues we have been talking about
> have to do with the fact that all these drugs are designed for adult
> indications. That is what goes through people\'s minds when they come
> up with the drug.
>
> \[Slide.\]
>
> Maybe now in the days of biologically-based and focused drugs, that
> may be less the case if there are biologically-based reasons that make
> the adult tumor and the pediatric tumor similar, but we think that the
> pharmaceutical sponsors have lacked an incentive to develop
> pediatric-specific targeted agents, and things such as the fusion
> proteins for Ewing\'s sarcoma or for the alveolar rhabdomyosarcoma,
> the PAX forkhead, those types of targets are not usually listed as
> what people are either testing their agents against or what people are
> focusing their drug development efforts at.
>
> So, we have asked in NCI whether through grant programs, is it
> possible to stimulate the development of agents that would be
> actually, from the moment they are designed, meant for pediatric
> development.
>
> There is the NCI RAID program that addresses this somewhat.
>
> \[Slide.\]
>
> But we currently have a solicitation that is a Small Business
> initiative within the NCI, a contract proposal for the development of
> novel agents directed against the childhood cancer molecular targets.
>
> This can be found on the web site. It actually closes in November. It
> is something that opened up in August of this year, but this is money
> that would be brought to a small business that had perhaps a series of
> agents that could be focused onto pediatric targets.
>
> \[Slide.\]
>
> Similarly, there is the FLAIR grant mechanism within NCI that would
> allow\--it also is a Small Business initiative\--but it would allow
> either an academic PI or a small business to bring forward their
> drugs, and could be used for pediatrics, as well. The current grant
> closes November 12th.
>
> \[Slide.\]
>
> In summary, we see the future progress depends upon a well-functioning
> and maintaining that well-functioning infrastructure for early phase
> studies in children, the prioritization among available agents through
> perhaps a preclinical testing program, access to new agents from
> pharmaceutical sponsors, innovative adaptations of clinical research
> approaches to the pediatric realities, and throughout all this,
> maintaining public confidence that pediatric cancer drug development
> is being done, conducted with the best interests of children in mind.
>
> Thank you.
>
> DR. SANTANA: Thank you, Barry.
>
> Could I ask Susan to give her presentation.
>
> **Children\'s Hospital & Specialty Group Perspective**
>
> **Susan Blaney, M.D.**
>
> DR. BLANEY: I would like to thank Steven for inviting me to address
> you this morning. What Steven asked me to do was to provide some input
> into the optimal timing of the initiation of pediatric clinical
> oncology studies from an institutional perspective and from a smaller
> consortium, such as the Pediatric Brain Tumor Consortium.
>
> Barry has given you some background on what the Pediatric Consortium
> is, and its primary focus as a smaller consortium is to develop new
> and innovative therapies specifically for children with brain tumors.
>
> I don\'t think I need to tell this audience that we have a long way to
> go in the progress for the treatment of children especially those
> children with brain stem gliomas, glioblastoma multiforme, and infants
> with brain tumors.
>
> A lot of this you have heard already, so I will try to be brief. I
> think we all have a lot of consensus on a lot of the issues that we
> need to address, but is a historical timing for the initiation of
> pediatric Phase I clinical trials.
>
> Historically, this has occurred following the assessment of initial
> safety data and reasonable evidence of potential benefit, so what does
> that translate into? As Peter told you earlier, for the most part, it
> is after the completion and publication of adult Phase I and usually
> Phase II clinical trials in adults, so that means when the Phase III
> studies are ongoing or nearing completion.
>
> \[Slide.\]
>
> However, in some cases, it is following the completion of adult Phase
> III clinical trials, and the worst case scenario is following the
> successful New Drug Application by the pharmaceutical company, but I
> have been involved in studies where the trials are initiated in
> children at the first signs of biologic activity in adults, and there
> are instances where the submission for the IND application included
> both the pediatric and adult Phase I studies.
>
> There are also other instances where pediatric Phase I studies are
> initiated in the pediatric population exclusively, for example,
> monoclonal antibodies that are specifically targeted to receptors on
> the tumor cells or cytotoxics for intrathecal administration.
>
> \[Slide.\]
>
> This has already been shown to you in several ways this morning, but
> just a different way of looking at it, is this bar graph where, on the
> y axis I show you the time in months, and then down on the x axis is a
> series of drugs.
>
> What this represents is the timing at the initiation of accrual to
> Phase I pediatric trials after publication of the adult Phase I
> results.
>
> Now, I have been very generous to our adult colleagues in this top,
> giving them a 12-month period for completion and publication of their
> results. I think that is overly optimistic. I think it is really
> closer to 24 months, in some cases even longer.
>
> If you just take this area that is more lightly shaded down here\--it
> doesn\'t project very well\--the average time is at least two years
> after publication of the adult Phase I trials, so that means when we
> have evidence of efficacy, usually in the Phase II setting, and as was
> mentioned before, when the Phase III trials are ongoing.
>
> But there is a lot of heterogeneity and with some of the newer agents,
> we are getting earlier access.
>
> \[Slide.\]
>
> This is just an example of one agent where a worst case scenario with
> the Phase I trial, the drug was initially developed overseas, and the
> Phase I trial results were published in 1991. The adult Phase I trials
> were published in \'93. The drug was approved for adults in 1996, and
> it wasn\'t until \'96 that the Phase I pediatric trials were
> initiated.
>
> \[Slide.\]
>
> Now, just to put this into perspective of what this means for children
> and the overall impact on pediatric drug development, that here we
> have the approval, here we have the initiation of the Phase I trial,
> which generally takes a period of two years to complete.
>
> The Phase II studies, which on average for broad-based Phase II
> studies of the cytotoxic agent take three to five years to complete,
> it doesn\'t mean that for some strata there is not earlier evidence of
> activity, but the overall study.
>
> Then, assuming that the agent goes to Phase III to see if it makes an
> impact, there is five years at a minimum until the completion of the
> trial and perhaps even longer until we know the improvement and
> progression for survival or long-term survival.
>
> So, this is overall from the time just taking preclinical into
> consideration for adults, and as we talked about before, sometimes we
> don\'t have that preclinical data until later in pediatrics, almost 20
> years, and that is a long time, and that is why it is critical for us
> to get earlier access to drugs, so we can shorten this timeline.
>
> \[Slide.\]
>
> Here is just another example of a drug that we did have earlier access
> to, and even still from the time the Phase I study was initiated until
> the time the Phase III trials will be completed, it is almost a
> 12-year period, so that is why early access is critical.
>
> \[Slide.\]
>
> So, what is the optimal timing for the initiation of pediatric
> clinical trials? I think that it is obvious there is not going to be
> one single answer, that we are going to have to look at these drugs on
> an individual basis, but here are some considerations that I think are
> important in looking at.
>
> The first is the type of agent and its mechanism of action. Is it a
> novel agent or is it an analogue, had aphasia for analogues. Some
> things aren\'t necessarily analogues, but they affect the same target.
>
> Is it a nonspecific cytotoxic agent or broad-based agent versus an
> agent that has a specific target, and I think we are naive to think
> that we have those agents yet, but as we become more sophisticated and
> know more about the biology of our tumors.
>
> What is the underlying disease being treated? Obviously, it is going
> to be very different if we are treating a patient for whom we have no
> effective therapy, no curative therapy versus relapse patients where
> we have a good chance of salvaging them with currently available
> agents, so I think that is a very important consideration, as well.
>
> \[Slide.\]
>
> In addition, what is the safety profile of the agent. I am taking this
> from the perspective that we have an ideal world and we know from our
> preclinical studies that we have an agent that looks very promising in
> pediatrics, so what is the safety profile of the agent from initial
> adult clinical trials, or is it specifically an agent that is targeted
> for pediatrics and the preclinical model systems that we use.
>
> Then, for agents, this has been alluded to this morning, the
> availability of pediatric formulations.
>
> \[Slide.\]
>
> The primary focus of considering when we should initiate pediatric
> trials I think should be for those novel agents and agents with novel
> mechanism of action, so what are the considerations and the timing for
> initiation of drugs with novel mechanisms of action.
>
> I think early initiation is critical, and that is a common theme this
> morning. We need to develop strategies and new agents to improve the
> outcome for children with incurable brain tumors or other high-risk
> pediatric tumors.
>
> As Peter talked about in his earlier slide, one example with
> cardiotoxicity from doxorubicin, however, in children with zenith
> tumors, in those children that do survive, many of them have severe
> morbidity or long-term neuropsychologic or neuroendocrine sequelae as
> a result of the need for radiation therapy. So we need to try to
> identify agents or treatment strategies that can minimize the toxicity
> for these patients.
>
> \[Slide.\]
>
> So, what is early initiation, how can we define that? I think there
> should be evidence of biologic activity in adult Phase I trials, and
> how do we define biologic activity, that is going to depend on whether
> the agent is a cytotoxic or whether it is an agent that we expect to
> have an impact on a target or a surrogate target that we are
> monitoring.
>
> I think we should initiate these trials upon determination of the MTD
> and/or optimal biologic dose, and sometimes even earlier depending on
> what the agent is and what our preclinical activity is.
>
> If the target is primarily pediatric, I think it goes without saying
> that upon the completion of adequate preclinical studies, and those
> could include both in vitro and in vivo studies.
>
> \[Slide.\]
>
> When should we initiate trials for new analogues, and this is a point
> that has already been raised this morning. I think there is a number
> of issues we need to consider - does the agent have equivalent or
> superior activity in preclinical studies, are there any advantages to
> the toxicity profile, are there advantages with regard to potential
> for drug interactions or lack thereof.
>
> Another advantage is with regard to the formulation for the pediatric
> population, but lastly, there should be evidence of at least
> equivalent or, if not, superior activity in the adult situation for
> development of analogues. Our focus should be primarily on developing
> new agents with novel mechanisms of action.
>
> \[Slide.\]
>
> In conclusion, I think that we are not going to have one uniform
> recommendation, that the timing of initiation of clinical trials
> historically has been highly variable and in many instances has not
> been optimal, that ongoing communication between the pediatric
> cooperative groups, industry, the FDA, the NCI, and our patient
> advocates is required to ensure the earliest possible access to
> promising new agents with novel mechanisms of action.
>
> \[Slide.\]
>
> Pediatric studies for novel agents should be initiated as soon as
> there is evidence of biologic activity and an acceptable safety
> profile in early Phase I adult clinical trials, and that early access
> requires ongoing vigilance and constant reevaluation to ensure optimal
> prioritization and potential for benefit for children with recurrent
> or refractory cancers.
>
> It is not a static process. It is going to continue to be an ongoing
> and dynamic process.
>
> DR. SANTANA: Thank you, Susan.
>
> We have a few minutes to entertain comments or questions to these
> three presenters, if anybody has any comments.
>
> Peter.
>
> DR. ADAMSON: I had a comment that stemmed from Barry\'s presentation,
> that I think is worth hearing perhaps from some other people. I think
> part of it has to do with perceptions and misperceptions with regard
> to the conduct of Phase I trials in children, as well as the ethical
> considerations.
>
> To start with, I think one misperception that industry has is that an
> obscure toxicity in a child could derail a drug approval process, and
> I think Dr. Pazdur at another meeting clearly came out and said that
> he knows of no example, and I certainly don\'t, of where a drug was
> not approved because of an obscure toxicity in a child. Drugs don\'t
> get approved in adults because they are not effective, and not because
> of toxicity.
>
> So, the fear that there is going to be a toxicity that will derail
> development is a perception that we need to correct and to overcome.
>
> The other point was that I think the ethical considerations for the
> conduct of Phase I studies in children are likely much more closer to
> that in adults than is recognized by our adult colleagues.
>
> Yes, children are afforded special protections, but when it comes to
> correlative studies, I think over time it will emerge that the ethical
> considerations we apply in children, in fact, ought to be applied to
> adults.
>
> I know this is not a topic for us because we are focusing on
> pediatrics, but requiring studies that are invasive and of no
> potential benefit, we will not do that in children, however, I think
> the requirement to do that in adult patients with refractory cancer is
> coercive, and the requirements about a study not being coercive are
> the same between pediatric studies and adult studies.
>
> Skip Nelson may want to comment on that, but I think the idea that you
> can require all these studies and therefore we can easily do these
> studies in adults is a misplaced one. Over time, when it is recognized
> that these invasive procedures that are of no direct benefit and the
> only way an adult patient can receive an investigational drug is to
> agree to that, is coercive.
>
> So, I think we are going to face the same set of challenges in adult
> Phase I trials as we face in pediatric Phase I trials, when the
> community arrives at that, I can\'t say, and if pediatrics leads the
> way in the discussion, it won\'t be the first time in oncology that
> pediatrics has led something.
>
> I don\'t know if others want to comment, but Skip, who is really much
> more eloquent at discussing ethical issues, may want to add to that.
>
> DR. SANTANA: Skip.
>
> DR. NELSON: I really don\'t have much to add, Peter. You just
> demonstrated why you are a valued member of one of our IRB committees.
>
> DR. PAZDUR: Let me follow up on that, though. I think in adult
> oncology also, that would be looked at as coercive, and there is very
> few IRBs that I know that would let that go by.
>
> Usually, the correlative study, when it does involve a biopsy, if it
> is labeled as an optional procedure, it generally requires a separate
> consent form, and if it is an integral part of determining whether the
> therapy goes on or assessment, then, it could be bought into as a
> required procedure, but that has to be, as was mentioned in the NCI
> presentation, an integral part of a decisionmaking process.
>
> So, a very similar philosophy that was presented for pediatrics also
> holds for adults, too.
>
> DR. ADAMSON: I don\'t think the NCI shares that philosophy.
>
> DR. PAZDUR: Do you not?
>
> DR. SAUSVILLE: I just would state that this is a fairly controversial
> area, and I also think it is colored by one\'s perceptions of degree
> of invasiveness and also, quite frankly, how the physician pitches it
> to the patient.
>
> I definitely agree with Rick that in any context to require it would
> be regarded as coercive, so there is clearly, you know, we buy into
> that.
>
> However, it is also true that we sometimes place trials\--and Malcolm
> or Barry may want to comment on this\--with patients that are likely
> to have accessible tumor because of the likelihood that the average
> adult would not consider it much of a big deal, for example, to get a
> skin biopsy.
>
> I could come back to you and say that if you even put it in the
> context of a relatively non-invasive treatment, and how would you
> shape a pediatric approach to this issue where at some level, a buy-in
> on the part of the patient is required, so I think it is complex.
>
> We share your goal of minimizing and indeed eliminating any perception
> or practice of coercion, but nonetheless, even in a minimally velvet
> glove scenario, one can imagine that adults are going to be
> intrinsically better able to enter into a decisionmaking process in
> children.
>
> DR. KODISH: I wanted to engage Barry in a little ethical discourse
> here, because I heard an interesting mismatch between what I perceived
> as Barry drawing a line in the sand about the appropriate timing for
> the cytotoxics that is based on completion of the adult Phase I, ready
> to go to Phase II, and it was different than what I heard Susan say,
> which is that we need to have more flexibility, that there may be some
> instances where it would be okay to do simultaneous studies or to
> start the pediatric Phase I study halfway through the adult study.
>
> I think that you are right on the money when it comes to the targeted
> agent issue and this idea of separating out the components of the
> research as you mentioned, but I think we need to work a little bit on
> this cytotoxic approach.
>
> The ethical argument I hear underlying your comments is that the
> imperative of avoiding toxicity in children is greater than the
> imperative of avoiding toxicity in adults, and I am not sure that is
> true necessarily.
>
> I think it gets to this issue of how vulnerable are children, are they
> biologically or physiologically vulnerable in some way or are they
> ethically vulnerable. The regs deal with the fact that they are
> perhaps ethically vulnerable, but in these studies, there is potential
> for direct benefit.
>
> So, to me that was a concern.
>
> DR. ANDERSON: I think that if you were to say we should start
> simultaneously, it would be a question of is there a benefit that has
> been demonstrated along the way. If you are not going to derive what I
> see for pediatrics, the benefit of defining the toxicities and
> starting the patients out closer to a potentially active dose, if
> there ever is one, then, it would be a question of what activity was
> seen early on as the adults were going up through their dose levels
> perhaps, towards an MTD, because that was the endpoint that they were
> ultimately focusing on that would bring you to do that in pediatrics.
>
> I don\'t know, you know, other people have other opinions about
> starting them simultaneously, and I would want to know what the
> benefit of doing that would be. If you had truly, you know, if Peter
> was saying, well, we now have 45 drugs that we are trying to do
> studies on, if it is a matter of we want to get access to this drug at
> the same time, but we don\'t know if it is active, I don\'t know if
> there is a benefit to that.
>
> DR. BLANEY: Two things. One, I think that we don\'t need to evidence
> of benefit in the adult Phase I study before we initiate a pediatric
> trial. We have to have potential for benefit, and usually that is
> based on our preclinical model systems in childhood tumors.
>
> Now, in most case scenarios, I would not argue that we should have
> simultaneous initiation in the trials, but we could have simultaneous
> submission of the protocols with the IND and have a predefined goal
> for what is going to allow us to initiate the pediatric study, is that
> biologic activity as evidence of myelosuppression for a cytotoxic, is
> that an effect on the target tumor in a range that we think based on
> preclinical pharmacokinetics and the pharmacokinetics from the adult
> Phase I study where we think there would be potential for benefit in
> our population.
>
> DR. SANTANA: I agree, Susan, but I heard a comment this morning from
> our friends from industry that we don\'t want to get into the trap, if
> they are not getting a hint that this drug is going to have activity
> in adults, they may drop it, and we would be faced with the same
> problems we have in the past, but there may be some drugs that we do
> want to develop, but if we can\'t get them to demonstrate at least
> some activity even in the Phase I, then, we may be losing our time and
> our patience and our resources.
>
> So, I think we have got to be careful. In the ideal world, I think you
> are absolutely right. In a very practical way, I heard them say this
> morning that to them, it is an important consideration to begin to get
> some evidence of activity, because if not, they are not going to
> develop it any further, and then nobody has access to it.
>
> One last comment?
>
> DR. HAGEY: I think now might be a good time to comment on attrition
> rates of drugs. The TUFF study for drug development looked at 671 new
> chemical entities which applied for an IND between the years of 1981
> and 1992, and of those, only about 135 were actually approved, which
> is around 20 percent.
>
> If you take that and break it down by oncology drugs, I think 33 with
> a final approval of 6, and 6 still waiting, I know that is the data as
> of 2000.
>
> About 26 to 30 percent of the attrition rates occur in Phase I with
> over 50 percent of the attrition occurring in Phase II, which would
> argue, in fact, for the current model, which seems to be most of the
> time pediatric studies are initiated in Phase III, which looks like
> about that time you have about a 75, 78 percent chance that indeed
> that drug will go to market.
>
> DR. SANTANA: I think with that, we are going to stop here for a lunch
> break.
>
> \[Whereupon, at 12:30 p.m., the proceedings were recessed, to be
> resumed at 1:10 p.m.\]
>
> AFTERNOON PROCEEDINGS
>
> \[1:10 p.m.\]
>
> DR. SANTANA: There were two individuals that were not present when we
> did the early introductions this morning, Dr. Emanuel and Dr. Kodish,
> so I am just going to ask them very briefly to identify themselves and
> their affiliations.
>
> DR. EMANUEL: I am David Emanuel, clinical oncologist out of Pharmacia
> Corporation.
>
> DR. KODISH: I am Eric Kodish, the Director of the Rainbow Center for
> Pediatric Ethics in Cleveland, Ohio.
>
> **Open Public Hearing**
>
> DR. SANTANA: The first item on the agenda for this afternoon, just to
> keep this item on schedule, is that we have an opportunity for an open
> public hearing, so if there is anybody in the audience that wishes to
> address the committee, please come forward at this moment and identify
> yourself at the podium.
>
> Please identify yourself and you may proceed.
>
> DR. RUGG: Good afternoon. Thank you. My name is Terry Rugg. I am
> currently at Immunomedics, Inc.
>
> I have just three comments I thought I would make. The first one is
> very specifically to I guess the regulatory aspects of getting studies
> done in children. I have had experience in prior companies where drugs
> have, from a regulatory perspective, been able to get in very quickly,
> and more recently, a highly targeted therapy in AFP-producing tumors,
> which you might argue is very different from hepatoblastoma and adult
> tumors, where there is a very definite view on the biological division
> of the FDA that closed the door very early.
>
> So, I think if this forum does focus in on the regulative
> facilitation, which I think is what the question is all about, I think
> that would be very important. That is one experience.
>
> The other two comments really I make now in reaction to some of the
> thoughts and some of the things that I have heard earlier this
> morning.
>
> Firstly, just a quick thought, the issues regarding getting material
> transferred to institutions for applying in the preclinical setting.
> In the spirit of very clear communication, I think it is important to
> say when you negotiate these things, never ask for that which the
> other party cannot give.
>
> The other party cannot give intellectual property away. From my
> experience, a number of times these agreements have fallen apart
> because the receiving institution has legal requirements, require
> intellectual property to be seeded by the pharmaceutical company, it
> is never going to happen. My colleagues I am sure will agree it is
> never going to happen.
>
> The final thing that I will comment on, which has been referred to a
> number of times, but always very subtly, very under the surface, and
> very not obviously, and that is the reality that a drug that will have
> only a pediatric indication cannot be commercialized, and when I look
> at all the participants here, every one of us are M.D.\'s, every one
> of us has research interests, I don\'t see anyone with an MBA or I
> don\'t see any of my marketing colleagues, I don\'t see anyone who
> would represent the finances, which means that a lot of what we talk
> about here cannot ultimately influence the practice. The practice has
> to be influenced at a political level that results in drugs being
> reimbursed in some way of another or a system that meets those needs.
>
> I think, David, you recognized that to an extent, but it is a barrier
> bigger than you would think. My nightmare would be having a drug that
> worked in the pediatric setting, but did not work in an adult setting,
> because I wouldn\'t really know what to do with it. I couldn\'t market
> it and I couldn\'t withdraw it, and I would be bankrupt.
>
> So, with those three observations, I leave the podium and I thank you
> for your opportunity.
>
> DR. SANTANA: Thank you. I am sure we will come back to your comments
> during the open discussion.
>
> I will ask David Emanuel to give his presentation.
>
> **Industry Perspective**
>
> **David Emanuel, M.D.**
>
> DR. EMANUEL: Thank you, Victor, and thank you, Steven, for the
> invitation. I greatly appreciate it.
>
> What I have decided to do is to gut my talk and to actually focus just
> on some issues that we haven\'t addressed up to date.
>
> Just before I start, I just wanted to make the point that we all agree
> that the status quo is unacceptable. Every person in the room, I think
> is on the same page with that. We all agree that we really have to
> move on. The question is how to get there.
>
> So, what I wanted to do is really not to talk about the barriers,
> because really the barriers that I saw are exactly the same as
> everybody else has seen. Let me just run through and go back to my
> final slide, in fact, I have only got one slide to show you, which is
> overcoming these issues.
>
> \[Slide.\]
>
> At the workshop that was held at the FDA in July of 2002, the issue
> was raised about lowering the regulatory hurdle as a means for
> encouraging development of drugs in the pediatric setting.
>
> I think this is an issue that the committee should really look at
> because I have heard a couple of times today that registration in a
> pediatric indication is quite important sometimes, not all the time,
> but it is important from the point of view of the reimbursement, et
> cetera, et cetera, and I think you raised this issue this morning in
> Europe.
>
> But from the pharmaceutical companies\' standpoint, from the dark
> side, registration is what we are all about, and I think it really
> does bear some thinking about when we discuss things like is it really
> necessary to do an adequately powered trial, I mean it is literally
> impossible to do this in the context of the pediatric setting. It
> would take years and years and years.
>
> So, I know this is a heretical statement, but how important is the
> randomized trial. That is the first question.
>
> The other two things relating to some of the regulatory issues are the
> definition of clinical, what does this term actually mean in the
> context of a child, clinical benefits. Clinical benefit is what we are
> all trying to achieve with our drugs, but in pediatrics, I would very
> much welcome input from the committee and from the FDA about what does
> this actually mean in a child with a malignancy.
>
> One possibility would be for us to prospectively define acceptable
> surrogate endpoints which could take place, which could be used in
> place of, quote, unquote \"clinical benefits.\" I am not sure what
> these are. It is not up to me to really define that, but I think input
> from the committee, input from the field would be extremely helpful.
> Clinical benefit is key here.
>
> The second point on here, increased access to the patients. I think
> the tables have turned. We have heard this many times today. There are
> too many drugs to get into too few, quote, unquote \"eligible
> patients,\" and this is a major problem, it is a major barrier, and it
> is one that we have to work on together and to support Greg on this.
>
> Communication is the absolute key. We are not talking to each other.
> We really need to increase the intensity and the depth and breadth of
> the communications across all these groups.
>
> I am talking about the COG, industry, NCI, FDA, all the cooperative
> groups outside the United States. We really need to communicate better
> because, quite frankly, it is not working, and I think the key to
> success is improving, is just getting us to really understand each
> other and to really talk to each other.
>
> Some of the benefits that might accrue from that - the issue about
> ex-U.S., how can we increase enrollment into trials outside the United
> States. There are lots of kids with the kinds of diseases that we are
> interested in, in Russia, in Eastern Europe, in Africa.
>
> The FDA has told us that they accept these places as sites for trials.
> How do we have access to those? I am proposing that we do joint
> transnational clinical trials, sponsored by both industry, by the NCI.
> We have to get access to the patients. That is absolutely key.
>
> Prioritization of scarce patient resources is exactly the same thing.
>
> Expedite initiation and execution of trials. From the industrial
> standpoint, this is a major problem. It takes forever to get these
> things done through the cooperative groups. I am being very frank
> here, but this is why we are here, to table issues.
>
> Industry lives and dies by the timeline, and the timelines that we
> work under are completely different to yours. We have to get ourselves
> aligned on that issue. We have to improve this.
>
> Jointly funded development of drugs. This is a whole issue unto
> itself, and we have just touched on the issue of MTAs and CRADAs and
> intellectual property.
>
> We were just talking at lunch. I want to again stress the point that
> was just actually made. Intellectual property to the pharmaceutical
> industry is its bread and butter. We will not give up on that.
> Intellectual property is a big deal for us.
>
> When somebody brought up the issues of how long it was taking for an
> MTA to get signed, I will guarantee you that that took that long
> because of an intellectual property issue. We have to work out ways to
> get around that, otherwise, it is just going to continue to take as
> long. Intellectual property is a big deal to us. This is something
> that we will absolutely refuse to budge on.
>
> Excuse me for jumping around. As I said, I gutted my talk.
>
> I guess the last point that I wanted to make, which has been raised by
> others, is we all agree that from the pharmaceutical company
> perspective, whether the Pediatric Rule, the exclusivity terms, et
> cetera, have worked, it is too early to tell, but I can tell you where
> it has worked.
>
> It has worked in internal discussions with our senior management. Any
> one of us who actually works in the industry will tell you that
> getting money from the people that control the funds is one of our
> biggest tasks. It doesn\'t matter what we want to do, it is what the
> corporation would like to do, and it is a challenge for all of us who
> happen to work in this type of environment now to actually convince
> our upper managers of this fact.
>
> The Pediatric Rule has worked from that regard. So, I make a very
> strong plea that the maintenance and expansion of, quote, unquote,
> \"incentive programs,\" is key to the success here. We absolutely have
> to continue these in some form or another.
>
> I also submit that pediatric oncology, in terms of the current ongoing
> pediatric drug development debate that is ongoing in the Senate, I
> guess today or tomorrow, I submit that pediatric oncology drug
> development is very unique and very different to other parts of that
> discussion.
>
> I am just sort of challenging us all to think about ways that we can
> think up incentives to develop pediatric drugs for use in oncology.
>
> I think that\'s it. Thank you very much.
>
> DR. SANTANA: We will come back during the comment discussion period,
> hopefully, to some of the issues that you have presented.
>
> Dr. Rackoff, are there on the phone?
>
> DR. RACKOFF: Yes. Victor, can you hear me?
>
> DR. SANTANA: Yes. People want to know where you are. Are you going to
> make some comments now, Wayne?
>
> DR. RACKOFF: Yes, from Bersa \[ph\] Belgium.
>
> **Industry Perspective**
>
> **Wayne Rackoff, M.D.**
>
> DR. RACKOFF: I have really only three comments, and I want to drop off
> soon.
>
> The first is that much of what has been said today has been said in
> the other three or four meetings we have had, and I think we have got
> enough information now to have the agency move forward with some sort
> of guidance on these issues.
>
> I think that two issues that are particularly pertinent that were
> touched on today have to do with preclinical testing, and I think what
> would be very helpful is if those that are involved in that consider
> not only the pediatric models, but also what correlations there are
> between their pediatric models and adult tumors, and actively work on
> identifying those correlations because they will provide further help
> to us in pushing these drugs toward children.
>
> The third and last point is that I think that there probably needs to
> be some sort of priority setting between the Children\'s Oncology
> Group and the Agency as part of this process, because I think it is
> much different to do studies and also much different to introduce a
> drug earlier in an area of more severe need like Stage IV
> neuroblastoma than it would be in ALL.
>
> I guess, as a last point, a sort of summary, I take a little bit of
> issue with some of the comments that have been made so far and agree
> more with I guess Greg Reaman and some of the others who have said I
> think we have made tremendous progress.
>
> I think that those who are not part of the dialogue either at these
> meetings or at the COG should become part of that, and I think the
> impetus is on individuals on all sides to participate and help this
> process move forward.
>
> DR. SANTANA: Just for the sake of completeness, is that it?
>
> DR. RACKOFF: Yes.
>
> DR. SANTANA: Thanks, Wayne.
>
> We are going to invite Ruth Hoffman to give the patient and parent
> perspective.
>
> **Patient and Family Perspective**
>
> **Ruth Hoffman**
>
> MS. HOFFMAN: I wanted to also thank Steven for the opportunity to
> speak from the parent-patient perspective, and I think it is a very
> important voice.
>
> \[Slide.\]
>
> First of all, this it not derived from a formal survey like the ASPH/O
> survey that was discussed earlier. It is basically a shared
> perspective from my position as a parent of a child, a 15-year
> survivor of AML, who actually is dealing with cardiotoxicity from 400
> mg/M^2^ of anthracyclines, as well as hormone replacement therapy, as
> well as interaction with thousands of families through Candlelighters.
>
> \[Slide.\]
>
> So, who is the constituency? Thirty-two years of supporting families
> of children with cancer, and they are very active as you can see. We
> receive about 6,000 phone calls a year, 14,000 e-mails, and 155,000
> web site visitors. That is about 14,000 unique visitors per month,
> which equates to 1.5 million hits, huge.
>
> What is it that they are asking? Approximately half the queries are
> connected to treatment-based questions like what are available
> clinical trials, what is a clinical trial, as well as institutional
> referrals, where is the best place to go with my kid who was just
> diagnosed with neuroblastoma, what are the best surgeons, where are
> they located. That is the sort of questions that we got. The rest are
> financial assistance, and that sort of thing.
>
> \[Slide.\]
>
> So, because of that, in the last month we actually\--I don\'t know if
> you know this web site or this service\--we just started HopeLink,
> which is a clinical trial service to our web site, which basically
> incorporates clinical trials from industry, from institutions, as well
> as from COG. At this point, there is 385 trials just children-based
> and they are Phase I to Phase III.
>
> \[Slide.\]
>
> What is it families want? They want hope. This was an example when I
> was putting this together, this came through that day. \"When the
> doctor explained to us about Melissa\'s leukemia, he said that APML is
> incurable and it\'s very rare and very deadly. Can you give us hope?\"
>
> \[Slide.\]
>
> What do they want? They want a magic bullet to treat their child with
> a resistant disease. This didn\'t come through. It did have a picture
> there of a little girl.
>
> \[Slide.\]
>
> This is the historical perspective. Grace Monaco was the founder of
> Candlelighters in 1970.
>
> \"The childhood cancer population is a small community in number, but
> large in spirit and used to success. The clinical trial process is
> what has brought pediatric oncology the cures that give hope and help
> to parents and survivors, and has created a foundation of trust upon
> which to build improved and novel treatments.\"
>
> \[Slide.\]
>
> So, the foundation of trust was based on, and must continue to be
> based on: Relative safety through the use of preclinical models, as we
> talked about, animal testing, and traditionally adult testing; the
> possible magic bullet versus the actual small percentage rate on the
> response to Phase I trials, and families want to know that
> information; and then, as well, the side effects of treatment, the
> toxicity and the effect on quality of life at the end of life.
>
> \[Slide.\]
>
> Families\--I think all my pictures aren\'t in here, which is actually
> too bad\--there was a picture of a child actually on his death bed. He
> was shown actually with large fungal infections on a Phase I trial,
> and the feedback from the families\--there was actually six pictures
> of kids\--and four of those children were on Phase I trials, and in
> discussing with them to prepare for this, none of them had realized
> what a small response rate the children were likely to get on that
> Phase I trial, and they were very surprised and somewhat disappointed,
> and really felt that the doctors had not been fair in disclosing that
> information.
>
> So, a need for greater information, that is the feedback we are
> hearing. And the option that discontinuing treatment isn\'t a valid
> option, families want to know that it doesn\'t mean you are a bad
> parent, it doesn\'t mean that you are giving up, and the child is not
> required to go down fighting, especially when you are talking about a
> two-year-old, and not making that choice for themselves.
>
> It is different if you are talking about an 18-year-old, who maybe
> wants to go down fighting, but for a parent making sometimes that
> decision for a two-year-old and continuing treatment when it can
> result in quality of life differences, then, that is something to be
> taken into consideration.
>
> \[Slide.\]
>
> A comment from Grace again. \"To keep the pediatric patient lot
> improving, the cures growing and the effects of therapy on quality of
> life, particularly in the hard to handle cancers, we need to innovate
> within the careful, patient-centered model that pediatricians have
> always utilized.\"
>
> \[Slide.\]
>
> Industry. These are the barriers we have talked about all day -
> unenthusiastic, the rare pediatric tumors, small population size. A
> couple things that haven\'t been addressed, problematic access to
> clinical trial information, health insurance and billing concerns. For
> families, often their choice is either/or. Their child can receive
> palliative care or they can continue on Phase I curative therapy.
>
> Actually, again, one of the pictures of the kids that was featured
> here went through that situation over and over. She was a
> neuroblastoma Stage IV child. She was on palliative hospice care.
> Then, she would go off palliative hospice care because insurance
> wouldn\'t cover it. She would go on a Phase I trial. Then, she would
> go off the Phase I trial. She would go back into hospice, back onto
> Phase I.
>
> It was very, very frustrating for her family because it was not both
> options offered to this child, it was an either/or situation. That is
> a policy that really needs to be address and a major barrier.
>
> Centralized trial information. We talk about all these drugs, not
> enough patients. Patients are very active, as I showed you at the
> beginning. They are very participatory and if we have a comprehensive
> web information or resource where families can go to, like HopeLink,
> it\'s not completely comprehensive, but basically incorporates COG
> trials, industry trials, institutional trials, again, that is
> information that families can use to make decisions.
>
> \[Slide.\]
>
> In terms of the innovations regarding small populations we talked
> about this morning, with molecular targeting of drugs and finding
> similar pathways, that barrier might be decreased, the correlation
> between genome anatomies between adults through expression profiles
> and somatic mutations might decrease some of that adult-child issue.
>
> I think that we have to ensure that existing programs, such as\--and
> maybe Malcolm can address this\--the Cancer Genome Anatomy Program,
> NIH program, that includes pediatric tumor initiatives.
>
> \[Slide.\]
>
> This is where it becomes controversial even with parents. This is from
> Grace\'s perspective. \"There is no reason that the pediatric oncology
> community should wait for results from any adult trial before
> designing their own Phase I\'s and pilots for the use of new and old
> agents in pediatric oncology.\"
>
> \[Slide.\]
>
> Now, we have varying degrees on this. Some parents feel that
> definitely we have to have adult studies done first for reasons of
> dose initiation, reducing overdosing, underdosing of the kids, and
> safety testing.
>
> This is a broad generalization, but it tends to lie this way. People
> that have lost or parents that have lost their child tend to feel
> there is no reason to wait. People whose children have survived, like
> my daughter, who are dealing with late effects, think no, the
> toxicities are very difficult, there is reasons to wait.
>
> Now, that is a broad generalization, but that tends to be how things
> tend to fall.
>
> \[Slide.\]
>
> In terms of the small pediatric population, and these of adults, maybe
> there needs to be more formalized, it gets expanded formalized
> coordination of U.S. adult cooperative group/clinical trial studies,
> and then COG/academic/pharmacy child studies for simultaneous access.
>
> The possibility of joint yearly symposiums on Phase I trials between
> the adults and between the children, and where you can just be
> discussing emergent targeted pathways that are shared by tumors, and
> possibly the design of consortiums based on molecular pathways, not
> based on tissue and cancer, so not the Brain Tumor Consortium, not
> necessarily the NAT Consortium, although those are wonderful
> consortiums, but possibly consortiums based on molecular pathways.
>
> \[Slide.\]
>
> If children are going to benefit from adults trials, we have some need
> to expand on that, and being a Canadian, I have to bop this one in, in
> Canada, most of you probably don\'t know, but we have between a 60 and
> 70 percent clinical trial rate of adults in Canada on cancer clinical
> trials, it is about 5 percent here.
>
> I don\'t know if they have an increased survival, as well, but it is a
> huge clinical trial participation of adults and about 90 percent of
> adults are treated in comprehensive cancer centers. Now, there is your
> market if you need to expand and need more adults, that is maybe a
> potential market.
>
> \[Slide.\]
>
> Another market that has been talked about is internationally. This was
> another e-mail that I received the same day I was putting this
> together.
>
> \"I am writing on behalf on my friend\'s sick child. Could you please
> send me some information on international treatment resources
> available for a child who has leukemia, acute lymphocytic form. This
> is a boy and he lives in Ukraine. Resources are limited there, but I
> heard that in Russia some clinics successfully treat this disease. If
> you need more information about him, please let me know\" -
> blah-blah-blah.
>
> \[Slide.\]
>
> So, again, increase the collaborative Phase I international trials.
> Increase the collaborative international preclinical trials.
>
> \[Slide.\]
>
> Finally, the point about communication. Utilization of a common,
> comprehensive child-specific clinical trial information service that
> is used by academia, by COG, by NIH, by industry, and by individual
> institutions.
>
> \[Slide.\]
>
> This actually was set up with several children. All of them have died.
> The one in the bottom lefthand corner was a little girl with
> osteosarcoma. She was 10. She actually used her legal right of assent
> and countered her mother. Her mother wanted her to go on trials, and
> she had already been on treatment for three years, and she refused. We
> were brought into the case at that point, and she actually spent the
> last four months of her life having a wonderful quality of life, went
> to Florida, went to California, and actually had a very peaceful
> death.
>
> A couple of the others who actually went on a Phase I trial had a very
> difficult death, and the one mother said to me that she has a double
> grief, you know, the grief of losing her child, but also the grief of
> putting that child through extra pain.
>
> Now, she also said she would do it again, and she felt that she had no
> choice, which gets into again other issues, but I guess the big point
> is, is I think we need to have a balance in what we do, and sometimes
> I think we need to keep this in mind as a guiding principle that life
> isn\'t measured by the number of breaths we take, but by the moments
> that take our breath away.
>
> DR. SANTANA: Thank you, Ruth.
>
> We had a couple presentations earlier today that we didn\'t have the
> opportunity to discuss and ask questions to the presenters. I know
> some members of the panel do want to do that, so this is an
> opportunity to start that.
>
> Donna.
>
> **Committee Discussion**
>
> DR. PRZEPIORKA: Two questions. First, for Dr. Adamson. A point just
> brought up by Ms. Hoffman regarding cooperation between adult and
> pediatric groups, we had once actually talked about that at a previous
> meeting, and I just wanted to know if any headway had been made in
> that direction, and if talks have begun, have you come up with any
> impediments from the adult side saying no, we don\'t want to deal with
> kids in our protocols.
>
> DR. ADAMSON: I think I can answer, but I am going to need some
> clarification on that. With the new Phase I consortium, we just had
> our first meeting, and we are going to be meeting semi-annually.
>
> The meeting was held in conjunction with the NCI CTEP-sponsored adult
> Phase I group, and we plan to continue that, so all the pediatric
> representatives were there to hear about what is happening on the
> adult side, and as importantly, we made our presence known to NCI CTEP
> that hold these meetings that didn\'t regularly include pediatric
> representation.
>
> So, I think from that standpoint, we have improved communication and,
> in general, we have a good sense of where the adults stand in
> reference to their trials, and this is I think just adding another
> layer to make certain that we are aware really of the most recent
> advances.
>
> Can you clarify your last point for me? Oh, that was it? Okay.
>
> DR. PRZEPIORKA: I think you should be lauded for getting that far in
> this short a period of time, to be sure.
>
> My other question is actually back to the FDA. I don\'t think I was
> clear when I was making my question earlier today.
>
> The usual paradigm in drug development and drug registration is for a
> pharmaceutical company to come by, do their studies with the idea of
> getting registration and selling their drug, and we are here talking
> today about where we can get the pediatric studies to get going either
> for registration for a pediatric indication or just to get some
> information for pediatrics.
>
> But what we have heard is that we don\'t need adult studies first, we
> could do this in pediatrics except we just heard that it is not really
> economically feasible to do that. There is one other paradigm that we
> need to talk about, which addresses directly the regulatory burden
> that Dr. Emanuel talked about, as well.
>
> As an example, there is an institution in the East which makes its own
> biologic and uses it to treat leukemia patients and has been doing so
> for about 12 years. They charge the patients, and they live happily
> ever after, and if you ask them for some, they say no, we only have it
> at our institution.
>
> They do that so that they actually get the market share of those
> patients with that disease, which will then feed their other protocols
> and bring in more grants. That is the only economic incentive that
> academics have to make their own drugs and to deal with the economics
> of doing clinical research.
>
> But for an academic institution to start any study of a drug in a
> pediatric population or any orphan disease, there has to be some sort
> of endpoints to the money that they invest, and they don\'t have
> anywhere near as much money as pharmaceutical companies do, and
> especially if it\'s an orphan disease.
>
> So, there is only an incentive to go and study pediatric drugs if at
> some point they can stop and start charging for the drugs they
> manufacture and stop having to deal with the paperwork burden of
> reporting.
>
> If an academician comes to you at the end of their Phase II study, and
> a disease which has absolutely no good therapy, and they say, look,
> our drug has a 30 percent response rate, can you just give us approval
> to deal with it, so that we could like start collecting money for it,
> and not have to tell you anything about adverse side effects, and we
> don\'t have enough patients in the world to do a randomized trial,
> what would you say?
>
> DR. HIRSCHFELD: Go for it. There is an orphan program that has been in
> existence for almost 30 years, and that program has successfully
> brought well over 100 drugs to be approved for marketing in a variety
> of diseases, many of which are rarer than pediatric oncology.
>
> To give some perspective, the number one medical reason that causes
> children to die are tumors, overall, it\'s access, but of all the
> diseases that affect children, the number one cause of death is
> tumors, and I think that can be used as a justification for entering
> into a program, but that is a whole other discussion in terms of the
> marketing strategies, and whatnot, which are certainly beyond the
> realm of not only what we are discussing today, but probably what I
> should be talking about.
>
> But I can address the idea of the orphan drug program, which offers
> people grants, it offers incentives, and there are dozens of cases of
> people who essentially in a single institution, develop, oh, an
> inhibitor of an enzyme that is over-expressed in some rare genetic
> disorder and then have successfully gone on to market that.
>
> There is no reason why it couldn\'t be applied more widely although
> the resources are limited in pediatric oncology, however, I will point
> out that we looked at how many people actually filed and asked a
> question we have a product, and here is our data, and can you give us
> marketing authorization for a pediatric tumor, and the last one we had
> was in 1990, and that was for a drug called teneposide.
>
> Since then, no one has filed a single application or a single
> supplement to an application. So, if it would come across our path,
> then, we could address and ask for it, but we can only indicate
> interest, we can\'t compel.
>
> We can provide incentives, however, and the incentive program I think
> has been reasonably successful and that we have had roughly 30
> invitations out. About 15 are for investigational drugs, and we have
> actually granted 2 of them to date, and there are several others. On
> reviewing, this had never happened before in the history of the
> regulatory aspect.
>
> Now, I wanted to introduce a term, since we brought it up, and the
> term I will try to introduce is the term \"orphan drug.\" The Office
> of Orphan Drugs is actually for orphan indications or orphan diseases,
> and they call it that, but I wanted to propose that the circumstance
> where a drug is born, and it is developed up through Phase I or early
> Phase II, and then abandoned by its parents, that that is the orphan
> drug.
>
> One approach to think about that orphan drug would be to go back to
> the ICH guidelines, which say that it is the shared responsibility of
> society to address these issues, and there could be, and maybe ought
> to be, programs to pick up these orphan drugs and develop them in
> niches where they may have activity or may have some benefit.
>
> I know Rick wanted to make a few comments, too.
>
> DR. SANTANA: Go ahead, Rick.
>
> DR. PAZDUR: There are several questions to answer there, Donna, and
> let me go through them.
>
> Number one, for somebody that is coming in with a hot drug on Phase II
> data, that has a 30 percent response rate in a disease situation where
> there is no other therapy, it is clear that that would be a situation
> for accelerated approval, and that would be a very, very hot drug. You
> do not know the numbers of companies that are coming to us seeking
> accelerated approval on that type of data, what is a niche indication
> that we could have.
>
> Remember, we are being asked to develop drugs or people are coming in
> to develop drugs with increasingly more refractory disease settings,
> fourth line lung cancer, fifth line breast cancer, fourth line
> colorectal cancer. That isn\'t because they have an interest in that
> population. Obviously, their business decisions are geared toward a
> much bigger population and they could get their foot in the door in
> these niche populations.
>
> So, the fact that pediatrics has a small market here should not be
> overlooked. That is a way that companies could get accelerated
> approval.
>
> But I want to go into a very important aspect that was made by Dr.
> Emanuel, and that was the slide that says \"lowering the barriers.\"
> Dr. Emanuel, I call that lowering the standards, okay, and I don\'t
> know if that is what you, as pediatric oncologists, want to get into
> as far as having your drugs approved on different standards, i.e.,
> potentially less effective drugs being approved.
>
> Let me go into some graphic detail. Do you want to throw out the baby
> with the bath water here? You have made tremendous strides as far as
> curing the diseases. The things that were listed on the slide, using
> less power or toning down the power of your studies, that really leads
> to faulty statistical decisions.
>
> That is not a regulatory issue to accept less powered studies or shaky
> studies just so you could get a drug on the market. Do you want to be
> in that predicament?
>
> That is a situation that you have to answer yourself. The situation of
> clinical benefit, we have defined that quite clearly in the adult
> population, and I don\'t see any designation of any difference with
> children. Basically, it is what is meaningful to the patient, and that
> generally has been assumed to be an increase in survival and increase
> in symptoms, or a surrogate that is well established for those two
> issues.
>
> Do you want to get into again lesser standards just to get drugs out
> on the market? That is a question again that you are going to have to
> answer.
>
> To get back to Donna\'s issue about the poor university person coming
> to the FDA, we do not have different standards for small drug
> companies versus big drug companies. It is an even playing field,
> okay, because that small drug company with a flick of the Bic could
> turn into a major pharmaceutical company with an infusion of one
> billion dollars. That happens every day with a hot idea.
>
> So, to say that we should have different standards for different drug
> companies is a thing that we cannot entertain. It just is not on the
> board here. These things change, we do not have different standards
> depending on what the size of drug companies are.
>
> One other aspect that was brought up was some priority, I believe
> Wayne had brought it up, between the FDA setting up a priority list
> for drugs that need to be developed in conjunction with COG.
>
> Again, we have to have an even playing field here. We cannot be the
> arbitrator of saying Johnson & Johnson, your drug is the better drug
> over Pharmacia. Why? Well, we believe it. It won\'t go down.
>
> We live by regulations here, and although you here in this committee
> have a point of view, remember, there is an equal and opposite point
> of view that will challenge your points of view in a court of law if
> we overstep our boundaries.
>
> So, I just want to set the kind of the tone of where we have to go
> with these discussions because we do live within the context of
> regulations here that have to be obeyed, and the interpretation of
> these regulations do have some flexibility, but they will be
> challenged if we cross the line.
>
> DR. SANTANA: Richard, thank you for so clearly articulating the
> mission of the FDA.
>
> DR. HIRSCHFELD: But I would to just add it is not only the size of the
> company, but the size of the patient population doesn\'t merit
> different standards either, and it has been the practice in orphan
> drugs and in pediatrics outside of oncology, where there has been a
> lot of activity, that the standards are the standards used in
> evidence-based medicine, and the patients, out of respect for the
> patients, do not merit a lower standard.
>
> DR. SANTANA: Peter.
>
> DR. ADAMSON: Two comments. The first is in response to Ms. Hoffman\'s
> presentation, which I really think touched upon some critical issues,
> and I wanted to focus on the informed consent.
>
> I think without question, and people on this committee, Rick Kodish
> and Skip Nelson have shown through studies that our ability to provide
> informed consent is nowhere close to where we think it ought to be.
>
> The reasons for that need further study and mechanisms to improve upon
> that certainly need to be developed. What physicians walk is a fine
> line between hope and false hope, and certainly in Phase I, we don\'t
> want to be giving false hope, but we also recognize that our ability
> to transmit that information in a fashion that families truly
> understand is quite limited even under ideal circumstances by very
> experienced clinicians.
>
> The other point I wanted to touch upon in the presentation is the
> toxicity and tolerability of Phase I studies. When we have looked at
> this, Phase I studies in fact carry remarkably low risks of mortality
> given the patient population, and relative to other things that we
> routinely do in pediatric oncology, carry quite acceptable morbidity
> in general.
>
> Part of what we haven\'t come to grips with as a pediatric oncology
> community is really following evidence-based medicine for some of what
> we do. Certainly, I think we are in an era, and hopefully leaving an
> era, where dose intensification transplantation was applied virtually
> to every known malignancy or the data to support the effectiveness of
> doing so is limited and confined to very few pediatric malignancies.
>
> We do that, and it doesn\'t come under the scrutiny of necessarily
> cooperative groups or industry, and so forth, but when talking about
> relapse patients, I think our need for improvement extends well beyond
> the conduct of Phase I trials.
>
> I then wanted to turn to issues raised by the comments from the public
> speaker, and I am sorry, I missed the name, as well as David Emanuel,
> and that is the issues surrounding intellectual property.
>
> Without question, that has been a major stumbling block for getting
> agents into preclinical testing, let alone Phase I study. I do want to
> state that from our perspective, it is very much a two-way street,
> that we are dealing with our own institutions and their interpretation
> of intellectual property rights, as well as industry.
>
> However, academic institutions are under some constraints from the
> National Institutes of Health as far as the ability to assign
> intellectual property, but having said that, I think industry also is
> going to have to move off their benchmark, and many industry
> representatives, in fact, have moved off that and saying no, it is not
> a two-way street, it is a railroad going in one direction.
>
> We are working with a number of people in this room, with the NCI,
> with our academic institutions, as well as with COG, in coming up with
> a master MTA that will be acceptable both to academia and industry
> when it comes to intellectual property, and when it comes to
> preclinical testing, I think one can do that.
>
> We are not necessarily playing around with these things in the lab
> where we may generate intellectual property, but are putting them
> through what we think will be well-defined studies with clear
> endpoints and what it will mean.
>
> Having said that, I think industry has to recognize that these are our
> children. This is not an obscure person. These are our children. We
> have a societal obligation to these children. I would invite any
> representative to come and sit with a family of a relapsed child and
> say it\'s the lawyers.
>
> So, yes, it is an emotional issue for clinicians and certainly beyond
> emotional for families. What we want to hear from industry is not that
> it can\'t be solved, but how can we go about together solving this
> problem, and if it takes changes in regulations or legislation, then,
> let\'s recognize that and move them forward, but we don\'t want
> intransigence, we want a cooperation.
>
> I think that is the intent of industry, and I think the intellectual
> property issue is solvable, we recognize it is important, but we
> can\'t come to the table saying it is not negotiable.
>
> DR. BOOS: I would like to respond to the FDA standpoint a little bit
> because you asked whether we were willing to accept different
> standards, and if you are honest, you have to agree that even the FDA
> accepts different standards.
>
> There are quite significant different standards in developing an ACE
> inhibitor if it comes, or if you have a new inhibitor drug, more than
> if you have new ACE inhibitor, you have some thousand patients on
> Phase III, and with Gleevec, I do not know whether there was even one
> Phase III trial finished, so you have to accept that the standards
> depend on the clinical need and on the patient population.
>
> If you summarize what the clinicians today said, then, there is one
> thing without any doubt. We have a lot of malignancies in pediatrics.
> We have part \[?\] malignancy only a few patients. We have established
> protocols to introduce the new drugs, which means lots of variables,
> and the amount of variables per patient in pediatric oncology is 3, 4,
> 5, 10-fold or 20-fold higher than in adult oncology.
>
> If you want to have significant data on such a big amount of
> variables, then, you have to be willing to compromise anywhere. This
> can be the time for development of a product, this can be the level of
> significance or the power.
>
> What you at the end want to have is safe treatment for children when
> the drug comes to the market, and the pediatric societies offer this
> opportunity because we have the networks, we treat the patients in
> quality controlling Phase III trials. We have the best
> pharmacovigilance system organized during the last 20 years ever has
> been organized for a specific population.
>
> Therefore, I would prefer to check specific toxicities for children
> and some effects, and then open the drug for a short time for one,
> two, three, four, five years to be just introduced, labeled in
> pediatric societies and pediatric Phase III trials, not for everybody,
> just for experienced persons in the concept of a pediatric trial.
>
> Then, you get all the safety data and all the efficacy data you need.
> The first proof of principle whether or not people are really willing
> to work on the off-label problem is, for me, whether or not the people
> in the industry and the regulatory offices would be now willing,
> perhaps tomorrow, to summarize what has been published by the
> Pediatric Societies.
>
> In carboplatinum, for example, there are more than 400 publications in
> children, more than 200 clinical trials, more than 40 pharmacokinetic
> observations and more than 5 population-based kinetics, everything in
> children, and there is no license or no labeling without
> contraindication in children, and this cannot be the truth, all these
> data having been published during the last years are not bull shit,
> they have to be recognized, and they have to be recognized by the
> companies and they have to take these informations and go to the
> regulatory offices and say, hey, these are the data and
> contraindication in children cannot be any longer the proof of the
> label.
>
> If this does not happen, and we ask several companies with several
> drugs, I am really in doubt whether they are willing to follow this
> way.
>
> There was one statement I want to comment on, and this is access to
> patients in Africa and Eastern countries. I think it would a good step
> forward if they could have access to the drugs.
>
> Germany is in the position in the middle of Europe that we cooperate
> very closely to eastern countries, and these cooperations become more
> and more effective, and the standards in the eastern countries like
> Poland, Russia increase dramatically.
>
> They increase because the Western countries support them with
> experience and with money and with everything, and it is only a short
> time I think, and then they will cooperate in the clinical trials and
> cooperate in the drug development trials.
>
> But this is not the major problem, because we do not have lack of
> patience, as we recognize today we have lack of drugs.
>
> Then, there was one statement that never a drug would be marketed or
> labeled only for pediatric use. That was your statement. Uricozyme was
> developed as a drug for palliative care against hyperuricemia in the
> pediatric situation, specifically pediatric drug development, Phase I,
> II, and III, and labeling, and this worked, and it worked together
> with the society sitting here around the table.
>
> DR. SANTANA: Pat.
>
> DR. REYNOLDS: I just wanted to echo some of Peter\'s comments about
> the intellectual property and the statements that were made earlier
> that that is something that the drug companies won\'t yield on.
>
> There has to be reasonableness here. The territorial demands that are
> conceded within the MTAs that we have seen from the drug companies are
> simply unacceptable to most academic institutions, and they are not
> consistent with U.S. patent law.
>
> That is where you are right, they do get stuck on people\'s tables
> because the institutional attorneys simply will not concede to
> territorial demands that are simply inconsistent with the normal
> practice of the institution.
>
> But I think that if the willingness is there from industry to be
> reasonable, and to come to the table and say, okay, what is fair and
> what is equitable and what protects their preexisting intellectual
> property and still allowing the institutions, if they come up with
> additional intellectual property, to share in that, then, we could all
> move forward and all benefit from these studies.
>
> DR. FINKLESTEIN: This question is really addressed to my colleagues at
> the FDA. Part of our charge today obviously, and the charge for the
> last few meetings, have been availability and access.
>
> Certainly, we are discussing it here in this subcommittee of ODAC.
> Malcolm referred to an NCI-COG effort that seemed to attack this, as
> well. I understand the Institute of Medicine has a cancer subcommittee
> which is also looking at this. COG has its own industry advisory
> committee, and we heard that Congress is busy today discussing
> something other than Iraq.
>
> So, my question really is, since we really are a subcommittee of ODAC,
> which is really in FDA, does the Agency now have\--and this is
> following up Wayne\'s comment\--enough information to come out with
> some new guidelines that we can then look at, struggle with, and
> advise you on?
>
> DR. HIRSCHFELD: Could I ask for clarification? Guidelines about what
> specifically?
>
> DR. FINKLESTEIN: Well, the challenge today, and the challenge for the
> last two and a half years, has been drug development availability. The
> algorithm that is current in force has been discussed by everyone from
> Pat Reynolds\' frustrations to Peter Adamson\'s comments, and the
> question is, this drug availability algorithm that is now operational,
> if indeed it is to be changed, has enough discussion taken place that
> since we are a subcommittee reporting to the FDA, that the FDA could
> come up with some new guidelines for us to struggle with.
>
> DR. HIRSCHFELD: Regarding availability, with regard to preclinical
> availability, that is outside our jurisdiction. With regard to
> availability under an IND, that is something we have an interest in,
> but in general, the availability has been determined by the sponsor,
> and it has not been in our practice certainly to stand in the way of
> availability.
>
> We had a program that we endorsed to a product mentioned earlier where
> there were I will say on the order of magnitude of 15,000 patients who
> had access outside the clinical trial system, and in general, if we
> have had a policy, it has been that if someone has access, and this
> has been tested in the courts, to a therapy that prolongs their life,
> and they haven\'t had exposure to that therapy, then, we can withhold
> permission to have exposure to the investigational\--but absent that,
> we tend to be very open in terms of our policies, it is a supply issue
> typically in that regard.
>
> I did want to address some other point that came up, and that was
> related to the exclusivity question. If I haven\'t answered you,
> Jerry, let me know, but someone said that it would be nice if we would
> grant an exclusivity extension for a negative preclinical screen, and
> that is not something we are authorized to do. We have to make a
> decision on clinical data.
>
> If there is a negative preclinical screen in an oncology context, I
> will point out that it doesn\'t necessarily exclude getting pediatric
> exclusivity in another arena.
>
> There are, for example, cytotoxic drugs that are used to treat a
> variety of immunologic conditions which might be of interest. Many of
> the signaling pathway drugs might be of interest in hormonal or other
> inherited diseases, and there would be other alternatives to pursue
> that avenue.
>
> DR. PAZDUR: Jerry, let me answer your question. You know this
> committee, what we have to work with. We have the Pediatric Rule. How
> successful is that? Well, it has its limitations in oncology because
> we don\'t have diseases that translate back and forth.
>
> The diseases that do, Hodgkin\'s disease, acute leukemia, some brain
> tumors, people in general or pharmaceutical firms in general are not
> developing drugs for their primary indications where they are coming
> in for that disease or those diseases.
>
> Yes, they occur. I could tell you probably 95 percent of the time, we
> are giving waivers away here for the Pediatric Rule because people are
> developing drugs in prostate cancer, in lung cancer, in colon cancer.
> That is what is market driven. This Pediatric Rule works probably
> better in other diseases.
>
> We have the exclusivity rules, not rules, but incentive programs that
> apply to us. We have discussed that. Dr. Emanuel asked or said that we
> should be different in pediatric oncology. Well, we are, and this
> exclusivity program that we designed when I came to the Agency with
> Steve and with Mack Lumpkin wouldn\'t fly in other disease areas.
>
> We are giving exclusivity for sponsors that do Phase I studies that
> can\'t go any further because of toxicity. That would not probably
> exist in other therapeutic areas. We are giving it for negative Phase
> II data for an attempt at a good-faith effort.
>
> I guess, you know, the question what you are looking for here is an
> answer to age-old problems of pediatric drug development in oncology,
> and is it solely an FDA problem, and it isn\'t.
>
> Therefore, I think we have to take a look at we are only part of the
> players, and we have certain tools here that we can work with, but how
> we work with those tools and how much leverage we have with them
> can\'t solve all your problems or cannot solve the problems of
> pediatric oncology.
>
> For example, you know, asking how we could encourage sponsors to
> introduce agents at the same time they are doing Phase I drug studies
> in adults, well, I have the pediatric exclusivity thing that I could
> work with. Does that mean that I could make a sponsor start a Phase I
> study if they are unwilling to do it? It\'s an incentive program, it
> is not obligatory, so I am limited in that aspect.
>
> If you could think of a way that I could make a sponsor do that, that
> would not come under some type of challenge from a legal point of
> view, I would be more than interested in hearing from it.
>
> How could we encourage preclinical testing of these drugs?
> Problematic. Generally, our preclinical aspects focus on safety. They
> are toxicology studies, not looking at where the drug should be
> developed.
>
> Could we somehow bring that into our guidance of a pediatric plan,
> potentially, you know, have some preclinical studies done before a
> Phase II program is initiated in pediatrics, that might be a case, but
> there are certain limitations here and we can\'t solve all these
> problems. It is impossible, we are only one piece of the pie here, and
> I don\'t want to belabor the point, but I think that we have to focus
> on what we have available.
>
> The likelihood of me changing Congress is like an ice cube\'s chance
> in hell that something is going to happen here, but if you do want
> that, then, you are going to have to really lobby in that effort, but
> what we have is what we could work with, and I think that is what we
> have to address.
>
> DR. HIRSCHFELD: Oh, but just a historical point.
>
> DR. PAZDUR: We have been successful.
>
> DR. HIRSCHFELD: We have been successful. This committee is through an
> act of Congress. The preclinical development program for pediatric
> oncology is through an act of Congress. Things can happen.
>
> DR. PAZDUR: But we can focus on what is available and how we could use
> those within the context of interpretation of existing rules and
> regulations, but it isn\'t going to solve everything, there are
> limitations here.
>
> DR. SANTANA: We have had a very interesting discussion today, and I
> think it is interesting sitting through these meetings on various
> occasions, how some themes tend to recur, and I think we are going to
> have to, at some point, decide how we are going to deal with that, so
> that we can really get to some of the issues that I think probably
> will help the Agency and be more fruitful, like the questions or the
> issues that they have posed to us today.
>
> I would like, with the permission of the committee, to try to start
> the discussion to specifically address the question that they want our
> advice on today, which is in this whole issue of drug development,
> when is the right timing to conduct pediatric studies, what kind of
> data would be helpful to the Agency, what type of data would be
> helpful to the Agency for them to make the determinations of whether
> they do accept or do not accept the pediatric developmental plan when
> a sponsor comes to them.
>
> So, I think with that, which is our focus today, although once again,
> there is a lot of issues that we need to resolve, I don\'t mean to
> minimize them or put them aside, but they keep recurring, and I think
> they are distracting us a little bit from the case at hand.
>
> So, I think with the permission of the FDA, I am going to go ahead and
> start the discussion on the questions, so that we could really give
> you the advice specifically that we can provide today.
>
> **Questions to the Panel**
>
> DR. SANTANA: The first question we have in front of us is\--remember
> that the theme that the FDA wants us to advise is the timing of
> initiation of pediatric clinical studies in any drug development plan
> that they may be faced with\--so, the first question, and I think that
> we did hear a little bit of discussion about this earlier today, was:
> Should adult safety studies precede the initiation of pediatric
> oncology clinical studies?
>
> I think I will give my perspective on it, and certainly I am going to
> welcome the opinion of others at the table, I think the answer is yes,
> that I think there may be exceptions with certain drugs that for some
> reason or another we may think will only be developed in pediatrics,
> in which probably this can be excluded, but those are so rare and far
> between that those have to be dealt with individually, but as a
> general statement I think that as a pediatric oncologist, which is
> what I am here today representing, is that yes, I would like to see
> some safety studies precede any involvement of myself in a clinical
> trial for a specific pediatric oncology indication.
>
> Others? Peter.
>
> DR. ADAMSON: I guess the caveat I would have to that is that
> safety\--and I will turn to my industry colleagues\--safety is global.
> It doesn\'t occur just in a Phase I study. It occurs throughout the
> entire drug development process.
>
> So, we have to be very careful when we answer should adult safety
> studies precede. Adult safety studies are the entire development
> process. Should we have adult Phase I data, I think is probably a
> better question to ask, and then I would agree that in most
> circumstances, we should have adult Phase I data.
>
> But I think we heard from Susan and others that there are going to be
> circumstances when we don\'t need and I actually believe in certain
> circumstances we should have some, but not necessarily complete,
> because no matter what we do, whenever we start, we are going to have
> a built-in safety net from the standpoint that the adults are going to
> get to where they are going before we get close.
>
> So, do we have to wait until their completion? I think in most
> circumstances, we likely will, but there may be some that we can see
> biologic activity and we can begin the pediatric trial realizing that
> adults will go to places that we haven\'t before we get there.
>
> DR. SANTANA: Susan.
>
> DR. BLANEY: I think that is especially true for biologics or targeted
> therapy, or whatever you want to call them, because we are going to
> want to see whatever surrogate endpoint that we choose to evaluate,
> see a spectrum of dose levels, and that may be different in pediatrics
> than adults.
>
> DR. SANTANA: Pat.
>
> DR. REYNOLDS: I echo what Peter said. I think that you shouldn\'t use
> the term \"safety,\" but the term \"Phase I.\" I think also that we
> should recognize that there will be circumstances where we might want
> to move an agent into pediatrics while the Phase I studies are being
> completed in adults if you have enough data from the adults to justify
> safely versus the risk-benefit ratio, which I will defer to Skip to
> talk about moving it into the pediatric setting.
>
> DR. SANTANA: What data would you advise the Agency that they would
> need to have in that scenario to allow, not concurrent, but closely
> concurrent Phase I adult and pediatric studies, how much weight of
> evidence would you want them to see before they would allow that
> scenario to go forward?
>
> DR. REYNOLDS: Well, I think that would depend on the particular entity
> that is being studied. If it is a new molecular entity and you have
> very little human experience, you may want to have more adult data to
> make sure there is not something that is really going to come up and
> surprise you in a major way.
>
> At the same time, if you have an entity that has moved forward and in
> the adult studies and in the Phase I\'s early on, you were seeing
> responses, and there wasn\'t a whole lot of toxicity, there may be
> some compelling reasons to start the pediatric trials fairly early.
>
> So, I don\'t think we can draw any lines in the sand here. I think
> there has to be some flexibility built into what we recommend to the
> Agency.
>
> DR. HIRSCHFELD: Victor, I would just like to clarify the question. The
> wording of this question is taken almost verbatim from the ICHE11
> document, and that document states, \"In the case where the disease is
> predominantly or exclusively affecting pediatric patients,\" which I
> think many of the pediatric tumors would fall into that category,
> then, the document states that the entire development program will be
> conducted in the pediatric population except for, \"initial safety and
> tolerability data,\" which will usually be obtained in adults.
>
> That document, we have already signed onto. What we are asking then
> and what the other questions would follow just to guide the
> discussion, is for some clarification on what would constitute initial
> safety and tolerability data, and would it usually occur in adults or
> were there circumstances where you would consider that it would not
> have to occur.
>
> So, the general principle we have already agreed to, it is the
> interpretation, if there are specific thoughts, that we would like to
> have those. Thank you.
>
> DR. SANTANA: I will reinstate my comment, which I think I was
> interpreting this also in the context of Phase I adult data as I
> interpreted the question, and I will go back to the way I answered it,
> which is, yes, I would like Phase I adult data to be a part of that,
> as a major component, before I make my decision about where this is
> going.
>
> Donna.
>
> DR. PRZEPIORKA: My question then would be, if this drug is actually a
> targeted drug specifically for a pediatric disorder, how would you
> ethically justify using it to treat adults.
>
> DR. SANTANA: That was my first answer, then, I did mention that there
> were some caveats to that and some examples were given on this side of
> the table, that there may be specific examples like the ones you
> posed, where the target is uniquely identified in the pediatric
> population.
>
> I think in that circumstance, I don\'t think it would be either
> practical or ethical to conduct studies in adults before you even have
> any development in pediatrics, but to me, that would be a very unique
> and narrow scenario.
>
> As we go along, it may be more and more as we learn more, but right
> now, to me, that is the caveat to the rule.
>
> DR. PRZEPIORKA: Could I just press the question a little further, if
> they are sitting in their office and they have an IND show up that is
> for a pediatric Phase I study and the drug has never been tested in
> adults at all, clearly, what I am hearing from the clinicians now,
> which is different from what I have heard in previous meetings, which
> is we don\'t care about other studies, other data, you know, kids
> should be able to get access to Phase I drugs as soon as possible.
>
> I don\'t think anybody here really wants to do that. I am starting to
> hear cold feet. But I guess the question is should that be a rule as
> opposed to let the clinician and investigators decide whether or not
> they want to proceed with a pediatric study without adult safety data
> or should the FDA have a rule that says no, we won\'t accept a study
> unless we have adult data first.
>
> DR. SANTANA: I will let others respond to that, but I think it is
> going to come primarily from the clinicians. If they don\'t have an
> interest in it, it ain\'t going to go anywhere no matter what the
> Agency says.
>
> Skip.
>
> DR. NELSON: In some sense, my comments are going to sort of lump the
> first five questions together, but not in specifics. I want to talk
> about it from an ethical perspective and using Ruth\'s slide where she
> titled it, \"Timing Access to New Drugs,\" where she presented from a
> parents\' perspective what they are looking for.
>
> I believe one way of understanding the sort of ethical and regulatory
> framework, which is for those who are into the Code of Federal
> Regulations, would be in 50.52, is what conditions should a Phase I
> trial meet where we would think it is reasonable for a parent to make
> a decision to enroll their child in that study.
>
> So, it comes down to what evidence do you need for there to be a
> reasonable assumption of potential benefit. Could that occur in a
> situation where there is no adult data, where there is only animal
> data? Possibly.
>
> I know in storage diseases, we have approved that under prospect of
> drug benefit, and it has gone forward. Now, I don\'t know oncology
> well enough to know if that has ever come up, if it will come up, but
> I could imagine it could come up.
>
> This notion of safety is really another question of risk, and so as
> you are looking at that possible benefit, an IRB has to say that the
> risk and the benefit are justified when you look at them together and
> are balanced with respect to the alternatives outside the trial, which
> in this case, since you are talking about using refractory or relapsed
> disease, are poor, but the quality of life is an issue, so I think
> Peter\'s comments about lack of toxicity, all of that will feed into
> the information you want to have to where, as a whole, you look at
> that protocol and say, yes, it is reasonable for us, as the
> investigative community, IRBs is sort of a part of that, to say it can
> be presented to a parent in a way that we deserve that foundation of
> trust, if you will, and that we are not taking advantage of the hope
> that inevitably is going to exist.
>
> The devil is in the details of how a protocol will look. It is sort of
> in my mind as how I would start to try and answer the specifics of the
> first five questions in a technical sense, but that is how I would at
> least frame it in a sort of broad ethical and regulatory sense.
>
> DR. BLANEY: The phrase came up as to rules. I don\'t think that there
> should be any rules, I think there should be guidelines that we
> follow, but the other issue is a lot of our fear about earlier
> introduction is not a safety concern.
>
> There is always a concern about treating patients at a dose that is
> too low to have benefit, and I think that is where we weigh
> information like pharmacokinetics and exposure from our preclinical
> models.
>
> But the bigger concern we have about early introduction is the lack of
> commitment to future drug supply if it is not going to be a drug that
> is brought forth through an NDA. I don\'t think that should come into
> play when we are making guidelines for access.
>
> I think each drug needs to be evaluated on its own merits, preclinical
> studies, prioritization within the Phase I consortium with the disease
> committees and the COG, one of the PBTC that are later going to be
> developing this drug, and those kind of concerns aren\'t what we
> should be\--yes, they are concerns that we will take into the process
> of prioritization, but shouldn\'t be the primary consideration.
>
> DR. WEINER: But the process of prioritization can\'t be sort of de
> facto an assessment of any drug that comes into the FDA, any oncology
> drug, for any indication.
>
> What you are really suggesting is that there needs to be\--and this is
> something that has been thematic today\--there needs to be some sort
> of mechanism, some sort of forum in which these considerations can be
> openly deliberated, so that the choices for children and for pediatric
> oncology and drug development don\'t depend solely on market factors,
> on legal constraints, or on communication, for that matter, which is
> another serious defect that people have alluded to today, that I think
> is fairly fixable, and would be allied to having the kind of open
> forum we are talking about.
>
> If it really takes accidental encounters for drugs, you know, in a
> company, that have activity in a particular disease, accidental
> encounters with Phase I docs to do something about that, that is not
> the right way to run a ship that is really going to help the families
> and their children.
>
> DR. SANTANA: Jody.
>
> DR. PELUSI: I am also struck by what not only we heard today, but the
> reading that we were given beforehand. To keep coming back to the fact
> that a third of the human toxicities aren\'t even predictable, the
> question again is, is there a way to collaborate, really move these
> things through quicker to find some of this stuff out.
>
> Again, I think it is this whole issue of collaboration and really
> setting guidelines, and not so much rules that cannot be flexible, so
> I think that becomes very important.
>
> I also think when we are looking at the issue of safety in Phase I
> studies, is this issue of access globally. I think that we really have
> to look at that significantly, because that may give us a lot more
> data quicker.
>
> DR. SANTANA: To kind of paraphrase what I have been hearing, to try to
> give some message to the Agency in regards to this question, is that I
> think the pediatric oncology community, first of all, does not want to
> put lines in the sand that are generalizable, but wants to consider
> each scenario specifically to the indication or to where the drug is
> ultimately going to go and how it relates to pediatrics.
>
> Susan had alluded to earlier today about whether it\'s an analogue, a
> biologic, a me-too drug, or a new entity, I think plays a lot into
> this decisionmaking of what kind of data you would want to see upfront
> versus how much more data you would want to see upfront, whether it is
> derived from preclinical or adult studies.
>
> So, I think the consensus that I think we are saying in answer to this
> question is that, in general\--I don\'t want to paraphrase what Donna
> said\--in general, it is not that we have cold feet, I think in
> general, it has served us well in the past, and it will continue to
> serve us well in the past to have some data in front of us, safety in
> adults with very few exceptions as we think of the applicability of
> these drugs in children.
>
> But, obviously, there may be scenarios in which we, as clinicians and
> oncologists, believe that for a particular entity, that may not be so
> necessary because it is unique to that tumor system or to that target,
> et cetera, et cetera.
>
> Dave.
>
> DR. POPLACK: I just want to make the comment that I am not so sure it
> has served us so well in the past. Just because a drug gets into
> pediatric studies based on the fact that there have been adult safety
> studies done before doesn\'t mean that it is ethical to expose a large
> population or any population of children to it if there isn\'t a
> significant reason or expectation that there is going to be benefit.
>
> I think we have probably done that a lot in the past because we
> haven\'t understood the basic biology of the agents and how they work,
> et cetera.
>
> I think what we might now say usually should be the case, we probably
> all agree that wherever possible, if we can realistically get adult
> safety data first, we will feel more comfortable, but I certainly hope
> that five years from now, that will be the minority of circumstances,
> because if it isn\'t, then none of us are doing our jobs properly.
>
> We ought to be using, five years from now, agents that are
> specifically targeted, as Barry pointed out in his slides, to unique
> translocations or other targets that are evident in pediatric
> malignancies particularly.
>
> Therefore, sooner rather than later, we are going to have to grab
> ahold of this issue of the fact that we are going to be doing Phase I
> studies in kids, not only simultaneously with adults, but before, and
> it may be even exclusively in kids.
>
> We need to be aware of it and realize that it is, frankly, very close
> to being here.
>
> DR. HIRSCHFELD: May I ask then, Dr. Poplack, what evidence would be
> appropriate in that case before you would put an investigational agent
> into the pediatric population?
>
> DR. POPLACK: I don\'t pretend to have all the answers to this, but I
> think it would be possible, for example, to construct an algorithm
> based on a variety of features, and they might include the novelty of
> the agent, the novelty of the agent as a general anti-cancer agent,
> novel mechanism of action, then might get a better score if it had
> novelty that was specifically targeted towards a biologic feature that
> was uniquely pediatric.
>
> On the other hand, one might take into account the particular illness,
> so that it may be more feasible to study an agent with a novel
> pediatrically oriented or specific mechanism of action if one was
> looking at gliomas rather than, in the first group of patients, at
> low-risk leukemia patients.
>
> It would be an interesting exercise, it goes beyond the scope of this
> group, to actually try and develop some type of an algorithm that
> might help us sort through those circumstances where we would feel
> more comfortable in getting started sooner in pediatric studies than
> later.
>
> DR. SANTANA: Skip, I think you had your hands up first.
>
> DR. NELSON: I am hearing a shift in emphasis, I guess, between issues
> of safety to issues of possible efficacy, in other words, will you
> have a tumor response, can you pick a dose, can you design a strategy
> where you can think it is reasonable to anticipate the possibility of
> benefit.
>
> So, the safety is still there, but I think it is appropriate to ask
> what is the evidence you need, which is sort of Questions 2 and 3, how
> much data do you need to where moving into a Phase I, you think it is
> reasonable to anticipate possible tumor effect/benefit, and then can
> you pick a dose that can be used safely as you are monitoring safety
> within that Phase I trial.
>
> There just seems to be a different shift in emphasis that the last few
> comments have made, which I think is appropriate. I would support that
> shift.
>
> DR. SAUSVILLE: I think it might be possible to begin to construct an
> algorithm that addresses some of David\'s concerns. It really builds
> on a number of the different strains that we have heard today, but
> also considering some additional issues.
>
> The idea of introducing a brand-new drug into a pediatric population,
> I agree, I hope we actually come to that point in the near term. That
> will have been preceded presumptively by the demonstration in an
> appropriate model that is addressing a pediatric situation, that there
> is biological activity in the animal milieu along with\--and I
> emphasize this\--pharmacology information.
>
> I think then the question that could be fruitfully discussed either by
> this group or maybe find appropriate expertise is whether one needs to
> have an animal model that adequately recapitulates the developmental
> stages that will be most prevalent in the tumor population.
>
> This was a point that actually was made to me on the break by Dr.
> Boos, a two- to four-year old\'s nervous system is not the same as a
> 16- to 18-year old. So, if you have a drug that is directed to
> neuroblastoma, you would want to consider whether the safety testing
> algorithms in the animals beforehand that will get you to that
> concentration are adequately studied in models that might detect or be
> responsive to issues there, because when you look back and see why
> toxicities aren\'t predicted, there is two basic reasons.
>
> One, we can\'t score them well. I mean alteration in sensorium, for
> example, it doesn\'t take much to be a successful mouse, whereas,
> obviously, humans operate at a higher level.
>
> The second major reason is that the pharmacology is grossly off for
> reasons that are trans-species differences.
>
> Okay. So, then you have established that this new agent, in an
> appropriate model, and this is where I am not sure that beagles and
> rats and whatnot that we use are adequate here to address all the
> pediatric circumstances, if you can get to that concentration safely
> that in other systems defines efficacy, then, the question is, then,
> judiciously, in a relatively small, focused study in humans bearing
> the disease, you try and choose doses that should get you at some
> reasonable level of confidence intervals to approach that
> concentration.
>
> Once you have that initial data, it then becomes a fairly simple
> matter for pharmacokineticists to then scope out a dose escalation
> scheme. Indeed, Jerry Collins, at this agency, a number of years ago
> actually proposed a very analogous scheme for adults, which to my
> chagrin has not been really adopted by many, but probably has much
> merit to be considered in this case.
>
> So, I think there is a way forward. It is just that it is going to
> have to be I think more thoughtful than the way that, in some
> senses\--again, this is not my customary collection of colleagues\--it
> is more thoughtful in how the data is applied to the initial
> experience in this very special population than you may have had
> previously.
>
> DR. SANTANA: Anne.
>
> DR. HAGEY: Broadly speaking, it is a sheer numbers issue when you get
> right down to it. A dose-finding study can take about 30 adult
> patients, and if you have formulation problems in Phase I and have to
> start with a new formulation, do another Phase I study, you are
> talking about 60 patients, which happens quite frequently in drug
> companies.
>
> Then, I don\'t want to say wasted, but you have used 60 children,
> which is about half of what you have available to us per year on a
> Phase 1 study that may not be the right way to go. If you have at
> least some dose finding data available in adults, you get a better
> starting point and thus would use less patients to find the maximum
> tolerated dose.
>
> DR. SAUSVILLE: But one must be concerned, though. Surely, if the
> agents are studied in adults, the data would be incorporated, but what
> about the possibility, the biologically real possibility that there is
> no basis to study the drug in adults. I mean that is I think the
> issue.
>
> DR. HAGEY: Yes, that is why I said broadly speaking. Again, there are
> exceptions.
>
> DR. SANTANA: Pat.
>
> DR. REYNOLDS: I think Ed makes a really good point, and I think that
> we should take that into consideration, and the Agency should, in the
> context of what David says about agents that may be specifically
> targeted to tumors in the pediatric population that have no adult
> component.
>
> Are the recommended animal toxicity studies to move an agent into the
> clinic sufficient for that population, meaning if you are doing
> studies in adult beagles and adult rats, does that tell you what you
> need to know if you are going to study it in children.
>
> I think if you have no adult human experience that at least the one
> thing we could require is that we have good pediatric animal
> experience. That would be difficult to do, but it could be done.
>
> DR. SANTANA: Bruce.
>
> DR. MORLAND: It is really just echoing some of the points that I think
> have already been made, but just to say that again, about three or
> four weeks ago, at a European New Agents Committee in Amsterdam, we
> debated exactly this issue, and came up with what I hear are broadly
> similar conclusions about the specific biological agents which will,
> in the near future, be developed specifically for childhood cancer and
> how you evaluate those.
>
> There are a number of relatively simple steps that one would need to
> do in order to get proof of principle to put those studies into
> children. It is really is the target there, and there certainly needs
> to be great cooperation and collaboration within the international
> groups to build a portfolio of profiles of pediatric achievements, so
> that there is almost like a directory that you can just tap into and
> say pediatric Ewing\'s tumors, yes, they express this, this, and this.
>
> Is that target relevant for the oncological potential of that tumor?
> There may be some work that will need to be done there. But assuming
> the answer to those two questions is yes, it is a relatively simple
> step to them move to introducing the agent, usually in vitro, to show
> that it actually reduces the proliferative effect. That is simple,
> that\'s a couple of weeks work for most people.
>
> But I think, going back to Ed\'s point, the critical thing for this is
> going to be having adequate and decent animal models, not just a
> xenograft efficacy, which may be the least important here, but it is
> actually the toxicity information for introducing these agents into
> children which I think is the critical step, which probably needs more
> thought than anything else.
>
> DR. BLANEY: None of those models have been validated, and nobody is
> going to go back to pay\--or I sincerely doubt\--to pay for validating
> such kind of models and developing animals for drugs that we use on an
> every-day basis.
>
> It is going to be stuff that, if that is what we do, we are going to
> learn information as we go along prospectively, but we are not going
> to know the meaning of if we give something to a young animal and we
> see toxicity, we are not going to know if that is predictive of what
> is going to happen in children or not.
>
> We don\'t want to set that bar when we don\'t know what it means.
>
> DR. SAUSVILLE: If I could just respond, I hear what you are saying,
> and we all like to concept of validation, but as I alluded to, in the
> data that exists both in a company data set and a separate dataset in
> our shop, if you regard one-third thereabouts not being detected or
> predicted, I could question that, in essence, no animal model is
> really valid.
>
> So, beyond that, you then create the scenario that you are really
> trying to find or make the best effort you can to do due diligence to
> avoid a catastrophic thing that might occur, recognizing that you
> probably are going to miss the fine points.
>
> DR. HIRSCHFELD: I wanted to share some information and then put a
> nuance onto the same question.
>
> The information I would like to share is that this entire discussion
> is occurring, not just within pediatric oncology, but pediatric
> broadly and what are the predictive models for safety, and what do we
> know.
>
> The Agency itself has been examining this for many drug classes,
> because you are only asking the safety question on classes of drugs,
> not related to diseases, and there is, let\'s say, a series of
> examinations of both the positive and negative predictive value of not
> only the two species of animals testing, but also asking questions
> about the value and validity of juvenile animals.
>
> There is one arena which we discussed at the meeting on material
> transfer agreements, and some of the questions that came up is what
> could be looked at, and we have been looking at the neonatal rat for
> nervous system, and there seems to be some validation to that at least
> in some classes of drugs.
>
> I think that would be one area which one could explore in terms of
> looking more systematically. In terms of if the pediatric oncology
> community were going to provide\--and this is again something we
> discussed at the NCI\--a service to the industry by saying give us
> your products and we will screen them for you through our screen and
> look for potential activity.
>
> You could also fold into that general program to be looking at those
> pediatric-specific safety issues, at least those that can be
> predicted.
>
> Now, the nuance to the question is if you had an investigational agent
> that was not pediatric specific, you know, not the PAX1 forkhead
> translocation or something like that, but just looked at, active and
> interesting, and Dr. Adamson and Dr. Reaman and Dr. Blaney said we are
> all ready, we have patients, give it to us, would you then still wait
> for an adult Phase I study before proceeding, or would you then
> proceed?
>
> DR. SANTANA: Malcolm.
>
> DR. SMITH: Let me make sure I understand. If you had some preclinical
> toxicity data in a pediatric model, would you accept that without the
> need for adult data even though there might be an adult indication in
> an adult study that could be done?
>
> DR. HIRSCHFELD: Correct. Let\'s just say that the adult pipeline is
> logjammed.
>
> DR. SMITH: We could say that, but I am not sure, it is kind of the
> converse. What I have seen time and time again and when we have done
> some pediatric and adult studies concurrently has been the adult study
> runs ahead, and the pediatric study has to leapfrog, skip dose levels,
> and so the rate-limiting step on completing the pediatric Phase I
> study, I think that is the key issue.
>
> The key time isn\'t when you start the Phase I study, the key time is
> when you finish it and when you have a Phase II recommended dose for
> further pediatric study, and what I have seen has been that the
> rate-limiting step is when the adult study ends because then you can
> jack the pediatric dose level up to that, you know, adjust it, and
> then complete the pediatric study.
>
> There will be exceptions to every rule, and there will be times, you
> know, Pat pointed out if you are seeing responses in every adult
> patient that enters the study from the first dose level, why wait with
> a scenario like that, but in general, if an adult Phase I study is
> being done, we are much better off to wait for that, to see the
> complete dose escalation, understand at least at that level what the
> toxicity experience is, and then make decisions about the pediatric
> study.
>
> I think the key is being efficient about having our studies ready to
> go if the agent is really a priority, and then having systems in place
> that open that study quickly and get it done.
>
> DR. HIRSCHFELD: Just to clarify, Malcolm, the evidence burden would be
> even if you have the opportunity to do a study before you get adult
> data, the recommendation would be that you wait until those adult data
> are available before initiating the pediatric study.
>
> DR. SMITH: Again, I would say if the rate-limiting step, because the
> adult study is going to escalate faster, in most cases, you know, that
> has been the experience, if that is the rate-limiting step and what we
> are really interested in is completing the Phase I study and having a
> recommended Phase II dose, in most cases, we are better served by
> waiting for the adult data, beginning the pediatric data quickly after
> that and proceeding, and I think the benefits that we learn from the
> adult experience in terms of informing patients, starting in a dose
> more likely associated with benefit are substantial, as well.
>
> There are examples where you start the adult Phase I, everything is
> going fine, and then there is a catastrophe, and that drug is dead. If
> we start the pediatric Phase I study early, then, we have wasted our
> time, our energy, and the patients who are enrolled on that study
> contribute nothing or little to our general knowledge about pediatric
> drug development.
>
> DR. WEITMAN: I think one other potential scenario, it gets back to
> maybe a little bit what Anne was bringing up before, is that maybe
> another potential pitfall, not to be too quick, is that frequently the
> first schedule that goes into the clinic does not turn out to be the
> most efficacious schedule.
>
> I think in pediatrics at least, we have seen drugs that if they don\'t
> make it on the first schedule we test in Phase I, it seems very
> difficult to get excitement built around the drug on a different
> schedule.
>
> So, my sense would be that there may be another pitfall, if we are too
> quick to go based on the first Phase I data in adults, and again this
> may speak to the need for more preclinical work, but if we go with
> that first schedule, it may not always be the most efficacious, as
> well.
>
> DR. SANTANA: I think, Steve, we have answered that question I think as
> best as we could. Was that helpful?
>
> DR. HIRSCHFELD: Yes, it was. If I understand now, unless it is a
> specific pediatric disease, the default condition should be always to
> wait for adult Phase I data and then move forward, is that correct?
>
> DR. SANTANA: No. The room over here is saying no, so let\'s have
> further discussion of that.
>
> DR. HIRSCHFELD: Okay, let\'s clarify that.
>
> DR. SANTANA: Greg.
>
> DR. REAMAN: I think one of the issues that really requires the
> clarification is adult Phase I data using the exact same schedule or
> if we have preliminary Phase I data from a schedule, have gleaned
> something different from preclinical testing.
>
> DR. SANTANA: Jerry, you had a very resounding no.
>
> DR. FINKLESTEIN: Well, I just thought maybe at a different voice
> octave, I could reemphasize what both David and Susan are saying.
> There are a couple of conditions to Steve\'s comment.
>
> One had to do with the nature of the tumor. I mean you have
> neuroblastoma, you have retinoblastoma doesn\'t occur in a child, I
> know malignant melanoma may be the same, but it really isn\'t, so that
> is one consideration.
>
> Then, David Poplack was pointing out in the next few years, and I am
> an optimist, that we are really going to have novel targeted, whatever
> you want to call it, molecular therapy, and we have to think about
> that.
>
> I mean I could see in acute lymphocytic leukemia, I could see a P190
> Gleevec coming out versus a P210. P190 is pediatric ALL. We are going
> to target for P190 right away, I am not going to wait around for some
> adult study.
>
> So, I mean the answer to your question is there are exceptions -
> molecular and histologic diagnosis. Have I emphasized what both of you
> are saying?
>
> DR. SANTANA: I think you said that early on, that we all recognize
> that as this evolves, the exceptions may be the more frequent scenario
> and more going to, under those circumstances, maybe modify the
> position that maybe we do not need adult Phase I data before we start
> that particular pediatric study with all that preclinical information
> telling us that it is uniquely to that target population. I think we
> all agree with that, I don\'t think anybody has disagreed with that.
>
> Susan.
>
> DR. BLANEY: Let me just ask the FDA. Is there a problem with the way
> the system is working now, because from our perspective, our problem
> is access. When we have come to the FDA with what we believe is
> rational information to start a trial concurrently or initially in
> pediatrics, the FDA has been very responsive and CTEP has been very
> responsive in almost all instances.
>
> Are there specific concerns from the FDA right now about the way the
> system is working?
>
> DR. HIRSCHFELD: Yes. The reason and the entire rationale for this
> discussion today is that we have been asking for studies without in
> any way indicating where in a drug development plan the pediatric
> component should begin.
>
> We have alluded to it. We have referred to the vague wording or what I
> feel is vague wording, I don\'t speak on behalf of the entire Agency,
> from ICHE11. But would like particularly in pediatric oncology to be
> as specific as possible.
>
> So, if we say do pediatric studies, then, some people interpret that
> as when they get around to it, and others interpret it when they feel
> pressured to do it, and then they ask us for clarification.
>
> We have some leverage in this in that if we are talking about an
> incentive program, we can set the deadline for when that study report
> should be in. So, if we have a rationale for saying that we feel that
> there is sufficient evidence to begin your pediatric program, we could
> set a due date for those studies to come in. That is a very concrete
> example.
>
> If we just generically say do pediatric studies, which is what we are
> saying now, it leaves it open and ambiguous.
>
> DR. ADAMSON: I don\'t want to add to the confusion, but what I would
> propose really is building on what Malcolm has said, and that is, in
> many circumstances, it is most efficient to get to a recommended
> pediatric Phase II dose when we have adult Phase I data in hand.
>
> I think it would be fair for the Agency when faced with a proposal, to
> start a pediatric Phase I trial before adult Phase I to say will you
> arrive at a recommended Phase II dose more efficiently now, and if so,
> please justify it or please explain it.
>
> If we can do that, then I think that would be sufficient for the
> Agency to say, okay, let\'s move forward. If, in fact, the Agency
> says, by the way, we know there is a proposal forthcoming or there is
> a proposal on the table here to start an adult Phase I, would you
> reconsider waiting for that, I think in most circumstances, if we know
> this is going forward, we are going to say okay, if they can knock off
> the first 30 patients in six months and get us five dose levels
> higher, then, yes, that is going to be worth their while.
>
> So, I don\'t think there is an absolute answer, Steve, other than
> saying what is going to get you the recommended Phase II dose in the
> most efficient manner, and if it is, in fact, more efficient to start
> the pediatric trial first, then, we just need to provide the rationale
> and the basis for doing so.
>
> Now, getting back to where the FDA can leverage, and Rick had
> mentioned this earlier, I think when a drug enters adult Phase I at
> the latest is when we should be looking at it preclinically, and no,
> you can\'t mandate it, but drug companies\--and correct me if I go
> wrong\--like to make the FDA happy.
>
> There are guidances, there are rules, but drug companies like to keep
> the FDA happy.
>
> DR. HIRSCHFELD: Never noticed.
>
> DR. ADAMSON: And if you were to have a guidance or, you know, a by the
> way that this is part of your pediatric development plan, it would be
> looked upon favorably if you, in fact, had preclinical pediatric data.
> My guess is we might start seeing some agents appear in our
> preclinical consortium.
>
> That is where specifically I would like to see the FDA help, and I
> recognize, and I think we all recognize, that the FDA is not the
> entire solution to all our problems, but I believe it does tie
> together to the question you are after.
>
> DR. HIRSCHFELD: Well, I am happy to hear that at least we are
> considered part of the solution, that is already progress.
>
> DR. SANTANA: Skip and then Pat.
>
> DR. NELSON: Just to modify Peter\'s comment about the endpoint of a
> Phase II dosing recommendation, I think it is also important in the
> first child in that Phase I study, that the dose selected has a
> reasonable expectation of benefit, so you can\'t start it 10 percent
> and then go whoops, we can go now to 90 percent. We need to be
> somewhere in the right ballpark.
>
> So, whatever sufficient evidence is necessary to accomplish that,
> which I heard could be potentially on preclinical modeling, depending
> upon the model.
>
> DR. REYNOLDS: Steve, you say that in the context of exclusivity, you
> can set a date for report. I presume you can set a date for multiple
> reports. In other words, you can only have one report, because what I
> would like to know is why you couldn\'t require a report on
> preclinical data for a new agent that is moving forward to be
> delivered, so that you could force the issue of getting these agents
> out for preclinical testing.
>
> DR. HIRSCHFELD: Right, we can only address clinical issues, and there
> is only one report.
>
> DR. SANTANA: Joachim, did you have your hand up?
>
> DR. BOOS: To this point, if you start with a very low dosage because
> you do not have any experience in adults, and the children expect the
> chance to benefit, we have to critically discuss the inter-individual
> or the individual dose escalation, which is a problem I think, but
> necessary in the situation.
>
> MS. HOFFMAN: To follow that, we have to remember we are a small
> community and we talk. There are tons of list servs out there, and the
> parents talk on a regular basis, and if we are giving children a drug
> on a dose basis and it is not effective, and they are seeing that, it
> gets around and it gets around very quickly, and that can basically
> torpedo other families from wanting to go into maybe a higher dose
> study. It is amazing, there are thousands of parents on line.
>
> DR. SANTANA: Donna.
>
> DR. PRZEPIORKA: Just from the perspective of an adult oncologist, I
> could tell you that adults going into a Phase I study also expect that
> there is some level of hope for activity even at the lowest dose, so I
> don\'t know that there is any difference between how you would
> approach a parent versus an adult subject for a Phase I study.
>
> But to address Steve\'s question about what is the latest time you
> want pediatric information, I would think that in your purview as
> being a steward of safety of drugs in the U.S., that you should have
> safety data by the time the drug is ready for use in pediatric
> patients, which is when it hits the market.
>
> If there is a new cytotoxic agent out there that is not specific for a
> target in an adult tumor, but is rather more broad, I would bet that
> any oncologist who has a kid with a refractory tumor is going to reach
> to the shelf for it, and we should have that safety information for
> them by that time.
>
> DR. SANTANA: Anne.
>
> DR. HAGEY: I was going to say that it is relatively easy to find a
> maximum tolerated dose when you are dealing with traditional cytotoxic
> agents because you treat to toxicity, but this issue is becoming
> muddied, and it is going to be more difficult than ever to find an
> efficacious dose given the new agents that are, as Judith alluded to,
> are in the pipelines of all the drug companies.
>
> I think I agree with her, about 80 percent of the agents in
> development now are not traditional cytotoxics, in which case it will
> take more patients than previous to find your correct dose.
>
> DR. SANTANA: Judy, one last comment on this question.
>
> DR. OCHS: One last comment. The other thing, again, I think it is
> largely pragmatic reasons that you are going ahead with Phase I
> studies in adults first. There may be exceptions, as David says, but I
> think the reality is it is going to be more pragmatic, and that is how
> the drugs are going to get developed.
>
> The other thing is the Phase I, and this was on one of the slides, is
> if you do find an effective dose range, then, you can get target it
> pharmacokinetically to achieve the same range in the pediatric
> patient, and again, Phase I doesn\'t necessarily have to be an MTD.
>
> The other thing to remember is Phase I is acute toxicity only, and one
> of the things for me was always the elephant in the room, is long-term
> toxicity, and that is where some of these models would be helpful,
> because one of the concerns with some of the newer agents where you
> are talking about giving them for years and years and years and years
> is what happens in that situation, and that is where pediatrics again
> continues to play a unique role in what happens in developing organ
> systems with truly chronic exposure.
>
> DR. SANTANA: Steve, I think we have given you all the advice we are
> going to give you on this question. I am making that pronouncement.
>
> So, let\'s move on to the second question, which is: Should
> demonstration of activity (emphasis by me) in any (emphasis by me)
> adult tumor precede pediatric oncology clinical studies?
>
> DR. ADAMSON: No.
>
> DR. SANTANA: Please use the microphone when you answer.
>
> DR. ADAMSON: No.
>
> DR. SANTANA: Any further explanation to the answer?
>
> DR. ADAMSON: I think again if we are starting on a timeline that we
> are recommending we start, it depends how you interpret this, but
> demonstration of activity to me means completion of Phase II trials.
> So, I don\'t think that should be the bar.
>
> You know, anecdotal report of a patient on the Phase I had a response,
> I don\'t think we should use that as information as far as deciding
> whether to move forward or not, so that underlies my answer of no.
>
> Now, if there is a different definition at work here, then, I might
> modify it.
>
> DR. SANTANA: Malcolm.
>
> DR. SMITH: As far as the general approach, if a drug is showing
> activity in 30 percent of the breast cancer patients or the renal cell
> patients on one of the several Phase I studies that is probably being
> done with the agent, that is going to be something that Peter and
> Susan and others will say okay, that makes us more interested in this
> agent, and we at CTEP would say yes, this looks like it may really be
> a drug, and not something that is going to be discarded along the way.
>
> So, I think it is a factor to consider. Should it be a mandate? Well,
> no, but it can\'t help but be a factor to consider both primarily in
> terms of is this going to be something that is going to be available
> in the long term because it really is an effective anti-cancer
> treatment for some tumors and rather than just another chemical that
> we can give to patients and cause toxicity.
>
> DR. SANTANA: So, the answer that you are saying is in general, no, but
> the information that is provided by those adult studies, number one,
> will help us prioritize what we want to do because of level of
> interest, and secondly, it will help us also in getting involved with
> a drug that ultimately, hopefully, will go somewhere, that doesn\'t
> get discarded.
>
> DR. SMITH: It is not a requirement for a study, but is a factor for
> prioritization, and all things considered, the drug that is showing
> activity in the Phase I and the company is enthusiastic about it and
> proceeding with a range of Phase II studies, that is a drug that there
> is more likely to be enthusiasm for opening a pediatric Phase I study
> quickly.
>
> So, it is an important factor, but it shouldn\'t be a required bar
> that an agent has to jump over.
>
> DR. SANTANA: Any further discussion on this question? The other
> question took an hour to discuss, this one took five minutes, so we
> are making progress.
>
> DR. REAMAN: We discussed a lot of the issues actually.
>
> DR. SANTANA: For the purpose of the Agency, I think we do have to go
> through the questions. It sounds difficult, but we have to do that.
>
> Question No. 3. Should activity in similar or related tumors in adults
> precede pediatric oncology clinical studies?
>
> There are a lot of no\'s around the table. Anybody want to elaborate
> on the answer?
>
> DR. ADAMSON: I think Malcolm\'s answer applies. It shouldn\'t be a
> bar, but it will certainly influence the priority that we give an
> agent, so I don\'t think it is a separate answer.
>
> DR. SANTANA: Is the Agency content, not happy, content with that
> answer?
>
> DR. HIRSCHFELD: Right.
>
> DR. SANTANA: This is the one that I think we have addressed during
> some part of the discussion, but I think the Agency is looking maybe
> for more specifics on this particular question.
>
> Question No. 4. On what basis can pediatric oncology clinical studies
> proceed if no activity is shown in adult studies?
>
> I think one of the answer is this whole issue, if it is a drug that is
> biologically relevant and already we have demonstrated in the
> preclinical models that that target is relevant to the pediatric
> condition, then, I think if that is unique to that population, then, I
> think we should proceed forward.
>
> Greg.
>
> DR. REAMAN: The only proviso would be ensuring that there is going to
> be adequate supply of that drug or that it is something that is going
> to complete development.
>
> DR. SANTANA: But I heard Steve mention that there may be other
> mechanisms that could, in an ideal world, allow that to happen under
> the orphan drug or whatever. I heard that answer before, and I want to
> bring it back.
>
> DR. SMITH: What I heard before, as well, is that this is a situation
> that becomes society\'s responsibility. If there is not a market for a
> drug, I doubt one of the companies on this side of the table is going
> to proceed in developing it, but it becomes society\'s responsibility.
> It is a place where the NCI in the past has done some of the work
> necessary to get the agent studied further in children.
>
> Right now we have got a Phase III trial in neuroblastoma of an agent
> for which there is not a company sponsor. We have studied other drugs
> where the company, by itself, would not have been able to go forward,
> but in collaboration with NCI, with COG, you know, studies have
> continued forward.
>
> So, I think there are ways of using public resources, orphan drug
> resources, NCI resources through COG and others to see that these
> agents do get some evaluation to whether they are truly beneficial.
>
> DR. SANTANA: Greg.
>
> DR. REAMAN: I didn\'t mean to imply that it was industry\'s
> responsibility to assure this. I mean whatever mechanism is possible,
> but that just has to be an assurance, I think.
>
> DR. FINKLESTEIN: Malcolm, I wonder if you would refresh my memory on a
> drug that industry decided not to proceed with for good industrial
> reasons, and that the other system of orphan drugs in pediatric
> oncology has identified it, taken it through completion, and we now
> use it.
>
> DR. SMITH: Jerry, the two that I was referring to, one is a chimeric
> 1418 monoclonal antibody that was studied in Phase I actually in
> adults and children. It was studied in adults primarily in melanoma
> since that expresses GD2, and studied in children in neuroblastoma.
>
> Phase II studies were done of the chimeric 1418 and now there is a
> Phase III randomized study as you know. So, that has been done with
> NCI support both in conducting the study, as well in this case as
> providing, you know, manufacturing the drug to be tested.
>
> We have collaborated with Glaxo/Smith/Kline in studying compound 506.
> It is a T cell ALL drug. There is not a huge market for T cell ALL
> drugs, but we have collaborated to this point with them in studying
> this, and have completed a Phase II study for that agent, so I think
> there are models for how this has worked.
>
> DR. FINKLESTEIN: What I wanted to do is take it historically, one step
> further and say, all right, that is one part because there is only so
> much money that is needed to carry out the Phase III study, but do we
> have any experience in pediatric oncology where the Phase III studies
> or Phase II studies were successful, and we now have a drug out there
> that we use in pediatrics because industry gave it up, and we gave it
> to someone else on a orphan drug basis.
>
> DR. SMITH: No, we don\'t have that, not that I am aware of.
>
> DR. FINKLESTEIN: I am getting to the point, which is I know the
> mechanism is out there, but if it hasn\'t happened in my career, which
> is 35-plus years, why will it happen in the next five years, and do we
> need another mechanism.
>
> DR. HIRSCHFELD: I could answer there and give an example in that case,
> and that is arsenic trioxide where the company that essentially was
> looking for a product, bought a dataset for studies that they hadn\'t
> done, someone else had done the studies, and they bought the dataset,
> prepared a submission package, and it got approved, and now it is
> their product. It doesn\'t have a huge market, but I think there is
> precedent for people who want to establish credibility or exposure to
> sell a niche product.
>
> DR. KODISH: My comment is an effort to be responsive to this Question
> 4, which is the question of what the basis of going on with pediatric
> studies are if there is no activity shown in adult studies.
>
> I think I have heard one basis is biologic plausibility. A second is
> some measure of being able to foresee that there would be an adequate
> supply, which is what we just were discussing.
>
> I think the third point that needs to be mentioned is that there is
> the reasonable expectation of safety, and I just think it is important
> to be explicit about that, and that that safety is in proportion to
> prospect of benefit to the child, but is one of the important bases, I
> think, ethically.
>
> DR. OCHS: Actually, I just wanted to bring up a horrible question,
> what is activity, because I think with some of these newer agents, you
> are not really expecting to get activity, whether we define this as
> response rate or time to progression or survival time, and some of
> these other agents are not necessarily cytotoxic where you see this
> kind of activity and rapidity of action.
>
> So, again, it gets to what is the definition of activity. I am
> grappling with that issue right now about how to define what activity
> is, and like most things, the answer depends on the question you ask,
> and you have to ask the right question.
>
> So, I can foresee a situation, for instance, if you did have some
> agent that there is either a biologic basis or there is some strong
> rationale and you are not seeing classic responses in a Phase I
> situation, but it is persuasive that there is activity, antitumor
> activity in some way, shape, or form going on, that might actually be
> translatable to another clinical situation, which gets to Jerry
> Finklestein, that there are those agents that we probably have seen
> that didn\'t necessarily show it the way we thought it should show it
> and that we have dropped.
>
> DR. SMITH: Judy makes a good point about the trend certainly in the
> adult world is to look for these alternative endpoints other than
> objective responses.
>
> I would caution the pediatric setting, though. A child who is six
> years old with rhabdomyosarcoma is very different from an 80-year-old
> with prostate cancer. A stable disease or stabilizing disease or
> slowing disease progression in the latter patient is a meaningful
> clinical benefit, and is less so in the six-year-old with
> rhabdomyosarcoma.
>
> I think primarily we are looking for the targeted agents that somehow
> are able to make tumors smaller, that are able to kill the tumor
> cells, and while there may be places for the cytostatic agents in
> pediatric cancer, I think our highest priority, if we are given our
> druthers, would be to pick the one that actually has an effect, by the
> effect that it has when it interacts with the target as to cause the
> tumor cell to die rather than just to stop it from growing.
>
> DR. ADAMSON: Malcolm, the one comment I would put to that, and I think
> you would agree, is that many of these agents in fact may find a home
> as synergistic or enhancing agents. So, the issue, we share the issues
> with the adults, what is your Phase II endpoint?
>
> We have the same problem in children as we do in adults for agents
> that, by themselves, are not intended or not anticipated to produce
> responses, but yes, I agree that these are not agents that we are
> likely to use as single-agent therapy, whereas, in the adults, they
> may in fact in certain situations be used as single agents.
>
> DR. SMITH: I modify my comment. The drug that is able to enhance the
> activity of cyclophosphamide by modifying its target in a favorable
> way, we are interested in that drug even though, as a single agent, it
> doesn\'t have any activity. Good point.
>
> DR. MORLAND: It is a critical issue, this defining of endpoints is
> going to be very critical for the future with these new biological
> agents.
>
> Maybe also it is worth reflecting back to\--I am sorry to raise
> it\--but Question 1 again, because many of these drugs, you probably
> will not need to test the toxicity. They are going to have biological
> endpoints, and as long as you can demonstrate a biological endpoint,
> you don\'t need necessarily to go slavishly taking these drugs to
> toxicity.
>
> So, I think all of the angst that people were expressing over Question
> 1, in the future may be significantly less relevant that it currently
> is with testing standard size toxic agents.
>
> DR. REYNOLDS: Malcolm, with respect to the situation that you
> described, which is a modulator of antitumor toxicity used in
> combination, I ask why would we consider studying that as a single
> agent in pediatrics then? Shouldn\'t we bring it forward then in the
> appropriate combination?
>
> DR. SMITH: 0-6-benzylguanine is probably the best example now of an
> agent that we are studying in combination that we never studied in
> pediatrics as a single agent, so it is a good point. If there is
> reason, we have been able to bring a combination forward and get PK
> data on the investigational agent, and not have to study the single
> agent by itself.
>
> DR. REYNOLDS: With that in mind, then, couldn\'t we use the adult data
> in terms of toxicity to then appropriately design combination studies
> and move directly into the combination studies in pediatrics rather
> than going into single-agent studies first?
>
> DR. SMITH: Potentially. It is like everything, there are case-by-case
> examples of the agent and its toxicity. My experience, relating to
> Bruce\'s comment, is we have got a lot of agents, but I am still
> seeing dose-limiting toxicities. I mean I think the histone
> deacetylase inhibitors, there is a target, but yet there is a
> dose-limiting toxicity that you are getting to when you are modulating
> that target, the proteosome inhibitors.
>
> I think there are clearly agents that have minimal toxicity at a dose
> where they are affecting their target, but many of the agents, in
> fact, have dose-limiting toxicities in the range where they are
> affecting their target in ways that we think are clinically important.
>
> DR. SANTANA: Skip.
>
> DR. NELSON: Maybe I am a little confused here, but let me just ask a
> question that has been occurring to me. From the previous discussion
> about the reluctance to study in Phase I pediatric trials, things that
> have not shown any efficacy in adult Phase I trials because the drug
> would basically just stop in its development, it is unclear to me what
> would then drive the drug into the pediatric testing arena if, in
> fact, there is no activity in adults. I mean I am struggling over that
> basic question.
>
> If we don\'t do Phase I studies in pediatrics, even in the absence of
> adult activity, we will never get, if you will, the political or
> social will to try and find ways to bring those products either under
> the Orphan Drug Act or through other ways.
>
> I don\'t intend to open up that other discussion, but I am struggling
> with how a drug would ever even go forward if, in fact, there is no
> adult activity given the marketing and economic realities and
> development realities people were talking about.
>
> DR. SANTANA: Susan.
>
> DR. BLANEY: I think part of that would be based on our preclinical
> models then, if we are able to validate them and show that activity in
> our models correlates with activity in patients, if we have an agent
> that is sky-high on the priority list as showing activity in the
> preclinical models independent of activity in adults, we would want to
> pursue it.
>
> DR. NELSON: So, you would pursue that even if potentially the drug
> development was stopped on the adult side, and you would be stuck\--
>
> DR. BLANEY: Through other mechanisms if we felt strongly about our
> preclinical model system and its validity.
>
> DR. SANTANA: From what I heard earlier, Skip, was that it is a
> responsibility of everybody to try to get a solution to that
> particular problem, and there would have to be both political and
> social pressure to somehow get the drug supplied.
>
> DR. NELSON: But part of that pressure would be showing activity in
> Phase I pediatric trials, so I guess if you don\'t do it, it would be
> hard maybe to generate that activity.
>
> DR. SANTANA: True, yes.
>
> MS. HOFFMAN: In terms of the toxicity with the molecular targeted
> drugs or therapies, I mean I don\'t think we could assume that there
> is no toxicity because we don\'t know long term, and it was like
> anthracyclines, I mean they thought they could give anthracyclines to
> kids, too, and then five, six years later, you start seeing
> cardiotoxicities.
>
> We don\'t know what is going to happen to the next generation, you
> know, is there going to be mutations to the germ cells, and these kids
> will able to produce, but, you know, they will reproduce and have
> major genetic mutations in their offspring, and I think we just can\'t
> assume that, oh, because we don\'t see an immediate toxicity, that
> there is not some downstream mutation that could really impact the
> child 20 years from now or their offspring.
>
> DR. SANTANA: Do you have a comment, Peter?
>
> DR. ADAMSON: I was going to respond that the Phase I study is a very
> limited study in what it can answer, and what our experience in
> pediatric oncology is, is that we now recognize that our surveillance
> for short- and long-term toxicities spans decades. We can\'t
> over-interpret the results of a Phase I study. All the Phase I gives
> us is a starting place to begin the true evaluation of both efficacy
> and safety of that drug.
>
> DR. SANTANA: Yes.
>
> MS. ETTINGER: I think it would be unethical for us to stop at that
> point, thinking, you know, looking back and saying well, maybe we will
> have a long-term sequelae at that point obviously, and we do have to
> follow our patients life long. I think that is a lesson we have
> learned.
>
> DR. SANTANA: I think to the credit of the pediatric oncologists, that
> is something that we do very well. I think that is an integral part of
> what we do in terms of both practice and research.
>
> Malcolm, one last comment on this.
>
> DR. SMITH: On this question that Skip was raising about pediatric
> oncology clinical studies, no activity, I mean the more common
> situation is that the pediatric Phase I trial does get started, and
> then sometime while it is being conducted or at the end of it, a
> decision is made to drop the drug.
>
> So, I don\'t know if the question, if the FDA wants a comment about
> that, as well, about continuing studies in that situation, that is
> really the situation for which we have experience. There, there may be
> Phase I responses in the pediatric setting or other reason to
> continue.
>
> DR. HIRSCHFELD: I will just try to clarify. The essence would be what
> is the evidence burden to move it into the clinic, and once it is
> moved into the clinic, then, that is a separate discussion.
>
> DR. SANTANA: Somebody mentioned that biological plausibility, if it is
> a biologic agent, would be something that we would want to know. We
> want to know something about the issues of safety, clearly, based on
> the limited Phase I trial that we may have done in pediatrics before a
> decision is made, and then the third, not necessarily last, but the
> prioritization of what are the things we have out there that may be
> important in terms of moving this drug versus another drug forward.
>
> I am going to go on with the next question, but I want Steve to
> clarify that question.
>
> DR. HIRSCHFELD: Five and 7 are essentially the same question, they are
> synonymous. We just had two different opinions on how to phrase it.
>
> DR. SANTANA: So, 5 and 7 are the same.
>
> DR. HIRSCHFELD: Yes.
>
> DR. SANTANA: So, we are going to scratch 5.
>
> DR. HIRSCHFELD: May I suggest that you look at 6 next and then come to
> 7.
>
> DR. SANTANA: Good, we will do that.
>
> The sixth question, which is now No. 5 is: Potential development plans
> for new cancer therapies could include combined adult and pediatric
> studies, another alternative would be separate but simultaneous adult
> and pediatric studies with continuous information sharing, sequential
> adult and pediatric studies with information sharing or completely
> independent programs. So, four possible scenarios.
>
> What are the potential advantages and drawbacks of coordinating adult
> and pediatric early clinical development?
>
> Malcolm.
>
> DR. SMITH: Didn\'t we answer this already? I mean in general you want
> adult data. There will be special situations in which it will be
> appropriate to either do pediatric first or to do pediatric
> concurrently, but those need to be well justified.
>
> I think it is the first question, you know, I think we have answered
> it.
>
> DR. HIRSCHFELD: Just to clarify the question. We want to make sure,
> not anticipating or not knowing what would come up in the discussion
> of any of these, that that issue would be presented, because we have
> discussed it before in this committee, and it is the theme that we
> think deserves continual reassessment.
>
> DR. SANTANA: Dr. Reaman.
>
> DR. REAMAN: I think we have made a number of positive comments about
> some of the parts of this question, but I think one thing we should
> definitively say is that they should not be completely independent
> programs, that there has to be communication.
>
> DR. SANTANA: Donna.
>
> DR. PRZEPIORKA: I guess the question comes back down to this just says
> development plans, not specifically Phase I, so we may be talking
> about Phase II or Phase III, as well. In those situations, we had
> talked at previous meetings about some of the tumors are very much
> similar, but the pharmacokinetics are very different in adults and
> pediatric patients for cytotoxics, but I am not sure that is true for
> biologics. I mean even in adults, it is one dose fits all.
>
> So, if Susan has any additional information about whether you think a
> biologic like a monoclonal for Hodgkin\'s disease would be appropriate
> to have both adults and pediatric patients at the same time, why not.
>
> DR. BLANEY: I guess I don\'t personally have a lot of experience with
> monoclonals. I think, however, for the patients with Hodgkin\'s
> disease are usually adolescents and older patients, it is not just the
> younger patients.
>
> So, taking that into consideration, there could be cases when it would
> be feasible, you know, would be recommended to expedite the
> development of the agent for the population that could benefit from
> it.
>
> DR. SANTANA: Donna, I was thinking about some of the recent
> initiatives that I think COG has been involved with, for example, in
> melanoma, which is a rare pediatric condition, but certainly our adult
> colleagues have a lot more information than we could ever get to, but
> there are efforts of doing combined Phase III trials in that
> population of patients because it is likely that new drugs and new
> therapies will be developed along that line in pediatric patients, and
> unless patients participate in those combined Phase III studies.
>
> So, although the question was for early clinical development, I do
> agree with you that I think there is going to be an extension to some
> Phase III studies, because we have very few patients and the diseases
> are fairly similar although there may be issues of dosing of drugs
> that hopefully will get resolved with some Phase I studies that I
> think we would want to do those studies.
>
> Greg.
>
> DR. REAMAN: That collaboration actually goes far beyond just rare
> tumors, I mean even into some of the sarcomas, that the rare part of
> the equation is the patients that are actually being accrued to these
> trials, because they are adolescents and young adults, and they
> aren\'t going on pediatric studies or the adult studies, so there is a
> lot of collaboration.
>
> DR. FINKLESTEIN: There is experience. In acute promyelocytic leukemia,
> this is a multi-group approach, and I am sure Donna is aware of that,
> and we are now trying to collaborate with GOG for our young females
> who have gynecologic cancer.
>
> So, I think cooperative groups working together is not going to be a
> difficult task for us.
>
> DR. SANTANA: This issue of APL reminded me of something that I think
> Malcolm, hopefully, or Peter can help me understand a little bit
> better. So, the studies that were done for APL, they were studies that
> were done together, if I remember those, at least the Phase III study
> was done together, but the Phase I studies were separate, am I
> correct, and so there was a different dose that ultimately was used in
> kids versus adults in the Phase III? Can you clarify that for me?
>
> DR. SMITH: I think the Phase III study was done with the dose of
> 60/M^2^ for retinoic acid. Children were more susceptible to some of
> the CNS effects of retinoic acid than adults, and so there were more
> problems with pseudotumor cerebri, but I think when you got to the
> Phase III study, it was the same dose that was used.
>
> DR. GOOTENBERG: Just speaking from a biologic viewpoint, it has taken
> me a while to get into the conversation here, I wouldn\'t agree that
> one dose fits all. We have many examples, one of which I will share
> with you, where children are unique in terms of their PK with
> biologics also, and one dose hasn\'t fit the same adults and children.
>
> I think if you look back at the history, for example, of IL-11, a
> cytokine which was originally licensed and labeled and had a suggested
> dose range for children, and when the studies came out, four children
> showed an unanticipated DLT of papilledema, and they were unable to
> demonstrate any efficacy at a safe range in children. I think the
> label now has been changed basically to say that this should not be
> used in children. Adults are not just large children, children aren\'t
> just small adults.
>
> DR. SANTANA: I didn\'t want to make a strong statement. I just wanted
> to say something that goes along with development of retinoic acid and
> APL, and how ultimately it resulted in a Phase III study in which I
> think the same dose was used for both populations.
>
> Joachim.
>
> DR. BOOS: In Germany, we try to cooperate with the adult oncologists
> as close as possible, and I think in situations like myeloid
> leukemias, lymphomas, or others, it is reasonable that Phase II trials
> for adults are open for children, too, and children is a broad range
> of people, as you know, but normally, we then can include more the
> adolescents, and there is no reason not to do that.
>
> So, I fight with a lot of energy and a little bit frustrated against
> the standard exclusion criteria 18 years because there is no reason
> for an exclusion criteria of 18 years, no physiological, no
> biological, and no ethical reason.
>
> I think if there are exclusion criterias, a patient with a specific
> malignancy which might profit from the drug, too, are excluded. This
> should be an argument, should be written down in the protocol with a
> specific reason, not the other way around.
>
> DR. SANTANA: Leukemia, in a practical sense, sometimes it is
> institutionally based because of the population that you are treating.
> For example, at St. Jude, we may have studies that other people accept
> patients up to 25 and 30, but with our institution, we cannot enroll
> anybody over 18, because that is part of the administrative
> requirement of the institution.
>
> Having said that, I think your point is well taken, that sometimes the
> age cutoff in terms of 18 versus older, younger adults, that is
> misnomer, but is not based on real facts.
>
> Dave.
>
> DR. POPLACK: I just think we have to be cautious about this because
> even in circumstances where our current biological thinking suggests
> unanimity in terms of disease biology, we, with more information, may
> find out that unanimity was not correct, and I think we found that out
> with Philadelphia chromosome positivity that there are some
> differences, and as we start using BAC arrays to examine some of these
> translocations, we are finding more differences.
>
> I think that we just have to be very careful because we can make some
> false assumptions about efficacy and thinking that we are treating the
> same entity when we are not.
>
> DR. SANTANA: If you remember, we at least spent two meetings of this
> committee discussing issues related to that.
>
> Peter.
>
> DR. ADAMSON: Steve, I am going to take a stab at this question, and I
> agree, we have covered many of the issues, but if we focus the
> question on Phase I, there, in fact, are potential advantages to
> having a combined trial, and I think Frank Bayliss, I don\'t know if
> he has spoken about it in this committee, has presented some of the
> advantages.
>
> But if one were to design a trial where adults would start and they
> would escalate until they hit biologic activity, defined whatever
> definition one uses, and then the pediatrics would then start and
> basically would always be following the adults.
>
> The advantage of that trial design is, one, the pediatric study is
> going to get initiated, by definition, at an earlier stage, but
> moreover, I think the endpoint that we sometimes arrive to in
> pediatric trials or even when comparing adult trials, we end up at
> different endpoints because we have different definitions.
>
> So, we may end up at a different MTD, not because the drug behaves any
> differently in our population, but we have defined dose-limiting
> toxicity differently, be it myelosuppression for seven days versus
> three days versus ever, and if one does it in the context of the same
> trial, one avoids that.
>
> Furthermore, everyone has their own slant on a modified Fibonacci, and
> I have yet to see a pediatric Phase I trial where the dose levels were
> the same as the adults, so we almost never have the same Phase II
> dose, and it has nothing to do with how the drug behaves. It is simply
> who had the calculator and how did you round.
>
> From an efficiency standpoint, from comparison between pediatric and
> adult populations, there would, in fact, be distinct advantages to
> combined studies, again with the caveat that we had before, when do
> you start it, and you would have to build into that trial that, in
> essence, you have gotten to a biologic active dose. Then, in fact, you
> are able to move pediatrics to keep in tandem, in step with the
> adults, one dose level behind.
>
> We have yet to try that experiment, but I wouldn\'t exclude proposals
> when there was sufficient data as far as this is relevant for
> pediatric malignancies, this is a high priority, and we are going to
> have a trial design that basically streamlines the whole process. I
> don\'t know if it will ever happen, but I wouldn\'t exclude it.
>
> DR. SANTANA: Susan.
>
> DR. BLANEY: I just wanted to make one point. Sometimes they are
> developed abroad before they are developed in this country, and then
> the Phase I trials are done in the U.S.
>
> I think that we should be able to build on Phase I data from foreign
> sites, and not necessarily have to wait until the Phase I data from
> the sponsor is this country is available before initiating clinical
> trials here.
>
> DR. SANTANA: You are talking about specifically pediatric Phase I
> studies?
>
> DR. BLANEY: Correct. So, if there is data that is available from Japan
> or France or Germany, wherever, that we should be able to build on
> that data, and not necessarily wait, if our preclinical evidence is
> very promising for the agent on the toxicity profile and schedules
> that we want to support.
>
> DR. SANTANA: Malcolm.
>
> DR. SMITH: To respond to Peter\'s comments, one is, you know, our
> primary purpose again for starting a Phase I study is to finish it,
> and that is I think what we should focus on is does it help us finish
> the Phase I study and establish a Phase II dose more quickly.
>
> I agree that it would help us to compare adult and pediatric better,
> but that is not the primary purpose that we are doing the Phase I
> study.
>
> And the problems that were cited before, you pick one schedule, it is
> one of two or three or four different schedules, it may not be the
> right schedule, and if you wait a while, you could have the pick of
> which schedule looked like it was best from the toxicity viewpoint
> after Phase I.
>
> There is the risk when you do that, and the one time that it has been
> done that I can remember is with CTEC, and there, the pediatric study
> essentially started once there was biologic activity in the adult
> Phase I study.
>
> Subsequently, the adult Phase I study had a couple of patients have
> unexpected deaths from unresponsive hypotension. The pediatric study
> fortunately didn\'t escalate to those levels, the adult study was
> ahead, but obviously, that drug hasn\'t gone very far since then.
>
> So, you still run the risk when you start early and you don\'t have
> the full toxicity experience of studying a drug that, in fact, is
> going to be not studied any further because it is just too toxic or
> unsuitable for using in humans.
>
> DR. ADAMSON: Malcolm, I guess in most circumstances I would agree, but
> there is a false sense of security here, because pediatric trials, as
> you know, have often escalated beyond what adults have been exposed
> to.
>
> So, we have higher MTDs in many of our drugs, so we are willing, as a
> community, when it is warranted, to take the risks if we believe that
> those higher exposures may be associated with increased benefits.
>
> So, similarly, you know, the issue here is are you willing to take the
> risk to expose small cohorts of children when this drug may not, in
> fact, go on to be the drug. Well, we do that all the time, here, we
> would be doing it at an earlier stage. But, yes, I agree, I think in
> most circumstances, we are not going to be pursuing this strategy, but
> I wouldn\'t exclude it.
>
> DR. HIRSCHFELD: So, Mr. Chairman, if I might try to capture what I
> think we have heard. It seems that in all circumstances, there should
> not be independent pediatric and adult development programs.
>
> So we could then turn to our sponsors when they come in to us and
> they, say, have a new product they wish to develop or new agent that
> they wish to see if it turns into a product, we can say that we have
> brought the issue of having some coordination between the adult and
> the pediatric program to our advisory committee, and that they have
> endorsed the idea that there should be communication and coordination,
> but some relatedness between them.
>
> I will take advantage of having the chairman of the ODAC here at the
> table, who I also should compliment, has been a steadfast and
> continuous participant in all these committee meetings, has been
> contributing not just her presence, but her expertise and enthusiasm
> in raising very important questions.
>
> I would then ask Dr. Przepiorka in this same sense, is that something
> that you would be comfortable that we could communicate to sponsors
> that we have discussed having some linkage between adult and pediatric
> plans, and that they should consider one in the context of the other.
>
> DR. PRZEPIORKA: I would say yes, and as I think back over the meetings
> where the final question that you posed to the committee is should
> this company get a pediatric waiver, I don\'t think we have said yes
> to any of them.
>
> So, you may as well let them know way ahead of time that that is going
> to be a probability.
>
> DR. HIRSCHFELD: Thank you.
>
> DR. SANTANA: With that, I will address the last question although
> there was a consensus already emerging that the committee doesn\'t
> want to give any hard rule, but rather general comments regarding this
> issue of within what context would include a general recommendation
> regarding the timing of the initiation of pediatric oncology clinical
> studies in a drug development plan.
>
> To paraphrase, to try to give an answer to this, to paraphrase some of
> the things that Susan Blaney said earlier, I think things that you
> need to consider are the type of drug, is it a new drug, is it an
> analogue, is it a biologic, is it a cytotoxic, the mechanism of action
> of that drug I think would be important.
>
> The safety profile of that drug, I think, and when you know that
> safety information is important in you deciding when the timing of
> pediatric studies should be initiated. Then, ultimately, what is the
> pediatric indication going to be, what is the disease that ultimately
> is going to have a role in pediatric oncology.
>
> I think with those four general\--and other people can add further\--I
> think with those four general points, I think you can begin to develop
> a general kind of framework of when you would tell sponsors what they
> need in terms of initiation of pediatric studies.
>
> I think Skip wanted to comment or add.
>
> DR. NELSON: I would just add sufficient information whether
> preclinical or adult early clinical to choose an appropriate dose for
> that testing.
>
> DR. SANTANA: Does anybody have any other comments?
>
> DR. PELUSI: I don\'t want to lose what Dr. Poplack mentioned earlier
> was this new mind-set in terms of how we look at what we are doing in
> clinical trials as things develop.
>
> The question is, is how do we begin to get the message down to the
> community level especially in the underserved communities that we are,
> and probably will be, starting clinical activity even earlier in this
> process, because I think it is an education process not only for us,
> but for the communities, as well.
>
> So, I just wanted to throw that out, as well, because we are going to
> have to look at that and what kind of questions will arise in that
> community, as well.
>
> DR. SANTANA: Well, as Ruth alluded to earlier, I think there is a
> greater consciousness at least in the families of pediatric oncology
> patients, and I think they are always linking to each other, they are
> always searching and calling different places, so I think at least in
> the pediatric oncology community, a lot of that already happens.
>
> Now, obviously, the ultimate goal for each parent is whether their
> child has access to that particular drug that they want to get
> enrolled on, so I think that is a much different type of discussion
> because they are interested in finding new solutions to try to cure
> their kid.
>
> DR. PELUSI: And I think where I am coming from is being somebody in
> the adult world where unless you do have a child or unless you work in
> pediatrics, you really don\'t think about this.
>
> I think that if you are trying to garner support and trying to look at
> really reaching all levels and getting that kind of support that you
> may need if indeed regulatory changes come up, legislation, that type
> of stuff, is that you do want everybody to really start to think about
> this and how it will impact everything especially if we are starting
> to look at global access to clinical trials, I mean we really need to
> start that.
>
> DR. SANTANA: Susan.
>
> DR. WEINER: I want to make a follow-up comment to what Steve just said
> and what Dr. Przepiorka just said.
>
> If it is the case that it is the consensus that there needs to be a
> close collaboration of adult and pediatric direct development programs
> in the consideration of each new agent, I guess that really places an
> obligation on each constituency here to make sure that the best data
> are available to each of us, that is, that the parents have access to
> the best outcomes, that the companies have access to the best of what
> academia can offer including the preclinical network, that the
> pediatric oncology research and cooperative community also tries to
> work with companies to make sure that the operations are sufficient as
> possible.
>
> I think that for those drugs that get aborted along the way, that
> there will have to be novel solutions, novel private or nonprofit
> solutions that will try to make sure that drugs that really look as if
> they only have use in pediatrics will not fall away.
>
> DR. HIRSCHFELD: Could I say orphaned and not aborted along the way,
> and then they can be picked up and carried through?
>
> DR. SANTANA: Steve, do you have any final comments?
>
> DR. HIRSCHFELD: I would like then to summarize what I think I heard,
> and that is that pediatric oncology clinical studies should start no
> later than after the adult Phase I clinical studies are completed, and
> that there may be circumstances depending upon a variety of factors
> which we have elaborated on, where one might consider that there is a
> rationale for starting the pediatric clinical studies without having
> the adult Phase I data.
>
> Is that an appropriate summary?
>
> DR. SANTANA: Yes.
>
> Malcolm.
>
> DR. SMITH: The phrase \"should start no later,\" I can\'t say that. I
> think generally, should start at the end. I think there will be
> situations in which we will want to see all of the Phase II data
> before we are convinced that this is really something that is good for
> pediatrics.
>
> I think generally, you know, at the end of Phase I is a good time, but
> there are agents for which we are going to want to see more
> information before we are convinced that there is a sufficient body of
> evidence that this should be studied in children.
>
> If that is available at the end of Phase I, fine, but it may be that a
> larger body of evidence needs to be developed to convince Peter or
> Susan, and others that the drug should be studied in children.
>
> DR. SANTANA: Peter.
>
> DR. ADAMSON: Steve, I know you can only comment on clinical, but in
> the spirit of keeping the Agency smiling, I think it is fair to say
> that the new agents should be made available for preclinical study in
> pediatrics no later than when they enter Phase I in adults.
> Recommended.
>
> DR. HIRSCHFELD: Peter, I would like to say that I think we have been
> smiling from the first moment that we got the acceptances from
> everyone here that they were willing to participate, and we
> anticipated, and I think we have received, a very thorough and
> thoughtful discussion on this issue, and I think from where we started
> this morning until now, we have made I think an enormous amount of
> progress in clarifying important issues, not just related to this
> question of timing, but to other critical questions related to
> pediatric oncology.
>
> I thank every one of you and also think that we can all be very proud
> of what we have accomplished today, have accomplished in the past, and
> anticipate we will accomplish in the future.
>
> DR. SANTANA: My thanks also to all the participants for a very
> professional and very high quality discussion, and we will consider
> this meeting adjourned.
>
> DR. HIRSCHFELD: I am sorry, I want to announce the next meetings. We
> will go on a cycle to coordinate with the general pediatric
> committees, and our next meeting will be February 10th or 11th, 2003,
> and the meeting after that will be the second week of June 2003, and
> then there will be a meeting in October 2003, probably the third week,
> and we already have selected some themes and questions for the meeting
> in February, and as soon as we have those adequately refined, you will
> be hearing from us.
>
> \[Whereupon, at 3:50 p.m., the hearing concluded.\]