FOOD AND DRUG ADMINISTRATION














                       Wednesday, March, 17, 2004


                               8:00 a.m.




                           5630 Fishers Lane

                      First Floor Conference Room

                          Rockville, Maryland







         Donna Przepiorka, MD., Ph.D., Chair, ODAC

         Johanna Clifford, M.S., RN, BSN


         Pamela J. Haylock, RN,

           Consumer Representative, ODAC




         Victor Santana, M.D., Chair

         Peter Adamson, M.D.

         Alice Ettinger, M.S., RN

         Peter Houghton, Ph.D.

         Eric Kodish, M.D.

         C. Patrick Reynolds, M.D., Ph.D.

         Susan Weiner, Ph.D.

         Ruth Hoffman, Patient Representative

         Barry Anderson, M.D., Ph.D.

         Lee J. Helman, M.D.

         Malcolm Smith, M.D., Ph.D.

         Paul Meltzer, M.D.

         Chand Khanna, DVM, Ph.D., DACVIM

         Kenneth Hastings, Ph.D.



         Antonio Grillo-Lopez, M.D.,


      FDA STAFF:


         Susan Ellenberg, Ph.D.

         Steven Hirschfeld, M.D., Ph.D.

         Ramzi Dagher, M.D.

         Richard Pazdur, M.D.

         Patricia Keegan, M.D.

         Pat Dinndorf, M.D.

         Grant Williams, M.D.




                            C O N T E N T S




      Call to Order, Victor Santana, M.D., Chair                 5


      Introductions                                              5


      Conflict of Interest Statement,

         Johanna Clifford, M.S., RN, BSN                         7


      Safety Monitoring in Clinical Studies Enrolling

      Children with Cancer:


      Opening Remarks, Richard Pazdur, Director,

         Division of Oncology Drug Products, FDA                10


      Introduction of Issues and Agenda,

         Steven Hirschfeld, M.D., Ph.D., Office

         of Cellular and Gene Therapy, FDA                      11


      Protecting Children in Cancer Research: What Really

         Matters, Eric Kodish, M.D., Director, Rainbow

         Center for Pediatric Ethics                            23


      Legal Responsibilities for HHS Supported Studies,

         Michael Carome, M.D., Office for Human Research

         Protection, HHS                                        49


      Legal Responsibilities for Studies with FDA

         Regulated Products, Steven Hirschfeld, M.D.,

         Ph.D., Office of Cellular and Gene Therapy,

         CBER, FDA                                              61


      Enrollment and Monitoring Procedures for NCI Funded

         Studies, Barry Anderson, M.D., Ph.D., Cancer

         Treatment Evaluation Program, NCI                      70


      Open Public Hearing:

         Wayne Rakoff, Johnson & Johnson                        87


      Monitoring Procedures in a Private

         Children's Hospital,

         Victor Santana, M.D., St. Jude

           Children's Hospital                                  88


      Committee Discussion                                     116


      Questions for Discussion                                 154




                      C O N T E N T S (Continued)



      Use of Nonclinical Data to Complement Clinical Data

      for Pediatric Oncology:


      What are Microarrays and How Can They Help Us

         with Clinical Studies in Pediatric Oncology,

         Paul Meltzer, National Human Genome Research

         Institute, NIH                                        198


      Advantages and Limitations of Cell Culture Models

         in Pediatric Drug Developments,

         Peter Adamson, M.D., Children's Hospital

         of Philadelphia                                       210


      Human Cell-Animal Xenografts: The Current Status,

         Potential and Limits of Informing Us About

         Clinical Studies, Peter Houghton, Ph.D., St.

         Jude Children's Research Hospital                     229


      An Integrated and Comparative Approach to

         Preclinical/Clinical Drug Development,

         Chand Khanna, DVM, Ph.D.,

         Tumor and Metastasis Biology Section, NIH             248


      What Can be Learned About Safety,

         Kenneth Hastings, Ph.D., CDER, FDA                    263


      Assessing Anti-Tumor Activity in Nonclinical Models

         of Childhood Cancer, Malcolm Smith, M.D., Ph.D.,

         Treatment Evaluation Program, National Cancer

         Institutes, NIH                                       280


      Committee Discussion                                     294


      Questions for Discussion                                 306




  1                      P R O C E E D I N G S


  2                          Call to Order


  3             DR. SANTANA:  Good morning to everyone.  I


  4   know Dr. Kodish is on the line so good morning to


  5   you too, Eric.  I hope you can hear us well.


  6             DR. KODISH:  Good morning, Victor.


  7             DR. SANTANA:  This is a meeting of the


  8   Pediatric Oncology Subcommittee of the Oncology


  9   Drugs Advisory Committee and we are here today to


 10   advise the agency on two issues.  In the morning we


 11   will deal with the issue of safety monitoring in


 12   clinical studies enrolling pediatric oncology


 13   patients.  Then, in the afternoon we will address


 14   issues related to the use of nonclinical data to


 15   complement clinical data for proposed pediatric


 16   oncology studies.  So, we have quite a busy agenda


 17   and I think we will go ahead and get started with


 18   the introductions, and I am feeling so sorry for


 19   Dr. Anderson who is sitting all by himself over


 20   there, but we will go ahead and get started with


 21   him and then move around.


 22                          Introductions


 23             DR. ANDERSON:  Barry Anderson, from NCI


 24   CTEP.


 25             DR. GRILLO-LOPEZ:  Antonio Grillo-Lopez,




  1   Neoplastic and Autoimmune Diseases Disorders


  2   Research Institute.


  3             DR. WEINER:  I am Susan Weiner, from The


  4   Children's Cause, a patient advocate.


  5             MS. HOFFMAN:  Ruth Hoffman, patient


  6   advocate.


  7             DR. PRZEPIORKA:  Donna Przepiorka,


  8   University of Tennessee, Memphis.


  9             MS. CLIFFORD:  Johanna Clifford, executive


 10   secretary to this meeting.


 11             DR. SANTANA:  Victor Santana, pediatric


 12   oncologist at St. Jude Children's Research


 13   Hospital, Memphis, Tennessee.


 14             DR. REYNOLDS:  Dr. Reynolds, Children's


 15   Hospital of Los Angeles.


 16             MS. ETTINGER:  Alice Ettinger, pediatric


 17   nurse practitioner, St. Peter's University Hospital


 18   in New Jersey.


 19             DR. PAZDUR:  This is Susan Ellenberg, who


 20   has laryngitis.  She is a statistician.  I am


 21   Richard Pazdur.


 22             DR. HIRSCHFELD:  Steven Hirschfeld, FDA.


 23             DR. DINNDORF:  Patricia Dinndorf, FDA.


 24             DR. DAGHER:  Ramzi Dagher, FDA.


 25             DR. SANTANA:  Eric, will you go ahead and




  1   announce your name and affiliation for the record?


  2             DR. KODISH:  I am Eric Kodish, from


  3   Cleveland, Ohio, Rainbow Babies & Children's


  4   Hospital.


  5             DR. SANTANA:  Thank you, Eric.  With that,


  6   we will go ahead and have Ms. Clifford read us the


  7   conflict of interest statement.


  8                  Conflict of Interest Statement


  9             MS. CLIFFORD:  Thank you.  The following


 10   announcement addresses conflict of interest issues


 11   associated with this meeting and is made a part of


 12   the record to preclude even the appearance of such


 13   at this meeting.


 14             Based on the agenda, it has been


 15   determined that the topics of today's meeting are


 16   issues of broad applicability and there are no


 17   products being approved at this meeting.  Unlike


 18   issues before a committee in which a particular


 19   product is discussed, issues of broader


 20   applicability involve many industrial sponsors and


 21   academic institutions.


 22             All special government employees have been


 23   screened for their financial interests as they may


 24   apply to the general topics at hand.  To determine


 25   if any conflict of interest existed, the agency has




  1   reviewed the agenda and all relevant financial


  2   interests reported by the meeting participants.


  3   The Food and Drug Administration has granted


  4   general matters waivers to the special government


  5   employees participating in this meeting who require


  6   a waiver under Title 18, United States Code,


  7   Section 208.


  8             A copy of the waiver statements may be


  9   obtained by submitting a written request to the


 10   agency's Freedom of Information Office, Room 12A-30


 11   of the Parklawn Building.


 12             Because general topics impact so many


 13   entities, it is not prudent to recite all potential


 14   conflicts of interest as they apply to each member


 15   and consultant and guest speaker.  FDA acknowledges


 16   that there may be potential conflicts of interest


 17   but, because of the general nature of the


 18   discussion before the committee, these potential


 19   conflicts are mitigated.


 20             With respect to FDA's invited industry


 21   representative, we would like to disclose that Dr.


 22   Antonio Grillo-Lopez is participating in this


 23   meeting as an acting industry representative,


 24   acting on behalf of regulated industry.  Dr.


 25   Grillo-Lopez is employed by Neoplastic and




  1   Autoimmune Diseases Research.


  2             In the event that the discussions involve


  3   any other products or firms not already on the


  4   agenda for which FDA participants have a financial


  5   interest, the participants' involvement and their


  6   exclusion will be noted for the record.


  7             With respect to all other participants, we


  8   ask in the interest of fairness that they address


  9   any current or previous financial involvement with


 10   any firm whose product they may with to comment


 11   upon.  Thank you.


 12             DR. SANTANA:  Thanks, Johanna.  Anybody


 13   else sitting at the table that wants to disclose


 14   anything publicly?  No?  Dr. Adamson just joined


 15   the group.  Do you want to introduce yourself,


 16   Peter, please?


 17             DR. ADAMSON:  Peter Adamson, from


 18   Children's Hospital of Philadelphia.


 19             DR. SANTANA:  Thanks, Peter.  Peter, do


 20   you want to introduce yourself?


 21             DR. HOUGHTON:  Peter Houghton, St. Jude


 22   Children's Research Hospital.


 23             DR. SANTANA:  With that, I will pass it


 24   over to Dr. Pazdur for his opening remarks.


 25                         Opening Remarks




  1             DR. PAZDUR:  Well, I would like to


  2   disclose something publicly, my disappointment with


  3   Victor and Johanna for not mentioning this but the


  4   disclosure is happy St. Patrick's Day.


  5             [Laughter]


  6             As you can see, we in the government have


  7   provided you with green folders for the day and,


  8   obviously, I am dressed in green but I would like


  9   to remind you Pazdur is not an Irish name.  The


 10   other thing I would like to just emphasize is that


 11   Donna and I, as compatriots from Chicago's Polish


 12   community, would like to emphasize that St.


 13   Patrick's Day is just a warm-up for St. Joseph's


 14   Day.  Okay?


 15             [Laughter]


 16             DR. SANTANA:  Which is Friday, March 19th.


 17             DR. PAZDUR:  Thanks for pointing that out.


 18             In all seriousness, I would like to go


 19   back to why we are here today, and that is for the


 20   subcommittee to discuss two important areas today,


 21   one in the morning discussing safety monitoring in


 22   clinical studies enrolling children with cancer and


 23   then, in the afternoon, discussing nonclinical data


 24   to complement clinical data for pediatric oncology.


 25             We look at these as very important




  1   thematic discussions to have.  How these areas


  2   impact on oncology drug development I think is very


  3   important.  One thing that I would ask the


  4   committee to do specifically is to concentrate


  5   really on the pediatric aspect of these.  I know


  6   that these areas have some tentacles to adult


  7   oncology and to other areas of oncology but I would


  8   like to remind you that the purpose of this


  9   subcommittee is to focus on the pediatric


 10   specificity of these issues and special


 11   considerations of these broad issues in pediatric


 12   oncology.


 13             I would like to thank everyone for being


 14   here.  I asked Steve what number meeting this is


 15   and we think it is the eighth.  We may be wrong but


 16   we are happy that the committee is meeting on a


 17   regular basis.  We intend to have the committee


 18   meet on a regular basis here and to continue this


 19   dialogue with the community.  So, Steve, I will


 20   turn it over to you.


 21                Introduction of Issues and Agenda


 22             DR. HIRSCHFELD:  Thank you.  It is


 23   customary at the end of remarks to give the


 24   acknowledgments but I wanted to give two


 25   acknowledgments initially.  The first one is to




  1   someone who is in the room right now and I am


  2   looking at her, and that is Johanna Clifford who


  3   has done I think a marvelous job in helping to


  4   organize this meeting, and we have had a number of


  5   challenges to overcome along the way, so many


  6   challenges that for a period of time we thought we


  7   were working under a curse, but Johanna has been


  8   steadfast, good humored, competent, rapid in her


  9   responses and has been I think a driving force in


 10   terms of having the meeting occur as it is and as


 11   well organized as it is today.  So, thank you,


 12   Johanna.


 13             I would also like to acknowledge someone


 14   who is in this room, although not physically, but


 15   someone who has had enormous influence on our


 16   thinking and on our policies toward patients


 17   enrollment in studies and in particular children


 18   enrolling in studies, and that is Bonnie Lee who


 19   has been with the FDA for many years and was


 20   associated with the initial hearings of the


 21   committee, which was mandated by Congress in the


 22   1970s, to examine the role of children in clinical


 23   research.  Bonnie has been a particular guide and


 24   inspiration for me and also a source of information


 25   and direction, which I think has been an asset not




  1   only to the agency but to the country and to all


  2   patients.  And, I wanted to dedicate the discussion


  3   this morning in her honor.  So, thank you, Bonnie.


  4             As Dr. Pazdur pointed out, we are going to


  5   be discussing the themes of safety and


  6   extrapolation.  Clinical research, which we have


  7   discussed in some detail in this forum over several


  8   of the meetings, has been recorded for at least


  9   2,400 years.  Children were often the first


 10   patients for new procedures and interventions.


 11   Part of this evolved from the concept that children


 12   were the property of parents so it was rather easy


 13   for parents to donate their children for whatever


 14   questions might be asked.  But along the way there


 15   were some founding principles because,


 16   unfortunately, children have also been the victims


 17   of clinical research.


 18             The founding principles of modern Food and


 19   Drug Administration regulation were, in large part,


 20   established for the purpose of protecting children


 21   and, yet, pediatric therapeutic development has


 22   never been as thorough and robust as adult


 23   therapeutic development, and most of the people in


 24   this room have been part of that process and


 25   witness to these inequities.  Many therapies are




  1   administered to children without adequate studies


  2   and, furthermore, many therapies are not made


  3   available for pediatric study until after adult


  4   marketing studies are completed and this is


  5   particularly true in oncology.  So, we have been


  6   working to overcome some of these barriers and


  7   challenges.  And, the challenges are to assemble


  8   sufficient data to establish efficacy and safety in


  9   the relevant population.  The relevant population


 10   may be sufficiently rare that confirmatory studies


 11   are not feasible, which is particularly the case


 12   for many of the childhood malignancies.


 13             There are concerns regarding the


 14   implications of adverse events in children and this


 15   has been a barrier to the further clinical


 16   development of some products because of these


 17   concerns.  It is also important that there is the


 18   establishment and maintenance of a framework that


 19   would support systematic clinical investigations


 20   for the relevant population.  This has been the


 21   case historically in pediatric oncology but that


 22   framework has always been challenged and is always


 23   competing with other priorities.  So, it is


 24   incumbent on us to make sure that that pediatric


 25   research framework has the best resources, and the




  1   best advice, and the best support, and the best


  2   regulatory environment to do its job.


  3             The particular issues regarding the safety


  4   monitoring in pediatric oncology clinical


  5   investigations are an acknowledgment that children


  6   require special protections.  Yet, on the other


  7   hand, there is also an acknowledgment that risk


  8   tolerance is higher in oncology therapeutics than


  9   in other therapeutic areas.  This sets up a


 10   potential tension.  Furthermore, there are no


 11   detailed consensus standards on study monitoring


 12   despite numerous international documents describing


 13   what could be termed good clinical practice.  We


 14   will examine those in some detail during the course


 15   of the morning.  So, the charge to the committee is


 16   to suggest ways to incorporate the fundamental


 17   ethical and scientific principles in protecting


 18   patients enrolled in clinical studies for pediatric


 19   malignancies while providing clear guidance and


 20   minimizing the resource burden.


 21             We have a series of questions directed


 22   toward the committee to help focus the discussion.


 23   These are questions which are meant to stimulate


 24   what we hope will be an informative exchange and do


 25   not have a yes/no or a definitive answer.




  1             The first questions revolves around the


  2   principles, what are the principles that should be


  3   addressed in safety monitoring of clinical studies


  4   that enroll children with cancer?  Dr. Kodish is


  5   going to provide us with some background on that


  6   particular topic.  If the principles are adequately


  7   stated in existing documents. statutes or


  8   regulations, please identify the relevant documents


  9   and sections.


 10             The second set of questions deals with the


 11   practice.  Recognizing that particular populations,


 12   disease settings and products may have specific


 13   requirements, what general parameters should be


 14   monitored for safety in all clinical studies?  Or,


 15   to rephrase that, what should the default position


 16   be for safety monitoring?


 17             Based on the response to the previous


 18   question, how often should these parameters be


 19   monitored?  Again, just giving a framework or


 20   guidelines.


 21             Based on the responses to the previous


 22   questions, who should do the monitoring?  Is it


 23   adequate to have the personnel involved in the


 24   study be responsible for safety monitoring?  When


 25   we discuss this in detail we may parse this out




  1   into the type of study, whether it is early


  2   development or later development or the type of


  3   disease or other risk factors.


  4             What circumstances would benefit from a


  5   data monitoring committee?  And, are there


  6   additional recommendations for safety monitoring?


  7             The afternoon will be devoted to a


  8   question which can be traced back to the principle


  9   of extrapolation.  Extrapolation has been a topic


 10   of interest within the Food and Drug Administration


 11   for many years.  In recent years there has been an


 12   FDA working group on pediatric extrapolation that


 13   has identified four domains that may provide a


 14   basis for extrapolation of adult data to the


 15   pediatric population.  These are nonclinical data,


 16   pathophysiology, natural history of the disease or


 17   condition, and response to therapy.


 18             When our group, noted at the bottom of the


 19   slide and some of the members are present here in


 20   the audience, asked ourselves the question how can


 21   we use nonclinical data to inform us about


 22   pediatric clinical studies, and in particular


 23   pediatric studies in clinical oncology, we realized


 24   we needed further background and further discussion


 25   before we could have an informed approach to it.




  1             We recognize that the absence of


  2   predictive or explanatory nonclinical models in


  3   pediatric oncology is today's status quo.  We know


  4   that safety prediction based on animal studies is


  5   estimated at approximately 65-70 percent for


  6   cytotoxic compounds and it is unknown for other


  7   classes of compounds, particularly the new biologic


  8   therapies, gene therapies, immunotherapy, and


  9   cellular-based therapies.  Efficacy prediction is


 10   unknown but low at best.  The findings in clinical


 11   studies, particularly negative studies, often


 12   remain unexplained.


 13             Therefore, further clinical studies that


 14   entail resources and risks are undertaken to


 15   further the field, and we are posing the paradigm


 16   is there a mechanism by which we can use


 17   nonclinical data to inform us and improve the


 18   clinical research in pediatric oncology.  There are


 19   potential advantages of using the nonclinical data:


 20   a lesser resource burden; the ability to answer


 21   questions not amenable to available clinical


 22   techniques.  There might be ethical or, in fact,


 23   legal considerations involved too; possibly a


 24   faster time frame to generate data; a dynamic


 25   interaction between clinical and nonclinical




  1   findings that can enhance understanding and


  2   confidence in results.  When we only have a


  3   sufficient population to do one definitive study,


  4   and that study takes three to five years and it is


  5   not feasible to do a confirmatory study, having


  6   confidence in those results is critical.  The


  7   avoidance of non-informative and minimization of


  8   negative outcome studies could be another outgrowth


  9   and an opportunity for new study designs.


 10             So, the charge to the committee for this


 11   afternoon is to provide advice on what types of


 12   nonclinical data are considered informative to


 13   complement or supplement clinical results.  What


 14   should the characteristics or properties of


 15   nonclinical models and data be to effectively add


 16   to the clinical results?


 17             If there are no satisfactory models that


 18   exist currently, and we will hear some discussion


 19   on approaches, what characteristics should a


 20   nonclinical model have to confirm, extend or


 21   substitute for clinical results?


 22             Lastly, is there a set of postulates that


 23   can be identified, or should a set be developed to


 24   help us make the transition for data extrapolation?


 25   So, the questions we are asking are what types of




  1   questions that are of potential clinical relevance


  2   but are not feasible or acceptable to answer in a


  3   clinical study could be addressed by nonclinical


  4   studies.


  5             Examples may include the need for repeated


  6   tissue sampling, always a contentious issue,


  7   particularly in children; the assessment of


  8   long-term effects of treatment; effects on


  9   reproduction; access to critical anatomic


 10   structures, and this is a consideration again


 11   particularly for some of the pediatric brain


 12   tumors; exposure to toxic reagents; evaluation of


 13   non-monitorable or irreversible toxicities;


 14   identification of biomarkers for clinical


 15   monitoring; and many others which I am sure will


 16   come up when we have our learned and motivated


 17   panel discuss the issue.


 18             What type of evidence and data would be


 19   recommended in each of the following domains to


 20   allow extrapolation from nonclinical data and be


 21   informative for a clinical condition?  There are


 22   listed here a few but there may be others.  These


 23   include, but are not limited to pharmacology and


 24   pharmacokinetics, safety, efficacy, behavior,


 25   long-term effects, developmental aspects and others




  1   which I am sure will come up.


  2             Are there additional recommendations for


  3   the effective use of nonclinical data?  For


  4   example, will open literature reports be generally


  5   acceptable?  Is documentation of compliance with


  6   Good Laboratory Practice necessary to evaluate


  7   animal data?  Should nonclinical data be submitted


  8   as an independent report with a presentation of


  9   primary data sufficient for verification and


 10   review?  These are all practical questions and we


 11   are looking for specific advice.


 12             So, with this charge and these questions


 13   before you, I would like to thank all the committee


 14   members and our speakers and guests, and everyone


 15   who has shown an interest here for participating in


 16   this discussion, and I will turn now the further


 17   presentation over to Dr. Eric Kodish, who will


 18   discuss the fundamental principles involved in


 19   clinical research and some of the issues of


 20   enrolling children.


 21             Dr. Santana, I think perhaps before we


 22   have Dr. Kodish speak--we have some more members of


 23   the panel that should be introduced.


 24             DR. SANTANA:  Yes.  Anybody that joined us


 25   a little bit late, could you please identify




  1   yourself into the microphone by name and


  2   affiliation, and any potential conflicts that may


  3   have arisen since we started?


  4             MS. HAYLOCK:  I am Pam Haylock.  I am an


  5   oncology nurse and I am at the University of Texas


  6   Medical Branch, in Galveston.


  7             DR. SMITH:  I am Malcolm Smith, pediatric


  8   oncologist at the Cancer Therapy Evaluation


  9   Program, NCI.


 10             DR. SANTANA:  Dr. Grillo, you had your


 11   hand up?


 12             DR. GRILLO-LOPEZ:  Yes, a point of


 13   clarification that I would like to propose to Dr.


 14   Hirschfeld.  On his first slide on the charge to


 15   the committee, which addresses the morning session,


 16   you used the phrase "providing clear guidance and


 17   minimizing the resource burden" which clearly


 18   applies to human resources and financial resources


 19   but perhaps doesn't quite stress time.  I would


 20   suggest that part of your charge to the committee


 21   should be that whatever recommendations we propose,


 22   and however the FDA understands and decides to


 23   apply those recommendations, should not affect the


 24   time lines for cancer drug development which today


 25   are already intolerably long, and we should be




  1   concerned that the cancer patient in general should


  2   not be subject to those too long time lines and


  3   that anything we do should, in fact, try to reduce


  4   the time lines for approval of new therapies.


  5             DR. HIRSCHFELD:  Thank you for your


  6   comments, Dr. Grillo-Lopez.  I think you touched on


  7   one of the themes which is implied.  I personally


  8   have always incorporated in the concept resource of


  9   time because time is, in fact, probably the most


 10   precious resource and, if one looks at biology as a


 11   broad spectrum, time is something which evolution


 12   and biologic processes look to, to conserve in many


 13   ways too.  So, I thank you for calling attention to


 14   the issue of time, and it is incorporated in that


 15   specific charge.


 16             DR. SANTANA:  One of the philosophic


 17   principles of stewardship is that it involves time,


 18   people and money resources.  So, I think those are


 19   all encompassed in your comments.


 20             With that, Eric, are you on line now?  Can


 21   we proceed with you?


 22             DR. KODISH:  I am on line, Victor.


 23             DR. SANTANA:  Good.  Go ahead, Eric.


 24             Protecting Children in Cancer Research:


 25                       What Really Matters




  1             DR. KODISH:  Good morning.  It is good to


  2   be with you virtually, if not physically.  I


  3   apologize for the inability to get to Washington.


  4   We have, hopefully, completed our last big


  5   snowstorm of the winter in Cleveland.


  6             I am going to be speaking this morning


  7   over the telephone and looking at a Webcast of the


  8   slides and this is a work in progress so, please,


  9   interrupt me if it is not going well and I will


 10   switch to my Power Point presentation. I am looking


 11   at the Webcast now and I don't see my Power Point


 12   slides yet.  What I plan to do is ask Johanna to


 13   put on the next slide before I move through them.


 14   So, let's give it a moment for me to see the first


 15   slide.


 16             I can introduce the talk by saying that I


 17   have always thought I had a face for radio and this


 18   is an example of that perhaps--


 19             [Laughter]


 20              I see my first slide.  the title of this


 21   presentation is "Protecting Children in Cancer


 22   Research: What Really Matters."


 23             Can I ask that we have the next slide,


 24   please?


 25             MS. CLIFFORD:  You know what, Dr. Kodish,




  1   if you just want to move on through your


  2   presentation--


  3             DR. KODISH:  I have it now.  Should I go


  4   to the Power Point instead?


  5             MS. CLIFFORD:  Yes, that would be great.


  6             DR. KODISH:  All right, the Webcast didn't


  7   work well and I will look forward to joining you on


  8   the Webcast after I have done my talk.


  9             MS. CLIFFORD:  Okay, there just seems to


 10   be a delay.


 11             DR. KODISH:  I figured that might happen.


 12   The Belmont report I think articulates the key


 13   principles of research involving human subjects.


 14   My purpose today is to respond to the charge that


 15   has been given to the committee and to paint in


 16   broad strokes what the key principles are for


 17   protection of children involved in cancer research.


 18   I think it starts with the Belmont report and the


 19   three key principles that are articulated there are


 20   beneficence, respect for persons and justice.


 21             The next slide, please.  This slide shows


 22   a concept of principles that move into practice.  I


 23   thought it was quite appropriate that the charge


 24   for the first half of the meeting talked about both


 25   principles and practice.  I view the regulations




  1   and their interpretation as a conduit, as a


  2   mechanism by which we move from principles to


  3   practice.  I want to emphasize the word


  4   "interpretation" here.  I think that the current


  5   set of regulations is subject to wide


  6   interpretation, as has been pointed out over and


  7   over again in the literature.  I don't view this as


  8   a negative.  I think that it allows for thoughtful


  9   IRBs, investigators, parents and others involved in


 10   the research process to move from principles to


 11   practice in an appropriate manner, and that


 12   interpretation is really the key step.


 13             The next slide, please.  This slide should


 14   show a triangle which points out that we are


 15   talking today about pediatric research ethics and


 16   that this is a more complicated system because of


 17   the involvement of a child.  The geometry of


 18   pediatric research ethics involves parents, on your


 19   lower left; the investigator, on your lower right;


 20   and the child at the top of the triangle.  If we


 21   keep the best interests of the child in mind at all


 22   points, I think we will be responding to perhaps


 23   the most fundamental issue in research involving


 24   children.


 25             The next slide, please.  This slide shows




  1   a recapitulation of the Belmont principles with an


  2   emphasis on beneficence in pediatric ethics.


  3   Respect for persons and justice remain important in


  4   pediatric ethics but it is my feeling that there is


  5   a special place for beneficence when we are talking


  6   about children, whether it is research involving


  7   children or in clinical ethics regarding children.


  8   In fact, more broadly in social policy regarding


  9   children it is important to remember that children


 10   are not able to vote; don't have economic


 11   resources; and we owe an advocacy role I think on


 12   behalf of children.  It is very important and, to


 13   me, prioritizes that beneficence as a concept for


 14   pediatric ethics.


 15             Can I have the next slide, please?  The


 16   principles of medical ethics then are different for


 17   children compared with adults.  I would say that


 18   respect for persons, for good or for bad, has


 19   become the dominant principle for adult ethics and


 20   this is seen in research ethics where there is a


 21   tremendous emphasis on informed consent, and this


 22   is out of the derivative concept of autonomy which


 23   comes from that principle of respect for persons.


 24   By contrast, as I said, I think the best interest


 25   of children has to dominate pediatric ethics and




  1   justifies an population that takes beneficence as


  2   the most important principles.


  3             I don't want you to move slides back but,


  4   if you recall a few slides ago, the slide that


  5   shows moving principles into practice, I think


  6   beneficence has to be the principle that drives our


  7   interpretation of the regulations and our actual


  8   practices.


  9             The next slide, please.  This slide


 10   dissects out some text from the Belmont report.


 11   The document itself talks about beneficence as an


 12   obligation with two general rules.  These are very


 13   interesting.  It had been sometime since I have


 14   looked at them and in preparing for this


 15   presentation I found the two general rules cited by


 16   Belmont are do not harm and, secondly, maximize


 17   possible benefits and minimize possible harms.


 18             On the face of it, these two general rules


 19   can be read as conflicting with one another.  That


 20   is, the charge do not harm is an absolute standard,


 21   whereas in the second rule of minimizing possible


 22   harms and maximizing possible benefits it is a


 23   relative standard and it calls for a weighing of


 24   benefit against harm.  Again, to put interpretation


 25   into play, I think it is the second rule that is




  1   most appropriate for pediatric oncology studies.


  2   That is to say, if one is talking about research


  3   involving healthy children with no prospect of


  4   benefit to that child, the first rule might be more


  5   appropriate to apply, do not harm, period.  But we


  6   are talking about a balance in pediatric oncology


  7   and I think the second general rule is more


  8   appropriate.


  9             Can I have the next slide, please?  If we


 10   are on the same page, this slide should continue to


 11   cite the Belmont report which says that beneficence


 12   is not always so unambiguous and goes on to say


 13   that prohibiting research that presents more than


 14   minimal risk without the immediate prospect of


 15   direct benefit to the children involved limits


 16   potential for great benefit to children in the


 17   future.


 18             This became, in some sense, the foundation


 19   for the different categories of research in subpart


 20   D that IRBs are able to approve and points out the


 21   key ethical dilemma, as far as I am concerned,


 22   which has to do with how we weigh benefits or which


 23   benefits count when we are weighing risk and


 24   benefit.


 25             The next slide, please.  The subtitle of




  1   my talk today is "What Really Matters" and as I


  2   thought about a way of presenting this I decided


  3   that it could be divided in three phases, what


  4   matters before a clinical trial begins; what


  5   matters during the conduct of the trial; and what


  6   matters after a trial has closed.


  7             One of the members of the panel pointed


  8   out the importance of time prior to the beginning


  9   of my talk, and I guess this is another way of


 10   looking at time as a divider for where the


 11   different ethical obligations come in.


 12             Speaking of time, I wanted to get some


 13   validation from Johanna.  Is the timing going


 14   better now with the slides?


 15             MS. CLIFFORD:  It is fine, Dr. Kodish.


 16             DR. KODISH:  Going fine?  Great!  So, I


 17   would like to now talk about what matters before a


 18   trial begins and I could think of at least three


 19   important issues.  The first is that it be


 20   significant science.  Again, interpretation is a


 21   key here.  My view of significant science is that


 22   it has the potential to help children with cancer.


 23   I think it is important that I am very specific


 24   about that.  I think that if there are going to be


 25   exposures of risk to children with cancer the




  1   potential to help children with cystic fibrosis,


  2   for example, may not be considered significant


  3   science by this test.  The potential to help adults


  4   with Alzheimer's disease may not be significant


  5   science by this test.


  6             I think that we need to be cognizant of


  7   the fact that research involving children with


  8   cancer needs to resound back to help children with


  9   cancer and that one should look for other avenues


 10   to study other important diseases.  It is difficult


 11   to think of children with cancer as a resource, but


 12   I think in some sense this really forces us to do


 13   that and, by limiting the risk of exposure to


 14   children to that which will come back to help


 15   children--and I know that scientifically it is


 16   often very difficult to predict in which direction


 17   the work will go and how the results will, in fact,


 18   play--ut but at the outset one can try to predict


 19   and think about a definition of significant as


 20   being that which has the potential to help children


 21   with cancer.


 22             The second thing that really matters


 23   before a clinical trial begins is a risk/benefit


 24   assessment.  I think in the next several slides I


 25   will talk more about what counts as risk and what




  1   counts as benefit.


  2             Finally, it is a study design that will


  3   answer the question and that also does not


  4   subjugate the interests of any single subject to


  5   the overall needs of the research.  Again, embedded


  6   there are a couple of important ethical principles


  7   that I think are perhaps specific--at least the


  8   second one under study design--specific to research


  9   with a vulnerable population and, as Dr. Hirschfeld


 10   said, children certainly are considered and should


 11   be considered.


 12             The next slide, please.  This slide shows


 13   the criteria for the 405 category.  As I think


 14   everybody is aware, there are four categories of


 15   research that can be approved by IRBs under subpart


 16   D.  Almost all cancer research I think is approved


 17   under 405, that is, pediatric cancer research.  It


 18   is research that involves more than minimal risk


 19   but presents the prospect of direct benefit to the


 20   individual subject if the risk is justified by the


 21   anticipated benefit to the subject; if the


 22   risk/benefit ratio is less than or equal to the


 23   alternatives; and if parental permission and assent


 24   are obtained.


 25             The next slide, please.  As we weigh risk




  1   and benefit in research ethics, it is important to


  2   remember that risk means risk to the subject but


  3   benefit may include benefits to the subject,


  4   benefits to other patients, benefits to society or


  5   benefits to an investigator or a sponsor.  I think


  6   what we are aiming for in research involving


  7   children in some sense is limiting the benefits


  8   that we think about in a risk/benefit analysis so


  9   that the benefits that come to the subject are the


 10   ones that we are thinking about as we weigh risk to


 11   the subject, and that we avoid a situation where


 12   children are used as a means to an end.  To go back


 13   to Emmanuel Kant and the idea that children are


 14   valued and protected, I think it is inherent in


 15   this sort of balancing.


 16             The next slide, please.  This is a slide


 17   that looks at some of the issues in early drug


 18   development involving children with cancer.  There


 19   has been a controversy over, what I have put in


 20   quotes here, therapeutic intent.  The point here is


 21   that the prospect of direct benefit is the key


 22   ethical and regulatory issue and, in my view, a


 23   percentage view of what that potential for


 24   therapeutic intent might be isn't that important.


 25   That is, I think even a very low chance of




  1   therapeutic benefit for the child should count as a


  2   prospect of direct benefit to the child.  Again, my


  3   interpretation of the word prospect is a very broad


  4   one, admittedly, but this is where the issue of


  5   interpretation comes in.  As the discussion goes


  6   on, we can talk about how prospect ought to be


  7   interpreted.


  8             The second bullet point you see on this


  9   slide has, in parentheses, the potential for 405


 10   creep, that is, moving this issue of commensurate


 11   experience that children with cancer have already


 12   been through a lot so that it is okay to put them


 13   through one more thing.  This doesn't stand up in


 14   my view as a valid justification for exposing


 15   children with cancer to risk.


 16             The alternatives is another key issue that


 17   is discussed, if you recall, in the 405 criteria.


 18   There needs to be favorable outcome for the child


 19   compared to the alternatives.


 20             The next slide, please.  If we are on the


 21   same page, this should be a slide that says options


 22   on top.  It has at least three different pathways


 23   that families and children can seek out when a


 24   child has refractory, untreatable cancer.  On your


 25   left is a Phase I study; in the middle is




  1   alternative medicine and on the right is hospice


  2   philosophy care.


  3             The next slide shows further


  4   considerations regarding Phase I oncology research


  5   in children.  The first is to point out that


  6   subject selection is not a major controversy in


  7   this realm, that is to say, Phase I studies are


  8   done involving healthy children but it is not an


  9   issue of wanting to do Phase I cancer research on


 10   healthy children.  That, to my knowledge, is not a


 11   controversy but I put it here because it is


 12   important to try to contextualize pediatric cancer


 13   research in the broader picture of research


 14   involving children.  As I said before, I think that


 15   Phase I research qualifies, in my mind, as research


 16   with the prospect or direct benefit.


 17             Most importantly on this slide, is that


 18   potential for benefit mitigates but does not


 19   eliminate the need for protection from research


 20   risk.  To be more clear about that, it is the


 21   potential for benefit that is balanced against the


 22   risk that mitigates it, but I think the charge to


 23   the committee and the work we are going to do this


 24   morning is still extremely important.  The need for


 25   protection from research risk is not eliminated by




  1   the potential for benefit.


  2             The next slide, please.  This points out


  3   some issues around alternative medicine.  The


  4   reason that I put this here is that I think there


  5   is a yardstick of fairness that we need to keep in


  6   mind.  It is often the case that when research is


  7   being done it is held to a higher standard or a


  8   different standard than what is happening in the


  9   non-research world, and it is very important I


 10   think to the families and the children involved


 11   that we try to put this in the lens that they are


 12   viewing this off from, and to make it difficult to


 13   access research or to have children participate in


 14   well-designed, safely monitored research, in some


 15   ways, runs the risk of shunting them to alternative


 16   medicine where there are vulnerability concerns.


 17   It is very prevalent phenomena for children with


 18   refractory cancer.  I think there are major ethical


 19   differences when it comes to children getting


 20   alternative therapy compared to adults who can make


 21   their own decision.  I think we have a very


 22   important obligation to prevent harm when it comes


 23   to children who are getting alternative medicine,


 24   and I think it is extremely important that


 25   alternative medicine possibilities be studied in a




  1   rigorous and careful way.  But the bottom line is


  2   that we need to communicate with families and


  3   children.  The ones that the research community


  4   encounters may also be taking alternative medicine


  5   and if we don't know what medications are being


  6   taken, then we won't have the ability to study drug


  7   interaction with alternative medications and the


  8   experimental agent, for example.  I just think that


  9   it is very important that we keep alternative


 10   medicine in mind as something that is out there and


 11   we shouldn't be blind to it.


 12             The next slide, please.  This slide has a


 13   few words about hospice care for children who have


 14   refractory disease.  Now, some people I think have


 15   the experience that those who come to Phase I


 16   studies are self-referred, not interested in


 17   hospice philosophy care, wanting to continue to


 18   pursue anti-neoplastic therapy but, in my


 19   experience, that is not the case.  In fact, many


 20   families who seek Phase I studies also are amenable


 21   to having their child get hospice philosophy care.


 22   So, the two are not incompatible.  I think it is an


 23   under-developed approach in children.  It is not


 24   the main focus of what we are here about today but


 25   I felt that it would be incomplete to give this




  1   talk without mentioning that hospice philosophy


  2   care should be part of the consent process for


  3   Phase I studies.


  4             The next slide, please.  This moves from


  5   what really matters before the conduct of the trial


  6   to during the conduct of the trial.  The three


  7   items that really matter during the conduct of the


  8   trial are informed consent which, in my view, is a


  9   communication process in addition to the


 10   documentation that happens; ongoing monitoring via


 11   a data safety monitoring board, if appropriate, and


 12   I understand that much of the discussion later on


 13   will have to do with when it is appropriate and


 14   when it is not necessary; and ethical action to


 15   suspend or stop a study at the right time.  It is


 16   easier said than done but in parentheses I thought


 17   I would say not too soon but not too late either.


 18   So, the question of when a study should be


 19   suspended or stopped is a key ethical question that


 20   happens during the conduct of a study and whether a


 21   study needs to be stopped at all.  I guess in most


 22   cases there is no need to stop it but that question


 23   needs to be always asked in the same way house


 24   officers always need to ask themselves does this


 25   child need a spinal tap.  It is a question that is




  1   part of the monitoring process as an embedded


  2   function.


  3             The next slide shows the Nuremberg code.


  4   This is a quick bit about informed consent.  The


  5   Nuremberg code said that the voluntary consent of


  6   the human subject is absolutely essential.  These


  7   are slides that I have shown at previous meetings


  8   so I think we can go fairly quickly through them.


  9             The next slide asks the rhetorical


 10   question of whether we can do any pediatric


 11   research at all, and just points out that if the


 12   answer is no, that is, if we have to adhere to


 13   strict interpretation of the Nuremberg or literal


 14   rather than in the spirit of the law


 15   interpretation, children as a group will suffer.


 16   You saw in the Belmont quotation earlier that there


 17   is a clear recognition that there needs to be some


 18   research involving children so that we can both


 19   protect children adequately but be sure that we


 20   make progress in childhood disease.


 21             The next slide talks about three ways of


 22   respecting Nuremberg and still doing pediatric


 23   research by using parents as surrogates and


 24   obtaining parental permission; by involving


 25   children when appropriate and obtaining their




  1   assent; and by providing societal protection with


  2   IRB approval as the most obvious but also meetings,


  3   similar to what we are doing this morning,


  4   investigator integrity and other things that


  5   provide societal protection for children, we can, I


  6   think, ethically do pediatric research.


  7             The next slide shows the difference


  8   between parental permission and informed consent


  9   and, again, says that the autonomous authorization


 10   of an adult--the difference between adult and


 11   pediatric ethics is more robust than a proxy


 12   decision and points out, from the Academy of


 13   Pediatrics, that the responsibilities of a


 14   pediatrician to his or her patient exist


 15   independent of parental desires or proxy consent.


 16   I think that there is a congruent statement that


 17   one could make here that says that an


 18   investigator's responsibility to his or her subject


 19   exists independent of parental desires or proxy


 20   consent.


 21             The next slide shows that parental


 22   permission is not the oral equivalent of informed


 23   consent, and that surrogate decision-making is


 24   necessarily less authentic.  I am going to skip


 25   past the next slide which shows proxy consent,




  1   substituted judgment and best interests, because I


  2   think this is familiar ground for most people and


  3   we have already emphasized best interests.


  4             I will go to a slide that says informed


  5   consent in pediatrics equals parental permission


  6   and the assent of the child.  Here I want to say


  7   that the combination of those two can potentially


  8   be more powerful, if done right, than an


  9   individual.  This has to do with family centered


 10   ethics that really seek to care for and do


 11   effective communication with a family, which is a


 12   dynamic and challenging process, admittedly.  But I


 13   think both of these issues are very important.


 14             The next slide, please.  This provides the


 15   regulatory definition of assent, which is a child's


 16   affirmative agreement to participate in research.


 17   The key point here is that mere failure to object


 18   should not be construed as assent.  That is, the


 19   silence of an older child for research


 20   participation can't be interpreted as their assent.


 21   Again, there is room for regulatory interpretation


 22   here.  There is a great deal of controversy around


 23   assent and requirements for assent, and I think


 24   there is likely to be a fair amount of variability


 25   across IRBs with regard to this issue and I would




  1   be happy to discuss this further during our


  2   discussion.


  3             The next slide, please.  This slide shows


  4   some differences between assent in the clinical and


  5   research context, and points out the fact that


  6   research is supererogatory, that is, as opposed to


  7   a clinical context where there is a strong best


  8   interests argument to be made.  Generally speaking,


  9   in research the decision is more voluntary and, for


 10   that reason, assent is more powerful phenomenon, in


 11   my view, ethically speaking in research than it


 12   would be in the clinical context.


 13             The bottom bullet point here is also


 14   important I think as a principle perhaps for us to


 15   consider, and that is the older the child, the more


 16   assent contributes to the ethical justification for


 17   the study.  This is a problem for diseases that


 18   happen in younger children certainly but, all


 19   things being equal, an older child I think who can


 20   participate in the decision gives us more ethical


 21   justification for proceeding in research endeavors.


 22             The next slide just points out a piece of


 23   data.  This is a scale that we did in our study of


 24   informed consent about decision-making preference.


 25   It shows everything from, number one, a parent who




  1   wants to leave all decisions to the doctor and


  2   perhaps to an investigator, and then a continuum to


  3   number five, a parent who wants to make final


  4   selection about which treatment their child will


  5   receive.


  6             The next slide shows a sample of 108


  7   parents.  The reason that I included it this


  8   morning is to point out the variability among


  9   parents and families when it comes to how they want


 10   to make decisions.  You see in this slide a large


 11   number of parents in the middle, within the green,


 12   red and grey columns, who fit into a shared


 13   decision-making model.  In my view, this is why


 14   informed consent is important during the conduct of


 15   research.  Most people want a shared


 16   decision-making approach whether it comes to


 17   treatment or research participation and


 18   communication.  Effective communication is really


 19   the key issue for informed consent.


 20             The next slide.  As I wind down the talk


 21   and get to the conclusion, I want to make the point


 22   that the over-interpretation of regulatory concerns


 23   can prevent the ethically meaningful participation


 24   of children in research.


 25             Can you still hear me?




  1             MS. CLIFFORD:  We can still hear you.


  2             DR. KODISH:  Great!  I heard a beep on the


  3   phone.  I am going to tell a quick story to


  4   illustrate this point.  Heather K was diagnosed


  5   with a vaginal rhabdomyosarcoma at a children's


  6   hospital in the Midwest within the past few months.


  7   At diagnosis, Heather had a tumor that was causing


  8   intestinal compression.  Her pediatric oncologist


  9   talked to the family about the diagnosis and then


 10   subsequently discussed a Phase III non-randomized


 11   study sponsored by the IRS/COG.  The family


 12   provided informed consent and signed a document at


 13   6:05 p.m.  The plan was to begin chemotherapy the


 14   following day but the patient developed a bowel


 15   obstruction at 11:00 p.m. and chemotherapy was


 16   emergently started.  At midnight nothing happened


 17   that was ethically significant.  Clinically, the


 18   patient was continuing to get her chemotherapy.


 19   But the next morning, when the CRA, the data


 20   person, came to enroll Heather in this Phase III


 21   study, the RDE, or the remote data entry system,


 22   made enrollment impossible.  The reason that


 23   enrollment was impossible was that the date


 24   chemotherapy was started was the previous date and


 25   the form would not permit enrollment to happen if




  1   chemotherapy had already been started.


  2             So, what was a well-intentioned regulation


  3   system designed to prevent people from being


  4   entered on study if consent had not yet been


  5   obtained--in fact, in this case everything went


  6   perfectly from an ethical perspective but the


  7   patient was not allowed to be entered on study.  I


  8   think that this is a cautionary tale and I wanted


  9   to bring it to the attention of the panel today.


 10             Next slide, please.  We see many


 11   well-intentioned regulatory protections and it is


 12   important to realize that they can paradoxically


 13   prevent the ethical participation of children in


 14   cancer research and Heather's story is one example


 15   of that.  The physician then needed to go back to


 16   the family and explain that, unfortunately, we


 17   weren't able to include her as a subject in the


 18   research.  It wasn't going to change her treatment


 19   at all but the future treatment of children with


 20   rhabdomyosarcoma in some ways is harmed by the fact


 21   that this regulatory mechanism prevented Heather


 22   from being a subject in the study.  The only


 23   alternative would have been for the person doing


 24   remote data entry to fabricate and to say that the


 25   date chemotherapy was started was the day that she




  1   was being entered on study, and that would have,


  2   number one, been an unethical lie and, number two,


  3   would have been picked up on an audit if the


  4   subject had been audited subsequently though it may


  5   have been, in fact, the ethical thing to do because


  6   consent was obtained in an appropriate way, it is


  7   an important study, and all of the things that we


  8   have bee talking about, but the regulatory


  9   apparatus prevented an ethical action from taking


 10   place and I think it is a disturbing story.


 11             The next slide shows a synergistic


 12   approach.  The protection of human subjects has


 13   been done both through education and regulation and


 14   we need to be concerned about developing too much


 15   regulation at the expense of education and the


 16   expense of thoughtful ethical action.


 17             The next slide just has a few quick points


 18   about what matters after a trial is closed.


 19   Monitoring for late effects of therapy is an


 20   important ethical issue after a trial has closed.


 21   The publication of results and dissemination of


 22   findings is ethically important.  If the science


 23   isn't disseminated, then it is like a tree falling


 24   in a forest that nobody hears.  Finally, the return


 25   of results to the subjects who participated is an




  1   ethically under-looked and I think very important


  2   issue that symbolizes the partnership that we have


  3   with subjects and their families, and I think we


  4   need to do a better job than we are doing currently


  5   after a trial has closed in getting results back to


  6   the subjects.


  7             The next slide shows conceptually the main


  8   balance as a point of conclusion in pediatric


  9   research ethics, that the best interests of the


 10   child-subject are, in fact, balanced against


 11   science to benefit others and we need to be


 12   cognizant of that balance at all times and be sure


 13   that the best interests of the child are not


 14   subjugated.


 15             The next slide shows a couple of


 16   conclusions.  The first is that beneficence, as


 17   described in the Belmont report, is the key ethical


 18   principle that I believe should guide monitoring of


 19   patients in studies.  Also, a risk/benefit


 20   assessment by the investigator, by the IRB and by


 21   others perhaps is more important than informed


 22   consent, and that is because I don't think informed


 23   consent has the ethical importance in pediatrics


 24   that it does in adult medicine, and also because of


 25   the relatively ineffective communication process




  1   that is currently happening with informed consent.


  2   I would be happy to talk more about that in the


  3   discussion.


  4             The next slide shows that the protection


  5   of children from research risk and the imperative


  6   to improve childhood cancer treatment are both


  7   ethically important.  The bottom point here is that


  8   regulatory fervor intended to protect children


  9   currently threatens the ethical conduct of


 10   pediatric cancer research, as I tried to illustrate


 11   in Heather's story, and we need to remember, I


 12   think, that there is an ethical imperative to do


 13   work in childhood cancer to improve the care of


 14   children with cancer.


 15             The final slide points out that children


 16   are both vulnerable subjects who need protection


 17   from research risk and a neglected class--and they


 18   continue to be a neglected class despite our best


 19   efforts--that need better access to the benefits of


 20   research.


 21             I thank you all for tolerating the virtual


 22   reality nature of this talk and hope that I have


 23   been able to make a contribution.  Thank you.


 24             DR. SANTANA:  Thanks, Eric.  Eric, are you


 25   planning to stay on line for the rest of the




  1   morning?


  2             DR. KODISH:  I am.  The only question is


  3   whether I should do it by phone or by Webcast.


  4             DR. SANTANA:  Okay, because if you are


  5   going to stay, then we will just hold the questions


  6   for the general discussion, if that is okay with


  7   you.


  8             DR. KODISH:  That is fine.


  9             DR. SANTANA:  But I do want you to stay on


 10   the phone line, if at all possible, for the


 11   discussion because I think we can communicate


 12   better that way.


 13             DR. KODISH:  Okay, what I will try to do


 14   is watch but mute the sound.


 15             DR. SANTANA:  That is fine.


 16             DR. KODISH:  Thank you, Victor.


 17             DR. SANTANA:  Okay, good.  I also want to


 18   thank John for advancing your slides on your


 19   behalf.  Dr. Carome, you are next.


 20         Legal Responsibilities for HHS Supported Studies


 21             DR. CAROME:  Good morning.  I would like


 22   to thank the subcommittee members for inviting me


 23   to give a brief presentation on legal


 24   responsibilities for studies conducted and


 25   supported I think originally by the federal




  1   government and since I speak on behalf of HHS, I


  2   have limited it to HHS, the Department of Health


  3   and Human Services.


  4             What I am quickly going to do is go over,


  5   first of all, the applicability of our regulations.


  6   Then I am going to talk very quickly about the


  7   major requirements of 45 CFR Part 46, Subpart A,


  8   which are the general protections for human subject


  9   research.  Then I am going to finish up by talking


 10   about the major requirements of 45 CFR, part 46,


 11   Subpart D, which are the additional protections for


 12   children involved as subjects in research.


 13             Again, the regulations I am referencing,


 14   45 CFR Part 46, are the HHS regulations for the


 15   protection of human subjects.  They have four


 16   subparts.  The regulations were last revised in


 17   2001.  One of the subparts, Subpart B, was revised


 18   at that point but most of the regulations remain


 19   the same as when they were promulgated more than


 20   two decades ago.


 21             So, what is the applicability of these


 22   regulations?  Our regulations apply in two


 23   circumstances.  The most common is research


 24   conducted or supported by the Department that are


 25   not otherwise exempt.  That includes clinical




  1   trials conducted intramurally by the NIH or funded


  2   by the NIH, as well as many other agencies within


  3   the Ddpartment.  A second way in which research can


  4   be covered by these regulations is research that is


  5   conducted at an institution holding an applicable


  6   assurance of compliance approved by our office.


  7   So, any institution that receives funding from our


  8   Department to conduct human subject research must


  9   execute a written agreement in which the


 10   institution pledges to comply with our regulations,


 11   and in that document many institutions voluntarily


 12   extend the same regulations to all research


 13   regardless of sponsorship.  In doing so, the


 14   assurance comes to cover privately sponsored


 15   research.


 16             This slide demonstrates the relationship


 17   and the overlap between the applicability of our


 18   regulations and the FDA regulations.  You can see


 19   that there is in the middle an overlap.  The


 20   overlap may occur in two circumstances.  One is


 21   where NIH sponsors a clinical trial or other


 22   clinical research, or any research, that involves


 23   an FDA-regulated test article.  Another


 24   circumstance is where an institution, holding an


 25   assurance with our office in which they voluntarily




  1   agreed to extend that assurance to all research, is


  2   engaged in an industry, privately sponsored


  3   research, project involving an FDA-regulated test


  4   article.


  5             Very quickly, what are the major


  6   provisions of Subpart A?  As was previously noted,


  7   the regulations, we believe, are clearly founded


  8   upon an ethical framework that was articulated in


  9   the Belmont report.  Its three basic ethical


 10   principles, and the fundamental provisions of the


 11   regulations can be divided in three groups.  One is


 12   the provisions related to and assurance of


 13   compliance.  The second is those related to the IRB


 14   requirements, institutional review boards, and the


 15   third is those requirements related to legally


 16   effective informed consent.


 17             With respect to assurances, the


 18   regulations stipulate that each institution engaged


 19   in research covered by the regulations and which is


 20   conducted or supported by the Department shall


 21   provide assurance satisfactory to the HHS Secretary


 22   that it will comply with the requirements set forth


 23   in the regulations.


 24             The regulations further stipulate specific


 25   elements that must be part of an assurance.  There




  1   must be a statement of principles governing the


  2   institution in the discharge of its


  3   responsibilities for protecting the rights and


  4   welfare of human subjects.  And, the regulations


  5   state that those principles must apply to all


  6   research regardless of whether or not it is covered


  7   by the assurance.


  8             The assurance must designate at least one,


  9   and many institutions designate more than one,


 10   institutional review board and that must include a


 11   list of the IRB members and their relative


 12   capacities, and there must be a reference to


 13   written IRB procedures.  There are requirements


 14   related to the IRB and they include specification


 15   of what the IRB membership must include, such as at


 16   least one person whose primary interests are in the


 17   scientific area and at least one member whose


 18   primary interests are in a non-scientific area, and


 19   at least one member who is not otherwise affiliated


 20   with the institution or a member of a family


 21   affiliated with the institution.


 22             The regulations have specific provisions


 23   related to how the IRB should function and operate;


 24   when it must conduct review in terms of initial and


 25   continuing review.  Then there are provisions




  1   related to expedited review for certain categories


  2   of minimal risk research and there are detailed


  3   lists of specific criteria an IRB must find in


  4   order to approve research.  For example, the


  5   regulations state that in order to approve research


  6   an IRB must find that the risks to the subjects are


  7   minimized and reasonable in relationship to the


  8   anticipated benefits, if any, to the subjects and


  9   the knowledge that is to be gained.  Then, there


 10   are other provisions for the records that an IRB


 11   must maintain.


 12             The last set or provisions in Subpart A


 13   deal with legally effective informed consent.  They


 14   include an introductory paragraph that talks about


 15   the general requirements.  For instance, no


 16   investigator may involve a human subject in


 17   research unless the informed consent of the subject


 18   or a legally authorized representative of the


 19   subject has been obtained, except in certain


 20   limited circumstances in which informed consent can


 21   be waived.


 22             The regulations go on to stipulate basic


 23   elements that I think most people are familiar


 24   with: the nature of the research; the reasonably


 25   foreseeable risks; the reasonably foreseeable




  1   benefits, if any, to the subject; and others, such


  2   as alternatives that a subject may choose instead


  3   of entering the research.  The regulations


  4   stipulate that consent must generally be


  5   documented, except in some limited circumstances.


  6   Then, there are waiver provisions both for


  7   obtaining informed consent at all or for documented


  8   informed consent, and I won't go into those in


  9   detail.


 10             Let's turn finally to the provisions for


 11   research involving children under Subpart D, the


 12   additional protections for children.  Again, this


 13   is a subpart that is unique to the Department of


 14   Health and Human Services.  Whereas all the Subpart


 15   A provisions that I just went over have been


 16   adopted by other departments and agencies, Subpart


 17   D has only been adopted by the Department of


 18   Education in addition to our department.


 19             Subpart D applies to all research


 20   involving children as subjects conducted or


 21   supported by our department.  It is important to


 22   note that there is a specific definition of


 23   children in the regulations, and they are persons


 24   who have not attained the legal age for consent to


 25   treatments or procedures involved in the research




  1   under the applicable law of the jurisdiction in


  2   which the research will be conducted.  It is


  3   important to note that in order to then understand


  4   who a child is with respect to the research


  5   regulations, you must understand state and local


  6   law that defines who can consent to what and at


  7   what age.  Therefore, a child in one state might


  8   not be a child in another state for the purposes of


  9   these regulations.


 10             The Subpart D requirements in


 11   general--first of all, you have to satisfy all the


 12   requirements of Subpart A.  So, if a research


 13   project involving children doesn't satisfy some


 14   provision of Subpart A, then it is moot about the


 15   additional provisions.  The research would not be


 16   approvable.  But if the research is approvable


 17   under Subpart A, there are additional requirements


 18   of Subpart D which must be fulfilled and satisfied.


 19             As Eric referenced, there are four


 20   categories of research that are approvable under


 21   Subpart D under our regulations.  These are


 22   primarily scaled to risk versus benefit as you walk


 23   through each of these categories, and I am going to


 24   do that very quickly.


 25             The first category, 404, is research not




  1   involving greater than minimal risk, and minimal


  2   risk is defined in Subpart A.  In order for this


  3   research to be approved under this category, an IRB


  4   must make one general finding.  It must find that


  5   there are adequate provisions for soliciting the


  6   assent of the child and permission of the parents


  7   or guardians, as set forth in Section 408.


  8             The next category, Section 405, which Eric


  9   went into more detail, is research involving


 10   greater than minimal risk but presenting the


 11   prospect of direct benefit to the individual


 12   subjects.  So, the benefit has to be tied to the


 13   subjects as opposed to society in general and the


 14   knowledge to be gained.  Here, the IRB must make


 15   three specific findings.  The IRB must find that


 16   the risk is justified by the anticipated benefits


 17   to the subject; the relationship of the anticipated


 18   benefit to the risk is at least as favorable to the


 19   subjects as that presented by available


 20   alternatives outside the research context; and,


 21   again, the same provisions for assent and


 22   permission apply throughout these four categories.


 23             The next category, 406, involves greater


 24   than minimal risk and no prospect of direct benefit


 25   to the individual subjects, but likely to yield




  1   generalizable knowledge about the subject's


  2   disorder or condition.  For this category there are


  3   four criteria that an IRB must find.  They must


  4   find that, first, that the risk represents a minor


  5   increase over minimal risk.  Whereas minimal risk


  6   is defined in the regulations, what a minor


  7   increase means is not defined so that is left up to


  8   the judgment of the IRBs.


  9             Next, the IRB must find that the


 10   intervention or procedure within the research


 11   presents experiences to the subjects that are


 12   reasonably commensurate with those inherent in the


 13   actual or expected medical, dental, psychological,


 14   social or educational situation of the child.


 15   Commensurability is one of the factors that Eric


 16   touched on but applies only in this category, 406.


 17             The next two provisions--the IRB must find


 18   under 406 that the intervention or procedure is


 19   likely to yield generalizable knowledge about the


 20   subject's disorder or condition which is of vital


 21   importance for the understanding or amelioration of


 22   the subject's disorder or condition.  I think the


 23   key words here are that you have to understand that


 24   the child must have a disorder or condition, two


 25   terms that are not otherwise defined in the




  1   regulation and are of vital importance.  So, it is


  2   sort of a higher standard than the usual


  3   generalizable knowledge standard that probably


  4   applies to research under Subpart A only.  Lastly


  5   is the assent or permission provisions.


  6             The fourth category and final category is


  7   research that is not otherwise approvable under one


  8   of these four categories which presents a


  9   reasonable opportunity to understand, prevent or


 10   alleviate a serious problem affecting the health or


 11   welfare of children.  For this, the IRB still must


 12   review and assess the research with respect to


 13   Subpart A and D, and must find that the research


 14   presents a reasonable opportunity to further the


 15   understanding, prevention or alleviation of a


 16   serious health problem affecting the health or


 17   welfare of children.


 18             The project is then forwarded to the


 19   Department.  They come through our office and we


 20   act on behalf of the Secretary to process these.


 21   In order for the research then to be approved, the


 22   Secretary, after consultation with a panel of


 23   experts in pertinent disciplines and following an


 24   opportunity for public review and comment, must


 25   determine either that the research in fact




  1   satisfies one of the other three categories, 404,


  2   405 or 406 or, if not, three things must be met:


  3   that research presents a reasonable opportunity


  4   standard that I previously went over; that the


  5   research will be conducted in accordance with sound


  6   ethical principles, and hopefully that is something


  7   that applies to all research conducted; and


  8   adequate provisions for the assent of the child and


  9   parental permission.


 10             Finally, there are some additional


 11   provisions of Subpart D that are provisions related


 12   to soliciting assent, and assent is not always


 13   required and an IRB may determine it is not


 14   warranted, particularly under category 405.  There


 15   are provisions for soliciting permission of


 16   parents, and the regulations speak to whether you


 17   need both parents' permission.  If the category is


 18   405 one parent's permission is sufficient but for


 19   406 or 407 two parents are required, except in very


 20   limited circumstances.


 21             It is important to note that there are


 22   provisions for waiving parental permission or


 23   guardian permission.  Just like informed consent


 24   can be waived under Subpart A for research


 25   involving adults, parental permission can be waived




  1   in certain circumstances and this is I think unique


  2   to our regulations and not found in the parallel


  3   regulations within the FDA.


  4             Finally, there are specific protections


  5   for subjects who are wards of the state or any


  6   other agency, institution or entity for research


  7   approved under 406 or 407.  Among those


  8   requirements, there must be a specific advocate


  9   appointed for each child who is participating in


 10   such research who is a ward.


 11             In summary, I have quickly tried to go


 12   over the applicability of our regulations and


 13   contrasted that with the FDA regulations


 14   applicability.  I have gone over the major


 15   requirements of Subpart A of our regulations and


 16   finished up with a discussion of Subpart D, and I


 17   thank you for your attention.


 18             DR. SANTANA:  Thanks, Dr. Carome.  Dr.


 19   Hirschfeld?


 20             Legal Responsibilities for Studies with


 21                      FDA Regulated Products


 22             DR. HIRSCHFELD:  I would also like to


 23   thank Dr. Carome and note that when he was wearing


 24   a uniform which was a color more consistent with


 25   the theme of the day, he was the head of the IRB at




  1   Walter Reed Army Medical Center.  I also want to


  2   thank him for his efforts on clarification of the


  3   regulations in ongoing discussions as they apply to


  4   pediatric oncology, and he has taken a leadership


  5   role in the Office for Human Research Protection in


  6   that regard.


  7             I am going to even more quickly, I hope,


  8   go through the FDA regulations.  One might ask what


  9   is a pediatric oncologist doing talking about FDA


 10   regulations, but that is one of the strengths of


 11   the FDA, that there are wonderful opportunities to


 12   be involved in many aspects or research in clinical


 13   medicine, including the development of regulations.


 14   I was on the working group that developed the


 15   Subpart D and, in fact, wrote the first draft of


 16   that document.


 17             As Dr. Carome pointed out, there is some


 18   overlap, and these slides have a lot of data which


 19   is intended for reference and I will not go through


 20   all the aspects of all the slides, but just to note


 21   that there are laws synonymous with an act or


 22   statute which are developed and passed by the


 23   Legislative Branch and signed by the President and


 24   these are published in the United States Code.


 25   Then there are regulations synonymous with rule,




  1   and these are developed and published by the


  2   Executive Branch, the various departments and


  3   agencies within the Executive Branch doing the


  4   detailed work, and these are published in the Code


  5   of Federal Regulations, which is referred to as the


  6   CFR.


  7             The FDA authority is derived from multiple


  8   laws and regulations, and the focus is on product


  9   and product use.  There are a number of applicable


 10   regulations for good clinical practice in the


 11   research setting, and these include the human


 12   subject protection, which is in 21 CFR, Part 50;


 13   financial disclosures, which is in Part 54;


 14   institutional review boards, which is in Part 56;


 15   and investigational new drugs, which is in part


 16   312.


 17             Part 50 has actually three sections to it.


 18   One is reserved for future use and Part D, you will


 19   notice, is the additional safeguards for children


 20   in clinical investigations, which is the focus of


 21   the discussion now.


 22   This is a catalog of all the various sections


 23   within Subpart D of 21 CFR, 50.  You will see that


 24   there is mapping and harmonization between the


 25   relevant sections of the HHS regulations.




  1             Now, the relationship--and this is just a


  2   textual representation of the schematic that Dr.


  3   Carome presented--is that FDA regulations apply to


  4   all research using FDA-regulated products.  In


  5   contrast, the HHS regulations apply to all research


  6   that is supported by HHS.  Research that is


  7   supported by HHS using FDA-regulated products is


  8   subject to both sets of regulations, and the


  9   regulations are harmonized although there are some


 10   differences which Dr. Carome elaborated on earlier.


 11   The definitions, you will see, parallel those


 12   definitions in the HHS regulations and put the onus


 13   of interpretation on the local jurisdiction and on


 14   the local IRBs, and that is the theme that persists


 15   throughout these regulations.  So, these


 16   definitions are included here to show that there is


 17   harmonization and in some cases, we believe, some


 18   clarification because the scope of FDA-regulated


 19   research is, in many ways, different and can apply


 20   to domains where HHS research is not applicable.


 21   So, it was important to have not only clarity on


 22   the definitions but consistency and, therefore,


 23   there are definitions that are included here so


 24   that there is not, we hope, much ambiguity in terms


 25   of how to apply and interpret these regulations at




  1   the local IRB level.


  2             Here, again, there is an emphasis on the


  3   concept that Eric Kodish developed for us a little


  4   earlier this morning, and that is children do not


  5   actually engage in a consent process.  Their


  6   parents provide permission for them to participate


  7   in the research.  Then, there is the same emphasis


  8   as in the HHS regulations that the child must at


  9   least be approached for assent.


 10             So, in addition to the other


 11   responsibilities assigned to IRBs, the FDA


 12   regulations ask that the IRB review clinical


 13   investigations involving children as subjects


 14   covered by Subpart D and approve only clinical


 15   investigations that satisfy the criteria which are


 16   described in Subpart 51, 52, 53 and the conditions


 17   of all other applicable sections of Subpart D.


 18             These are again mapped to the four risk


 19   categories which were developed in the 1970s and


 20   which, because of their serviceability and their


 21   flexibility, have been maintained to this date.


 22   These, again, discuss the concept of minimal risk


 23   here with specific examples of how it applies to


 24   pediatric research.


 25             Since the IRBs are a conduit through which




  1   research occurs, there are specific instructions on


  2   when IRBs may approve clinical investigations, and


  3   these are divided into the specific risk


  4   categories.  So, there is greater than minimal risk


  5   under 50.51.  In 50.52 there is greater than


  6   minimal risk presenting the prospect of direct


  7   benefit and the conditions, again, are analogous to


  8   the HHS regulations; and 50.53 shows that the IRBs


  9   can approve clinical investigations involving


 10   greater than minimal risk and no prospect of direct


 11   benefit but likely to yield generalizable knowledge


 12   about the subject's disorder or condition, and the


 13   same caveats about having a disorder or condition


 14   and having the prospect of generalizable knowledge


 15   apply, and these are addressed in some detail.


 16             In addition, there are IRB approval


 17   criteria which are explicitly stated and these


 18   include not only minimization of risk and that the


 19   risks are anticipated in relation to the benefit,


 20   but that the informed consent process is adequate


 21   and appropriately documented and looking for


 22   safeguards.  That is going to be theme which we are


 23   going to look at in detail, what safeguards can be


 24   and ought to be implemented.


 25             Subpart D addresses this explicitly. 




  1   There is a paragraph devoted to monitoring which I


  2   will quote briefly:  While the level of risk in a


  3   clinical investigation may change during the course


  4   of a study, appropriate strategies may be included


  5   in the study design that may mitigate risks.  These


  6   might include exit strategies in the case of


  7   adverse events or a lack of efficacy, or


  8   establishing a data monitoring committee to review


  9   ongoing data collection and recommend study


 10   changes, including stopping a trial on the basis of


 11   safety information.


 12             Part 56 addresses institutional review


 13   boards, and the general provisions and organization


 14   are discussed in the first part; IRB functions and


 15   operations in the second part; records and


 16   reporting in the fourth part; and the


 17   administrative actions for non-compliance in the


 18   fifth part.


 19             Now we come to the IND regulations, 312


 20   Subpart A, which are the general provisions which


 21   are outlined here.


 22             Subpart B, which are in essence the


 23   mechanics of an investigational new drug


 24   application and the obligations under those


 25   sections.




  1             Subpart C, which discusses the


  2   administrative actions, and Subpart D which goes


  3   into detail of the responsibilities of the sponsors


  4   and investigators.


  5             There is a Subpart E, which doesn't map


  6   explicitly to other HHS regulations, which


  7   addresses the drugs intended to treat


  8   life-threatening and severely debilitating


  9   illnesses which apply to pediatric oncology


 10   studies.  You will notice in the various paragraphs


 11   here that in 312.87 there is a requirement for


 12   active monitoring of conduct and evaluation of


 13   clinical trials.  It reads, for drugs covered under


 14   this section, the Commissioner and other agency


 15   officials will monitor the progress of the conduct


 16   and evaluation of clinical trials and be involved


 17   in facilitating their appropriate progress.  So,


 18   this places an FDA role in a dynamic way in the


 19   research being conducted in the realm of


 20   life-threatening illnesses.


 21             In addition, 312.88 has specific


 22   safeguards for patient safety which refer back to


 23   the other sections that were discussed, Parts 50,


 24   56, 312.  We didn't discuss 314 which is the NDA


 25   regulations and 600 which apply to the biologics




  1   but there are analogous regulations in these areas.


  2             I will just abstract from here that this


  3   includes the requirements for informed consent and


  4   institutional review boards, and that these


  5   safeguards further include the review of animal


  6   studies prior to initial human testing; the


  7   monitoring of adverse drug experience through the


  8   requirements of IND safety reports; safety update


  9   reports for marketing and postmarketing.


 10             So, our conclusions from this section are


 11   that the FDA has authority to regulate clinical


 12   studies using FDA-regulated products; that FDA


 13   regulations incorporate both IRB and FDA oversight


 14   of studies; that regulations exist for studies


 15   using products intended to treat life-threatening


 16   illnesses; and that regulations exist for providing


 17   additional safeguards for children enrolled in


 18   clinical investigations; and, as noted, HHS and FDA


 19   regulations are intended to be harmonized.  Thank


 20   you.


 21             DR. SANTANA:  Thank you, Dr. Hirschfeld.


 22   I think we will hold our questions until we


 23   reconvene at the point for discussion.  I think we


 24   are just a few minutes behind time.  We will take a


 25   15-minute break--Dr. Hirschfeld wants a 10-minute




  1   break.  We will take a 10-minute break and try to


  2   reconvene at almost 9:45.  Thank you.


  3             [Brief recess]


  4             DR. SANTANA:  We will go ahead and get


  5   started with the second part of the morning


  6   presentations.  To initiate that, Dr. Anderson,


  7   from CTEP, will be our next speaker.  Barry?  Eric,


  8   are you back on board?


  9             DR. KODISH:  I am here.


 10             DR. SANTANA:  Thank you, Eric.


 11             Enrollment and Monitoring Procedures for


 12                        NCI Funded Studies


 13             DR. ANDERSON:  I am Barry Anderson, from


 14   NCI CTEP, and I want to thank the FDA and Steven


 15   for inviting us to provide information about the


 16   enrollment and monitoring procedures for


 17   NCI-supported clinical trials.


 18             For pediatric cancer clinical trials, the


 19   appropriate enrollment of the individual patient,


 20   the child who is going to come onto the trial, as


 21   well as the monitoring of that individual patient's


 22   experience during the trial and the cumulative


 23   experience of all children who are involved in a


 24   clinical trial I think are necessary components in


 25   terms of trying to enhance the patient safety and




  1   the scientific validity of the trial itself.


  2             So, at the onset, from NCI's point of


  3   view, it is important to work to assure that each


  4   child accrued to a trial is receiving the


  5   appropriate treatment within the clinical trial


  6   itself, and that monitoring that is associated with


  7   the trial monitors the toxicity and effectiveness


  8   of the treatment intervention within each clinical


  9   trial both for that individual child, as well as


 10   for the trial overall.


 11             The words "safe" and "effective" can be


 12   applied to many of the standard treatments we use


 13   in pediatric oncology to treat various childhood


 14   cancers.  These words have special meaning in


 15   pediatric oncology.  As Dr. Kodish mentioned, there


 16   is a special sort of risk/benefit ratio that we


 17   always consider because, while therapy for


 18   childhood cancer is often successful and that is


 19   something that differs from much of medical


 20   oncology, the therapies that we use are always


 21   toxic in pediatric oncology and they always carry a


 22   risk of treatment-related morbidity and perhaps


 23   even death in many cases.


 24             So, selecting the proper treatment I think


 25   is essential because compared with other serious




  1   childhood diseases, such as asthma or cystic


  2   fibrosis, childhood cancer includes many distinct


  3   histologic diagnoses, and each tumor histology


  4   requires a distinct treatment appropriate with its


  5   own risks and benefits.  The chances of cure also


  6   diminish quickly if the proper therapy is not used


  7   at the outset.  That differs, I think, from some of


  8   the other more chronic diseases that are serious


  9   within childhood diseases but can have chances to


 10   change the therapeutic approach over time.


 11             In regards to enrollment, a question for


 12   the clinical trials done in pediatric oncology is


 13   who should be enrolled.  Pediatric oncology has


 14   evolved an approach of risk stratified treatment


 15   regimens and within each tumor histology the


 16   patient characteristics and the tumor


 17   characteristics establish a risk of relapse.  This


 18   risk of relapse then is used to stratify the


 19   treatment assignment for each child in terms of the


 20   type of clinical trial or the specific clinical


 21   trial they would be appropriate for.  Using this


 22   risk of relapse the intensity of the treatment that


 23   the child receives--and for intensity you can also


 24   say increased toxicity--is then set to best fit the


 25   child's cancer.  So, it is vital to treat the




  1   child, as best we can ascertain at the time they


  2   first present, according to the appropriate


  3   treatment regimen.


  4             By following this treatment stratification


  5   approach, the goal in pediatric oncology is to


  6   minimize the exposure to highly toxic therapies for


  7   those children who don't need that much treatment,


  8   in a relative sense, and also for the oncologists


  9   to have some comfort in knowing that another child


 10   who has a high-risk chance of relapse, that they


 11   will in fact potentially benefit from using a more


 12   intensive and more toxic treatment regimen.


 13             To apply this treatment stratification


 14   approach across an entire clinical trial, it is


 15   important that the eligibility criteria within the


 16   protocol by which all the patients are brought into


 17   the trial--that those protocol eligibility criteria


 18   are clear in regards to the clinical


 19   characteristics of the patient and the pathologic


 20   and biologic characteristics of the tumor--that all


 21   these characteristics are clear and easy to


 22   understand.


 23             The pediatric oncologists that are


 24   involved in the trial and who would be enrolling


 25   patients must be properly informed on how to apply




  1   the eligibility criteria that are presented in the


  2   eligibility section of the protocol itself.  If


  3   anyone has ever had experience in trying to bring a


  4   patient with rhabdomyosarcoma into a sarcoma trial,


  5   it can be a be very complicated endeavor and many


  6   mechanisms have been put in place to assist the


  7   pediatric oncologist to make sure that the proper


  8   decision is made in terms of treatment.


  9             As technology has advanced, eligibility


 10   criteria have moved beyond what they have been in


 11   the past, just being tumor histology and perhaps


 12   the staging of the patient.  As histologic and


 13   biologic characteristics of tumors are better


 14   defined and refined, we also are incorporating in


 15   many cases in pediatric oncology central input on


 16   the pathology and biology, such that central review


 17   of the patient's tumor pathology and diagnostic


 18   biology assays are used to improve the likelihood


 19   that a child receives the best available therapy


 20   for their specific tumor pathology and for their


 21   risk of relapse.


 22             This has been used in a variety of tumors


 23   in pediatric oncology in the recent past.  With


 24   rhabdomyosarcoma there is central review of


 25   alveolar versus embryonal rhabdomyosarcoma




  1   pathology that is used basically in real time so as


  2   to assure that the patient goes on the proper


  3   risk-stratified treatment regimen.  For


  4   neuroblastoma there are a variety of biologic


  5   characteristics that make amplification and other


  6   genetic changes that are characteristic to each


  7   tumor, and that is also looked at in real time.


  8   For Wilms tumor there has been a central review of


  9   that tumor histology for favorable histology versus


 10   focal or diffuse anaplasia that all distinguish


 11   patients for their appropriate trial, and there are


 12   a variety of genetic studies that are done, both


 13   centrally and locally, to establish the appropriate


 14   treatment for children with acute lymphoblastic


 15   leukemia, the most common diagnosis in childhood


 16   cancer.


 17             Phase I and pilot studies also have


 18   specific eligibility criteria.  In these cases, it


 19   may not necessarily be the case that you need to be


 20   concerned about the tumor histology so much,


 21   especially in Phase I where a child has already


 22   received treatment, but it is important to ensure


 23   that those patients who are enrolled in a trial


 24   have no other treatments that provide a reasonable


 25   potential for cure or substantial clinical benefit. 




  1   For patients who have newly diagnosed tumors but


  2   have a type of tumor that historically has a poor


  3   response to therapeutic interventions, we want to


  4   make sure that any sort of pilot treatment


  5   interventions that have been tried balance


  6   appropriately the benefits and likely risks in the


  7   child's prognosis.  So, before considering trial


  8   monitoring we consider that getting the right


  9   patient on the right trial is vital given the


 10   stratified approach we have to treatment in


 11   pediatric oncology.


 12             NCI supports a variety of investigator


 13   groups to do clinical trials in children with


 14   cancer.  The largest is the Children's Oncology


 15   Group, which pretty much every pediatric oncologist


 16   in North America is a member of.  That is the group


 17   that does the Phase III studies primarily as well


 18   as Phase II studies and pilot studies.  There is


 19   the COG Phase I Pilot Consortium that is a smaller


 20   group, about 20 institutions, that is assigned to


 21   do Phase I studies.  The Pediatric Brain Tumor


 22   Consortium I think is around 10 institutions as


 23   well.  Their focus is on newer therapies for brain


 24   tumors in children.  The new approaches to


 25   neuroblastoma therapy is a program project grant




  1   that NCI supports that is now 12 or 14 institutions


  2   I think, focused on early phase studies for


  3   children with neuroblastoma, high risk


  4   neuroblastoma.  There are also individual grants to


  5   investigators that may include clinical trial


  6   research.


  7             All these, because of the nature of


  8   pediatric oncology and the relative lack of number


  9   of patients, are usually multi-institutional.


 10   Given that they are multi-institutional, that


 11   brings on special responsibilities in terms of


 12   trying to conduct a trial at multiple sites


 13   simultaneously and trying to have all the


 14   investigators that are enrolling new patients and


 15   treating ongoing patients aware of what is going on


 16   with the trial.  So, the NCI has worked with these


 17   various groups that we support to facilitate this


 18   sort of intake of information and distribution of


 19   information.


 20             The investigators that are part of these


 21   various groups are committed to report toxicities,


 22   the regimen delivery and the ability to deliver the


 23   regimen as defined in the protocol and the response


 24   data in a timely fashion.  Some things such as


 25   remote data entry have been put in place now to




  1   help facilitate that.  There is a data center


  2   assigned with each of these groups that we support


  3   that is capable of readily receiving the data,


  4   analyzing the data and then reporting important


  5   data trends to the investigators, be it the study


  6   committee and perhaps beyond if necessary.  There


  7   is an operations office component.  They are able


  8   to communicate with investigators continuously


  9   throughout the clinical trial by email, by web


 10   site, by the phone, etc.  There is sort of this


 11   continuous back and forth going on between the


 12   investigators at the local institutions and a more


 13   centralized body that is helping to run the trial.


 14             In terms of monitoring, again it starts, I


 15   think just like enrollment, at the individual child


 16   level where there, is within the protocol, guidance


 17   provided to the local institutional clinicians as


 18   to what sort of laboratory results for


 19   tumor-related or treatment-related abnormalities


 20   need to be done and at what interval.  There are


 21   radiologic characterizations of the tumor and the


 22   consequent organ dysfunction that are also asked


 23   for in terms of the initial diagnosis of the child


 24   and then subsequently during their course of


 25   treatment.  Then there are interval evaluations to




  1   establish the tumor response to the treatment


  2   interventions that are being conducted during the


  3   study.


  4             The protocol--and we look for this at NCI


  5   when we review the protocols that come to us--must


  6   provide sort of a consistent and uniform approach


  7   to all these aspects of monitoring of the


  8   individual patient.  The frequency by which these


  9   studies are performed would be consistent with or


 10   greater than good clinical practice.  Because the


 11   children are on a clinical study, oftentimes they


 12   get more frequent monitoring of some of these


 13   aspects than they would if they received standard


 14   of care treatment off the protocol.  But, again, it


 15   depends on the intervention that is being


 16   undertaken and the specific tumor diagnosis under


 17   consideration.


 18             When you accumulate all this information,


 19   the monitoring and the clinical trial itself, that


 20   is where some of the infrastructure that NCI


 21   supports comes into play because, as I mentioned


 22   before, it is very important that patient data is


 23   submitted at protocol-defined intervals; that the


 24   data is accumulated, analyzed and then reported;


 25   and then that the significance of this data, be it




  1   the toxicity data or the effectiveness data, is


  2   interpreted so that appropriate patients are being


  3   accrued to the study; that treatment toxicity is


  4   acceptable and that there is some efficacy of the


  5   treatment interventions as defined in the protocol


  6   beforehand.


  7             There is some debate and discussion and


  8   variability in terms of who and how often this data


  9   that is accumulated and reported on is reviewed.


 10   Within NCI, we work with the guidelines established


 11   by NIH for data and safety monitoring and these


 12   requirements call for the oversight and monitoring


 13   of all human intervention studies to ensure the


 14   patient safety and the validity and integrity of


 15   the data itself for the study.  The monitoring in


 16   the study is to be done at sort of a level that is


 17   commensurate with the risks and size and complexity


 18   of the clinical trial.


 19             The oversight monitoring under Phase III


 20   clinical trials, which many of the pediatric


 21   oncology trials are, calls for the establishment of


 22   a DSMB.  The DSMB, according to NIH, is also


 23   appropriate for Phase I and Phase II clinical


 24   trials if the studies have such things as multiple


 25   clinical sites, are blinded or masked or employ




  1   particularly high-risk vulnerable patient


  2   populations.  In pediatric oncology we sort of hit


  3   throughout this so we call for sort of the default


  4   to be towards some sort of formalized monitoring


  5   committee for most of the studies that we do.


  6             The NCI, in response to NIH sort of


  7   formalizing its approach to data and safety


  8   monitoring, in the not too distant past has


  9   finished reviewing all the data and safety


 10   monitoring plans for the cancer centers that NCI


 11   supports across the country.  That was I think an


 12   education for both NCI as well as for the cancer


 13   centers, for them to really kind of fess up and


 14   look at what they actually do in terms of the


 15   monitoring; what goes on in their human subject


 16   clinical trials within their cancer centers.  But


 17   they all submitted them and they were all reviewed.


 18             Some of the key, essential elements for


 19   these monitoring plans that we had to consider, and


 20   that then subsequently have also been extended to


 21   some pediatric groups, are the monitoring and


 22   progress of the trials and safety of the


 23   participants; the plans for assuring compliance


 24   with adverse event reporting; and plans for


 25   assuring that data accuracy and protocol compliance




  1   are performed.


  2             As I mentioned, while in pediatric


  3   oncology basically we don't work from a cancer


  4   center model, we work more in a multi-institutional


  5   approach so it is a more distributed coverage in


  6   terms of who is performing the trials.


  7   Nevertheless, these particular essential elements


  8   were taken on by pretty much all the groups that we


  9   have that I mentioned earlier that NCI supports in


 10   one form or another, again, moving to the default


 11   of having some sort of more formalized data


 12   monitoring committees for all the trials.


 13             The composition of the DSMB and the


 14   various data monitoring committees may differ


 15   between the different groups that I mentioned that


 16   NCI supports for pediatric oncology but the goal is


 17   the same, and it is to have capable and informed


 18   observers be responsible for the oversight of the


 19   trial.  The reviewers are people that are outside


 20   of, and in addition to the study committee, and


 21   they evaluate the trial data at regular intervals


 22   to monitor the treatment toxicity and the


 23   effectiveness of the treatments that are being


 24   used.  Then, the review determines whether the


 25   continued accrual to the trial is safe and




  1   appropriate.  COG itself has two DSMBs, one for


  2   solid tumors and one for the leukemia and lymphoma


  3   studies, and they meet twice a year, each one of


  4   those DSMBs, to go over the studies.  Actually we


  5   go over pilot, Phase II and Phase III studies in


  6   those sessions.  The Phase I Consortia also has a


  7   DSMB that meets twice a year to go over all those


  8   Phase I studies.  In addition to the Phase I


  9   Consortia, the PBTC and the NANT, all of which have


 10   a DSMB type of component, have more frequent


 11   discussions with the groups that are beyond just


 12   the study investigator and any sort of data


 13   personnel or statistician directly involved.  They


 14   have a discussion of their studies sometimes on a


 15   weekly basis, sometimes on a monthly basis, and


 16   sometimes it also includes people from outside the


 17   group itself to overlook what is going on with


 18   their particular studies.


 19             In terms of compliance with adverse event


 20   reporting, another one of the essential elements


 21   that NCI has, NCI-funded studies use the adverse


 22   event expedited reporting system, or the AdEERS


 23   system to report toxicities.  This is a


 24   computerized system that is available now to all


 25   the funded groups with which they can fairly easily




  1   report adverse events that occur during their


  2   clinical trials.  That data can then be accumulated


  3   easily within their group, but also important


  4   things can be sent off to the FDA or to drug


  5   sponsors or the NCI as appropriate, especially for


  6   studies that involve IND agents.


  7             Then, it is the institutional principal


  8   investigator that is ultimately responsible to


  9   assure that the AEs are reported in a timely


 10   manner.  Whenever we review the cancer center


 11   approaches, they list out that sort of the CRA


 12   should submit this and then there is a nurse


 13   practitioner or someone that is behind the CR to


 14   make sure it gets submitted, and at some interval


 15   the principal investigator locally is responsible


 16   to make sure that all the AEs that may have


 17   occurred had been properly reported.


 18             Finally, for assuring data accuracy and


 19   protocol compliance, the cooperative groups and


 20   these consortia practice ongoing quality control


 21   and interval quality assessments such as by using


 22   institutional audits.  This has been something that


 23   has been ongoing throughout the creation of each of


 24   these groups.


 25             In summary, NCI has worked to establish a




  1   framework to allow appropriate monitoring and


  2   oversight of pediatric oncology clinical trials.


  3   To address some of the issues that Steven had


  4   brought up before in terms of the general


  5   parameters that we look at, we first want to make


  6   sure that the enrollment of patients is appropriate


  7   to the diagnosis and risk of relapse for the


  8   patient or the availability of standard treatments


  9   for recurrent and relapsed disease, and that


 10   laboratory and radiologic monitoring for toxicity


 11   and response to treatments is established within


 12   the protocol before any patients are accrued.


 13             The frequency of monitoring would be equal


 14   to or greater than standard of care for the


 15   individual patient that is enrolled on a clinical


 16   study, and there would be continuous protocol


 17   monitoring by the study committee because they


 18   receive this data on a daily basis.  There would be


 19   interval protocol monitoring on a monthly to


 20   biannual basis, depending on the risk and specifics


 21   of the trial, by a group outside of the study


 22   committee itself.


 23             Who does the monitoring?  The daily


 24   monitoring is by the study committee itself.  The


 25   interval monitoring usually involves concentrations




  1   and statisticians that are not directly involved in


  2   the trial.


  3             When is a data monitoring committee


  4   needed?  For Phase III studies you need a DSMB.


  5   For multi-institutional trials you need to have a


  6   monitoring committee for high-risk populations.


  7   You need to have a monitoring committee for complex


  8   treatment.  For studies with early stopping rules,


  9   which many pediatric studies have, you have to have


 10   a monitoring committee.  With conflicts of


 11   interest, which may not be as much of a case in


 12   pediatrics as it might be in medical oncology, you


 13   need to have a monitoring committee.


 14             I think that with pediatric oncology


 15   trials we hit many of the points that are brought


 16   up by various agencies of situations where a


 17   monitoring committee is required so that virtually


 18   always in pediatric oncology some sort of


 19   monitoring committee is involved in the oversight


 20   of the practices of the group, as well as the


 21   conduct of individual clinical trials.  Thank you.


 22             DR. SANTANA:  Thanks, Barry.  Before I


 23   stand up to give the last presentation of the


 24   morning, we have an opportunity for an open public


 25   hearing.  So, if there is anybody in the audience




  1   that wishes to address the committee, this is the


  2   opportunity to do so.  I would ask that if you are


  3   going to do that you come to the front of the room


  4   to the podium and identify yourself by name and


  5   affiliation.


  6                       Open Public Hearing


  7             MR. RAKOFF:  Wayne Rakoff, Johnson &


  8   Johnson.  Just a quick question, that came up this


  9   morning that I would like to hear discussed during


 10   the discussion, is with regard to the FDA guidance


 11   on data reduction in oncology trials.  It would be


 12   important to us to know if there are any variances


 13   in that with regard to pediatric studies.


 14             DR. SANTANA:  Steve or Rick, do you want


 15   to address that now or do you want to address it


 16   during the discussion period?


 17             DR. HIRSCHFELD:  We can address it in a


 18   little more detail but, in brief, that is a global


 19   commentary and there isn't a specific pediatric


 20   component to it.  I think that is a good suggestion


 21   that maybe we should consider in the future, a


 22   pediatric specific component.


 23             DR. SANTANA:  Any other comments from the


 24   audience?


 25             [No response]




  1                Monitoring Procedures at a Private


  2                       Children's Hospital


  3             DR. SANTANA:  First of all, I want to


  4   thank Steve, Richard and the rest of the FDA for


  5   always bringing the pediatric oncologists to set


  6   examples in these initiatives.  I am personally


  7   very appreciative of all the efforts that we have


  8   had on behalf of the issues that we deal with in


  9   pediatric oncology.


 10             My task this morning, as I was charged to


 11   do, is to bring a perspective from a private


 12   institution with the caveat that St. Jude really is


 13   an NCI cancer designated center so a lot of what we


 14   do in terms of our own monitoring is reflective of


 15   what we have to do to comply with the NCI


 16   regulations.


 17             What I would like to do over the next 20


 18   minutes or 25 minutes or so is talk to you about


 19   two issues.  One is how we set forth monitoring of


 20   our St. Jude studies--not the cooperative group


 21   studies for which we still have to comply with COG,


 22   but our own intra-institutional studies that follow


 23   a parallel system to the NCI monitoring plan, and


 24   what that monitoring plan involves and what


 25   parameters we have designated for monitoring. 




  1   Then, a bigger part of my talk will be on a project


  2   that Don Workman and I worked on in terms of trying


  3   to handle adverse event reporting within the


  4   institution and tried to develop an interactive


  5   web-based model to try to get a handle on that.


  6             With that, I will go ahead and get


  7   started.  As Barry has already said, monitoring of


  8   trials is really an ongoing, continuous review of


  9   the conduct of the trial.  For the purpose of


 10   distinction, I will make the note that to me


 11   monitoring occurs while the study is ongoing.


 12   Whereas a lot of people use the word auditing, to


 13   me auditing is a post facto thing that happens


 14   after the study has been completed.  Then you go


 15   back and see if the study was conducted the way it


 16   was supposed to be; if the data is good enough; if


 17   there is quality in the data; and if there have


 18   been any other issues that occurred during that


 19   post facto process.  So, to me, monitoring occurs


 20   real time whereas auditing occurs after the study


 21   has been completed.


 22             Monitoring is really a shared


 23   responsibility of many individuals.  We always talk


 24   about monitoring being the responsibility of maybe


 25   one particular group but at St. Jude we have the




  1   notion that this is really the responsibility of


  2   the research team.  We always talk about the


  3   principal investigator but it is really the


  4   research team.  The research team has many


  5   components to it of which, hopefully, the principal


  6   investigator is the lead person but there are


  7   research nurses, there are CRAs, there are other


  8   members of the study team who also have


  9   responsibility for this process.


 10             Institutional officials have a major role


 11   in this, not only in terms or providing


 12   infrastructure resources to conduct some of this


 13   monitoring, but also to set a culture and example


 14   that is transparent to make sure that things occur


 15   very openly and that everybody is knowledgeable


 16   about what is happening.  Then, the oversight


 17   committee--you heard a little bit about DSMBs which


 18   I won't talk about and IRBs and other committees


 19   that may be involved in this process.


 20             Eric had a little figure this morning of a


 21   triangle.  I didn't know he had a triangle so I


 22   brought a triangle too, but my triangle is a little


 23   bit different.  It makes a different point.  The


 24   point of this triangle is that in the center of the


 25   process are the participant in the research but




  1   there are many other people involved in this whole


  2   process in which, as I mentioned to you earlier,


  3   the partnership includes the investigator, the


  4   research team, the IRB, other oversight committees


  5   and then institutional officials.  So, I view this


  6   more as a partnership, not just the responsibility


  7   of one individual.


  8             One of the things I want to cover is point


  9   number one and point number three on this slide,


 10   which is how can we systematically approach some of


 11   these problems in terms of monitoring and adverse


 12   event reporting.


 13             So, I think the first step whenever you


 14   deal with a promise to define a problem in this


 15   case is what needs to be monitored and what needs


 16   to be reported.  I think that is a good point to


 17   start and I will talk about that in a minute; then,


 18   dividing the role, the different committees that


 19   provide some of this oversight and I really won't


 20   go into detail on that although I could during the


 21   discussion if anybody has any questions; and,


 22   lastly, developing an infrastructure to allow this


 23   to happen so that the reporting occurs, that there


 24   is a process of evaluating the reports, and then a


 25   process of acting in a timely manner when there are




  1   concerns.  So, that will be the latter part of my


  2   talk.


  3             As I mentioned to you, we are an NCI


  4   cancer designated center so we also had to comply


  5   and submit an institutional data safety monitoring


  6   plan to the NCI a few years back that was reviewed,


  7   approved, etc., etc., and now we provide our


  8   monitoring under the umbrella of what that plan


  9   says.


 10             So, the first thing was to define what


 11   elements we were going to monitor.  So, we have


 12   kind of followed the parallel system that the NCI


 13   designated in the clinical data update system of


 14   what data should be collected.  We look at patient


 15   specific data, the demographics, date of birth,


 16   gender, those things that we have to collect; the


 17   date of entry into the study; the treatment status,


 18   if the patient has been previously treated, on what


 19   protocols and what therapy the patient was on; and,


 20   if they were off therapy, for what reasons.  All


 21   that gets captured as part of the monitoring of the


 22   patient on the study.


 23             Then, there are subgroup data elements


 24   that are also captured.  Barry mentioned, very


 25   appropriately in his talk, the issue of eligibility




  1   and determining that the right patients go on the


  2   right studies.  One of the things we have done at


  3   St. Jude in the last ten years is we have


  4   established a separate office, which is called the


  5   protocol office which is actually an office that


  6   provides the infrastructure to help investigators


  7   deal with many of these issues.  The protocol


  8   office, obviously, is manned by a group of people


  9   and one of the responsibilities, for example, is


 10   that when an investigator enrolls a patient on a


 11   study we have to fill out electronically an


 12   eligibility check list.  The eligibility check list


 13   gets faxed to that office and a patient-specific


 14   consent is generated for that patient on that


 15   study.  So, right at the beginning there are some


 16   checks and balances in terms of the eligibility of


 17   the patient so that the right patient is put on the


 18   right study and the correct consent is used for


 19   that patient.  So, that is an ongoing process that


 20   occurs early on during the trial and the patient


 21   enrollment of the trial.


 22             Once the patient receives the therapy,


 23   they monitor the cycle or the course of therapy.


 24   If is a Phase I study, what dose level the patient


 25   is currently being treated with; the start date;




  1   some other parameters like BSA and weight.  They


  2   monitor, particularly in Phase I studies, the


  3   agent; the dose of the agent; if there have been


  4   any modifications, why there have been


  5   modifications.  We will talk a little bit about


  6   adverse event reporting later on.  Then, as part of


  7   the monitoring during certain periods of the trial,


  8   the patients will be monitored in terms of response


  9   because the trials will have stopping rules based


 10   on response, not only in terms of toxicity but also


 11   in terms of response so a Phase II trial that has


 12   some response built-in stopping rules will be


 13   stopped at the right point once the monitoring is


 14   occurring in terms of the response that has been


 15   achieved.


 16             I tried to summarize this in two or three


 17   slides.  This is kind of how we do it at St. Jude


 18   in terms of our own institutional Phase I/Phase II.


 19   We don't do many Phase III but we do have an


 20   auditing plan for Phase III studies and for some


 21   studies in which we hold the IND.


 22             So, for Phase I studies the central


 23   elements in terms of demographics, eligibility and


 24   informed consent, that is monitored continuously.


 25   It is monitored continuously because I told you




  1   that there is a check at the beginning in terms of


  2   eligibility and in terms of informed consent that


  3   occurs in real time when the patient gets


  4   registered.  So, that is done continuously as the


  5   patients go on a study in a Phase I study.


  6             The protocol office also is monitoring the


  7   study in terms of the data elements for the study


  8   so there are templates very similar to the RDE


  9   system that is developed by COG, templates of data


 10   capture forms.  Those data capture forms are


 11   electronic and the monitor on a monthly basis that


 12   he or she is assigned will go through those and


 13   will see if there is data that is missing.  If


 14   there is data that is missing, a report is


 15   generated to the principal investigator that data


 16   is missing on a monthly basis.  So, it is a good


 17   system in terms that it keeps the research team


 18   kind of continuously on top of making sure the data


 19   is being collected.


 20             On a quarterly basis for a Phase I study


 21   there is a report that is generated.  I will show


 22   you in a minute where the reports go but, in a


 23   nutshell, it goes, obviously, to the principal


 24   investigator and to the research team, and then it


 25   goes to the subcommittee of the scientific review




  1   committee that also oversees monitoring to make


  2   sure that they are separate from the protocol


  3   office and from the investigator looking at this


  4   data.


  5             Then, for every Phase I study that we are


  6   the primary sponsor of at St. Jude, the first three


  7   patients enrolled in the study are monitored.


  8   Then, once the first three patients are monitored,


  9   one additional patient per dose level is monitored


 10   in real time.  The idea of doing the first three


 11   patients is that in many studies usually within the


 12   first three patients you know if your systems are


 13   in the right checks and balances so that you want


 14   to monitor those first three patients very acutely


 15   so if there is a problem with the system, with the


 16   templates, with potentially things not going right,


 17   you can pick it up very quickly and make the right


 18   adjustment so that for the subsequent dose levels,


 19   if you monitor one patient in real time, you should


 20   have resolved all of that.


 21             We do a lot of Phase II studies at St.


 22   Jude and we also do the eligibility, essential


 23   elements and consents as outlined here.  We also do


 24   missing data reports on a quarterly basis.


 25   Obviously, in Phase II, just like in Phase I, you




  1   are interested in adverse events and those are


  2   reported quarterly.  Then, on a semiannual basis


  3   the monitors will verify the coding of response so


  4   that the studies can be stopped if the response


  5   criteria for stopping rules have been met.  There


  6   are reports semiannually or more frequently or less


  7   frequently, as defined by the protocol, in terms of


  8   the individual monitoring plan that the protocol


  9   may have.


 10             In Phase II we always monitor the first


 11   two patients plus at least--and the clever word


 12   here is "at least" ten percent of the total


 13   patients that are being accrued.  It could be


 14   greater than ten percent.  It depends obviously on


 15   the resources that you have available and the


 16   workload that the specific monitor may have but at


 17   a minimum ten percent of the patients on any Phase


 18   II study at any given time should be under active


 19   monitoring.


 20             We don't do many Phase III studies at St.


 21   Jude but we do have a marching plan in the event


 22   that there is a Phase III study and it parallels


 23   the Phase II monitoring plan, with the exception


 24   that there may be other primary objectives in the


 25   Phase III trials that also require some monitoring.




  1             St. Jude holds INDs or IDEs for a few


  2   products so under those circumstances, they could


  3   be Phase I or Phase II trials or whatever, but


  4   separately from those, if there is a particular IND


  5   or IDE for which St. Jude is the "sponsor" then


  6   there is a specific monitoring plan that is


  7   assigned to that study, and it will depend on the


  8   risk, what is known about the IND drug, what is


  9   known about the device, etc., etc., and may be more


 10   strict but at least it will be just like Phase I or


 11   Phase II studies I described to you before.


 12   Usually, under some circumstances like some novel


 13   therapy, it may be a little bit stricter in that


 14   the studies are being monitored a little bit more


 15   aggressively.


 16             So, this is kind of in a nutshell how we


 17   kind of agree with the NCI in our data safety


 18   monitoring plan and how we would monitor our


 19   studies.  Having said that, there is also auditing


 20   that occurs.  So, there is a different auditing


 21   plan that I am going to give a lot of detail about,


 22   but for most auditing plans the monitors, once the


 23   study is done, will make sure that at least 20


 24   percent of the patients have had a full audit of


 25   their records.  But that is after the study is done




  1   and that occurs over a long period of time.  It is


  2   not as active as the actual monitoring which is


  3   occurring in real time.


  4             I want to switch now and talk a little bit


  5   about the issue of adverse event reporting which


  6   has to do with monitoring and safety.  We, at St.


  7   Jude, also have struggled with this issue and we


  8   struggle because there are a lot of problems in


  9   reporting.  There tends to be a lot of


 10   over-reporting.  That is, anticipated adverse


 11   events that are known in the investigator's


 12   brochure or known from other clinical trials are


 13   being reported on a continuous basis and that


 14   creates a big backlog of data that is important but


 15   not important in real time in terms of monitoring.


 16             As you all know, there is increased


 17   research in new drugs and biologics.  There is more


 18   oversight and scrutiny by federal agencies.  Just


 19   like in many other places, we tend to get


 20   saturation effects.  There comes a point where you


 21   see so many reports that it doesn't ring a bell; it


 22   doesn't ring any whistles or anything like that.


 23   So, we have to be careful that we don't over-report


 24   because then it gets us into the saturation effect


 25   and we don't react appropriately when there are red




  1   flags that we should be paying attention to.


  2             But one of the problems we have at St.


  3   Jude, which is very common for pediatric


  4   institutions, is that there are no denominators for


  5   how to make any sense of this; what constitutes a


  6   red flag?  Where do you cut the line to say this is


  7   important or this is not important?  There is no


  8   normative data for each of the populations that we


  9   have to deal with for Phase I studies, for Phase II


 10   studies and for the studies I mentioned to you.


 11   So, trying to approach this problem, we have tried


 12   to deal with this I think in a prospective way.


 13             In terms of review, there are a lot of


 14   external events that we get from study sponsors.


 15   If there happens to be a drug that we are doing a


 16   study with but the drug is being used in adult


 17   studies or in other institutions, you know, the


 18   sponsors package a lot AEs and send them to you and


 19   we have to deal with those too.  The problem with


 20   those is that sometimes the information is very


 21   sketchy and there is no opportunity for


 22   clarifications or for questions so that then you


 23   can put that in the context of your own experience


 24   with your own patients at your own institution.


 25             The other thing is that the IRB is not a




  1   DSMB.  A DSMB has a very specific role; the IRB has


  2   to deal with a lot of other issues.  They have to


  3   deal with adverse events and they should be looking


  4   at them and they should be judging them, but it is


  5   clearly in the context of the whole package of the


  6   research, whereas the DSMB has very specific roles


  7   and responsibilities.


  8             The IRB is not the FDA who holds the IND


  9   file for the drug and knows everything.  So, the


 10   IRB over here is getting little pieces of


 11   information and trying to make sense out of it in a


 12   more global sense.  Then, the IRB also needs to


 13   rely on the local investigators to interpret the


 14   meaning of the adverse events that they are


 15   receiving from the outside, from the sponsors,


 16   because clearly the IRB doesn't have the expertise


 17   or the knowledge to put that in contextual features


 18   in terms of the study as it is being conducted at


 19   other institutions.


 20             So, at St. Jude we decided to approach


 21   this problem first by doing quality improvement


 22   projects, trying to figure out where the problems


 23   were and where we could attach the problems.  One


 24   of the first issues that we addressed is that at


 25   the beginning the PI or the research team needs to




  1   report and categorize the events, but there was no


  2   systematic way of doing that.  I mean, it was being


  3   done in paper form; there were different versions


  4   of that paper form.


  5             One of the things that Don Workman and I


  6   recognized is that at least if at the beginning we


  7   could make this a standardized way and force


  8   everybody to do it the same way, then five, ten


  9   years later we actually would have a system in


 10   place that would provide a lot of the normative


 11   data that we would need in order then to do some


 12   process improvement.


 13             So, the first thing that we did is to


 14   create this electronic submission that I will


 15   describe to you in a few minutes.  This electronic


 16   submission is pretty neat I think, to use words of


 17   my nephew--it is pretty neat because it allows you


 18   then to disseminate that information very quickly


 19   to all the key players in the field and then they


 20   can do their own assessment the same time that the


 21   IRB is doing their assessment.  So, the IRB will


 22   get a copy of this electronic adverse event and the


 23   IRB will do their own assessment of the adverse


 24   event and certainly give feedback and follow-up to


 25   the investigator.  At the same time that it goes to




  1   the IRB, it goes to our office of regulatory


  2   affairs which is also charged with making sure that


  3   agencies that have to be notified about these


  4   adverse events are also notified.  So, it kind of


  5   takes the IRB and the investigator away from that


  6   responsibility of having do to that paperwork but


  7   it goes to a central office that then now deals


  8   with all the external agencies that have to look at


  9   this data.


 10             Internally, it goes in a different


 11   direction.  It goes to the vice president of


 12   clinical trials for internal reporting and internal


 13   processing so that the St. Jude DSMB or what we


 14   call our scientific review council which is called


 15   the CPSRMC, the clinical protocol scientific review


 16   monitoring committee, is really the scientific


 17   council which also has a function in terms of the


 18   cancer center doing monitoring.  They also get a


 19   copy of the report and then they deal with it


 20   internally and then they can give also feedback to


 21   the principal investigator.


 22             Don and I were very concerned with the


 23   first step in this process to try and make it


 24   uniform and to try to make it normative so that we


 25   could then create a system that, hopefully, would




  1   help us in retrospect.  So, we started this about


  2   18 months ago.  The first thing we did is we said


  3   let's create a form that is standardized.  We can


  4   then make sure that people understand what is


  5   important in that form before we convert it into an


  6   electronic format.  Then we were able, as we


  7   designed the form, to start thinking prospectively


  8   of how that same data could be captured


  9   electronically.


 10             Then we developed a flow diagram as a


 11   quality improvement project of where this web-based


 12   report could go, which is a little bit of what I


 13   just showed you.  We had to deal with some issues


 14   of security access and then we also had to deal


 15   with some issues of electronic signature that we


 16   eventually resolved.


 17             One of the key features of this, which is


 18   a recurrent problem in adverse event reporting, is


 19   that there are databases and the databases don't


 20   talk to each other.  So, one of the key features


 21   that we wanted to cover in this was to make sure


 22   that this adverse event electronic reporter was


 23   talking to the other databases in the hospital and


 24   was capturing information from the protocol office


 25   in terms of the protocol that the patient was




  1   registered on and the additional protocols was that


  2   the patient was registered on because there could


  3   be some cross-talk between adverse events on


  4   different protocols or different PIs.  I will show


  5   you an example at the end.


  6             We also wanted to make this user friendly


  7   and make sure that anybody who is part of the


  8   research team could do this at any place in the


  9   hospital.  Through a security pass they could


 10   access this web site and could potentially feed in


 11   the information in a very quick manner, without


 12   having to go to a dark office somewhere and grab


 13   papers and try to do it.  So, there were some


 14   security access issues that got resolved but it was


 15   made available to anybody on the research team


 16   electronically.


 17             We then tried to address the issue of


 18   internal reporting, that is studies in which


 19   adverse events are occurring in our patients at our


 20   institution versus the information of adverse


 21   events that are occurring at other sites that are


 22   being fed into our protocols in terms of the


 23   cooperative group studies, and so on and so forth.


 24   So, one of the things that we had to address is how


 25   we could link protocols so that the information




  1   could be identified very easily.  If a patient was


  2   registered on one protocol and the adverse event


  3   occurred on that protocol, we wanted to know what


  4   additional studies that patient was enrolled on so


  5   that when the IRB or the subcommittees reviewed


  6   this they could begin to get trends if there were


  7   complementary adverse events that were occurring


  8   from complementary studies and there could have


  9   been a red flag there that we needed to address.


 10             In addition, we could share the


 11   information with the PIs of the other studies


 12   because they also have to be kept in the loop in


 13   terms of what is happening to patients that


 14   potentially may also be enrolled in their own


 15   studies concomitantly, for example therapeutic


 16   versus non-therapeutic studies.


 17             Then, for external reports we wanted the


 18   investigators to help us sort that out because we


 19   couldn't sort it out.  So, the investigators had to


 20   invest some time at the beginning sorting out


 21   external reports before they submitted them to us


 22   so that they would be more meaningful to us.


 23             Then, the functional outcomes would be


 24   that there would be real-time reporting and that


 25   the IRB would acknowledge that through some




  1   electronic time stamping mechanism.  There are


  2   forced choices so that everybody has to do it the


  3   same way; no incomplete data submissions so we


  4   wouldn't have to address the issue of going back


  5   and asking for more clarification and more


  6   questions; easy access so it would be friendly;


  7   ability to generate single incident reports;


  8   ability to generate reports in a given time period.


  9   If you were noting a trend that something was


 10   occurring in a particular study over some period of


 11   time, you could capture that and, as you will see


 12   in the end, provide cumulative data that you could


 13   sort out to look at trends that potentially could


 14   be occurring.  Quicker reporting times; ability for


 15   the IRB office to generate reports based on


 16   protocols; specific events across subjects, across


 17   protocols to give us some functionality at the IRB


 18   level to look at the data in different ways;


 19   generate internal denominators of trends that we


 20   wanted to look at; use standardized NCI toxicity


 21   tables for the oncology trials; and be able to


 22   record the IRB actions and updates from


 23   investigators onto previous reports.  So, it wasn't


 24   a dead system.  It was a system that the


 25   investigator could go back and add more information




  1   or, when the IRB reviewed it, could add more


  2   information so it became a living document as the


  3   report was being done.


  4             Let me give you an example of how this


  5   works.  I couldn't get it electronically.  It was


  6   going to cost me money to be able to do this


  7   electronically so I did some snapshots of what it


  8   looks like.


  9             So, this page is accessible to anybody who


 10   is identified at St. Jude as a principal


 11   investigator or a member of a research team.  So,


 12   if you are listed on the protocol as the nurse for


 13   that study, as the statistician for that study, as


 14   a pharmacist for that study, automatically you get


 15   access to this through a user ID and your own


 16   password.  So, it is available to anybody who is


 17   part of the research team.


 18             This is how you log in.  Here I logged in


 19   and it says, "welcome, Victor Santana."  Then it


 20   gives a listing of all the events that have


 21   accumulated during a particular period of time.  It


 22   gives the event ID which is an internal working


 23   number.  It gives the event date.  It gives an


 24   identifier that I have erased here for a particular


 25   patient.  It is usually a numerical number.  If it




  1   is an external event, then there is a way to code


  2   that to an external number.  Sometimes you get an


  3   event from a sponsor and it is coded ABXY235, well,


  4   there is a way that you can code that the same way


  5   here so you can track it and use the same codifier


  6   if you ever have to go back to the data.


  7             The status tells me, as an investigator,


  8   whether I have reviewed this or not.  So, when I


  9   copied this the other day I only had one adverse


 10   event that I had yet to review that somebody sent


 11   to me for comment.  Then, it tells me the date that


 12   the event was reviewed by me or that I modified it


 13   or I did anything to it.


 14             Very quickly, it goes through a couple of


 15   screens that provide some general information.  It


 16   tells you whether it is a St. Jude patient or not


 17   because if it is not, it throws you in a different


 18   direction in terms of the data that you need to


 19   capture because, clearly, the data is being


 20   captured for external adverse events a little bit


 21   differently than it is for internal.  There is some


 22   information here in terms of the patient.


 23             Then, it begins to do its own internal


 24   processing once it identifies the patient.  It


 25   tells us, as you see at the top of the screen, all




  1   the protocols that this patient is registered on.


  2   So, it goes back and talks to the data warehouse.


  3   If this patient is enrolled on ten studies, it will


  4   pull and identify all those ten studies.  Then it


  5   will ask me, as the person putting in the


  6   information, under what study am I following this


  7   report.  So, it identifies primarily the study and


  8   the adverse event, but it also tells me all the


  9   other studies the patient is on, and this is


 10   critical because this report will go to the PIs of


 11   all those other studies too.  You will see it at


 12   the end for their comments.  So, it provides a


 13   little bit of a cross-talk among studies.


 14             Then, it clearly identifies the type of


 15   adverse event that is being reported.  You have all


 16   seen this in different variations.  For adverse


 17   events that require a CTC code it takes you to the


 18   CTC code so there is a link too so you don't have


 19   to scramble through 50 books looking for those


 20   codes but automatically it links you to those


 21   codes.  Then, it allows you to put the descriptor,


 22   etc., etc.  So, it is all being captured in a


 23   uniform language.


 24             Then it goes to a page that allows the


 25   person who is submitting the information to do some




  1   attribution on the adverse event.  It is a click


  2   system but it reminds people, because we all tend


  3   to forget, what each one of those words means.  So,


  4   it reminds me that I need to read when something is


  5   serious; when something is unexpected.  It defines


  6   it very clearly because there are always a lot of


  7   questions from members of the research team what


  8   constitutes something that is unexpected versus


  9   expected.  Well, there it is.  It is, hopefully,


 10   black and white and then you select, based on your


 11   interpretation.  It allows you to do one selection


 12   across lines horizontally for each one of those.


 13             Then, there is a page that allows you to


 14   provide more information.  One of the problems


 15   always with electronic information is that


 16   sometimes you can't capture everything in a unique


 17   format.  So, there is a page that allows you to do


 18   a little more narrative form of how this all


 19   happened, and so on and so forth, so it can give


 20   you some additional data that you can comment on.


 21             Then it asks you do you think, based on


 22   your interpretation of what has happened with the


 23   adverse event, that there is a follow-up that is


 24   needed.  If you say there is a follow-up needed,


 25   then it links back to a reminder within 30 days




  1   that you owe us a follow-up.  The IRB reviews it


  2   and they also communicate directly.  But if you


  3   think you have enough information and you want to


  4   submit a follow-up, within 30 days you will get a


  5   reminder that you owe us a follow-up.


  6             Then it tells you something about what


  7   happened to the patient based on that adverse


  8   event.  Then it asks the investigator or the


  9   research team to make some judgments based on the


 10   information that they have on that particular


 11   adverse event, and in terms of what they know is


 12   going on in the study does this alter the