1

 

                DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

                      FOOD AND DRUG ADMINISTRATION

 

                CENTER FOR DRUG EVALUATION AND RESEARCH

 

 

 

               PEDIATRIC ONCOLOGY SUBCOMMITTEE COMMITTEE

 

               OF THE ONCOLOGIC DRUGS ADVISORY COMMITTEE

 

 

 

 

 

                       Wednesday, March, 17, 2004

 

                               8:00 a.m.

 

 

 

                           5630 Fishers Lane

                      First Floor Conference Room

                          Rockville, Maryland

 

                                                                 2

                              PARTICIPANTS

 

      ONCOLOGIC DRUGS ADVISORY COMMITTEE:

 

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

         Johanna Clifford, M.S., RN, BSN

 

         Pamela J. Haylock, RN,

           Consumer Representative, ODAC

 

      CONSULTANTS (VOTING):

 

         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.

      ACTING INDUSTRY REPRESENTATIVE (NON-VOTING):

 

         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.

 

                                                                 3

 

                            C O N T E N T S

 

                                                              PAGE

 

      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

 

                                                                 4

 

                      C O N T E N T S (Continued)

 

                                                              PAGE

      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

 

                                                                 5

 

  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,

 

                                                                 6

 

  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

 

                                                                 7

 

  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

 

                                                                 8

 

  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

 

                                                                 9

 

  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

 

                                                                10

 

  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

 

                                                                11

 

  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

 

                                                                12

 

  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

 

                                                                13

 

  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

 

                                                                14

 

  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

 

                                                                15

 

  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.

 

                                                                16

 

  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

 

                                                                17

 

  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.

 

                                                                18

 

  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

 

                                                                19

 

  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

 

                                                                20

 

  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

 

                                                                21

 

  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

 

                                                                22

 

  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

 

                                                                23

 

  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

 

                                                                24

 

  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,

 

                                                                25

 

  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

 

                                                                26

 

  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

 

                                                                27

 

  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

 

                                                                28

 

  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

 

                                                                29

 

  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

 

                                                                30

 

  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

 

                                                                31

 

  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

 

                                                                32

 

  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

 

                                                                33

 

  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

 

                                                                34

 

  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

 

                                                                35

 

  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

 

                                                                36

 

  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

 

                                                                37

 

  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

 

                                                                38

 

  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

 

                                                                39

 

  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

 

                                                                40

 

  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,

 

                                                                41

 

  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

 

                                                                42

 

  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

 

                                                                43

 

  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?

 

                                                                44

 

  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

 

                                                                45

 

  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

 

                                                                46

 

  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

 

                                                                47

 

  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

 

                                                                48

 

  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

 

                                                                49

 

  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

 

                                                                50

 

  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

 

                                                                51

 

  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

 

                                                                52

 

  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

 

                                                                53

 

  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

 

                                                                54

 

  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

 

                                                                55

 

  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

 

                                                                56

 

  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

 

                                                                57

 

  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

 

                                                                58

 

  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

 

                                                                59

 

  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

 

                                                                60

 

  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

 

                                                                61

 

  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

 

                                                                62

 

  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,

 

                                                                63

 

  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.

 

                                                                64

 

  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

 

                                                                65

 

  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

 

                                                                66

 

  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. 

 

                                                                67

 

  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.

 

                                                                68

 

  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

 

                                                                69

 

  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

 

                                                                70

 

  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

 

                                                                71

 

  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

 

                                                                72

 

  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

 

                                                                73

 

  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

 

                                                                74

 

  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

 

                                                                75

 

  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. 

 

                                                                76

 

  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

 

                                                                77

 

  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

 

                                                                78

 

  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

 

                                                                79

 

  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

 

                                                                80

 

  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

 

                                                                81

 

  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

 

                                                                82

 

  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

 

                                                                83

 

  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

 

                                                                84

 

  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

 

                                                                85

 

  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

 

                                                                86

 

  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

 

                                                                87

 

  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]

 

                                                                88

 

  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. 

 

                                                                89

 

  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

 

                                                                90

 

  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

 

                                                                91

 

  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

 

                                                                92

 

  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

 

                                                                93

 

  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;

 

                                                                94

 

  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

 

                                                                95

 

  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

 

                                                                96

 

  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

 

                                                                97

 

  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.

 

                                                                98

 

  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

 

                                                                99

 

  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

 

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  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

 

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  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

 

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  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

 

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  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

 

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  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

 

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  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

 

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  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

 

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  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

 

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  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

 

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  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

 

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  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

 

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  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

 

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  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