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
First Floor Conference Room
ONCOLOGIC DRUGS ADVISORY COMMITTEE:
Donna Przepiorka, MD., Ph.D., Chair, ODAC
Johanna Clifford, M.S., RN, BSN
Pamela J. Haylock, RN,
Consumer Representative, ODAC
Victor Santana, M.D., Chair
Peter Adamson, M.D.
Alice Ettinger, M.S., RN
Peter Houghton, Ph.D.
Eric Kodish, M.D.
C. Patrick Reynolds, M.D., Ph.D.
Susan Weiner, Ph.D.
Ruth Hoffman, Patient Representative
Barry Anderson, M.D., Ph.D.
Lee J. Helman, M.D.
Malcolm Smith, M.D., Ph.D.
Paul Meltzer, M.D.
Chand Khanna, DVM, Ph.D., DACVIM
Kenneth Hastings, Ph.D.
ACTING INDUSTRY REPRESENTATIVE (NON-VOTING):
Antonio Grillo-Lopez, M.D.,
Susan Ellenberg, Ph.D.
Steven Hirschfeld, M.D., Ph.D.
Ramzi Dagher, M.D.
Richard Pazdur, M.D.
Patricia Keegan, M.D.
Pat Dinndorf, M.D.
Grant Williams, M.D.
C O N T E N T S
Call to Order, Victor Santana, M.D., Chair 5
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
Victor Santana, M.D., St. Jude
Children's Hospital 88
Committee Discussion 116
Questions for Discussion 154
C O N T E N T S (Continued)
Use of Nonclinical Data to Complement Clinical Data
for Pediatric Oncology:
What are Microarrays and How Can They Help Us
with Clinical Studies in Pediatric Oncology,
Paul Meltzer, National Human Genome Research
Institute, NIH 198
Advantages and Limitations of Cell Culture Models
in Pediatric Drug Developments,
Peter Adamson, M.D., Children's Hospital
of Philadelphia 210
Human Cell-Animal Xenografts: The Current Status,
Potential and Limits of Informing Us About
Clinical Studies, Peter Houghton, Ph.D., St.
Jude Children's Research Hospital 229
An Integrated and Comparative Approach to
Preclinical/Clinical Drug Development,
Chand Khanna, DVM, Ph.D.,
Tumor and Metastasis Biology Section, NIH 248
What Can be Learned About Safety,
Kenneth Hastings, Ph.D., CDER, FDA 263
Assessing Anti-Tumor Activity in Nonclinical Models
of Childhood Cancer, Malcolm Smith, M.D., Ph.D.,
Treatment Evaluation Program, National Cancer
Institutes, NIH 280
Committee Discussion 294
Questions for Discussion 306
1 P R O C E E D I N G S
2 Call to Order
3 DR. SANTANA: Good morning to everyone. I
4 know Dr. Kodish is on the line so good morning to
5 you too, Eric. I hope you can hear us well.
6 DR. KODISH: Good morning, Victor.
7 DR. SANTANA: This is a meeting of the
8 Pediatric Oncology Subcommittee of the Oncology
9 Drugs Advisory Committee and we are here today to
10 advise the agency on two issues. In the morning we
11 will deal with the issue of safety monitoring in
12 clinical studies enrolling pediatric oncology
13 patients. Then, in the afternoon we will address
14 issues related to the use of nonclinical data to
15 complement clinical data for proposed pediatric
16 oncology studies. So, we have quite a busy agenda
17 and I think we will go ahead and get started with
18 the introductions, and I am feeling so sorry for
19 Dr. Anderson who is sitting all by himself over
20 there, but we will go ahead and get started with
21 him and then move around.
23 DR. ANDERSON: Barry Anderson, from NCI
DR. GRILLO-LOPEZ: Antonio
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
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.
DR. SANTANA: Eric, will you go
1 announce your name and affiliation for the record?
2 DR. KODISH: I am Eric Kodish, from
3 Cleveland, Ohio, Rainbow Babies & Children's
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
any conflict of interest existed, the agency has
1 reviewed the agenda and all relevant financial
2 interests reported by the meeting participants.
3 The Food and Drug Administration has granted
4 general matters waivers to the special government
5 employees participating in this meeting who require
6 a waiver under Title 18, United States Code,
7 Section 208.
8 A copy of the waiver statements may be
9 obtained by submitting a written request to the
10 agency's Freedom of Information Office, Room 12A-30
11 of the Parklawn Building.
12 Because general topics impact so many
13 entities, it is not prudent to recite all potential
14 conflicts of interest as they apply to each member
15 and consultant and guest speaker. FDA acknowledges
16 that there may be potential conflicts of interest
17 but, because of the general nature of the
18 discussion before the committee, these potential
19 conflicts are mitigated.
20 With respect to FDA's invited industry
21 representative, we would like to disclose that Dr.
22 Antonio Grillo-Lopez is participating in this
23 meeting as an acting industry representative,
24 acting on behalf of regulated industry. Dr.
Grillo-Lopez is employed by Neoplastic and
1 Autoimmune Diseases Research.
2 In the event that the discussions involve
3 any other products or firms not already on the
4 agenda for which FDA participants have a financial
5 interest, the participants' involvement and their
6 exclusion will be noted for the record.
7 With respect to all other participants, we
8 ask in the interest of fairness that they address
9 any current or previous financial involvement with
10 any firm whose product they may with to comment
11 upon. Thank you.
12 DR. SANTANA: Thanks, Johanna. Anybody
13 else sitting at the table that wants to disclose
14 anything publicly? No? Dr. Adamson just joined
15 the group. Do you want to introduce yourself,
16 Peter, please?
17 DR. ADAMSON: Peter Adamson, from
18 Children's Hospital of Philadelphia.
19 DR. SANTANA: Thanks, Peter. Peter, do
20 you want to introduce yourself?
21 DR. HOUGHTON: Peter Houghton, St. Jude
22 Children's Research Hospital.
23 DR. SANTANA: With that, I will pass it
24 over to Dr. Pazdur for his opening remarks.
25 Opening Remarks
1 DR. PAZDUR: Well, I would like to
2 disclose something publicly, my disappointment with
3 Victor and Johanna for not mentioning this but the
4 disclosure is happy St. Patrick's Day.
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?
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.
We look at these as very important
1 thematic discussions to have. How these areas
2 impact on oncology drug development I think is very
3 important. One thing that I would ask the
4 committee to do specifically is to concentrate
5 really on the pediatric aspect of these. I know
6 that these areas have some tentacles to adult
7 oncology and to other areas of oncology but I would
8 like to remind you that the purpose of this
9 subcommittee is to focus on the pediatric
10 specificity of these issues and special
11 considerations of these broad issues in pediatric
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
acknowledgments initially. The
first one is to
1 someone who is in the room right now and I am
2 looking at her, and that is Johanna Clifford who
3 has done I think a marvelous job in helping to
4 organize this meeting, and we have had a number of
5 challenges to overcome along the way, so many
6 challenges that for a period of time we thought we
7 were working under a curse, but Johanna has been
8 steadfast, good humored, competent, rapid in her
9 responses and has been I think a driving force in
10 terms of having the meeting occur as it is and as
11 well organized as it is today. So, thank you,
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
direction, which I think has been an asset not
1 only to the agency but to the country and to all
2 patients. And, I wanted to dedicate the discussion
3 this morning in her honor. So, thank you, Bonnie.
4 As Dr. Pazdur pointed out, we are going to
5 be discussing the themes of safety and
6 extrapolation. Clinical research, which we have
7 discussed in some detail in this forum over several
8 of the meetings, has been recorded for at least
9 2,400 years. Children were often the first
10 patients for new procedures and interventions.
11 Part of this evolved from the concept that children
12 were the property of parents so it was rather easy
13 for parents to donate their children for whatever
14 questions might be asked. But along the way there
15 were some founding principles because,
16 unfortunately, children have also been the victims
17 of clinical research.
18 The founding principles of modern Food and
19 Drug Administration regulation were, in large part,
20 established for the purpose of protecting children
21 and, yet, pediatric therapeutic development has
22 never been as thorough and robust as adult
23 therapeutic development, and most of the people in
24 this room have been part of that process and
witness to these inequities. Many
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
research framework has the best resources, and the
1 best advice, and the best support, and the best
2 regulatory environment to do its job.
3 The particular issues regarding the safety
4 monitoring in pediatric oncology clinical
5 investigations are an acknowledgment that children
6 require special protections. Yet, on the other
7 hand, there is also an acknowledgment that risk
8 tolerance is higher in oncology therapeutics than
9 in other therapeutic areas. This sets up a
10 potential tension. Furthermore, there are no
11 detailed consensus standards on study monitoring
12 despite numerous international documents describing
13 what could be termed good clinical practice. We
14 will examine those in some detail during the course
15 of the morning. So, the charge to the committee is
16 to suggest ways to incorporate the fundamental
17 ethical and scientific principles in protecting
18 patients enrolled in clinical studies for pediatric
19 malignancies while providing clear guidance and
20 minimizing the resource burden.
21 We have a series of questions directed
22 toward the committee to help focus the discussion.
23 These are questions which are meant to stimulate
24 what we hope will be an informative exchange and do
have a yes/no or a definitive answer.
1 The first questions revolves around the
2 principles, what are the principles that should be
3 addressed in safety monitoring of clinical studies
4 that enroll children with cancer? Dr. Kodish is
5 going to provide us with some background on that
6 particular topic. If the principles are adequately
7 stated in existing documents. statutes or
8 regulations, please identify the relevant documents
9 and sections.
10 The second set of questions deals with the
11 practice. Recognizing that particular populations,
12 disease settings and products may have specific
13 requirements, what general parameters should be
14 monitored for safety in all clinical studies? Or,
15 to rephrase that, what should the default position
16 be for safety monitoring?
17 Based on the response to the previous
18 question, how often should these parameters be
19 monitored? Again, just giving a framework or
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
discuss this in detail we may parse this out
1 into the type of study, whether it is early
2 development or later development or the type of
3 disease or other risk factors.
4 What circumstances would benefit from a
5 data monitoring committee? And, are there
6 additional recommendations for safety monitoring?
7 The afternoon will be devoted to a
8 question which can be traced back to the principle
9 of extrapolation. Extrapolation has been a topic
10 of interest within the Food and Drug Administration
11 for many years. In recent years there has been an
12 FDA working group on pediatric extrapolation that
13 has identified four domains that may provide a
14 basis for extrapolation of adult data to the
15 pediatric population. These are nonclinical data,
16 pathophysiology, natural history of the disease or
17 condition, and response to therapy.
18 When our group, noted at the bottom of the
19 slide and some of the members are present here in
20 the audience, asked ourselves the question how can
21 we use nonclinical data to inform us about
22 pediatric clinical studies, and in particular
23 pediatric studies in clinical oncology, we realized
24 we needed further background and further discussion
before we could have an informed approach to it.
1 We recognize that the absence of
2 predictive or explanatory nonclinical models in
3 pediatric oncology is today's status quo. We know
4 that safety prediction based on animal studies is
5 estimated at approximately 65-70 percent for
6 cytotoxic compounds and it is unknown for other
7 classes of compounds, particularly the new biologic
8 therapies, gene therapies, immunotherapy, and
9 cellular-based therapies. Efficacy prediction is
10 unknown but low at best. The findings in clinical
11 studies, particularly negative studies, often
12 remain unexplained.
13 Therefore, further clinical studies that
14 entail resources and risks are undertaken to
15 further the field, and we are posing the paradigm
16 is there a mechanism by which we can use
17 nonclinical data to inform us and improve the
18 clinical research in pediatric oncology. There are
19 potential advantages of using the nonclinical data:
20 a lesser resource burden; the ability to answer
21 questions not amenable to available clinical
22 techniques. There might be ethical or, in fact,
23 legal considerations involved too; possibly a
24 faster time frame to generate data; a dynamic
interaction between clinical and nonclinical
1 findings that can enhance understanding and
2 confidence in results. When we only have a
3 sufficient population to do one definitive study,
4 and that study takes three to five years and it is
5 not feasible to do a confirmatory study, having
6 confidence in those results is critical. The
7 avoidance of non-informative and minimization of
8 negative outcome studies could be another outgrowth
9 and an opportunity for new study designs.
10 So, the charge to the committee for this
11 afternoon is to provide advice on what types of
12 nonclinical data are considered informative to
13 complement or supplement clinical results. What
14 should the characteristics or properties of
15 nonclinical models and data be to effectively add
16 to the clinical results?
17 If there are no satisfactory models that
18 exist currently, and we will hear some discussion
19 on approaches, what characteristics should a
20 nonclinical model have to confirm, extend or
21 substitute for clinical results?
22 Lastly, is there a set of postulates that
23 can be identified, or should a set be developed to
24 help us make the transition for data extrapolation?
the questions we are asking are what types of
1 questions that are of potential clinical relevance
2 but are not feasible or acceptable to answer in a
3 clinical study could be addressed by nonclinical
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,
long-term effects, developmental aspects and others
1 which I am sure will come up.
2 Are there additional recommendations for
3 the effective use of nonclinical data? For
4 example, will open literature reports be generally
5 acceptable? Is documentation of compliance with
6 Good Laboratory Practice necessary to evaluate
7 animal data? Should nonclinical data be submitted
8 as an independent report with a presentation of
9 primary data sufficient for verification and
10 review? These are all practical questions and we
11 are looking for specific advice.
12 So, with this charge and these questions
13 before you, I would like to thank all the committee
14 members and our speakers and guests, and everyone
15 who has shown an interest here for participating in
16 this discussion, and I will turn now the further
17 presentation over to Dr. Eric Kodish, who will
18 discuss the fundamental principles involved in
19 clinical research and some of the issues of
20 enrolling children.
21 Dr. Santana, I think perhaps before we
22 have Dr. Kodish speak--we have some more members of
23 the panel that should be introduced.
24 DR. SANTANA: Yes. Anybody that joined us
little bit late, could you please identify
1 yourself into the microphone by name and
2 affiliation, and any potential conflicts that may
3 have arisen since we started?
4 MS. HAYLOCK: I am Pam Haylock. I am an
5 oncology nurse and I am at the University of Texas
6 Medical Branch, in Galveston.
7 DR. SMITH: I am Malcolm Smith, pediatric
8 oncologist at the Cancer Therapy Evaluation
9 Program, NCI.
10 DR. SANTANA: Dr. Grillo, you had your
11 hand up?
12 DR. GRILLO-LOPEZ: Yes, a point of
13 clarification that I would like to propose to Dr.
14 Hirschfeld. On his first slide on the charge to
15 the committee, which addresses the morning session,
16 you used the phrase "providing clear guidance and
17 minimizing the resource burden" which clearly
18 applies to human resources and financial resources
19 but perhaps doesn't quite stress time. I would
20 suggest that part of your charge to the committee
21 should be that whatever recommendations we propose,
22 and however the FDA understands and decides to
23 apply those recommendations, should not affect the
24 time lines for cancer drug development which today
already intolerably long, and we should be
1 concerned that the cancer patient in general should
2 not be subject to those too long time lines and
3 that anything we do should, in fact, try to reduce
4 the time lines for approval of new therapies.
5 DR. HIRSCHFELD: Thank you for your
6 comments, Dr. Grillo-Lopez. I think you touched on
7 one of the themes which is implied. I personally
8 have always incorporated in the concept resource of
9 time because time is, in fact, probably the most
10 precious resource and, if one looks at biology as a
11 broad spectrum, time is something which evolution
12 and biologic processes look to, to conserve in many
13 ways too. So, I thank you for calling attention to
14 the issue of time, and it is incorporated in that
15 specific charge.
16 DR. SANTANA: One of the philosophic
17 principles of stewardship is that it involves time,
18 people and money resources. So, I think those are
19 all encompassed in your comments.
20 With that, Eric, are you on line now? Can
21 we proceed with you?
22 DR. KODISH: I am on line, Victor.
23 DR. SANTANA: Good. Go ahead, Eric.
24 Protecting Children in Cancer Research:
25 What Really Matters
1 DR. KODISH: Good morning. It is good to
2 be with you virtually, if not physically. I
3 apologize for the inability to get to Washington.
4 We have, hopefully, completed our last big
5 snowstorm of the winter in Cleveland.
6 I am going to be speaking this morning
7 over the telephone and looking at a Webcast of the
8 slides and this is a work in progress so, please,
9 interrupt me if it is not going well and I will
10 switch to my Power Point presentation. I am looking
11 at the Webcast now and I don't see my Power Point
12 slides yet. What I plan to do is ask Johanna to
13 put on the next slide before I move through them.
14 So, let's give it a moment for me to see the first
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--
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,
MS. CLIFFORD: You know what, Dr.
1 if you just want to move on through your
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
principles and practice. I view
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
The next slide, please. This
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
children has to dominate pediatric ethics and
1 justifies an population that takes beneficence as
2 the most important principles.
3 I don't want you to move slides back but,
4 if you recall a few slides ago, the slide that
5 shows moving principles into practice, I think
6 beneficence has to be the principle that drives our
7 interpretation of the regulations and our actual
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
into play, I think it is the second rule that is
1 most appropriate for pediatric oncology studies.
2 That is to say, if one is talking about research
3 involving healthy children with no prospect of
4 benefit to that child, the first rule might be more
5 appropriate to apply, do not harm, period. But we
6 are talking about a balance in pediatric oncology
7 and I think the second general rule is more
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
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
The next slide, please. The
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
exposures of risk to children with cancer the
1 potential to help children with cystic fibrosis,
2 for example, may not be considered significant
3 science by this test. The potential to help adults
4 with Alzheimer's disease may not be significant
5 science by this test.
6 I think that we need to be cognizant of
7 the fact that research involving children with
8 cancer needs to resound back to help children with
9 cancer and that one should look for other avenues
10 to study other important diseases. It is difficult
11 to think of children with cancer as a resource, but
12 I think in some sense this really forces us to do
13 that and, by limiting the risk of exposure to
14 children to that which will come back to help
15 children--and I know that scientifically it is
16 often very difficult to predict in which direction
17 the work will go and how the results will, in fact,
18 play--ut but at the outset one can try to predict
19 and think about a definition of significant as
20 being that which has the potential to help children
21 with cancer.
22 The second thing that really matters
23 before a clinical trial begins is a risk/benefit
24 assessment. I think in the next several slides I
will talk more about what counts as risk and what
1 counts as benefit.
2 Finally, it is a study design that will
3 answer the question and that also does not
4 subjugate the interests of any single subject to
5 the overall needs of the research. Again, embedded
6 there are a couple of important ethical principles
7 that I think are perhaps specific--at least the
8 second one under study design--specific to research
9 with a vulnerable population and, as Dr. Hirschfeld
10 said, children certainly are considered and should
11 be considered.
12 The next slide, please. This slide shows
13 the criteria for the 405 category. As I think
14 everybody is aware, there are four categories of
15 research that can be approved by IRBs under subpart
16 D. Almost all cancer research I think is approved
17 under 405, that is, pediatric cancer research. It
18 is research that involves more than minimal risk
19 but presents the prospect of direct benefit to the
20 individual subject if the risk is justified by the
21 anticipated benefit to the subject; if the
22 risk/benefit ratio is less than or equal to the
23 alternatives; and if parental permission and assent
24 are obtained.
The next slide, please. As we
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.
That is, I think even a very low chance of
1 therapeutic benefit for the child should count as a
2 prospect of direct benefit to the child. Again, my
3 interpretation of the word prospect is a very broad
4 one, admittedly, but this is where the issue of
5 interpretation comes in. As the discussion goes
6 on, we can talk about how prospect ought to be
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
left is a Phase I study; in the middle is
1 alternative medicine and on the right is hospice
2 philosophy care.
3 The next slide shows further
4 considerations regarding Phase I oncology research
5 in children. The first is to point out that
6 subject selection is not a major controversy in
7 this realm, that is to say, Phase I studies are
8 done involving healthy children but it is not an
9 issue of wanting to do Phase I cancer research on
10 healthy children. That, to my knowledge, is not a
11 controversy but I put it here because it is
12 important to try to contextualize pediatric cancer
13 research in the broader picture of research
14 involving children. As I said before, I think that
15 Phase I research qualifies, in my mind, as research
16 with the prospect or direct benefit.
17 Most importantly on this slide, is that
18 potential for benefit mitigates but does not
19 eliminate the need for protection from research
20 risk. To be more clear about that, it is the
21 potential for benefit that is balanced against the
22 risk that mitigates it, but I think the charge to
23 the committee and the work we are going to do this
24 morning is still extremely important. The need for
protection from research risk is not eliminated by
1 the potential for benefit.
2 The next slide, please. This points out
3 some issues around alternative medicine. The
4 reason that I put this here is that I think there
5 is a yardstick of fairness that we need to keep in
6 mind. It is often the case that when research is
7 being done it is held to a higher standard or a
8 different standard than what is happening in the
9 non-research world, and it is very important I
10 think to the families and the children involved
11 that we try to put this in the lens that they are
12 viewing this off from, and to make it difficult to
13 access research or to have children participate in
14 well-designed, safely monitored research, in some
15 ways, runs the risk of shunting them to alternative
16 medicine where there are vulnerability concerns.
17 It is very prevalent phenomena for children with
18 refractory cancer. I think there are major ethical
19 differences when it comes to children getting
20 alternative therapy compared to adults who can make
21 their own decision. I think we have a very
22 important obligation to prevent harm when it comes
23 to children who are getting alternative medicine,
24 and I think it is extremely important that
alternative medicine possibilities be studied in a
1 rigorous and careful way. But the bottom line is
2 that we need to communicate with families and
3 children. The ones that the research community
4 encounters may also be taking alternative medicine
5 and if we don't know what medications are being
6 taken, then we won't have the ability to study drug
7 interaction with alternative medications and the
8 experimental agent, for example. I just think that
9 it is very important that we keep alternative
10 medicine in mind as something that is out there and
11 we shouldn't be blind to it.
12 The next slide, please. This slide has a
13 few words about hospice care for children who have
14 refractory disease. Now, some people I think have
15 the experience that those who come to Phase I
16 studies are self-referred, not interested in
17 hospice philosophy care, wanting to continue to
18 pursue anti-neoplastic therapy but, in my
19 experience, that is not the case. In fact, many
20 families who seek Phase I studies also are amenable
21 to having their child get hospice philosophy care.
22 So, the two are not incompatible. I think it is an
23 under-developed approach in children. It is not
24 the main focus of what we are here about today but
felt that it would be incomplete to give this
1 talk without mentioning that hospice philosophy
2 care should be part of the consent process for
3 Phase I studies.
4 The next slide, please. This moves from
5 what really matters before the conduct of the trial
6 to during the conduct of the trial. The three
7 items that really matter during the conduct of the
8 trial are informed consent which, in my view, is a
9 communication process in addition to the
10 documentation that happens; ongoing monitoring via
11 a data safety monitoring board, if appropriate, and
12 I understand that much of the discussion later on
13 will have to do with when it is appropriate and
14 when it is not necessary; and ethical action to
15 suspend or stop a study at the right time. It is
16 easier said than done but in parentheses I thought
17 I would say not too soon but not too late either.
18 So, the question of when a study should be
19 suspended or stopped is a key ethical question that
20 happens during the conduct of a study and whether a
21 study needs to be stopped at all. I guess in most
22 cases there is no need to stop it but that question
23 needs to be always asked in the same way house
24 officers always need to ask themselves does this
child need a spinal tap. It is a
question that is
1 part of the monitoring process as an embedded
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
children when appropriate and obtaining their
1 assent; and by providing societal protection with
2 IRB approval as the most obvious but also meetings,
3 similar to what we are doing this morning,
4 investigator integrity and other things that
5 provide societal protection for children, we can, I
6 think, ethically do pediatric research.
7 The next slide shows the difference
8 between parental permission and informed consent
9 and, again, says that the autonomous authorization
10 of an adult--the difference between adult and
11 pediatric ethics is more robust than a proxy
12 decision and points out, from the Academy of
13 Pediatrics, that the responsibilities of a
14 pediatrician to his or her patient exist
15 independent of parental desires or proxy consent.
16 I think that there is a congruent statement that
17 one could make here that says that an
18 investigator's responsibility to his or her subject
19 exists independent of parental desires or proxy
21 The next slide shows that parental
22 permission is not the oral equivalent of informed
23 consent, and that surrogate decision-making is
24 necessarily less authentic. I am going to skip
25 past the next slide which shows proxy consent,
1 substituted judgment and best interests, because I
2 think this is familiar ground for most people and
3 we have already emphasized best interests.
4 I will go to a slide that says informed
5 consent in pediatrics equals parental permission
6 and the assent of the child. Here I want to say
7 that the combination of those two can potentially
8 be more powerful, if done right, than an
9 individual. This has to do with family centered
10 ethics that really seek to care for and do
11 effective communication with a family, which is a
12 dynamic and challenging process, admittedly. But I
13 think both of these issues are very important.
14 The next slide, please. This provides the
15 regulatory definition of assent, which is a child's
16 affirmative agreement to participate in research.
17 The key point here is that mere failure to object
18 should not be construed as assent. That is, the
19 silence of an older child for research
20 participation can't be interpreted as their assent.
21 Again, there is room for regulatory interpretation
22 here. There is a great deal of controversy around
23 assent and requirements for assent, and I think
24 there is likely to be a fair amount of variability
across IRBs with regard to this issue and I would
1 be happy to discuss this further during our
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.
shows everything from, number one, a parent who
1 wants to leave all decisions to the doctor and
2 perhaps to an investigator, and then a continuum to
3 number five, a parent who wants to make final
4 selection about which treatment their child will
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.
Can you still hear me?
1 MS. CLIFFORD: We can still hear you.
2 DR. KODISH: Great! I heard a beep on the
3 phone. I am going to tell a quick story to
4 illustrate this point. Heather K was diagnosed
5 with a vaginal rhabdomyosarcoma at a children's
6 hospital in the Midwest within the past few months.
7 At diagnosis, Heather had a tumor that was causing
8 intestinal compression. Her pediatric oncologist
9 talked to the family about the diagnosis and then
10 subsequently discussed a Phase III non-randomized
11 study sponsored by the IRS/COG. The family
12 provided informed consent and signed a document at
13 6:05 p.m. The plan was to begin chemotherapy the
14 following day but the patient developed a bowel
15 obstruction at 11:00 p.m. and chemotherapy was
16 emergently started. At midnight nothing happened
17 that was ethically significant. Clinically, the
18 patient was continuing to get her chemotherapy.
19 But the next morning, when the CRA, the data
20 person, came to enroll Heather in this Phase III
21 study, the RDE, or the remote data entry system,
22 made enrollment impossible. The reason that
23 enrollment was impossible was that the date
24 chemotherapy was started was the previous date and
form would not permit enrollment to happen if
1 chemotherapy had already been started.
2 So, what was a well-intentioned regulation
3 system designed to prevent people from being
4 entered on study if consent had not yet been
5 obtained--in fact, in this case everything went
6 perfectly from an ethical perspective but the
7 patient was not allowed to be entered on study. I
8 think that this is a cautionary tale and I wanted
9 to bring it to the attention of the panel today.
10 Next slide, please. We see many
11 well-intentioned regulatory protections and it is
12 important to realize that they can paradoxically
13 prevent the ethical participation of children in
14 cancer research and Heather's story is one example
15 of that. The physician then needed to go back to
16 the family and explain that, unfortunately, we
17 weren't able to include her as a subject in the
18 research. It wasn't going to change her treatment
19 at all but the future treatment of children with
20 rhabdomyosarcoma in some ways is harmed by the fact
21 that this regulatory mechanism prevented Heather
22 from being a subject in the study. The only
23 alternative would have been for the person doing
24 remote data entry to fabricate and to say that the
date chemotherapy was started was the day that she
1 was being entered on study, and that would have,
2 number one, been an unethical lie and, number two,
3 would have been picked up on an audit if the
4 subject had been audited subsequently though it may
5 have been, in fact, the ethical thing to do because
6 consent was obtained in an appropriate way, it is
7 an important study, and all of the things that we
8 have bee talking about, but the regulatory
9 apparatus prevented an ethical action from taking
10 place and I think it is a disturbing story.
11 The next slide shows a synergistic
12 approach. The protection of human subjects has
13 been done both through education and regulation and
14 we need to be concerned about developing too much
15 regulation at the expense of education and the
16 expense of thoughtful ethical action.
17 The next slide just has a few quick points
18 about what matters after a trial is closed.
19 Monitoring for late effects of therapy is an
20 important ethical issue after a trial has closed.
21 The publication of results and dissemination of
22 findings is ethically important. If the science
23 isn't disseminated, then it is like a tree falling
24 in a forest that nobody hears. Finally, the return
results to the subjects who participated is an
1 ethically under-looked and I think very important
2 issue that symbolizes the partnership that we have
3 with subjects and their families, and I think we
4 need to do a better job than we are doing currently
5 after a trial has closed in getting results back to
6 the subjects.
7 The next slide shows conceptually the main
8 balance as a point of conclusion in pediatric
9 research ethics, that the best interests of the
10 child-subject are, in fact, balanced against
11 science to benefit others and we need to be
12 cognizant of that balance at all times and be sure
13 that the best interests of the child are not
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
relatively ineffective communication process
1 that is currently happening with informed consent.
2 I would be happy to talk more about that in the
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
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
planning to stay on line for the rest of the
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
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
supported I think originally by the federal
1 government and since I speak on behalf of HHS, I
2 have limited it to HHS, the Department of Health
3 and Human Services.
4 What I am quickly going to do is go over,
5 first of all, the applicability of our regulations.
6 Then I am going to talk very quickly about the
7 major requirements of 45 CFR Part 46, Subpart A,
8 which are the general protections for human subject
9 research. Then I am going to finish up by talking
10 about the major requirements of 45 CFR, part 46,
11 Subpart D, which are the additional protections for
12 children involved as subjects in research.
13 Again, the regulations I am referencing,
14 45 CFR Part 46, are the HHS regulations for the
15 protection of human subjects. They have four
16 subparts. The regulations were last revised in
17 2001. One of the subparts, Subpart B, was revised
18 at that point but most of the regulations remain
19 the same as when they were promulgated more than
20 two decades ago.
21 So, what is the applicability of these
22 regulations? Our regulations apply in two
23 circumstances. The most common is research
24 conducted or supported by the Department that are
otherwise exempt. That includes clinical
1 trials conducted intramurally by the NIH or funded
2 by the NIH, as well as many other agencies within
3 the Ddpartment. A second way in which research can
4 be covered by these regulations is research that is
5 conducted at an institution holding an applicable
6 assurance of compliance approved by our office.
7 So, any institution that receives funding from our
8 Department to conduct human subject research must
9 execute a written agreement in which the
10 institution pledges to comply with our regulations,
11 and in that document many institutions voluntarily
12 extend the same regulations to all research
13 regardless of sponsorship. In doing so, the
14 assurance comes to cover privately sponsored
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
assurance with our office in which they voluntarily
1 agreed to extend that assurance to all research, is
2 engaged in an industry, privately sponsored
3 research, project involving an FDA-regulated test
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
elements that must be part of an assurance. There
1 must be a statement of principles governing the
2 institution in the discharge of its
3 responsibilities for protecting the rights and
4 welfare of human subjects. And, the regulations
5 state that those principles must apply to all
6 research regardless of whether or not it is covered
7 by the assurance.
8 The assurance must designate at least one,
9 and many institutions designate more than one,
10 institutional review board and that must include a
11 list of the IRB members and their relative
12 capacities, and there must be a reference to
13 written IRB procedures. There are requirements
14 related to the IRB and they include specification
15 of what the IRB membership must include, such as at
16 least one person whose primary interests are in the
17 scientific area and at least one member whose
18 primary interests are in a non-scientific area, and
19 at least one member who is not otherwise affiliated
20 with the institution or a member of a family
21 affiliated with the institution.
22 The regulations have specific provisions
23 related to how the IRB should function and operate;
24 when it must conduct review in terms of initial and
continuing review. Then there are
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
foreseeable risks; the reasonably foreseeable
1 benefits, if any, to the subject; and others, such
2 as alternatives that a subject may choose instead
3 of entering the research. The regulations
4 stipulate that consent must generally be
5 documented, except in some limited circumstances.
6 Then, there are waiver provisions both for
7 obtaining informed consent at all or for documented
8 informed consent, and I won't go into those in
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
treatments or procedures involved in the research
1 under the applicable law of the jurisdiction in
2 which the research will be conducted. It is
3 important to note that in order to then understand
4 who a child is with respect to the research
5 regulations, you must understand state and local
6 law that defines who can consent to what and at
7 what age. Therefore, a child in one state might
8 not be a child in another state for the purposes of
9 these regulations.
10 The Subpart D requirements in
11 general--first of all, you have to satisfy all the
12 requirements of Subpart A. So, if a research
13 project involving children doesn't satisfy some
14 provision of Subpart A, then it is moot about the
15 additional provisions. The research would not be
16 approvable. But if the research is approvable
17 under Subpart A, there are additional requirements
18 of Subpart D which must be fulfilled and satisfied.
19 As Eric referenced, there are four
20 categories of research that are approvable under
21 Subpart D under our regulations. These are
22 primarily scaled to risk versus benefit as you walk
23 through each of these categories, and I am going to
24 do that very quickly.
The first category, 404, is research not
1 involving greater than minimal risk, and minimal
2 risk is defined in Subpart A. In order for this
3 research to be approved under this category, an IRB
4 must make one general finding. It must find that
5 there are adequate provisions for soliciting the
6 assent of the child and permission of the parents
7 or guardians, as set forth in Section 408.
8 The next category, Section 405, which Eric
9 went into more detail, is research involving
10 greater than minimal risk but presenting the
11 prospect of direct benefit to the individual
12 subjects. So, the benefit has to be tied to the
13 subjects as opposed to society in general and the
14 knowledge to be gained. Here, the IRB must make
15 three specific findings. The IRB must find that
16 the risk is justified by the anticipated benefits
17 to the subject; the relationship of the anticipated
18 benefit to the risk is at least as favorable to the
19 subjects as that presented by available
20 alternatives outside the research context; and,
21 again, the same provisions for assent and
22 permission apply throughout these four categories.
23 The next category, 406, involves greater
24 than minimal risk and no prospect of direct benefit
the individual subjects, but likely to yield
1 generalizable knowledge about the subject's
2 disorder or condition. For this category there are
3 four criteria that an IRB must find. They must
4 find that, first, that the risk represents a minor
5 increase over minimal risk. Whereas minimal risk
6 is defined in the regulations, what a minor
7 increase means is not defined so that is left up to
8 the judgment of the IRBs.
9 Next, the IRB must find that the
10 intervention or procedure within the research
11 presents experiences to the subjects that are
12 reasonably commensurate with those inherent in the
13 actual or expected medical, dental, psychological,
14 social or educational situation of the child.
15 Commensurability is one of the factors that Eric
16 touched on but applies only in this category, 406.
17 The next two provisions--the IRB must find
18 under 406 that the intervention or procedure is
19 likely to yield generalizable knowledge about the
20 subject's disorder or condition which is of vital
21 importance for the understanding or amelioration of
22 the subject's disorder or condition. I think the
23 key words here are that you have to understand that
24 the child must have a disorder or condition, two
terms that are not otherwise defined in the
1 regulation and are of vital importance. So, it is
2 sort of a higher standard than the usual
3 generalizable knowledge standard that probably
4 applies to research under Subpart A only. Lastly
5 is the assent or permission provisions.
6 The fourth category and final category is
7 research that is not otherwise approvable under one
8 of these four categories which presents a
9 reasonable opportunity to understand, prevent or
10 alleviate a serious problem affecting the health or
11 welfare of children. For this, the IRB still must
12 review and assess the research with respect to
13 Subpart A and D, and must find that the research
14 presents a reasonable opportunity to further the
15 understanding, prevention or alleviation of a
16 serious health problem affecting the health or
17 welfare of children.
18 The project is then forwarded to the
19 Department. They come through our office and we
20 act on behalf of the Secretary to process these.
21 In order for the research then to be approved, the
22 Secretary, after consultation with a panel of
23 experts in pertinent disciplines and following an
24 opportunity for public review and comment, must
determine either that the research in fact
1 satisfies one of the other three categories, 404,
2 405 or 406 or, if not, three things must be met:
3 that research presents a reasonable opportunity
4 standard that I previously went over; that the
5 research will be conducted in accordance with sound
6 ethical principles, and hopefully that is something
7 that applies to all research conducted; and
8 adequate provisions for the assent of the child and
9 parental permission.
10 Finally, there are some additional
11 provisions of Subpart D that are provisions related
12 to soliciting assent, and assent is not always
13 required and an IRB may determine it is not
14 warranted, particularly under category 405. There
15 are provisions for soliciting permission of
16 parents, and the regulations speak to whether you
17 need both parents' permission. If the category is
18 405 one parent's permission is sufficient but for
19 406 or 407 two parents are required, except in very
20 limited circumstances.
21 It is important to note that there are
22 provisions for waiving parental permission or
23 guardian permission. Just like informed consent
24 can be waived under Subpart A for research
involving adults, parental permission can be waived
1 in certain circumstances and this is I think unique
2 to our regulations and not found in the parallel
3 regulations within the FDA.
4 Finally, there are specific protections
5 for subjects who are wards of the state or any
6 other agency, institution or entity for research
7 approved under 406 or 407. Among those
8 requirements, there must be a specific advocate
9 appointed for each child who is participating in
10 such research who is a ward.
11 In summary, I have quickly tried to go
12 over the applicability of our regulations and
13 contrasted that with the FDA regulations
14 applicability. I have gone over the major
15 requirements of Subpart A of our regulations and
16 finished up with a discussion of Subpart D, and I
17 thank you for your attention.
18 DR. SANTANA: Thanks, Dr. Carome. Dr.
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
theme of the day, he was the head of the IRB at
1 Walter Reed Army Medical Center. I also want to
2 thank him for his efforts on clarification of the
3 regulations in ongoing discussions as they apply to
4 pediatric oncology, and he has taken a leadership
5 role in the Office for Human Research Protection in
6 that regard.
7 I am going to even more quickly, I hope,
8 go through the FDA regulations. One might ask what
9 is a pediatric oncologist doing talking about FDA
10 regulations, but that is one of the strengths of
11 the FDA, that there are wonderful opportunities to
12 be involved in many aspects or research in clinical
13 medicine, including the development of regulations.
14 I was on the working group that developed the
15 Subpart D and, in fact, wrote the first draft of
16 that document.
17 As Dr. Carome pointed out, there is some
18 overlap, and these slides have a lot of data which
19 is intended for reference and I will not go through
20 all the aspects of all the slides, but just to note
21 that there are laws synonymous with an act or
22 statute which are developed and passed by the
23 Legislative Branch and signed by the President and
24 these are published in the United States Code.
Then there are regulations synonymous with rule,
1 and these are developed and published by the
2 Executive Branch, the various departments and
3 agencies within the Executive Branch doing the
4 detailed work, and these are published in the Code
5 of Federal Regulations, which is referred to as the
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
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
relevant sections of the HHS regulations.
1 Now, the relationship--and this is just a
2 textual representation of the schematic that Dr.
3 Carome presented--is that FDA regulations apply to
4 all research using FDA-regulated products. In
5 contrast, the HHS regulations apply to all research
6 that is supported by HHS. Research that is
7 supported by HHS using FDA-regulated products is
8 subject to both sets of regulations, and the
9 regulations are harmonized although there are some
10 differences which Dr. Carome elaborated on earlier.
11 The definitions, you will see, parallel those
12 definitions in the HHS regulations and put the onus
13 of interpretation on the local jurisdiction and on
14 the local IRBs, and that is the theme that persists
15 throughout these regulations. So, these
16 definitions are included here to show that there is
17 harmonization and in some cases, we believe, some
18 clarification because the scope of FDA-regulated
19 research is, in many ways, different and can apply
20 to domains where HHS research is not applicable.
21 So, it was important to have not only clarity on
22 the definitions but consistency and, therefore,
23 there are definitions that are included here so
24 that there is not, we hope, much ambiguity in terms
how to apply and interpret these regulations at
1 the local IRB level.
2 Here, again, there is an emphasis on the
3 concept that Eric Kodish developed for us a little
4 earlier this morning, and that is children do not
5 actually engage in a consent process. Their
6 parents provide permission for them to participate
7 in the research. Then, there is the same emphasis
8 as in the HHS regulations that the child must at
9 least be approached for assent.
10 So, in addition to the other
11 responsibilities assigned to IRBs, the FDA
12 regulations ask that the IRB review clinical
13 investigations involving children as subjects
14 covered by Subpart D and approve only clinical
15 investigations that satisfy the criteria which are
16 described in Subpart 51, 52, 53 and the conditions
17 of all other applicable sections of Subpart D.
18 These are again mapped to the four risk
19 categories which were developed in the 1970s and
20 which, because of their serviceability and their
21 flexibility, have been maintained to this date.
22 These, again, discuss the concept of minimal risk
23 here with specific examples of how it applies to
24 pediatric research.
Since the IRBs are a conduit through which
1 research occurs, there are specific instructions on
2 when IRBs may approve clinical investigations, and
3 these are divided into the specific risk
4 categories. So, there is greater than minimal risk
5 under 50.51. In 50.52 there is greater than
6 minimal risk presenting the prospect of direct
7 benefit and the conditions, again, are analogous to
8 the HHS regulations; and 50.53 shows that the IRBs
9 can approve clinical investigations involving
10 greater than minimal risk and no prospect of direct
11 benefit but likely to yield generalizable knowledge
12 about the subject's disorder or condition, and the
13 same caveats about having a disorder or condition
14 and having the prospect of generalizable knowledge
15 apply, and these are addressed in some detail.
16 In addition, there are IRB approval
17 criteria which are explicitly stated and these
18 include not only minimization of risk and that the
19 risks are anticipated in relation to the benefit,
20 but that the informed consent process is adequate
21 and appropriately documented and looking for
22 safeguards. That is going to be theme which we are
23 going to look at in detail, what safeguards can be
24 and ought to be implemented.
Subpart D addresses this explicitly.
1 There is a paragraph devoted to monitoring which I
2 will quote briefly: While the level of risk in a
3 clinical investigation may change during the course
4 of a study, appropriate strategies may be included
5 in the study design that may mitigate risks. These
6 might include exit strategies in the case of
7 adverse events or a lack of efficacy, or
8 establishing a data monitoring committee to review
9 ongoing data collection and recommend study
10 changes, including stopping a trial on the basis of
11 safety information.
12 Part 56 addresses institutional review
13 boards, and the general provisions and organization
14 are discussed in the first part; IRB functions and
15 operations in the second part; records and
16 reporting in the fourth part; and the
17 administrative actions for non-compliance in the
18 fifth part.
19 Now we come to the IND regulations, 312
20 Subpart A, which are the general provisions which
21 are outlined here.
22 Subpart B, which are in essence the
23 mechanics of an investigational new drug
24 application and the obligations under those
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
regulations and 600 which apply to the biologics
1 but there are analogous regulations in these areas.
2 I will just abstract from here that this
3 includes the requirements for informed consent and
4 institutional review boards, and that these
5 safeguards further include the review of animal
6 studies prior to initial human testing; the
7 monitoring of adverse drug experience through the
8 requirements of IND safety reports; safety update
9 reports for marketing and postmarketing.
10 So, our conclusions from this section are
11 that the FDA has authority to regulate clinical
12 studies using FDA-regulated products; that FDA
13 regulations incorporate both IRB and FDA oversight
14 of studies; that regulations exist for studies
15 using products intended to treat life-threatening
16 illnesses; and that regulations exist for providing
17 additional safeguards for children enrolled in
18 clinical investigations; and, as noted, HHS and FDA
19 regulations are intended to be harmonized. Thank
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
15-minute break--Dr. Hirschfeld wants a 10-minute
1 break. We will take a 10-minute break and try to
2 reconvene at almost 9:45. Thank you.
3 [Brief recess]
4 DR. SANTANA: We will go ahead and get
5 started with the second part of the morning
6 presentations. To initiate that, Dr. Anderson,
7 from CTEP, will be our next speaker. Barry? Eric,
8 are you back on board?
9 DR. KODISH: I am here.
10 DR. SANTANA: Thank you, Eric.
11 Enrollment and Monitoring Procedures for
12 NCI Funded Studies
13 DR. ANDERSON: I am Barry Anderson, from
14 NCI CTEP, and I want to thank the FDA and Steven
15 for inviting us to provide information about the
16 enrollment and monitoring procedures for
17 NCI-supported clinical trials.
18 For pediatric cancer clinical trials, the
19 appropriate enrollment of the individual patient,
20 the child who is going to come onto the trial, as
21 well as the monitoring of that individual patient's
22 experience during the trial and the cumulative
23 experience of all children who are involved in a
24 clinical trial I think are necessary components in
terms of trying to enhance the patient safety and
1 the scientific validity of the trial itself.
2 So, at the onset, from NCI's point of
3 view, it is important to work to assure that each
4 child accrued to a trial is receiving the
5 appropriate treatment within the clinical trial
6 itself, and that monitoring that is associated with
7 the trial monitors the toxicity and effectiveness
8 of the treatment intervention within each clinical
9 trial both for that individual child, as well as
10 for the trial overall.
11 The words "safe" and "effective" can be
12 applied to many of the standard treatments we use
13 in pediatric oncology to treat various childhood
14 cancers. These words have special meaning in
15 pediatric oncology. As Dr. Kodish mentioned, there
16 is a special sort of risk/benefit ratio that we
17 always consider because, while therapy for
18 childhood cancer is often successful and that is
19 something that differs from much of medical
20 oncology, the therapies that we use are always
21 toxic in pediatric oncology and they always carry a
22 risk of treatment-related morbidity and perhaps
23 even death in many cases.
24 So, selecting the proper treatment I think
essential because compared with other serious
1 childhood diseases, such as asthma or cystic
2 fibrosis, childhood cancer includes many distinct
3 histologic diagnoses, and each tumor histology
4 requires a distinct treatment appropriate with its
5 own risks and benefits. The chances of cure also
6 diminish quickly if the proper therapy is not used
7 at the outset. That differs, I think, from some of
8 the other more chronic diseases that are serious
9 within childhood diseases but can have chances to
10 change the therapeutic approach over time.
11 In regards to enrollment, a question for
12 the clinical trials done in pediatric oncology is
13 who should be enrolled. Pediatric oncology has
14 evolved an approach of risk stratified treatment
15 regimens and within each tumor histology the
16 patient characteristics and the tumor
17 characteristics establish a risk of relapse. This
18 risk of relapse then is used to stratify the
19 treatment assignment for each child in terms of the
20 type of clinical trial or the specific clinical
21 trial they would be appropriate for. Using this
22 risk of relapse the intensity of the treatment that
23 the child receives--and for intensity you can also
24 say increased toxicity--is then set to best fit the
child's cancer. So, it is vital
to treat the
1 child, as best we can ascertain at the time they
2 first present, according to the appropriate
3 treatment regimen.
4 By following this treatment stratification
5 approach, the goal in pediatric oncology is to
6 minimize the exposure to highly toxic therapies for
7 those children who don't need that much treatment,
8 in a relative sense, and also for the oncologists
9 to have some comfort in knowing that another child
10 who has a high-risk chance of relapse, that they
11 will in fact potentially benefit from using a more
12 intensive and more toxic treatment regimen.
13 To apply this treatment stratification
14 approach across an entire clinical trial, it is
15 important that the eligibility criteria within the
16 protocol by which all the patients are brought into
17 the trial--that those protocol eligibility criteria
18 are clear in regards to the clinical
19 characteristics of the patient and the pathologic
20 and biologic characteristics of the tumor--that all
21 these characteristics are clear and easy to
23 The pediatric oncologists that are
24 involved in the trial and who would be enrolling
patients must be properly informed on how to apply
1 the eligibility criteria that are presented in the
2 eligibility section of the protocol itself. If
3 anyone has ever had experience in trying to bring a
4 patient with rhabdomyosarcoma into a sarcoma trial,
5 it can be a be very complicated endeavor and many
6 mechanisms have been put in place to assist the
7 pediatric oncologist to make sure that the proper
8 decision is made in terms of treatment.
9 As technology has advanced, eligibility
10 criteria have moved beyond what they have been in
11 the past, just being tumor histology and perhaps
12 the staging of the patient. As histologic and
13 biologic characteristics of tumors are better
14 defined and refined, we also are incorporating in
15 many cases in pediatric oncology central input on
16 the pathology and biology, such that central review
17 of the patient's tumor pathology and diagnostic
18 biology assays are used to improve the likelihood
19 that a child receives the best available therapy
20 for their specific tumor pathology and for their
21 risk of relapse.
22 This has been used in a variety of tumors
23 in pediatric oncology in the recent past. With
24 rhabdomyosarcoma there is central review of
alveolar versus embryonal rhabdomyosarcoma
1 pathology that is used basically in real time so as
2 to assure that the patient goes on the proper
3 risk-stratified treatment regimen. For
4 neuroblastoma there are a variety of biologic
5 characteristics that make amplification and other
6 genetic changes that are characteristic to each
7 tumor, and that is also looked at in real time.
8 For Wilms tumor there has been a central review of
9 that tumor histology for favorable histology versus
10 focal or diffuse anaplasia that all distinguish
11 patients for their appropriate trial, and there are
12 a variety of genetic studies that are done, both
13 centrally and locally, to establish the appropriate
14 treatment for children with acute lymphoblastic
15 leukemia, the most common diagnosis in childhood
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
potential for cure or substantial clinical benefit.
1 For patients who have newly diagnosed tumors but
2 have a type of tumor that historically has a poor
3 response to therapeutic interventions, we want to
4 make sure that any sort of pilot treatment
5 interventions that have been tried balance
6 appropriately the benefits and likely risks in the
7 child's prognosis. So, before considering trial
8 monitoring we consider that getting the right
9 patient on the right trial is vital given the
10 stratified approach we have to treatment in
11 pediatric oncology.
12 NCI supports a variety of investigator
13 groups to do clinical trials in children with
14 cancer. The largest is the Children's Oncology
15 Group, which pretty much every pediatric oncologist
16 in North America is a member of. That is the group
17 that does the Phase III studies primarily as well
18 as Phase II studies and pilot studies. There is
19 the COG Phase I Pilot Consortium that is a smaller
20 group, about 20 institutions, that is assigned to
21 do Phase I studies. The Pediatric Brain Tumor
22 Consortium I think is around 10 institutions as
23 well. Their focus is on newer therapies for brain
24 tumors in children. The new approaches to
neuroblastoma therapy is a program project grant
1 that NCI supports that is now 12 or 14 institutions
2 I think, focused on early phase studies for
3 children with neuroblastoma, high risk
4 neuroblastoma. There are also individual grants to
5 investigators that may include clinical trial
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
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
remote data entry have been put in place now to
1 help facilitate that. There is a data center
2 assigned with each of these groups that we support
3 that is capable of readily receiving the data,
4 analyzing the data and then reporting important
5 data trends to the investigators, be it the study
6 committee and perhaps beyond if necessary. There
7 is an operations office component. They are able
8 to communicate with investigators continuously
9 throughout the clinical trial by email, by web
10 site, by the phone, etc. There is sort of this
11 continuous back and forth going on between the
12 investigators at the local institutions and a more
13 centralized body that is helping to run the trial.
14 In terms of monitoring, again it starts, I
15 think just like enrollment, at the individual child
16 level where there, is within the protocol, guidance
17 provided to the local institutional clinicians as
18 to what sort of laboratory results for
19 tumor-related or treatment-related abnormalities
20 need to be done and at what interval. There are
21 radiologic characterizations of the tumor and the
22 consequent organ dysfunction that are also asked
23 for in terms of the initial diagnosis of the child
24 and then subsequently during their course of
treatment. Then there are
interval evaluations to
1 establish the tumor response to the treatment
2 interventions that are being conducted during the
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
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;
then that the significance of this data, be it
1 the toxicity data or the effectiveness data, is
2 interpreted so that appropriate patients are being
3 accrued to the study; that treatment toxicity is
4 acceptable and that there is some efficacy of the
5 treatment interventions as defined in the protocol
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
clinical sites, are blinded or masked or employ
1 particularly high-risk vulnerable patient
2 populations. In pediatric oncology we sort of hit
3 throughout this so we call for sort of the default
4 to be towards some sort of formalized monitoring
5 committee for most of the studies that we do.
6 The NCI, in response to NIH sort of
7 formalizing its approach to data and safety
8 monitoring, in the not too distant past has
9 finished reviewing all the data and safety
10 monitoring plans for the cancer centers that NCI
11 supports across the country. That was I think an
12 education for both NCI as well as for the cancer
13 centers, for them to really kind of fess up and
14 look at what they actually do in terms of the
15 monitoring; what goes on in their human subject
16 clinical trials within their cancer centers. But
17 they all submitted them and they were all reviewed.
18 Some of the key, essential elements for
19 these monitoring plans that we had to consider, and
20 that then subsequently have also been extended to
21 some pediatric groups, are the monitoring and
22 progress of the trials and safety of the
23 participants; the plans for assuring compliance
24 with adverse event reporting; and plans for
assuring that data accuracy and protocol compliance
1 are performed.
2 As I mentioned, while in pediatric
3 oncology basically we don't work from a cancer
4 center model, we work more in a multi-institutional
5 approach so it is a more distributed coverage in
6 terms of who is performing the trials.
7 Nevertheless, these particular essential elements
8 were taken on by pretty much all the groups that we
9 have that I mentioned earlier that NCI supports in
10 one form or another, again, moving to the default
11 of having some sort of more formalized data
12 monitoring committees for all the trials.
13 The composition of the DSMB and the
14 various data monitoring committees may differ
15 between the different groups that I mentioned that
16 NCI supports for pediatric oncology but the goal is
17 the same, and it is to have capable and informed
18 observers be responsible for the oversight of the
19 trial. The reviewers are people that are outside
20 of, and in addition to the study committee, and
21 they evaluate the trial data at regular intervals
22 to monitor the treatment toxicity and the
23 effectiveness of the treatments that are being
24 used. Then, the review determines whether the
continued accrual to the trial is safe and
1 appropriate. COG itself has two DSMBs, one for
2 solid tumors and one for the leukemia and lymphoma
3 studies, and they meet twice a year, each one of
4 those DSMBs, to go over the studies. Actually we
5 go over pilot, Phase II and Phase III studies in
6 those sessions. The Phase I Consortia also has a
7 DSMB that meets twice a year to go over all those
8 Phase I studies. In addition to the Phase I
9 Consortia, the PBTC and the NANT, all of which have
10 a DSMB type of component, have more frequent
11 discussions with the groups that are beyond just
12 the study investigator and any sort of data
13 personnel or statistician directly involved. They
14 have a discussion of their studies sometimes on a
15 weekly basis, sometimes on a monthly basis, and
16 sometimes it also includes people from outside the
17 group itself to overlook what is going on with
18 their particular studies.
19 In terms of compliance with adverse event
20 reporting, another one of the essential elements
21 that NCI has, NCI-funded studies use the adverse
22 event expedited reporting system, or the AdEERS
23 system to report toxicities. This is a
24 computerized system that is available now to all
funded groups with which they can fairly easily
1 report adverse events that occur during their
2 clinical trials. That data can then be accumulated
3 easily within their group, but also important
4 things can be sent off to the FDA or to drug
5 sponsors or the NCI as appropriate, especially for
6 studies that involve IND agents.
7 Then, it is the institutional principal
8 investigator that is ultimately responsible to
9 assure that the AEs are reported in a timely
10 manner. Whenever we review the cancer center
11 approaches, they list out that sort of the CRA
12 should submit this and then there is a nurse
13 practitioner or someone that is behind the CR to
14 make sure it gets submitted, and at some interval
15 the principal investigator locally is responsible
16 to make sure that all the AEs that may have
17 occurred had been properly reported.
18 Finally, for assuring data accuracy and
19 protocol compliance, the cooperative groups and
20 these consortia practice ongoing quality control
21 and interval quality assessments such as by using
22 institutional audits. This has been something that
23 has been ongoing throughout the creation of each of
24 these groups.
In summary, NCI has worked to establish a
1 framework to allow appropriate monitoring and
2 oversight of pediatric oncology clinical trials.
3 To address some of the issues that Steven had
4 brought up before in terms of the general
5 parameters that we look at, we first want to make
6 sure that the enrollment of patients is appropriate
7 to the diagnosis and risk of relapse for the
8 patient or the availability of standard treatments
9 for recurrent and relapsed disease, and that
10 laboratory and radiologic monitoring for toxicity
11 and response to treatments is established within
12 the protocol before any patients are accrued.
13 The frequency of monitoring would be equal
14 to or greater than standard of care for the
15 individual patient that is enrolled on a clinical
16 study, and there would be continuous protocol
17 monitoring by the study committee because they
18 receive this data on a daily basis. There would be
19 interval protocol monitoring on a monthly to
20 biannual basis, depending on the risk and specifics
21 of the trial, by a group outside of the study
22 committee itself.
23 Who does the monitoring? The daily
24 monitoring is by the study committee itself. The
interval monitoring usually involves concentrations
1 and statisticians that are not directly involved in
2 the trial.
3 When is a data monitoring committee
4 needed? For Phase III studies you need a DSMB.
5 For multi-institutional trials you need to have a
6 monitoring committee for high-risk populations.
7 You need to have a monitoring committee for complex
8 treatment. For studies with early stopping rules,
9 which many pediatric studies have, you have to have
10 a monitoring committee. With conflicts of
11 interest, which may not be as much of a case in
12 pediatrics as it might be in medical oncology, you
13 need to have a monitoring committee.
14 I think that with pediatric oncology
15 trials we hit many of the points that are brought
16 up by various agencies of situations where a
17 monitoring committee is required so that virtually
18 always in pediatric oncology some sort of
19 monitoring committee is involved in the oversight
20 of the practices of the group, as well as the
21 conduct of individual clinical trials. Thank you.
22 DR. SANTANA: Thanks, Barry. Before I
23 stand up to give the last presentation of the
24 morning, we have an opportunity for an open public
hearing. So, if there is anybody
in the audience
1 that wishes to address the committee, this is the
2 opportunity to do so. I would ask that if you are
3 going to do that you come to the front of the room
4 to the podium and identify yourself by name and
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
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
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
parameters we have designated for monitoring.
1 Then, a bigger part of my talk will be on a project
2 that Don Workman and I worked on in terms of trying
3 to handle adverse event reporting within the
4 institution and tried to develop an interactive
5 web-based model to try to get a handle on that.
6 With that, I will go ahead and get
7 started. As Barry has already said, monitoring of
8 trials is really an ongoing, continuous review of
9 the conduct of the trial. For the purpose of
10 distinction, I will make the note that to me
11 monitoring occurs while the study is ongoing.
12 Whereas a lot of people use the word auditing, to
13 me auditing is a post facto thing that happens
14 after the study has been completed. Then you go
15 back and see if the study was conducted the way it
16 was supposed to be; if the data is good enough; if
17 there is quality in the data; and if there have
18 been any other issues that occurred during that
19 post facto process. So, to me, monitoring occurs
20 real time whereas auditing occurs after the study
21 has been completed.
22 Monitoring is really a shared
23 responsibility of many individuals. We always talk
24 about monitoring being the responsibility of maybe
particular group but at St. Jude we have the
1 notion that this is really the responsibility of
2 the research team. We always talk about the
3 principal investigator but it is really the
4 research team. The research team has many
5 components to it of which, hopefully, the principal
6 investigator is the lead person but there are
7 research nurses, there are CRAs, there are other
8 members of the study team who also have
9 responsibility for this process.
10 Institutional officials have a major role
11 in this, not only in terms or providing
12 infrastructure resources to conduct some of this
13 monitoring, but also to set a culture and example
14 that is transparent to make sure that things occur
15 very openly and that everybody is knowledgeable
16 about what is happening. Then, the oversight
17 committee--you heard a little bit about DSMBs which
18 I won't talk about and IRBs and other committees
19 that may be involved in this process.
20 Eric had a little figure this morning of a
21 triangle. I didn't know he had a triangle so I
22 brought a triangle too, but my triangle is a little
23 bit different. It makes a different point. The
24 point of this triangle is that in the center of the
process are the participant in the research but
1 there are many other people involved in this whole
2 process in which, as I mentioned to you earlier,
3 the partnership includes the investigator, the
4 research team, the IRB, other oversight committees
5 and then institutional officials. So, I view this
6 more as a partnership, not just the responsibility
7 of one individual.
8 One of the things I want to cover is point
9 number one and point number three on this slide,
10 which is how can we systematically approach some of
11 these problems in terms of monitoring and adverse
12 event reporting.
13 So, I think the first step whenever you
14 deal with a promise to define a problem in this
15 case is what needs to be monitored and what needs
16 to be reported. I think that is a good point to
17 start and I will talk about that in a minute; then,
18 dividing the role, the different committees that
19 provide some of this oversight and I really won't
20 go into detail on that although I could during the
21 discussion if anybody has any questions; and,
22 lastly, developing an infrastructure to allow this
23 to happen so that the reporting occurs, that there
24 is a process of evaluating the reports, and then a
process of acting in a timely manner when there are
1 concerns. So, that will be the latter part of my
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
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
appropriately in his talk, the issue of eligibility
1 and determining that the right patients go on the
2 right studies. One of the things we have done at
3 St. Jude in the last ten years is we have
4 established a separate office, which is called the
5 protocol office which is actually an office that
6 provides the infrastructure to help investigators
7 deal with many of these issues. The protocol
8 office, obviously, is manned by a group of people
9 and one of the responsibilities, for example, is
10 that when an investigator enrolls a patient on a
11 study we have to fill out electronically an
12 eligibility check list. The eligibility check list
13 gets faxed to that office and a patient-specific
14 consent is generated for that patient on that
15 study. So, right at the beginning there are some
16 checks and balances in terms of the eligibility of
17 the patient so that the right patient is put on the
18 right study and the correct consent is used for
19 that patient. So, that is an ongoing process that
20 occurs early on during the trial and the patient
21 enrollment of the trial.
22 Once the patient receives the therapy,
23 they monitor the cycle or the course of therapy.
24 If is a Phase I study, what dose level the patient
currently being treated with; the start date;
1 some other parameters like BSA and weight. They
2 monitor, particularly in Phase I studies, the
3 agent; the dose of the agent; if there have been
4 any modifications, why there have been
5 modifications. We will talk a little bit about
6 adverse event reporting later on. Then, as part of
7 the monitoring during certain periods of the trial,
8 the patients will be monitored in terms of response
9 because the trials will have stopping rules based
10 on response, not only in terms of toxicity but also
11 in terms of response so a Phase II trial that has
12 some response built-in stopping rules will be
13 stopped at the right point once the monitoring is
14 occurring in terms of the response that has been
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.
is monitored continuously because I told you
1 that there is a check at the beginning in terms of
2 eligibility and in terms of informed consent that
3 occurs in real time when the patient gets
4 registered. So, that is done continuously as the
5 patients go on a study in a Phase I study.
6 The protocol office also is monitoring the
7 study in terms of the data elements for the study
8 so there are templates very similar to the RDE
9 system that is developed by COG, templates of data
10 capture forms. Those data capture forms are
11 electronic and the monitor on a monthly basis that
12 he or she is assigned will go through those and
13 will see if there is data that is missing. If
14 there is data that is missing, a report is
15 generated to the principal investigator that data
16 is missing on a monthly basis. So, it is a good
17 system in terms that it keeps the research team
18 kind of continuously on top of making sure the data
19 is being collected.
20 On a quarterly basis for a Phase I study
21 there is a report that is generated. I will show
22 you in a minute where the reports go but, in a
23 nutshell, it goes, obviously, to the principal
24 investigator and to the research team, and then it
goes to the subcommittee of the scientific review
1 committee that also oversees monitoring to make
2 sure that they are separate from the protocol
3 office and from the investigator looking at this
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.
Obviously, in Phase II, just like in Phase I, you
1 are interested in adverse events and those are
2 reported quarterly. Then, on a semiannual basis
3 the monitors will verify the coding of response so
4 that the studies can be stopped if the response
5 criteria for stopping rules have been met. There
6 are reports semiannually or more frequently or less
7 frequently, as defined by the protocol, in terms of
8 the individual monitoring plan that the protocol
9 may have.
10 In Phase II we always monitor the first
11 two patients plus at least--and the clever word
12 here is "at least" ten percent of the total
13 patients that are being accrued. It could be
14 greater than ten percent. It depends obviously on
15 the resources that you have available and the
16 workload that the specific monitor may have but at
17 a minimum ten percent of the patients on any Phase
18 II study at any given time should be under active
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
Phase III trials that also require some monitoring.
1 St. Jude holds INDs or IDEs for a few
2 products so under those circumstances, they could
3 be Phase I or Phase II trials or whatever, but
4 separately from those, if there is a particular IND
5 or IDE for which St. Jude is the "sponsor" then
6 there is a specific monitoring plan that is
7 assigned to that study, and it will depend on the
8 risk, what is known about the IND drug, what is
9 known about the device, etc., etc., and may be more
10 strict but at least it will be just like Phase I or
11 Phase II studies I described to you before.
12 Usually, under some circumstances like some novel
13 therapy, it may be a little bit stricter in that
14 the studies are being monitored a little bit more
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
their records. But that is after
the study is done
1 and that occurs over a long period of time. It is
2 not as active as the actual monitoring which is
3 occurring in real time.
4 I want to switch now and talk a little bit
5 about the issue of adverse event reporting which
6 has to do with monitoring and safety. We, at St.
7 Jude, also have struggled with this issue and we
8 struggle because there are a lot of problems in
9 reporting. There tends to be a lot of
10 over-reporting. That is, anticipated adverse
11 events that are known in the investigator's
12 brochure or known from other clinical trials are
13 being reported on a continuous basis and that
14 creates a big backlog of data that is important but
15 not important in real time in terms of monitoring.
16 As you all know, there is increased
17 research in new drugs and biologics. There is more
18 oversight and scrutiny by federal agencies. Just
19 like in many other places, we tend to get
20 saturation effects. There comes a point where you
21 see so many reports that it doesn't ring a bell; it
22 doesn't ring any whistles or anything like that.
23 So, we have to be careful that we don't over-report
24 because then it gets us into the saturation effect
we don't react appropriately when there are red
1 flags that we should be paying attention to.
2 But one of the problems we have at St.
3 Jude, which is very common for pediatric
4 institutions, is that there are no denominators for
5 how to make any sense of this; what constitutes a
6 red flag? Where do you cut the line to say this is
7 important or this is not important? There is no
8 normative data for each of the populations that we
9 have to deal with for Phase I studies, for Phase II
10 studies and for the studies I mentioned to you.
11 So, trying to approach this problem, we have tried
12 to deal with this I think in a prospective way.
13 In terms of review, there are a lot of
14 external events that we get from study sponsors.
15 If there happens to be a drug that we are doing a
16 study with but the drug is being used in adult
17 studies or in other institutions, you know, the
18 sponsors package a lot AEs and send them to you and
19 we have to deal with those too. The problem with
20 those is that sometimes the information is very
21 sketchy and there is no opportunity for
22 clarifications or for questions so that then you
23 can put that in the context of your own experience
24 with your own patients at your own institution.
The other thing is that the IRB is not a
1 DSMB. A DSMB has a very specific role; the IRB has
2 to deal with a lot of other issues. They have to
3 deal with adverse events and they should be looking
4 at them and they should be judging them, but it is
5 clearly in the context of the whole package of the
6 research, whereas the DSMB has very specific roles
7 and responsibilities.
8 The IRB is not the FDA who holds the IND
9 file for the drug and knows everything. So, the
10 IRB over here is getting little pieces of
11 information and trying to make sense out of it in a
12 more global sense. Then, the IRB also needs to
13 rely on the local investigators to interpret the
14 meaning of the adverse events that they are
15 receiving from the outside, from the sponsors,
16 because clearly the IRB doesn't have the expertise
17 or the knowledge to put that in contextual features
18 in terms of the study as it is being conducted at
19 other institutions.
20 So, at St. Jude we decided to approach
21 this problem first by doing quality improvement
22 projects, trying to figure out where the problems
23 were and where we could attach the problems. One
24 of the first issues that we addressed is that at
beginning the PI or the research team needs to
1 report and categorize the events, but there was no
2 systematic way of doing that. I mean, it was being
3 done in paper form; there were different versions
4 of that paper form.
5 One of the things that Don Workman and I
6 recognized is that at least if at the beginning we
7 could make this a standardized way and force
8 everybody to do it the same way, then five, ten
9 years later we actually would have a system in
10 place that would provide a lot of the normative
11 data that we would need in order then to do some
12 process improvement.
13 So, the first thing that we did is to
14 create this electronic submission that I will
15 describe to you in a few minutes. This electronic
16 submission is pretty neat I think, to use words of
17 my nephew--it is pretty neat because it allows you
18 then to disseminate that information very quickly
19 to all the key players in the field and then they
20 can do their own assessment the same time that the
21 IRB is doing their assessment. So, the IRB will
22 get a copy of this electronic adverse event and the
23 IRB will do their own assessment of the adverse
24 event and certainly give feedback and follow-up to
investigator. At the same time that it
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
could then create a system that, hopefully, would
1 help us in retrospect. So, we started this about
2 18 months ago. The first thing we did is we said
3 let's create a form that is standardized. We can
4 then make sure that people understand what is
5 important in that form before we convert it into an
6 electronic format. Then we were able, as we
7 designed the form, to start thinking prospectively
8 of how that same data could be captured
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
terms of the protocol that the patient was
1 registered on and the additional protocols was that
2 the patient was registered on because there could
3 be some cross-talk between adverse events on
4 different protocols or different PIs. I will show
5 you an example at the end.
6 We also wanted to make this user friendly
7 and make sure that anybody who is part of the
8 research team could do this at any place in the
9 hospital. Through a security pass they could
10 access this web site and could potentially feed in
11 the information in a very quick manner, without
12 having to go to a dark office somewhere and grab
13 papers and try to do it. So, there were some
14 security access issues that got resolved but it was
15 made available to anybody on the research team
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
could link protocols so that the information
1 could be identified very easily. If a patient was
2 registered on one protocol and the adverse event
3 occurred on that protocol, we wanted to know what
4 additional studies that patient was enrolled on so
5 that when the IRB or the subcommittees reviewed
6 this they could begin to get trends if there were
7 complementary adverse events that were occurring
8 from complementary studies and there could have
9 been a red flag there that we needed to address.
10 In addition, we could share the
11 information with the PIs of the other studies
12 because they also have to be kept in the loop in
13 terms of what is happening to patients that
14 potentially may also be enrolled in their own
15 studies concomitantly, for example therapeutic
16 versus non-therapeutic studies.
17 Then, for external reports we wanted the
18 investigators to help us sort that out because we
19 couldn't sort it out. So, the investigators had to
20 invest some time at the beginning sorting out
21 external reports before they submitted them to us
22 so that they would be more meaningful to us.
23 Then, the functional outcomes would be
24 that there would be real-time reporting and that
IRB would acknowledge that through some
1 electronic time stamping mechanism. There are
2 forced choices so that everybody has to do it the
3 same way; no incomplete data submissions so we
4 wouldn't have to address the issue of going back
5 and asking for more clarification and more
6 questions; easy access so it would be friendly;
7 ability to generate single incident reports;
8 ability to generate reports in a given time period.
9 If you were noting a trend that something was
10 occurring in a particular study over some period of
11 time, you could capture that and, as you will see
12 in the end, provide cumulative data that you could
13 sort out to look at trends that potentially could
14 be occurring. Quicker reporting times; ability for
15 the IRB office to generate reports based on
16 protocols; specific events across subjects, across
17 protocols to give us some functionality at the IRB
18 level to look at the data in different ways;
19 generate internal denominators of trends that we
20 wanted to look at; use standardized NCI toxicity
21 tables for the oncology trials; and be able to
22 record the IRB actions and updates from
23 investigators onto previous reports. So, it wasn't
24 a dead system. It was a system that the
investigator could go back and add more information
1 or, when the IRB reviewed it, could add more
2 information so it became a living document as the
3 report was being done.
4 Let me give you an example of how this
5 works. I couldn't get it electronically. It was
6 going to cost me money to be able to do this
7 electronically so I did some snapshots of what it
8 looks like.
9 So, this page is accessible to anybody who
10 is identified at St. Jude as a principal
11 investigator or a member of a research team. So,
12 if you are listed on the protocol as the nurse for
13 that study, as the statistician for that study, as
14 a pharmacist for that study, automatically you get
15 access to this through a user ID and your own
16 password. So, it is available to anybody who is
17 part of the research team.
18 This is how you log in. Here I logged in
19 and it says, "welcome, Victor Santana." Then it
20 gives a listing of all the events that have
21 accumulated during a particular period of time. It
22 gives the event ID which is an internal working
23 number. It gives the event date. It gives an
24 identifier that I have erased here for a particular
patient. It is usually a
numerical number. If it
1 is an external event, then there is a way to code
2 that to an external number. Sometimes you get an
3 event from a sponsor and it is coded ABXY235, well,
4 there is a way that you can code that the same way
5 here so you can track it and use the same codifier
6 if you ever have to go back to the data.
7 The status tells me, as an investigator,
8 whether I have reviewed this or not. So, when I
9 copied this the other day I only had one adverse
10 event that I had yet to review that somebody sent
11 to me for comment. Then, it tells me the date that
12 the event was reviewed by me or that I modified it
13 or I did anything to it.
14 Very quickly, it goes through a couple of
15 screens that provide some general information. It
16 tells you whether it is a St. Jude patient or not
17 because if it is not, it throws you in a different
18 direction in terms of the data that you need to
19 capture because, clearly, the data is being
20 captured for external adverse events a little bit
21 differently than it is for internal. There is some
22 information here in terms of the patient.
23 Then, it begins to do its own internal
24 processing once it identifies the patient. It
tells us, as you see at the top of the screen, all
1 the protocols that this patient is registered on.
2 So, it goes back and talks to the data warehouse.
3 If this patient is enrolled on ten studies, it will
4 pull and identify all those ten studies. Then it
5 will ask me, as the person putting in the
6 information, under what study am I following this
7 report. So, it identifies primarily the study and
8 the adverse event, but it also tells me all the
9 other studies the patient is on, and this is
10 critical because this report will go to the PIs of
11 all those other studies too. You will see it at
12 the end for their comments. So, it provides a
13 little bit of a cross-talk among studies.
14 Then, it clearly identifies the type of
15 adverse event that is being reported. You have all
16 seen this in different variations. For adverse
17 events that require a CTC code it takes you to the
18 CTC code so there is a link too so you don't have
19 to scramble through 50 books looking for those
20 codes but automatically it links you to those
21 codes. Then, it allows you to put the descriptor,
22 etc., etc. So, it is all being captured in a
23 uniform language.
24 Then it goes to a page that allows the
person who is submitting the information to do some
1 attribution on the adverse event. It is a click
2 system but it reminds people, because we all tend
3 to forget, what each one of those words means. So,
4 it reminds me that I need to read when something is
5 serious; when something is unexpected. It defines
6 it very clearly because there are always a lot of
7 questions from members of the research team what
8 constitutes something that is unexpected versus
9 expected. Well, there it is. It is, hopefully,
10 black and white and then you select, based on your
11 interpretation. It allows you to do one selection
12 across lines horizontally for each one of those.
13 Then, there is a page that allows you to
14 provide more information. One of the problems
15 always with electronic information is that
16 sometimes you can't capture everything in a unique
17 format. So, there is a page that allows you to do
18 a little more narrative form of how this all
19 happened, and so on and so forth, so it can give
20 you some additional data that you can comment on.
21 Then it asks you do you think, based on
22 your interpretation of what has happened with the
23 adverse event, that there is a follow-up that is
24 needed. If you say there is a follow-up needed,
then it links back to a reminder within 30 days
1 that you owe us a follow-up. The IRB reviews it
2 and they also communicate directly. But if you
3 think you have enough information and you want to
4 submit a follow-up, within 30 days you will get a
5 reminder that you owe us a follow-up.
6 Then it tells you something about what
7 happened to the patient based on that adverse
8 event. Then it asks the investigator or the
9 research team to make some judgments based on the
10 information that they have on that particular
11 adverse event, and in terms of what they know is
12 going on in the study does this alter the