1
DEPARTMENT OF HEALTH AND HUMAN
SERVICES
FOOD AND DRUG
ADMINISTRATION
CENTER FOR DRUG EVALUATION AND
RESEARCH
PEDIATRIC ONCOLOGY SUBCOMMITTEE
COMMITTEE
OF THE ONCOLOGIC DRUGS ADVISORY
COMMITTEE
First Floor Conference Room
2
PARTICIPANTS
ONCOLOGIC DRUGS ADVISORY COMMITTEE:
Donna Przepiorka, MD., Ph.D., Chair,
ODAC
Johanna Clifford, M.S., RN, BSN
Pamela J. Haylock, RN,
Consumer Representative, ODAC
CONSULTANTS (VOTING):
Victor Santana, M.D., Chair
Peter Adamson, M.D.
Alice Ettinger, M.S., RN
Peter Houghton, Ph.D.
Eric Kodish, M.D.
C. Patrick Reynolds, M.D., Ph.D.
Susan Weiner, Ph.D.
Ruth Hoffman, Patient Representative
Barry Anderson, M.D., Ph.D.
Lee J. Helman, M.D.
Malcolm Smith, M.D., Ph.D.
Paul Meltzer, M.D.
Chand Khanna, DVM, Ph.D., DACVIM
Kenneth Hastings, Ph.D.
ACTING INDUSTRY REPRESENTATIVE
(NON-VOTING):
Antonio Grillo-Lopez,
M.D.,
FDA STAFF:
Susan Ellenberg, Ph.D.
Steven Hirschfeld, M.D.,
Ph.D.
Ramzi
Dagher, M.D.
Richard Pazdur, M.D.
Patricia
Keegan, M.D.
Pat
Dinndorf, M.D.
Grant Williams, M.D.
3
C O N T E N T S
PAGE
Call to Order, Victor Santana, M.D.,
Chair 5
Introductions 5
Conflict of Interest Statement,
Johanna Clifford, M.S., RN, BSN 7
Safety Monitoring in Clinical Studies
Enrolling
Children with Cancer:
Opening Remarks, Richard Pazdur, Director,
Division of Oncology Drug Products,
FDA 10
Introduction of Issues and Agenda,
Steven Hirschfeld, M.D., Ph.D., Office
of Cellular and Gene Therapy, FDA 11
Protecting Children in Cancer Research:
What Really
Matters, Eric Kodish, M.D., Director,
Rainbow
Center for Pediatric Ethics 23
Legal Responsibilities for HHS Supported
Studies,
Michael Carome, M.D., Office for Human
Research
Protection, HHS 49
Legal Responsibilities for Studies with
FDA
Regulated Products, Steven Hirschfeld,
M.D.,
Ph.D., Office of Cellular and Gene
Therapy,
CBER, FDA
61
Enrollment and Monitoring Procedures for
NCI Funded
Studies, Barry Anderson, M.D., Ph.D.,
Cancer
Treatment Evaluation Program, NCI 70
Open Public Hearing:
Wayne Rakoff, Johnson &
Johnson 87
Monitoring Procedures in a Private
Children's Hospital,
Victor Santana, M.D., St. Jude
Children's Hospital 88
Committee Discussion 116
Questions for Discussion 154
4
C O N T E N T S
(Continued)
PAGE
Use of Nonclinical Data to Complement
Clinical Data
for Pediatric Oncology:
What are Microarrays and How Can They
Help Us
with Clinical Studies in Pediatric
Oncology,
Paul Meltzer, National Human Genome
Research
Institute, NIH 198
Advantages and Limitations of Cell
Culture Models
in Pediatric Drug Developments,
Peter Adamson, M.D., Children's
Hospital
of Philadelphia 210
Human Cell-Animal Xenografts: The Current
Status,
Potential and Limits of Informing Us
About
Clinical Studies, Peter Houghton,
Ph.D., St.
Jude Children's Research Hospital 229
An Integrated and Comparative Approach to
Preclinical/Clinical Drug Development,
Chand Khanna, DVM, Ph.D.,
Tumor and Metastasis Biology Section,
NIH 248
What Can be Learned About Safety,
Kenneth Hastings, Ph.D., CDER,
FDA 263
Assessing Anti-Tumor Activity in
Nonclinical Models
of Childhood Cancer, Malcolm Smith,
M.D., Ph.D.,
Treatment Evaluation Program, National
Cancer
Institutes, NIH 280
Committee Discussion 294
Questions for Discussion 306
5
1 P R O C E E D I N G S
2 Call to Order
3
DR. SANTANA: Good morning to
everyone. I
4
know Dr. Kodish is on the line so good morning to
5 you
too, Eric. I hope you can hear us well.
6
DR. KODISH: Good morning, Victor.
7
DR. SANTANA: This is a meeting of
the
8
Pediatric Oncology Subcommittee of the Oncology
9
Drugs Advisory Committee and we are here today to
10
advise the agency on two issues.
In the morning we
11
will deal with the issue of safety monitoring in
12
clinical studies enrolling pediatric oncology
13
patients. Then, in the afternoon
we will address
14
issues related to the use of nonclinical data to
15
complement clinical data for proposed pediatric
16
oncology studies. So, we have
quite a busy agenda
17 and
I think we will go ahead and get started with
18 the
introductions, and I am feeling so sorry for
19 Dr.
Anderson who is sitting all by himself over
20
there, but we will go ahead and get started with
21 him
and then move around.
22 Introductions
23
DR. ANDERSON: Barry Anderson,
from NCI
24 CTEP.
25
DR. GRILLO-LOPEZ: Antonio
Grillo-Lopez,
6
1
Neoplastic and Autoimmune Diseases Disorders
2
Research Institute.
3
DR. WEINER: I am Susan Weiner,
from The
4
Children's Cause, a patient advocate.
5
MS. HOFFMAN: Ruth Hoffman,
patient
6
advocate.
7
DR. PRZEPIORKA: Donna Przepiorka,
8
University of Tennessee, Memphis.
9
MS. CLIFFORD: Johanna Clifford,
executive
10
secretary to this meeting.
11
DR. SANTANA: Victor Santana,
pediatric
12
oncologist at St. Jude Children's Research
13
Hospital, Memphis, Tennessee.
14
DR. REYNOLDS: Dr. Reynolds,
Children's
15
Hospital of Los Angeles.
16
MS. ETTINGER: Alice Ettinger,
pediatric
17
nurse practitioner, St. Peter's University Hospital
18 in
New Jersey.
19
DR. PAZDUR: This is Susan
Ellenberg, who
20 has
laryngitis. She is a statistician. I am
21
Richard Pazdur.
22
DR. HIRSCHFELD: Steven
Hirschfeld, FDA.
23
DR. DINNDORF: Patricia Dinndorf,
FDA.
24
DR. DAGHER: Ramzi Dagher, FDA.
25
DR. SANTANA: Eric, will you go
ahead and
7
1
announce your name and affiliation for the record?
2
DR. KODISH: I am Eric Kodish,
from
3
Cleveland, Ohio, Rainbow Babies & Children's
4 Hospital.
5
DR. SANTANA: Thank you,
Eric. With that,
6 we
will go ahead and have Ms. Clifford read us the
7
conflict of interest statement.
8 Conflict of Interest
Statement
9
MS. CLIFFORD: Thank you. The following
10
announcement addresses conflict of interest issues
11
associated with this meeting and is made a part of
12 the
record to preclude even the appearance of such
13 at
this meeting.
14
Based on the agenda, it has been
15
determined that the topics of today's meeting are
16
issues of broad applicability and there are no
17
products being approved at this meeting.
Unlike
18
issues before a committee in which a particular
19
product is discussed, issues of broader
20
applicability involve many industrial sponsors and
21
academic institutions.
22
All special government employees have been
23
screened for their financial interests as they may
24
apply to the general topics at hand.
To determine
25 if
any conflict of interest existed, the agency has
8
1
reviewed the agenda and all relevant financial
2
interests reported by the meeting participants.
3 The
Food and Drug Administration has granted
4
general matters waivers to the special government
5
employees participating in this meeting who require
6 a
waiver under Title 18, United States Code,
7
Section 208.
8
A copy of the waiver statements may be
9
obtained by submitting a written request to the
10
agency's Freedom of Information Office, Room 12A-30
11 of
the Parklawn Building.
12
Because general topics impact so many
13
entities, it is not prudent to recite all potential
14
conflicts of interest as they apply to each member
15 and
consultant and guest speaker. FDA
acknowledges
16
that there may be potential conflicts of interest
17
but, because of the general nature of the
18
discussion before the committee, these potential
19
conflicts are mitigated.
20
With respect to FDA's invited industry
21
representative, we would like to disclose that Dr.
22
Antonio Grillo-Lopez is participating in this
23
meeting as an acting industry representative,
24
acting on behalf of regulated industry.
Dr.
25
Grillo-Lopez is employed by Neoplastic and
9
1
Autoimmune Diseases Research.
2
In the event that the discussions involve
3 any
other products or firms not already on the
4
agenda for which FDA participants have a financial
5
interest, the participants' involvement and their
6
exclusion will be noted for the record.
7
With respect to all other participants, we
8 ask
in the interest of fairness that they address
9 any
current or previous financial involvement with
10 any
firm whose product they may with to comment
11
upon. Thank you.
12
DR. SANTANA: Thanks,
Johanna. Anybody
13
else sitting at the table that wants to disclose
14
anything publicly? No? Dr. Adamson just joined
15 the
group. Do you want to introduce
yourself,
16
Peter, please?
17
DR. ADAMSON: Peter Adamson, from
18
Children's Hospital of Philadelphia.
19
DR. SANTANA: Thanks, Peter. Peter, do
20 you
want to introduce yourself?
21
DR. HOUGHTON: Peter Houghton, St.
Jude
22
Children's Research Hospital.
23
DR. SANTANA: With that, I will
pass it
24
over to Dr. Pazdur for his opening remarks.
25 Opening Remarks
10
1
DR. PAZDUR: Well, I would like to
2
disclose something publicly, my disappointment with
3
Victor and Johanna for not mentioning this but the
4
disclosure is happy St. Patrick's Day.
5
[Laughter]
6
As you can see, we in the government have
7
provided you with green folders for the day and,
8
obviously, I am dressed in green but I would like
9 to
remind you Pazdur is not an Irish name.
The
10
other thing I would like to just emphasize is that
11
Donna and I, as compatriots from Chicago's Polish
12
community, would like to emphasize that St.
13
Patrick's Day is just a warm-up for St. Joseph's
14
Day. Okay?
15
[Laughter]
16
DR. SANTANA: Which is Friday,
March 19th.
17
DR. PAZDUR: Thanks for pointing
that out.
18
In all seriousness, I would like to go
19
back to why we are here today, and that is for the
20 subcommittee
to discuss two important areas today,
21 one
in the morning discussing safety monitoring in
22
clinical studies enrolling children with cancer and
23
then, in the afternoon, discussing nonclinical data
24 to
complement clinical data for pediatric oncology.
25
We look at these as very important
11
1
thematic discussions to have. How
these areas
2
impact on oncology drug development I think is very
3
important. One thing that I would
ask the
4
committee to do specifically is to concentrate
5
really on the pediatric aspect of these.
I know
6
that these areas have some tentacles to adult
7
oncology and to other areas of oncology but I would
8
like to remind you that the purpose of this
9
subcommittee is to focus on the pediatric
10
specificity of these issues and special
11
considerations of these broad issues in pediatric
12
oncology.
13
I would like to thank
everyone for being
14
here. I asked Steve what number
meeting this is
15 and
we think it is the eighth. We may be
wrong but
16 we
are happy that the committee is meeting on a
17
regular basis. We intend to have
the committee
18
meet on a regular basis here and to continue this
19
dialogue with the community. So,
Steve, I will
20
turn it over to you.
21 Introduction of Issues and
Agenda
22
DR. HIRSCHFELD: Thank you. It is
23
customary at the end of remarks to give the
24
acknowledgments but I wanted to give two
25
acknowledgments initially. The
first one is to
12
1
someone who is in the room right now and I am
2
looking at her, and that is Johanna Clifford who
3 has
done I think a marvelous job in helping to
4
organize this meeting, and we have had a number of
5
challenges to overcome along the way, so many
6 challenges
that for a period of time we thought we
7
were working under a curse, but Johanna has been
8
steadfast, good humored, competent, rapid in her
9
responses and has been I think a driving force in
10
terms of having the meeting occur as it is and as
11
well organized as it is today.
So, thank you,
12
Johanna.
13
I would also like to acknowledge someone
14 who
is in this room, although not physically, but
15
someone who has had enormous influence on our
16
thinking and on our policies toward patients
17
enrollment in studies and in particular children
18
enrolling in studies, and that is Bonnie Lee who
19 has
been with the FDA for many years and was
20
associated with the initial hearings of the
21
committee, which was mandated by Congress in the
22
1970s, to examine the role of children in clinical
23
research. Bonnie has been a
particular guide and
24
inspiration for me and also a source of information
25 and
direction, which I think has been an asset not
13
1
only to the agency but to the country and to all
2
patients. And, I wanted to
dedicate the discussion
3
this morning in her honor. So,
thank you, Bonnie.
4
As Dr. Pazdur pointed out, we are going to
5 be
discussing the themes of safety and
6
extrapolation. Clinical research,
which we have
7
discussed in some detail in this forum over several
8 of
the meetings, has been recorded for at least
9
2,400 years. Children were often
the first
10
patients for new procedures and interventions.
11
Part of this evolved from the concept that children
12
were the property of parents so it was rather easy
13 for
parents to donate their children for whatever
14
questions might be asked. But
along the way there
15
were some founding principles because,
16
unfortunately, children have also been the victims
17 of
clinical research.
18
The founding principles of modern Food and
19
Drug Administration regulation were, in large part,
20
established for the purpose of protecting children
21
and, yet, pediatric therapeutic development has
22
never been as thorough and robust as adult
23
therapeutic development, and most of the people in
24
this room have been part of that process and
25
witness to these inequities. Many
therapies are
14
1
administered to children without adequate studies
2
and, furthermore, many therapies are not made
3
available for pediatric study until after adult
4
marketing studies are completed and this is
5
particularly true in oncology.
So, we have been
6
working to overcome some of these barriers and
7
challenges. And, the challenges
are to assemble
8
sufficient data to establish efficacy and safety in
9 the
relevant population. The relevant
population
10 may
be sufficiently rare that confirmatory studies
11 are
not feasible, which is particularly the case
12 for
many of the childhood malignancies.
13
There are concerns regarding the
14
implications of adverse events in children and this
15 has
been a barrier to the further clinical
16
development of some products because of these
17
concerns. It is also important
that there is the
18
establishment and maintenance of a framework that
19
would support systematic clinical investigations
20 for
the relevant population. This has been
the
21
case historically in pediatric oncology but that
22
framework has always been challenged and is always
23
competing with other priorities.
So, it is
24
incumbent on us to make sure that that pediatric
25
research framework has the best resources, and the
15
1
best advice, and the best support, and the best
2
regulatory environment to do its job.
3
The particular issues regarding the safety
4
monitoring in pediatric oncology clinical
5
investigations are an acknowledgment that children
6
require special protections. Yet,
on the other
7 hand,
there is also an acknowledgment that risk
8
tolerance is higher in oncology therapeutics than
9 in
other therapeutic areas. This sets up a
10
potential tension. Furthermore,
there are no
11
detailed consensus standards on study monitoring
12
despite numerous international documents describing
13
what could be termed good clinical practice. We
14
will examine those in some detail during the course
15 of
the morning. So, the charge to the
committee is
16 to
suggest ways to incorporate the fundamental
17
ethical and scientific principles in protecting
18
patients enrolled in clinical studies for pediatric
19
malignancies while providing clear guidance and
20
minimizing the resource burden.
21
We have a series of
questions directed
22
toward the committee to help focus the discussion.
23
These are questions which are meant to stimulate
24
what we hope will be an informative exchange and do
25 not
have a yes/no or a definitive answer.
16
1
The first questions revolves around the
2
principles, what are the principles that should be
3
addressed in safety monitoring of clinical studies
4 that enroll children with cancer? Dr. Kodish is
5
going to provide us with some background on that
6
particular topic. If the
principles are adequately
7
stated in existing documents. statutes or
8
regulations, please identify the relevant documents
9 and
sections.
10
The second set of questions deals with the
11
practice. Recognizing that
particular populations,
12
disease settings and products may have specific
13
requirements, what general parameters should be
14
monitored for safety in all clinical studies? Or,
15 to
rephrase that, what should the default position
16 be
for safety monitoring?
17
Based on the response to the previous
18
question, how often should these parameters be
19
monitored? Again, just giving a
framework or
20
guidelines.
21
Based on the responses to the previous
22
questions, who should do the monitoring?
Is it
23
adequate to have the personnel involved in the
24
study be responsible for safety monitoring? When
25 we
discuss this in detail we may parse this out
17
1
into the type of study, whether it is early
2
development or later development or the type of
3
disease or other risk factors.
4
What circumstances would benefit from a
5
data monitoring committee? And,
are there
6
additional recommendations for safety monitoring?
7
The afternoon will be devoted to a
8
question which can be traced back to the principle
9 of
extrapolation. Extrapolation has been a
topic
10 of
interest within the Food and Drug Administration
11 for
many years. In recent years there has
been an
12 FDA
working group on pediatric extrapolation that
13 has
identified four domains that may provide a
14
basis for extrapolation of adult data to the
15
pediatric population. These are
nonclinical data,
16
pathophysiology, natural history of the disease or
17
condition, and response to therapy.
18
When our group, noted at the bottom of the
19
slide and some of the members are present here in
20 the
audience, asked ourselves the question how can
21 we
use nonclinical data to inform us about
22
pediatric clinical studies, and in particular
23
pediatric studies in clinical oncology, we realized
24 we
needed further background and further discussion
25
before we could have an informed approach to it.
18
1
We recognize that the absence of
2
predictive or explanatory nonclinical models in
3
pediatric oncology is today's status quo. We know
4
that safety prediction based on animal studies is
5
estimated at approximately 65-70 percent for
6
cytotoxic compounds and it is unknown for other
7
classes of compounds, particularly the new biologic
8
therapies, gene therapies, immunotherapy, and
9
cellular-based therapies.
Efficacy prediction is
10
unknown but low at best. The
findings in clinical
11
studies, particularly negative studies, often
12
remain unexplained.
13
Therefore, further clinical studies that
14
entail resources and risks are undertaken to
15
further the field, and we are posing the paradigm
16 is
there a mechanism by which we can use
17
nonclinical data to inform us and improve the
18
clinical research in pediatric oncology.
There are
19
potential advantages of using the nonclinical data:
20 a
lesser resource burden; the ability to answer
21
questions not amenable to available clinical
22
techniques. There might be
ethical or, in fact,
23
legal considerations involved too; possibly a
24
faster time frame to generate data; a dynamic
25
interaction between clinical and nonclinical
19
1
findings that can enhance understanding and
2
confidence in results. When we
only have a
3
sufficient population to do one definitive study,
4 and
that study takes three to five years and it is
5 not
feasible to do a confirmatory study, having
6
confidence in those results is critical.
The
7
avoidance of non-informative and minimization of
8
negative outcome studies could be another outgrowth
9 and
an opportunity for new study designs.
10
So, the charge to the committee for this
11 afternoon
is to provide advice on what types of
12
nonclinical data are considered informative to
13
complement or supplement clinical results. What
14
should the characteristics or properties of
15
nonclinical models and data be to effectively add
16 to
the clinical results?
17
If there are no satisfactory models that
18
exist currently, and we will hear some discussion
19 on
approaches, what characteristics should a
20
nonclinical model have to confirm, extend or
21
substitute for clinical results?
22
Lastly, is there a set of postulates that
23 can
be identified, or should a set be developed to
24
help us make the transition for data extrapolation?
25 So,
the questions we are asking are what types of
20
1
questions that are of potential clinical relevance
2 but
are not feasible or acceptable to answer in a
3
clinical study could be addressed by nonclinical
4
studies.
5
Examples may include the need for repeated
6
tissue sampling, always a contentious issue,
7
particularly in children; the assessment of
8
long-term effects of treatment; effects on
9
reproduction; access to critical anatomic
10
structures, and this is a consideration again
11
particularly for some of the pediatric brain
12
tumors; exposure to toxic reagents; evaluation of
13
non-monitorable or irreversible toxicities;
14
identification of biomarkers for clinical
15
monitoring; and many others which I am sure will
16
come up when we have our learned and motivated
17
panel discuss the issue.
18
What type of evidence and data would be
19
recommended in each of the following domains to
20
allow extrapolation from nonclinical data and be
21
informative for a clinical condition?
There are
22
listed here a few but there may be others. These
23
include, but are not limited to pharmacology and
24
pharmacokinetics, safety, efficacy, behavior,
25
long-term effects, developmental aspects and others
21
1
which I am sure will come up.
2
Are there additional recommendations for
3 the
effective use of nonclinical data? For
4
example, will open literature reports be generally
5
acceptable? Is documentation of
compliance with
6
Good Laboratory Practice necessary to evaluate
7
animal data? Should nonclinical
data be submitted
8 as
an independent report with a presentation of
9
primary data sufficient for verification and
10
review? These are all practical
questions and we
11 are
looking for specific advice.
12
So, with this charge and
these questions
13
before you, I would like to thank all the committee
14
members and our speakers and guests, and everyone
15 who
has shown an interest here for participating in
16
this discussion, and I will turn now the further
17
presentation over to Dr. Eric Kodish, who will
18
discuss the fundamental principles involved in
19
clinical research and some of the issues of
20
enrolling children.
21
Dr. Santana, I think perhaps before we
22
have Dr. Kodish speak--we have some more members of
23 the
panel that should be introduced.
24
DR. SANTANA: Yes. Anybody that joined us
25 a
little bit late, could you please identify
22
1
yourself into the microphone by name and
2
affiliation, and any potential conflicts that may
3
have arisen since we started?
4
MS. HAYLOCK: I am Pam
Haylock. I am an
5
oncology nurse and I am at the University of Texas
6
Medical Branch, in Galveston.
7
DR. SMITH: I am Malcolm Smith,
pediatric
8
oncologist at the Cancer Therapy Evaluation
9
Program, NCI.
10
DR. SANTANA: Dr. Grillo, you had
your
11
hand up?
12
DR. GRILLO-LOPEZ: Yes, a point of
13
clarification that I would like to propose to Dr.
14
Hirschfeld. On his first slide on
the charge to
15 the
committee, which addresses the morning session,
16 you
used the phrase "providing clear guidance and
17
minimizing the resource burden" which clearly
18
applies to human resources and financial resources
19 but
perhaps doesn't quite stress time. I
would
20
suggest that part of your charge to the committee
21
should be that whatever recommendations we propose,
22 and
however the FDA understands and decides to
23
apply those recommendations, should not affect the
24
time lines for cancer drug development which today
25 are
already intolerably long, and we should be
23
1
concerned that the cancer patient in general should
2 not
be subject to those too long time lines and
3
that anything we do should, in fact, try to reduce
4 the
time lines for approval of new therapies.
5
DR. HIRSCHFELD: Thank you for
your
6
comments, Dr. Grillo-Lopez. I
think you touched on
7 one
of the themes which is implied. I
personally
8 have always incorporated in the concept
resource of
9
time because time is, in fact, probably the most
10
precious resource and, if one looks at biology as a
11
broad spectrum, time is something which evolution
12 and
biologic processes look to, to conserve in many
13
ways too. So, I thank you for
calling attention to
14 the
issue of time, and it is incorporated in that
15
specific charge.
16
DR. SANTANA: One of the
philosophic
17
principles of stewardship is that it involves time,
18
people and money resources. So, I
think those are
19 all
encompassed in your comments.
20
With that, Eric, are you on line now?
Can
21 we
proceed with you?
22
DR. KODISH: I am on line, Victor.
23
DR. SANTANA: Good. Go ahead, Eric.
24
Protecting Children in Cancer Research:
25 What Really Matters
24
1
DR. KODISH: Good morning. It is good to
2 be
with you virtually, if not physically. I
3
apologize for the inability to get to Washington.
4 We
have, hopefully, completed our last big
5
snowstorm of the winter in Cleveland.
6
I am going to be speaking this
morning
7
over the telephone and looking at a Webcast of the
8
slides and this is a work in progress so, please,
9
interrupt me if it is not going well and I will
10
switch to my Power Point presentation. I am looking
11 at
the Webcast now and I don't see my Power Point
12
slides yet. What I plan to do is
ask Johanna to
13 put
on the next slide before I move through them.
14 So,
let's give it a moment for me to see the first
15
slide.
16
I can introduce the talk by saying that I
17
have always thought I had a face for radio and this
18 is
an example of that perhaps--
19
[Laughter]
20
I see my first slide. the title
of this
21 presentation
is "Protecting Children in Cancer
22
Research: What Really Matters."
23
Can I ask that we have the next slide,
24
please?
25
MS. CLIFFORD: You know what, Dr.
Kodish,
25
1 if
you just want to move on through your
2
presentation--
3
DR. KODISH: I have it now. Should I go
4 to
the Power Point instead?
5
MS. CLIFFORD: Yes, that would be
great.
6 DR. KODISH: All right, the Webcast didn't
7
work well and I will look forward to joining you on
8 the
Webcast after I have done my talk.
9
MS. CLIFFORD: Okay, there just
seems to
10 be
a delay.
11
DR. KODISH: I figured that might
happen.
12 The
Belmont report I think articulates the key
13
principles of research involving human subjects.
14 My
purpose today is to respond to the charge that
15 has
been given to the committee and to paint in
16
broad strokes what the key principles are for
17
protection of children involved in cancer research.
18 I
think it starts with the Belmont report and the
19
three key principles that are articulated there are
20
beneficence, respect for persons and justice.
21
The next slide, please. This
slide shows
22 a
concept of principles that move into practice.
I
23
thought it was quite appropriate that the charge
24 for
the first half of the meeting talked about both
25
principles and practice. I view
the regulations
26
1 and
their interpretation as a conduit, as a
2
mechanism by which we move from principles to
3
practice. I want to emphasize the
word
4
"interpretation" here.
I think that the current
5 set
of regulations is subject to wide
6
interpretation, as has been pointed out over and
7
over again in the literature. I
don't view this as
8 a
negative. I think that it allows for
thoughtful
9
IRBs, investigators, parents and others involved in
10 the
research process to move from principles to
11
practice in an appropriate manner, and that
12
interpretation is really the key step.
13
The next slide, please. This
slide should
14
show a triangle which points out that we are
15
talking today about pediatric research ethics and
16
that this is a more complicated system because of
17 the
involvement of a child. The geometry of
18
pediatric research ethics involves parents, on your
19
lower left; the investigator, on your lower right;
20 and
the child at the top of the triangle. If
we
21
keep the best interests of the child in mind at all
22
points, I think we will be responding to perhaps
23 the
most fundamental issue in research involving
24
children.
25
The next slide, please. This
slide shows
27
1 a
recapitulation of the Belmont principles with an
2
emphasis on beneficence in pediatric ethics.
3
Respect for persons and justice remain important in
4
pediatric ethics but it is my feeling that there is
5 a
special place for beneficence when we are talking
6
about children, whether it is research involving
7
children or in clinical ethics regarding children.
8 In
fact, more broadly in social policy regarding
9
children it is important to remember that children
10 are
not able to vote; don't have economic
11
resources; and we owe an advocacy role I think on
12
behalf of children. It is very
important and, to
13 me,
prioritizes that beneficence as a concept for
14
pediatric ethics.
15 Can I have the next slide, please? The
16
principles of medical ethics then are different for
17
children compared with adults. I
would say that
18
respect for persons, for good or for bad, has
19
become the dominant principle for adult ethics and
20
this is seen in research ethics where there is a
21
tremendous emphasis on informed consent, and this
22 is
out of the derivative concept of autonomy which
23
comes from that principle of respect for persons.
24 By contrast,
as I said, I think the best interest
25 of
children has to dominate pediatric ethics and
28
1
justifies an population that takes beneficence as
2 the
most important principles.
3
I don't want you to move slides back but,
4 if
you recall a few slides ago, the slide that
5
shows moving principles into practice, I think
6
beneficence has to be the principle that drives our
7
interpretation of the regulations and our actual
8
practices.
9
The next slide, please. This
slide
10
dissects out some text from the Belmont report.
11 The
document itself talks about beneficence as an
12
obligation with two general rules.
These are very
13
interesting. It had been sometime
since I have
14
looked at them and in preparing for this
15
presentation I found the two general rules cited by
16
Belmont are do not harm and, secondly, maximize
17
possible benefits and minimize possible harms.
18
On the face of it, these two general rules
19 can
be read as conflicting with one another.
That
20 is,
the charge do not harm is an absolute standard,
21
whereas in the second rule of minimizing possible
22
harms and maximizing possible benefits it is a
23
relative standard and it calls for a weighing of
24
benefit against harm. Again, to
put interpretation
25
into play, I think it is the second rule that is
29
1
most appropriate for pediatric oncology studies.
2
That is to say, if one is talking about research
3
involving healthy children with no prospect of
4
benefit to that child, the first rule might be more
5
appropriate to apply, do not harm, period. But we
6 are
talking about a balance in pediatric oncology
7 and
I think the second general rule is more
8
appropriate.
9
Can I have the next slide, please?
If we
10 are
on the same page, this slide should continue to
11
cite the Belmont report which says that beneficence
12 is
not always so unambiguous and goes on to say
13
that prohibiting research that presents more than
14
minimal risk without the immediate prospect of
15
direct benefit to the children involved limits
16
potential for great benefit to children in the
17
future.
18
This became, in some sense, the foundation
19 for
the different categories of research in subpart
20 D
that IRBs are able to approve and points out the
21 key
ethical dilemma, as far as I am concerned,
22
which has to do with how we weigh benefits or which
23
benefits count when we are weighing risk and
24 benefit.
25
The next slide, please. The
subtitle of
30
1 my
talk today is "What Really Matters" and as I
2
thought about a way of presenting this I decided
3 that
it could be divided in three phases, what
4
matters before a clinical trial begins; what
5
matters during the conduct of the trial; and what
6
matters after a trial has closed.
7
One of the members of the panel pointed
8 out the importance of time prior to the
beginning
9 of
my talk, and I guess this is another way of
10
looking at time as a divider for where the
11
different ethical obligations come in.
12
Speaking of time, I wanted to get some
13
validation from Johanna. Is the
timing going
14
better now with the slides?
15
MS. CLIFFORD: It is fine, Dr.
Kodish.
16
DR. KODISH: Going fine? Great!
So, I
17
would like to now talk about what matters before a
18
trial begins and I could think of at least three
19
important issues. The first is
that it be
20
significant science. Again,
interpretation is a
21 key
here. My view of significant science is
that
22 it
has the potential to help children with cancer.
23 I
think it is important that I am very specific
24
about that. I think that if there
are going to be
25
exposures of risk to children with cancer the
31
1
potential to help children with cystic fibrosis,
2 for
example, may not be considered significant
3
science by this test. The
potential to help adults
4
with Alzheimer's disease may not be significant
5
science by this test.
6
I think that we need to be cognizant of
7 the
fact that research involving children with
8
cancer needs to resound back to help children with
9
cancer and that one should look for other avenues
10 to
study other important diseases. It is
difficult
11 to
think of children with cancer as a resource, but
12 I
think in some sense this really forces us to do
13
that and, by limiting the risk of exposure to
14
children to that which will come back to help
15
children--and I know that scientifically it is
16
often very difficult to predict in which direction
17 the
work will go and how the results will, in fact,
18
play--ut but at the outset one can try to predict
19 and
think about a definition of significant as
20
being that which has the potential to help children
21
with cancer.
22
The second thing that really matters
23
before a clinical trial begins is a risk/benefit
24
assessment. I think in the next several
slides I
25
will talk more about what counts as risk and what
32
1
counts as benefit.
2
Finally, it is a study design that will
3
answer the question and that also does not
4
subjugate the interests of any single subject to
5 the
overall needs of the research. Again,
embedded
6
there are a couple of important ethical principles
7
that I think are perhaps specific--at least the
8 second
one under study design--specific to research
9
with a vulnerable population and, as Dr. Hirschfeld
10
said, children certainly are considered and should
11 be
considered.
12
The next slide, please. This
slide shows
13 the criteria for the 405 category. As I think
14
everybody is aware, there are four categories of
15
research that can be approved by IRBs under subpart
16
D. Almost all cancer research I
think is approved
17
under 405, that is, pediatric cancer research. It
18 is
research that involves more than minimal risk
19 but
presents the prospect of direct benefit to the
20
individual subject if the risk is justified by the
21
anticipated benefit to the subject; if the
22
risk/benefit ratio is less than or equal to the
23
alternatives; and if parental permission and assent
24 are
obtained.
25
The next slide, please. As we
weigh risk
33
1 and
benefit in research ethics, it is important to
2
remember that risk means risk to the subject but
3
benefit may include benefits to the subject,
4
benefits to other patients, benefits to society or
5
benefits to an investigator or a sponsor. I think
6
what we are aiming for in research involving
7
children in some sense is limiting the benefits
8
that we think about in a risk/benefit analysis so
9
that the benefits that come to the subject are the
10
ones that we are thinking about as we weigh risk to
11 the
subject, and that we avoid a situation where
12
children are used as a means to an end.
To go back
13 to
Emmanuel Kant and the idea that children are
14
valued and protected, I think it is inherent in
15
this sort of balancing.
16
The next slide, please. This is a
slide
17
that looks at some of the issues in early drug
18
development involving children with cancer. There
19 has
been a controversy over, what I have put in
20
quotes here, therapeutic intent.
The point here is
21
that the prospect of direct benefit is the key
22
ethical and regulatory issue and, in my view, a
23
percentage view of what that potential for
24
therapeutic intent might be isn't that important.
25
That is, I think even a very low chance of
34
1
therapeutic benefit for the child should count as a
2
prospect of direct benefit to the child.
Again, my
3
interpretation of the word prospect is a very broad
4
one, admittedly, but this is where the issue of
5
interpretation comes in. As the
discussion goes
6 on,
we can talk about how prospect ought to be
7
interpreted.
8
The second bullet point you see on this
9
slide has, in parentheses, the potential for 405
10
creep, that is, moving this issue of commensurate
11
experience that children with cancer have already
12
been through a lot so that it is okay to put them
13
through one more thing. This
doesn't stand up in
14 my
view as a valid justification for exposing
15
children with cancer to risk.
16
The alternatives is another key issue that
17 is
discussed, if you recall, in the 405 criteria.
18
There needs to be favorable outcome for the child
19
compared to the alternatives.
20
The next slide, please. If we are
on the
21
same page, this should be a slide that says options
22 on
top. It has at least three different
pathways
23
that families and children can seek out when a
24
child has refractory, untreatable cancer. On your
25
left is a Phase I study; in the middle is
35
1
alternative medicine and on the right is hospice
2
philosophy care.
3
The next slide shows further
4
considerations regarding Phase I oncology research
5 in
children. The first is to point out that
6
subject selection is not a major controversy in
7
this realm, that is to say, Phase I studies are
8
done involving healthy children but it is not an
9
issue of wanting to do Phase I cancer research on
10
healthy children. That, to my
knowledge, is not a
11
controversy but I put it here because it is
12
important to try to contextualize pediatric cancer
13
research in the broader picture of research
14
involving children. As I said
before, I think that
15
Phase I research qualifies, in my mind, as research
16
with the prospect or direct benefit.
17
Most importantly on this slide, is that
18
potential for benefit mitigates but does not
19
eliminate the need for protection from research
20
risk. To be more clear about
that, it is the
21
potential for benefit that is balanced against the
22
risk that mitigates it, but I think the charge to
23 the
committee and the work we are going to do this
24
morning is still extremely important.
The need for
25
protection from research risk is not eliminated by
36
1 the
potential for benefit.
2
The next slide, please. This
points out
3
some issues around alternative medicine.
The
4
reason that I put this here is that I think there
5 is
a yardstick of fairness that we need to keep in
6
mind. It is often the case that
when research is
7
being done it is held to a higher standard or a
8
different standard than what is happening in the
9
non-research world, and it is very important I
10
think to the families and the children involved
11
that we try to put this in the lens that they are
12 viewing
this off from, and to make it difficult to
13
access research or to have children participate in
14
well-designed, safely monitored research, in some
15
ways, runs the risk of shunting them to alternative
16
medicine where there are vulnerability concerns.
17 It
is very prevalent phenomena for children with
18
refractory cancer. I think there
are major ethical
19
differences when it comes to children getting
20
alternative therapy compared to adults who can make
21 their own decision. I think we have a very
22
important obligation to prevent harm when it comes
23 to
children who are getting alternative medicine,
24 and
I think it is extremely important that
25
alternative medicine possibilities be studied in a
37
1
rigorous and careful way. But the
bottom line is
2
that we need to communicate with families and
3
children. The ones that the
research community
4 encounters
may also be taking alternative medicine
5 and
if we don't know what medications are being
6
taken, then we won't have the ability to study drug
7
interaction with alternative medications and the
8
experimental agent, for example.
I just think that
9 it
is very important that we keep alternative
10
medicine in mind as something that is out there and
11 we
shouldn't be blind to it.
12
The next slide, please. This
slide has a
13 few
words about hospice care for children who have
14
refractory disease. Now, some
people I think have
15 the
experience that those who come to Phase I
16
studies are self-referred, not interested in
17
hospice philosophy care, wanting to continue to
18 pursue anti-neoplastic therapy but, in my
19
experience, that is not the case.
In fact, many
20
families who seek Phase I studies also are amenable
21 to
having their child get hospice philosophy care.
22 So,
the two are not incompatible. I think it
is an
23
under-developed approach in children.
It is not
24 the
main focus of what we are here about today but
25 I
felt that it would be incomplete to give this
38
1
talk without mentioning that hospice philosophy
2
care should be part of the consent process for
3
Phase I studies.
4
The next slide, please. This
moves from
5
what really matters before the conduct of the trial
6 to
during the conduct of the trial. The
three
7
items that really matter during the conduct of the
8
trial are informed consent which, in my view, is a
9
communication process in addition to the
10
documentation that happens; ongoing monitoring via
11 a
data safety monitoring board, if appropriate, and
12 I
understand that much of the discussion later on
13
will have to do with when it is appropriate and
14
when it is not necessary; and ethical action to
15
suspend or stop a study at the right time. It is
16
easier said than done but in parentheses I thought
17 I
would say not too soon but not too late either.
18 So,
the question of when a study should be
19
suspended or stopped is a key ethical question that
20
happens during the conduct of a study and whether a
21
study needs to be stopped at all.
I guess in most
22
cases there is no need to stop it but that question
23
needs to be always asked in the same way house
24
officers always need to ask themselves does this
25
child need a spinal tap. It is a
question that is
39
1
part of the monitoring process as an embedded
2
function.
3
The next slide shows the Nuremberg code.
4
This is a quick bit about informed consent. The
5
Nuremberg code said that the voluntary consent of
6 the
human subject is absolutely essential.
These
7 are
slides that I have shown at previous meetings
8 so
I think we can go fairly quickly through them.
9
The next slide asks the rhetorical
10
question of whether we can do any pediatric
11
research at all, and just points out that if the
12
answer is no, that is, if we have to adhere to
13
strict interpretation of the Nuremberg or literal
14
rather than in the spirit of the law
15
interpretation, children as a group will suffer.
16 You
saw in the Belmont quotation earlier that there
17 is
a clear recognition that there needs to be some
18
research involving children so that we can both
19
protect children adequately but be sure that we
20
make progress in childhood disease.
21
The next slide talks about three ways of
22
respecting Nuremberg and still doing pediatric
23
research by using parents as surrogates and
24
obtaining parental permission; by involving
25
children when appropriate and obtaining their
40
1
assent; and by providing societal protection with
2 IRB
approval as the most obvious but also meetings,
3
similar to what we are doing this morning,
4
investigator integrity and other things that
5
provide societal protection for children, we can, I
6
think, ethically do pediatric research.
7
The next slide shows the difference
8
between parental permission and informed consent
9
and, again, says that the autonomous authorization
10 of
an adult--the difference between adult and
11
pediatric ethics is more robust than a proxy
12
decision and points out, from the Academy of
13
Pediatrics, that the responsibilities of a
14
pediatrician to his or her patient exist
15
independent of parental desires or proxy consent.
16 I
think that there is a congruent statement that
17 one
could make here that says that an
18
investigator's responsibility to his or her subject
19
exists independent of parental desires or proxy
20
consent.
21
The next slide shows that parental
22
permission is not the oral equivalent of informed
23
consent, and that surrogate decision-making is
24
necessarily less authentic. I am
going to skip
25 past the next slide which shows proxy consent,
41
1
substituted judgment and best interests, because I
2
think this is familiar ground for most people and
3 we
have already emphasized best interests.
4
I will go to a slide that says informed
5
consent in pediatrics equals parental permission
6 and
the assent of the child. Here I want to
say
7
that the combination of those two can potentially
8 be
more powerful, if done right, than an
9
individual. This has to do with
family centered
10
ethics that really seek to care for and do
11
effective communication with a family, which is a
12
dynamic and challenging process, admittedly. But I
13
think both of these issues are very important.
14
The next slide, please. This
provides the
15
regulatory definition of assent, which is a child's
16
affirmative agreement to participate in research.
17 The
key point here is that mere failure to object
18
should not be construed as assent.
That is, the
19
silence of an older child for research
20
participation can't be interpreted as their assent.
21
Again, there is room for regulatory interpretation
22
here. There is a great deal of
controversy around
23
assent and requirements for assent, and I think
24
there is likely to be a fair amount of variability
25
across IRBs with regard to this issue and I would
42
1 be
happy to discuss this further during our
2
discussion.
3
The next slide, please. This
slide shows
4
some differences between assent in the clinical and
5
research context, and points out the fact that
6
research is supererogatory, that is, as opposed to
7 a
clinical context where there is a strong best
8
interests argument to be made.
Generally speaking,
9 in
research the decision is more voluntary and, for
10
that reason, assent is more powerful phenomenon, in
11 my
view, ethically speaking in research than it
12
would be in the clinical context.
13
The bottom bullet point here is also
14
important I think as a principle perhaps for us to
15
consider, and that is the older the child, the more
16
assent contributes to the ethical justification for
17 the
study. This is a problem for diseases
that
18
happen in younger children certainly but, all
19
things being equal, an older child I think who can
20
participate in the decision gives us more ethical
21
justification for proceeding in research endeavors.
22
The next slide just points out a piece of
23
data. This is a scale that we did
in our study of
24
informed consent about decision-making preference.
25 It
shows everything from, number one, a parent who
43
1
wants to leave all decisions to the doctor and
2
perhaps to an investigator, and then a continuum to
3
number five, a parent who wants to make final
4
selection about which treatment their child will
5
receive.
6
The next slide shows a sample of 108
7 parents. The reason that I included it this
8
morning is to point out the variability among
9
parents and families when it comes to how they want
10 to
make decisions. You see in this slide a
large
11
number of parents in the middle, within the green,
12 red
and grey columns, who fit into a shared
13
decision-making model. In my
view, this is why
14
informed consent is important during the conduct of
15
research. Most people want a
shared
16
decision-making approach whether it comes to
17
treatment or research participation and
18
communication. Effective
communication is really
19 the
key issue for informed consent.
20
The next slide. As I wind down
the talk
21 and
get to the conclusion, I want to make the point
22
that the over-interpretation of regulatory concerns
23 can
prevent the ethically meaningful participation
24 of
children in research.
25
Can you still hear me?
44
1
MS. CLIFFORD: We can still hear
you.
2
DR. KODISH: Great! I heard a beep on the
3
phone. I am going to tell a quick
story to
4
illustrate this point. Heather K
was diagnosed
5 with a vaginal rhabdomyosarcoma at a
children's
6
hospital in the Midwest within the past few months.
7 At
diagnosis, Heather had a tumor that was causing
8
intestinal compression. Her
pediatric oncologist
9
talked to the family about the diagnosis and then
10
subsequently discussed a Phase III non-randomized
11
study sponsored by the IRS/COG.
The family
12
provided informed consent and signed a document at
13
6:05 p.m. The plan was to begin
chemotherapy the
14 following
day but the patient developed a bowel
15
obstruction at 11:00 p.m. and chemotherapy was
16
emergently started. At midnight
nothing happened
17
that was ethically significant.
Clinically, the
18
patient was continuing to get her chemotherapy.
19 But
the next morning, when the CRA, the data
20
person, came to enroll Heather in this Phase III
21
study, the RDE, or the remote data entry system,
22
made enrollment impossible. The
reason that
23
enrollment was impossible was that the date
24
chemotherapy was started was the previous date and
25 the
form would not permit enrollment to happen if
45
1
chemotherapy had already been started.
2 So, what was a well-intentioned
regulation
3
system designed to prevent people from being
4
entered on study if consent had not yet been
5
obtained--in fact, in this case everything went
6
perfectly from an ethical perspective but the
7
patient was not allowed to be entered on study. I
8
think that this is a cautionary tale and I wanted
9 to
bring it to the attention of the panel today.
10
Next slide, please. We see many
11
well-intentioned regulatory protections and it is
12
important to realize that they can paradoxically
13
prevent the ethical participation of children in
14
cancer research and Heather's story is one example
15 of
that. The physician then needed to go back
to
16 the
family and explain that, unfortunately, we
17
weren't able to include her as a subject in the
18
research. It wasn't going to
change her treatment
19 at
all but the future treatment of children with
20
rhabdomyosarcoma in some ways is harmed by the fact
21
that this regulatory mechanism prevented Heather
22
from being a subject in the study.
The only
23
alternative would have been for the person doing
24
remote data entry to fabricate and to say that the
25
date chemotherapy was started was the day that she
46
1 was
being entered on study, and that would have,
2
number one, been an unethical lie and, number two,
3
would have been picked up on an audit if the
4
subject had been audited subsequently though it may
5
have been, in fact, the ethical thing to do because
6
consent was obtained in an appropriate way, it is
7 an
important study, and all of the things that we
8
have bee talking about, but the regulatory
9
apparatus prevented an ethical action from taking
10
place and I think it is a disturbing story.
11
The next slide shows a synergistic
12
approach. The protection of human
subjects has
13
been done both through education and regulation and
14 we
need to be concerned about developing too much
15
regulation at the expense of education and the
16
expense of thoughtful ethical action.
17
The next slide just has a few quick points
18
about what matters after a trial is closed.
19
Monitoring for late effects of therapy is an
20
important ethical issue after a trial has closed.
21 The
publication of results and dissemination of
22
findings is ethically important.
If the science
23
isn't disseminated, then it is like a tree falling
24 in
a forest that nobody hears. Finally, the
return
25 of
results to the subjects who participated is an
47
1
ethically under-looked and I think very important
2
issue that symbolizes the partnership that we have
3
with subjects and their families, and I think we
4
need to do a better job than we are doing currently
5
after a trial has closed in getting results back to
6 the
subjects.
7
The next slide shows conceptually the main
8
balance as a point of conclusion in pediatric
9
research ethics, that the best interests of the
10
child-subject are, in fact, balanced against
11
science to benefit others and we need to be
12
cognizant of that balance at all times and be sure
13
that the best interests of the child are not
14
subjugated.
15
The next slide shows a couple
of
16
conclusions. The first is that
beneficence, as
17
described in the Belmont report, is the key ethical
18
principle that I believe should guide monitoring of
19
patients in studies. Also, a
risk/benefit
20
assessment by the investigator, by the IRB and by
21
others perhaps is more important than informed
22
consent, and that is because I don't think informed
23
consent has the ethical importance in pediatrics
24
that it does in adult medicine, and also because of
25 the
relatively ineffective communication process
48
1
that is currently happening with informed consent.
2 I
would be happy to talk more about that in the
3
discussion.
4
The next slide shows that the protection
5 of
children from research risk and the imperative
6 to
improve childhood cancer treatment are both
7
ethically important. The bottom
point here is that
8
regulatory fervor intended to protect children
9
currently threatens the ethical conduct of
10
pediatric cancer research, as I tried to illustrate
11 in
Heather's story, and we need to remember, I
12
think, that there is an ethical imperative to do
13
work in childhood cancer to improve the care of
14
children with cancer.
15
The final slide points out that children
16 are
both vulnerable subjects who need protection
17
from research risk and a neglected class--and they
18
continue to be a neglected class despite our best
19
efforts--that need better access to the benefits of
20
research.
21
I thank you all for tolerating the virtual
22
reality nature of this talk and hope that I have
23
been able to make a contribution.
Thank you.
24
DR. SANTANA: Thanks, Eric. Eric, are you
25
planning to stay on line for the rest of the
49
1 morning?
2
DR. KODISH: I am. The only question is
3
whether I should do it by phone or by Webcast.
4
DR. SANTANA: Okay, because if you
are
5
going to stay, then we will just hold the questions
6 for
the general discussion, if that is okay with
7
you.
8
DR. KODISH: That is fine.
9
DR. SANTANA: But I do want you to
stay on
10 the
phone line, if at all possible, for the
11
discussion because I think we can communicate
12
better that way.
13
DR. KODISH: Okay, what I will try
to do
14 is
watch but mute the sound.
15
DR. SANTANA: That is fine.
16
DR. KODISH: Thank you, Victor.
17
DR. SANTANA: Okay, good. I also want to
18
thank John for advancing your slides on your
19
behalf. Dr. Carome, you are next.
20
Legal Responsibilities for HHS Supported Studies
21
DR. CAROME: Good morning. I would like
22 to
thank the subcommittee members for inviting me
23 to
give a brief presentation on legal
24
responsibilities for studies conducted and
25
supported I think originally by the federal
50
1 government
and since I speak on behalf of HHS, I
2
have limited it to HHS, the Department of Health
3 and
Human Services.
4
What I am quickly going to do is go over,
5
first of all, the applicability of our regulations.
6 Then
I am going to talk very quickly about the
7
major requirements of 45 CFR Part 46, Subpart A,
8
which are the general protections for human subject
9
research. Then I am going to
finish up by talking
10
about the major requirements of 45 CFR, part 46,
11
Subpart D, which are the additional protections for
12
children involved as subjects in research.
13
Again, the regulations I am referencing,
14 45
CFR Part 46, are the HHS regulations for the
15
protection of human subjects.
They have four
16
subparts. The regulations were
last revised in
17
2001. One of the subparts,
Subpart B, was revised
18 at
that point but most of the regulations remain
19 the
same as when they were promulgated more than
20 two
decades ago.
21
So, what is the applicability of these
22
regulations? Our regulations
apply in two
23
circumstances. The most common is
research
24
conducted or supported by the Department that are
25 not
otherwise exempt. That includes clinical
51
1
trials conducted intramurally by the NIH or funded
2 by
the NIH, as well as many other agencies within
3 the
Ddpartment. A second way in which
research can
4 be
covered by these regulations is research that is
5
conducted at an institution holding an applicable
6
assurance of compliance approved by our office.
7 So,
any institution that receives funding from our
8
Department to conduct human subject research must
9
execute a written agreement in which the
10
institution pledges to comply with our regulations,
11 and
in that document many institutions voluntarily
12
extend the same regulations to all research
13
regardless of sponsorship. In
doing so, the
14
assurance comes to cover privately sponsored
15
research.
16
This slide demonstrates the relationship
17 and
the overlap between the applicability of our
18
regulations and the FDA regulations.
You can see
19
that there is in the middle an overlap.
The
20
overlap may occur in two circumstances.
One is
21
where NIH sponsors a clinical trial or other
22
clinical research, or any research, that involves
23 an
FDA-regulated test article. Another
24
circumstance is where an institution, holding an
25
assurance with our office in which they voluntarily
52
1 agreed
to extend that assurance to all research, is
2
engaged in an industry, privately sponsored
3
research, project involving an FDA-regulated test
4
article.
5
Very quickly, what are the major
6
provisions of Subpart A? As was
previously noted,
7 the
regulations, we believe, are clearly founded
8
upon an ethical framework that was articulated in
9 the
Belmont report. Its three basic ethical
10
principles, and the fundamental provisions of the
11 regulations can be divided in three
groups. One is
12 the
provisions related to and assurance of
13
compliance. The second is those
related to the IRB
14
requirements, institutional review boards, and the
15
third is those requirements related to legally
16
effective informed consent.
17
With respect to assurances, the
18
regulations stipulate that each institution engaged
19 in
research covered by the regulations and which is
20
conducted or supported by the Department shall
21
provide assurance satisfactory to the HHS Secretary
22
that it will comply with the requirements set forth
23 in
the regulations.
24
The regulations further stipulate specific
25
elements that must be part of an assurance. There
53
1
must be a statement of principles governing the
2
institution in the discharge of its
3
responsibilities for protecting the rights and
4 welfare
of human subjects. And, the regulations
5
state that those principles must apply to all
6
research regardless of whether or not it is covered
7 by
the assurance.
8
The assurance must designate at least one,
9 and
many institutions designate more than one,
10
institutional review board and that must include a
11
list of the IRB members and their relative
12
capacities, and there must be a reference to
13
written IRB procedures. There are
requirements
14
related to the IRB and they include specification
15 of
what the IRB membership must include, such as at
16
least one person whose primary interests are in the
17
scientific area and at least one member whose
18
primary interests are in a non-scientific area, and
19 at
least one member who is not otherwise affiliated
20
with the institution or a member of a family
21
affiliated with the institution.
22
The regulations have specific provisions
23
related to how the IRB should function and operate;
24
when it must conduct review in terms of initial and
25
continuing review. Then there are
provisions
54
1
related to expedited review for certain categories
2 of
minimal risk research and there are detailed
3
lists of specific criteria an IRB must find in
4
order to approve research. For
example, the
5
regulations state that in order to approve research
6 an
IRB must find that the risks to the subjects are
7
minimized and reasonable in relationship to the
8
anticipated benefits, if any, to the subjects and
9 the
knowledge that is to be gained. Then,
there
10 are
other provisions for the records that an IRB
11
must maintain.
12
The last set or provisions in Subpart A
13
deal with legally effective informed consent. They
14
include an introductory paragraph that talks about
15 the
general requirements. For instance, no
16
investigator may involve a human subject in
17
research unless the informed consent of the subject
18 or
a legally authorized representative of the
19
subject has been obtained, except in certain
20
limited circumstances in which informed consent can
21 be
waived.
22
The regulations go on to stipulate basic
23
elements that I think most people are familiar
24
with: the nature of the research; the reasonably
25
foreseeable risks; the reasonably foreseeable
55
1
benefits, if any, to the subject; and others, such
2 as
alternatives that a subject may choose instead
3 of
entering the research. The regulations
4 stipulate
that consent must generally be
5
documented, except in some limited circumstances.
6
Then, there are waiver provisions both for
7
obtaining informed consent at all or for documented
8
informed consent, and I won't go into those in
9
detail.
10
Let's turn finally to the provisions for
11
research involving children under Subpart D, the
12
additional protections for children.
Again, this
13 is
a subpart that is unique to the Department of
14
Health and Human Services.
Whereas all the Subpart
15 A
provisions that I just went over have been
16
adopted by other departments and agencies, Subpart
17 D
has only been adopted by the Department of
18
Education in addition to our department.
19
Subpart D applies to all research
20
involving children as subjects conducted or
21
supported by our department. It
is important to
22
note that there is a specific definition of
23
children in the regulations, and they are persons
24 who
have not attained the legal age for consent to
25
treatments or procedures involved in the research
56
1
under the applicable law of the jurisdiction in
2 which the research will be conducted. It is
3
important to note that in order to then understand
4 who
a child is with respect to the research
5
regulations, you must understand state and local
6 law
that defines who can consent to what and at
7
what age. Therefore, a child in
one state might
8 not
be a child in another state for the purposes of
9
these regulations.
10
The Subpart D requirements in
11
general--first of all, you have to satisfy all the
12
requirements of Subpart A. So, if
a research
13
project involving children doesn't satisfy some
14
provision of Subpart A, then it is moot about the
15
additional provisions. The
research would not be
16
approvable. But if the research
is approvable
17
under Subpart A, there are additional requirements
18 of
Subpart D which must be fulfilled and satisfied.
19
As Eric referenced, there are four
20
categories of research that are approvable under
21 Subpart
D under our regulations. These are
22
primarily scaled to risk versus benefit as you walk
23
through each of these categories, and I am going to
24 do
that very quickly.
25
The first category, 404, is research not
57
1
involving greater than minimal risk, and minimal
2
risk is defined in Subpart A. In
order for this
3
research to be approved under this category, an IRB
4
must make one general finding. It
must find that
5
there are adequate provisions for soliciting the
6
assent of the child and permission of the parents
7 or
guardians, as set forth in Section 408.
8
The next category, Section 405, which Eric
9
went into more detail, is research involving
10
greater than minimal risk but presenting the
11
prospect of direct benefit to the individual
12
subjects. So, the benefit has to
be tied to the
13
subjects as opposed to society in general and the
14
knowledge to be gained. Here, the
IRB must make
15
three specific findings. The IRB
must find that
16 the
risk is justified by the anticipated benefits
17 to
the subject; the relationship of the anticipated
18
benefit to the risk is at least as favorable to the
19
subjects as that presented by available
20
alternatives outside the research context; and,
21
again, the same provisions for assent and
22
permission apply throughout these four categories.
23
The next category, 406, involves greater
24
than minimal risk and no prospect of direct benefit
25 to
the individual subjects, but likely to yield
58
1
generalizable knowledge about the subject's
2
disorder or condition. For this
category there are
3
four criteria that an IRB must find.
They must
4
find that, first, that the risk represents a minor
5
increase over minimal risk.
Whereas minimal risk
6 is
defined in the regulations, what a minor
7
increase means is not defined so that is left up to
8 the
judgment of the IRBs.
9
Next, the IRB must find that the
10
intervention or procedure within the research
11
presents experiences to the subjects that are
12
reasonably commensurate with those inherent in the
13
actual or expected medical, dental, psychological,
14
social or educational situation of the child.
15
Commensurability is one of the factors that Eric
16
touched on but applies only in this category, 406.
17
The next two provisions--the IRB must find
18
under 406 that the intervention or procedure is
19
likely to yield generalizable knowledge about the
20 subject's
disorder or condition which is of vital
21
importance for the understanding or amelioration of
22 the
subject's disorder or condition. I think
the
23 key
words here are that you have to understand that
24 the
child must have a disorder or condition, two
25
terms that are not otherwise defined in the
59
1
regulation and are of vital importance.
So, it is
2
sort of a higher standard than the usual
3 generalizable knowledge standard that
probably
4
applies to research under Subpart A only. Lastly
5 is
the assent or permission provisions.
6
The fourth category and final category is
7
research that is not otherwise approvable under one
8 of
these four categories which presents a
9
reasonable opportunity to understand, prevent or
10
alleviate a serious problem affecting the health or
11
welfare of children. For this,
the IRB still must
12
review and assess the research with respect to
13
Subpart A and D, and must find that the research
14
presents a reasonable opportunity to further the
15
understanding, prevention or alleviation of a
16
serious health problem affecting the health or
17
welfare of children.
18
The project is then forwarded to the
19
Department. They come through our
office and we
20 act
on behalf of the Secretary to process these.
21 In
order for the research then to be approved, the
22 Secretary, after consultation with a panel of
23
experts in pertinent disciplines and following an
24
opportunity for public review and comment, must
25
determine either that the research in fact
60
1
satisfies one of the other three categories, 404,
2 405
or 406 or, if not, three things must be met:
3
that research presents a reasonable opportunity
4
standard that I previously went over; that the
5
research will be conducted in accordance with sound
6
ethical principles, and hopefully that is something
7
that applies to all research conducted; and
8
adequate provisions for the assent of the child and
9
parental permission.
10
Finally, there are some
additional
11
provisions of Subpart D that are provisions related
12 to
soliciting assent, and assent is not always
13
required and an IRB may determine it is not
14
warranted, particularly under category 405. There
15 are
provisions for soliciting permission of
16
parents, and the regulations speak to whether you
17
need both parents' permission. If
the category is
18 405
one parent's permission is sufficient but for
19 406
or 407 two parents are required, except in very
20
limited circumstances.
21
It is important to note that there are
22
provisions for waiving parental permission or
23
guardian permission. Just like
informed consent
24 can
be waived under Subpart A for research
25
involving adults, parental permission can be waived
61
1 in
certain circumstances and this is I think unique
2 to
our regulations and not found in the parallel
3
regulations within the FDA.
4
Finally, there are specific protections
5 for
subjects who are wards of the state or any
6
other agency, institution or entity for research
7
approved under 406 or 407. Among
those
8
requirements, there must be a specific advocate
9
appointed for each child who is participating in
10
such research who is a ward.
11
In summary, I have quickly tried to go
12
over the applicability of our regulations and
13
contrasted that with the FDA regulations
14
applicability. I have gone over
the major
15
requirements of Subpart A of our regulations and
16
finished up with a discussion of Subpart D, and I
17
thank you for your attention.
18 DR. SANTANA: Thanks, Dr. Carome. Dr.
19
Hirschfeld?
20
Legal Responsibilities for Studies with
21 FDA Regulated Products
22
DR. HIRSCHFELD: I would also like
to
23
thank Dr. Carome and note that when he was wearing
24 a
uniform which was a color more consistent with
25 the
theme of the day, he was the head of the IRB at
62
1
Walter Reed Army Medical Center.
I also want to
2
thank him for his efforts on clarification of the
3
regulations in ongoing discussions as they apply to
4
pediatric oncology, and he has taken a leadership
5
role in the Office for Human Research Protection in
6 that regard.
7
I am going to even more quickly, I hope,
8 go
through the FDA regulations. One might
ask what
9 is
a pediatric oncologist doing talking about FDA
10
regulations, but that is one of the strengths of
11 the
FDA, that there are wonderful opportunities to
12 be
involved in many aspects or research in clinical
13
medicine, including the development of regulations.
14 I
was on the working group that developed the
15
Subpart D and, in fact, wrote the first draft of
16
that document.
17
As Dr. Carome pointed out, there is some
18
overlap, and these slides have a lot of data which
19 is
intended for reference and I will not go through
20 all
the aspects of all the slides, but just to note
21
that there are laws synonymous with an act or
22
statute which are developed and passed by the
23
Legislative Branch and signed by the President and
24
these are published in the United States Code.
25
Then there are regulations synonymous with rule,
63
1 and
these are developed and published by the
2
Executive Branch, the various departments and
3
agencies within the Executive Branch doing the
4
detailed work, and these are published in the Code
5 of
Federal Regulations, which is referred to as the
6
CFR.
7
The FDA authority is derived from multiple
8
laws and regulations, and the focus is on product
9 and product use. There are a number of applicable
10
regulations for good clinical practice in the
11
research setting, and these include the human
12
subject protection, which is in 21 CFR, Part 50;
13
financial disclosures, which is in Part 54;
14
institutional review boards, which is in Part 56;
15 and
investigational new drugs, which is in part
16
312.
17
Part 50 has actually three sections to it.
18 One
is reserved for future use and Part D, you will
19
notice, is the additional safeguards for children
20 in
clinical investigations, which is the focus of
21 the
discussion now.
22
This is a catalog of all the various sections
23
within Subpart D of 21 CFR, 50.
You will see that
24
there is mapping and harmonization between the
25
relevant sections of the HHS regulations.
64
1
Now, the relationship--and this is just a
2
textual representation of the schematic that Dr.
3
Carome presented--is that FDA regulations apply to
4 all
research using FDA-regulated products.
In
5
contrast, the HHS regulations apply to all research
6
that is supported by HHS.
Research that is
7 supported by HHS using FDA-regulated products
is
8
subject to both sets of regulations, and the
9
regulations are harmonized although there are some
10
differences which Dr. Carome elaborated on earlier.
11 The
definitions, you will see, parallel those
12
definitions in the HHS regulations and put the onus
13 of
interpretation on the local jurisdiction and on
14 the
local IRBs, and that is the theme that persists
15
throughout these regulations. So,
these
16
definitions are included here to show that there is
17
harmonization and in some cases, we believe, some
18
clarification because the scope of FDA-regulated
19
research is, in many ways, different and can apply
20 to
domains where HHS research is not applicable.
21 So,
it was important to have not only clarity on
22 the
definitions but consistency and, therefore,
23
there are definitions that are included here so
24
that there is not, we hope, much ambiguity in terms
25 of
how to apply and interpret these regulations at
65
1 the
local IRB level.
2
Here, again, there is an emphasis on the
3
concept that Eric Kodish developed for us a little
4
earlier this morning, and that is children do not
5
actually engage in a consent process.
Their
6
parents provide permission for them to participate
7 in
the research. Then, there is the same
emphasis
8 as
in the HHS regulations that the child must at
9
least be approached for assent.
10
So, in addition to the other
11
responsibilities assigned to IRBs, the FDA
12
regulations ask that the IRB review clinical
13
investigations involving children as subjects
14
covered by Subpart D and approve only clinical
15
investigations that satisfy the criteria which are
16
described in Subpart 51, 52, 53 and the conditions
17 of
all other applicable sections of Subpart D.
18
These are again mapped to the four risk
19
categories which were developed in the 1970s and
20
which, because of their serviceability and their
21
flexibility, have been maintained to this date.
22
These, again, discuss the concept of minimal risk
23
here with specific examples of how it applies to
24
pediatric research.
25
Since the IRBs are a conduit through which
66
1
research occurs, there are specific instructions on
2
when IRBs may approve clinical investigations, and
3
these are divided into the specific risk
4
categories. So, there is greater
than minimal risk
5
under 50.51. In 50.52 there is
greater than
6
minimal risk presenting the prospect of direct
7
benefit and the conditions, again, are analogous to
8 the
HHS regulations; and 50.53 shows that the IRBs
9 can
approve clinical investigations involving
10
greater than minimal risk and no prospect of direct
11
benefit but likely to yield generalizable knowledge
12
about the subject's disorder or condition, and the
13
same caveats about having a disorder or condition
14 and
having the prospect of generalizable knowledge
15
apply, and these are addressed in some detail.
16
In addition, there are IRB approval
17
criteria which are explicitly stated and these
18
include not only minimization of risk and that the
19
risks are anticipated in relation to the benefit,
20 but
that the informed consent process is adequate
21 and
appropriately documented and looking for
22
safeguards. That is going to be
theme which we are
23
going to look at in detail, what safeguards can be
24 and
ought to be implemented.
25
Subpart D addresses this explicitly.
67
1
There is a paragraph devoted to monitoring which I
2
will quote briefly: While the
level of risk in a
3 clinical
investigation may change during the course
4 of
a study, appropriate strategies may be included
5 in
the study design that may mitigate risks.
These
6
might include exit strategies in the case of
7
adverse events or a lack of efficacy, or
8
establishing a data monitoring committee to review
9
ongoing data collection and recommend study
10
changes, including stopping a trial on the basis of
11
safety information.
12
Part 56 addresses institutional review
13
boards, and the general provisions and organization
14 are
discussed in the first part; IRB functions and
15
operations in the second part; records and
16
reporting in the fourth part; and the
17
administrative actions for non-compliance in the
18
fifth part.
19
Now we come to the IND regulations, 312
20
Subpart A, which are the general provisions which
21 are
outlined here.
22
Subpart B, which are in essence the
23
mechanics of an investigational new drug
24
application and the obligations under those
25
sections.
68
1
Subpart C, which discusses the
2
administrative actions, and Subpart D which goes
3
into detail of the responsibilities of the sponsors
4 and
investigators.
5
There is a Subpart E, which doesn't map
6
explicitly to other HHS regulations, which
7
addresses the drugs intended to treat
8
life-threatening and severely debilitating
9
illnesses which apply to pediatric oncology
10
studies. You will notice in the
various paragraphs
11
here that in 312.87 there is a requirement for
12
active monitoring of conduct and evaluation of
13
clinical trials. It reads, for
drugs covered under
14
this section, the Commissioner and other agency
15
officials will monitor the progress of the conduct
16 and
evaluation of clinical trials and be involved
17 in
facilitating their appropriate progress.
So,
18
this places an FDA role in a dynamic way in the
19
research being conducted in the realm of
20
life-threatening illnesses.
21
In addition, 312.88 has specific
22
safeguards for patient safety which refer back to
23 the
other sections that were discussed, Parts 50,
24 56,
312. We didn't discuss 314 which is the
NDA
25
regulations and 600 which apply to the biologics
69
1 but
there are analogous regulations in these areas.
2
I will just abstract from here that this
3
includes the requirements for informed consent and
4
institutional review boards, and that these
5
safeguards further include the review of animal
6
studies prior to initial human testing; the
7
monitoring of adverse drug experience through the
8
requirements of IND safety reports; safety update
9
reports for marketing and postmarketing.
10
So, our conclusions from this
section are
11
that the FDA has authority to regulate clinical
12
studies using FDA-regulated products; that FDA
13
regulations incorporate both IRB and FDA oversight
14 of
studies; that regulations exist for studies
15
using products intended to treat life-threatening
16
illnesses; and that regulations exist for providing
17
additional safeguards for children enrolled in
18
clinical investigations; and, as noted, HHS and FDA
19
regulations are intended to be harmonized. Thank
20
you.
21
DR. SANTANA: Thank you, Dr.
Hirschfeld.
22 I
think we will hold our questions until we
23
reconvene at the point for discussion.
I think we
24 are
just a few minutes behind time. We will
take a
25
15-minute break--Dr. Hirschfeld wants a 10-minute
70
1
break. We will take a 10-minute
break and try to
2
reconvene at almost 9:45. Thank
you.
3 [Brief recess]
4
DR. SANTANA: We will go ahead and
get
5
started with the second part of the morning
6
presentations. To initiate that,
Dr. Anderson,
7
from CTEP, will be our next speaker.
Barry? Eric,
8 are
you back on board?
9
DR. KODISH: I am here.
10
DR. SANTANA: Thank you, Eric.
11
Enrollment and Monitoring Procedures for
12 NCI Funded Studies
13
DR. ANDERSON: I am Barry
Anderson, from
14 NCI
CTEP, and I want to thank the FDA and Steven
15 for
inviting us to provide information about the
16
enrollment and monitoring procedures for
17
NCI-supported clinical trials.
18
For pediatric cancer clinical trials, the
19
appropriate enrollment of the individual patient,
20 the
child who is going to come onto the trial, as
21
well as the monitoring of that individual patient's
22
experience during the trial and the cumulative
23
experience of all children who are involved in a
24
clinical trial I think are necessary components in
25
terms of trying to enhance the patient safety and
71
1 the
scientific validity of the trial itself.
2
So, at the onset, from NCI's point of
3
view, it is important to work to assure that each
4
child accrued to a trial is receiving the
5
appropriate treatment within the clinical trial
6
itself, and that monitoring that is associated with
7 the
trial monitors the toxicity and effectiveness
8 of
the treatment intervention within each clinical
9
trial both for that individual child, as well as
10 for
the trial overall.
11
The words "safe"
and "effective" can be
12
applied to many of the standard treatments we use
13 in
pediatric oncology to treat various childhood
14
cancers. These words have special
meaning in
15
pediatric oncology. As Dr. Kodish
mentioned, there
16 is
a special sort of risk/benefit ratio that we
17
always consider because, while therapy for
18
childhood cancer is often successful and that is
19
something that differs from much of medical
20
oncology, the therapies that we use are always
21
toxic in pediatric oncology and they always carry a
22
risk of treatment-related morbidity and perhaps
23
even death in many cases.
24
So, selecting the proper treatment I think
25 is
essential because compared with other serious
72
1
childhood diseases, such as asthma or cystic
2
fibrosis, childhood cancer includes many distinct
3
histologic diagnoses, and each tumor histology
4
requires a distinct treatment appropriate with its
5 own
risks and benefits. The chances of cure
also
6
diminish quickly if the proper therapy is not used
7 at
the outset. That differs, I think, from
some of
8 the
other more chronic diseases that are serious
9
within childhood diseases but can have chances to
10
change the therapeutic approach over time.
11
In regards to enrollment, a question for
12 the
clinical trials done in pediatric oncology is
13 who
should be enrolled. Pediatric oncology
has
14
evolved an approach of risk stratified treatment
15
regimens and within each tumor histology the
16
patient characteristics and the tumor
17
characteristics establish a risk of relapse. This
18
risk of relapse then is used to stratify the
19
treatment assignment for each child in terms of the
20
type of clinical trial or the specific clinical
21
trial they would be appropriate for.
Using this
22
risk of relapse the intensity of the treatment that
23 the
child receives--and for intensity you can also
24 say
increased toxicity--is then set to best fit the
25
child's cancer. So, it is vital
to treat the
73
1
child, as best we can ascertain at the time they
2
first present, according to the appropriate
3
treatment regimen.
4
By following this treatment stratification
5
approach, the goal in pediatric oncology is to
6
minimize the exposure to highly toxic therapies for
7
those children who don't need that much treatment,
8 in
a relative sense, and also for the oncologists
9 to
have some comfort in knowing that another child
10 who
has a high-risk chance of relapse, that they
11
will in fact potentially benefit from using a more
12
intensive and more toxic treatment regimen.
13
To apply this treatment stratification
14
approach across an entire clinical trial, it is
15
important that the eligibility criteria within the
16
protocol by which all the patients are brought into
17 the
trial--that those protocol eligibility criteria
18 are
clear in regards to the clinical
19
characteristics of the patient and the pathologic
20 and
biologic characteristics of the tumor--that all
21
these characteristics are clear and easy to
22
understand.
23
The pediatric oncologists that are
24
involved in the trial and who would be enrolling
25
patients must be properly informed on how to apply
74
1 the
eligibility criteria that are presented in the
2
eligibility section of the protocol itself. If
3
anyone has ever had experience in trying to bring a
4
patient with rhabdomyosarcoma into a sarcoma trial,
5 it
can be a be very complicated endeavor and many
6
mechanisms have been put in place to assist the
7
pediatric oncologist to make sure that the proper
8
decision is made in terms of treatment.
9
As technology has advanced, eligibility
10
criteria have moved beyond what they have been in
11 the
past, just being tumor histology and perhaps
12 the
staging of the patient. As histologic
and
13
biologic characteristics of tumors are better
14
defined and refined, we also are incorporating in
15
many cases in pediatric oncology central input on
16 the
pathology and biology, such that central review
17 of
the patient's tumor pathology and diagnostic
18
biology assays are used to improve the likelihood
19
that a child receives the best available therapy
20 for
their specific tumor pathology and for their
21
risk of relapse.
22
This has been used in a variety of tumors
23 in
pediatric oncology in the recent past.
With
24
rhabdomyosarcoma there is central review of
25
alveolar versus embryonal rhabdomyosarcoma
75
1
pathology that is used basically in real time so as
2 to
assure that the patient goes on the proper
3
risk-stratified treatment regimen.
For
4
neuroblastoma there are a variety of biologic
5 characteristics
that make amplification and other
6
genetic changes that are characteristic to each
7
tumor, and that is also looked at in real time.
8 For
Wilms tumor there has been a central review of
9
that tumor histology for favorable histology versus
10
focal or diffuse anaplasia that all distinguish
11
patients for their appropriate trial, and there are
12 a
variety of genetic studies that are done, both
13
centrally and locally, to establish the appropriate
14 treatment for children with acute
lymphoblastic
15
leukemia, the most common diagnosis in childhood
16
cancer.
17
Phase I and pilot studies also have
18
specific eligibility criteria. In
these cases, it
19 may
not necessarily be the case that you need to be
20
concerned about the tumor histology so much,
21
especially in Phase I where a child has already
22
received treatment, but it is important to ensure
23
that those patients who are enrolled in a trial
24
have no other treatments that provide a reasonable
25
potential for cure or substantial clinical benefit.
76
1 For
patients who have newly diagnosed tumors but
2
have a type of tumor that historically has a poor
3
response to therapeutic interventions, we want to
4
make sure that any sort of pilot treatment
5
interventions that have been tried balance
6
appropriately the benefits and likely risks in the
7
child's prognosis. So, before
considering trial
8
monitoring we consider that getting the right
9
patient on the right trial is vital given the
10
stratified approach we have to treatment in
11
pediatric oncology.
12
NCI supports a variety of
investigator
13
groups to do clinical trials in children with
14
cancer. The largest is the
Children's Oncology
15
Group, which pretty much every pediatric oncologist
16 in
North America is a member of. That is
the group
17
that does the Phase III studies primarily as well
18 as
Phase II studies and pilot studies.
There is
19 the
COG Phase I Pilot Consortium that is a smaller
20
group, about 20 institutions, that is assigned to
21 do
Phase I studies. The Pediatric Brain
Tumor
22
Consortium I think is around 10 institutions as
23
well. Their focus is on newer
therapies for brain
24
tumors in children. The new
approaches to
25
neuroblastoma therapy is a program project grant
77
1
that NCI supports that is now 12 or 14 institutions
2 I
think, focused on early phase studies for
3
children with neuroblastoma, high risk
4
neuroblastoma. There are also
individual grants to
5
investigators that may include clinical trial
6
research.
7
All these, because of the nature of
8
pediatric oncology and the relative lack of number
9 of
patients, are usually multi-institutional.
10
Given that they are multi-institutional, that
11
brings on special responsibilities in terms of
12
trying to conduct a trial at multiple sites
13
simultaneously and trying to have all the
14
investigators that are enrolling new patients and
15
treating ongoing patients aware of what is going on
16
with the trial. So, the NCI has
worked with these
17
various groups that we support to facilitate this
18
sort of intake of information and distribution of
19 information.
20
The investigators that are part of these
21
various groups are committed to report toxicities,
22 the
regimen delivery and the ability to deliver the
23
regimen as defined in the protocol and the response
24
data in a timely fashion. Some
things such as
25
remote data entry have been put in place now to
78
1
help facilitate that. There is a
data center
2
assigned with each of these groups that we support
3
that is capable of readily receiving the data,
4
analyzing the data and then reporting important
5
data trends to the investigators, be it the study
6
committee and perhaps beyond if necessary. There
7 is
an operations office component. They are
able
8 to
communicate with investigators continuously
9
throughout the clinical trial by email, by web
10
site, by the phone, etc. There is
sort of this
11
continuous back and forth going on between the
12
investigators at the local institutions and a more
13
centralized body that is helping to run the trial.
14
In terms of monitoring, again it starts, I
15
think just like enrollment, at the individual child
16
level where there, is within the protocol, guidance
17
provided to the local institutional clinicians as
18 to
what sort of laboratory results for
19
tumor-related or treatment-related abnormalities
20
need to be done and at what interval.
There are
21
radiologic characterizations of the tumor and the
22
consequent organ dysfunction that are also asked
23 for
in terms of the initial diagnosis of the child
24 and
then subsequently during their course of
25
treatment. Then there are
interval evaluations to
79
1
establish the tumor response to the treatment
2
interventions that are being conducted during the
3
study.
4
The protocol--and we look for this at NCI
5
when we review the protocols that come to us--must
6
provide sort of a consistent and uniform approach
7 to
all these aspects of monitoring of the
8
individual patient. The frequency
by which these
9 studies
are performed would be consistent with or
10
greater than good clinical practice.
Because the
11
children are on a clinical study, oftentimes they
12 get
more frequent monitoring of some of these
13
aspects than they would if they received standard
14 of
care treatment off the protocol. But,
again, it
15
depends on the intervention that is being
16
undertaken and the specific tumor diagnosis under
17
consideration.
18
When you accumulate all this information,
19 the
monitoring and the clinical trial itself, that
20 is
where some of the infrastructure that NCI
21
supports comes into play because, as I mentioned
22
before, it is very important that patient data is
23
submitted at protocol-defined intervals; that the
24
data is accumulated, analyzed and then reported;
25 and
then that the significance of this data, be it
80
1 the
toxicity data or the effectiveness data, is
2
interpreted so that appropriate patients are being
3
accrued to the study; that treatment toxicity is
4
acceptable and that there is some efficacy of the
5
treatment interventions as defined in the protocol
6
beforehand.
7
There is some debate and discussion and
8
variability in terms of who and how often this data
9
that is accumulated and reported on is reviewed.
10
Within NCI, we work with the guidelines established
11 by
NIH for data and safety monitoring and these
12
requirements call for the oversight and monitoring
13 of
all human intervention studies to ensure the
14
patient safety and the validity and integrity of
15 the
data itself for the study. The monitoring
in
16 the
study is to be done at sort of a level that is
17
commensurate with the risks and size and complexity
18 of
the clinical trial.
19
The oversight monitoring under Phase III
20
clinical trials, which many of the pediatric
21
oncology trials are, calls for the establishment of
22 a
DSMB. The DSMB, according to NIH, is
also
23
appropriate for Phase I and Phase II clinical
24
trials if the studies have such things as multiple
25
clinical sites, are blinded or masked or employ
81
1
particularly high-risk vulnerable patient
2
populations. In pediatric
oncology we sort of hit
3
throughout this so we call for sort of the default
4 to
be towards some sort of formalized monitoring
5
committee for most of the studies that we do.
6
The NCI, in response to NIH sort of
7
formalizing its approach to data and safety
8
monitoring, in the not too distant past has
9
finished reviewing all the data and safety
10
monitoring plans for the cancer centers that NCI
11
supports across the country. That
was I think an
12
education for both NCI as well as for the cancer
13
centers, for them to really kind of fess up and
14
look at what they actually do in terms of the
15
monitoring; what goes on in their human subject
16
clinical trials within their cancer centers. But
17
they all submitted them and they were all reviewed.
18
Some of the key, essential elements for
19
these monitoring plans that we had to consider, and
20
that then subsequently have also been extended to
21
some pediatric groups, are the monitoring and
22
progress of the trials and safety of the
23
participants; the plans for assuring compliance
24
with adverse event reporting; and plans for
25
assuring that data accuracy and protocol compliance
82
1 are
performed.
2
As I mentioned, while in pediatric
3
oncology basically we don't work from a cancer
4
center model, we work more in a multi-institutional
5
approach so it is a more distributed coverage in
6
terms of who is performing the trials.
7
Nevertheless, these particular essential elements
8
were taken on by pretty much all the groups that we
9
have that I mentioned earlier that NCI supports in
10 one
form or another, again, moving to the default
11 of
having some sort of more formalized data
12
monitoring committees for all the trials.
13
The composition of the DSMB and the
14
various data monitoring committees may differ
15
between the different groups that I mentioned that
16 NCI
supports for pediatric oncology but the goal is
17 the
same, and it is to have capable and informed
18
observers be responsible for the oversight of the
19
trial. The reviewers are people
that are outside
20 of,
and in addition to the study committee, and
21
they evaluate the trial data at regular intervals
22 to
monitor the treatment toxicity and the
23
effectiveness of the treatments that are being
24
used. Then, the review determines
whether the
25
continued accrual to the trial is safe and
83
1
appropriate. COG itself has two
DSMBs, one for
2
solid tumors and one for the leukemia and lymphoma
3
studies, and they meet twice a year, each one of
4
those DSMBs, to go over the studies.
Actually we
5 go
over pilot, Phase II and Phase III studies in
6
those sessions. The Phase I
Consortia also has a
7
DSMB that meets twice a year to go over all those
8
Phase I studies. In addition to
the Phase I
9
Consortia, the PBTC and the NANT, all of which have
10 a
DSMB type of component, have more frequent
11
discussions with the groups that are beyond just
12 the
study investigator and any sort of data
13
personnel or statistician directly involved. They
14
have a discussion of their studies sometimes on a
15
weekly basis, sometimes on a monthly basis, and
16
sometimes it also includes people from outside the
17
group itself to overlook what is going on with
18
their particular studies.
19
In terms of compliance with adverse event
20
reporting, another one of the essential elements
21
that NCI has, NCI-funded studies use the adverse
22 event
expedited reporting system, or the AdEERS
23
system to report toxicities. This
is a
24
computerized system that is available now to all
25 the
funded groups with which they can fairly easily
84
1
report adverse events that occur during their
2
clinical trials. That data can
then be accumulated
3
easily within their group, but also important
4
things can be sent off to the FDA or to drug
5
sponsors or the NCI as appropriate, especially for
6
studies that involve IND agents.
7
Then, it is the institutional principal
8
investigator that is ultimately responsible to
9
assure that the AEs are reported in a timely
10
manner. Whenever we review the
cancer center
11
approaches, they list out that sort of the CRA
12
should submit this and then there is a nurse
13
practitioner or someone that is behind the CR to
14
make sure it gets submitted, and at some interval
15 the
principal investigator locally is responsible
16 to
make sure that all the AEs that may have
17
occurred had been properly reported.
18
Finally, for assuring data accuracy and
19
protocol compliance, the cooperative groups and
20
these consortia practice ongoing quality control
21 and
interval quality assessments such as by using
22
institutional audits. This has
been something that
23 has
been ongoing throughout the creation of each of
24
these groups.
25
In summary, NCI has worked to establish a
85
1
framework to allow appropriate monitoring and
2
oversight of pediatric oncology clinical trials.
3 To address
some of the issues that Steven had
4
brought up before in terms of the general
5
parameters that we look at, we first want to make
6
sure that the enrollment of patients is appropriate
7 to
the diagnosis and risk of relapse for the
8
patient or the availability of standard treatments
9 for
recurrent and relapsed disease, and that
10
laboratory and radiologic monitoring for toxicity
11 and
response to treatments is established within
12 the
protocol before any patients are accrued.
13
The frequency of monitoring would be equal
14 to
or greater than standard of care for the
15
individual patient that is enrolled on a clinical
16
study, and there would be continuous protocol
17
monitoring by the study committee because they
18
receive this data on a daily basis.
There would be
19
interval protocol monitoring on a monthly to
20
biannual basis, depending on the risk and specifics
21 of
the trial, by a group outside of the study
22
committee itself.
23
Who does the monitoring? The
daily
24
monitoring is by the study committee itself. The
25
interval monitoring usually involves concentrations
86
1 and
statisticians that are not directly involved in
2 the
trial.
3
When is a data monitoring committee
4
needed? For Phase III studies you
need a DSMB.
5 For
multi-institutional trials you need to have a
6
monitoring committee for high-risk populations.
7 You
need to have a monitoring committee for complex
8
treatment. For studies with early
stopping rules,
9
which many pediatric studies have, you have to have
10 a
monitoring committee. With conflicts of
11
interest, which may not be as much of a case in
12
pediatrics as it might be in medical oncology, you
13
need to have a monitoring committee.
14
I think that with pediatric oncology
15
trials we hit many of the points that are brought
16 up
by various agencies of situations where a
17
monitoring committee is required so that virtually
18
always in pediatric oncology some sort of
19
monitoring committee is involved in the oversight
20 of
the practices of the group, as well as the
21
conduct of individual clinical trials.
Thank you.
22
DR. SANTANA: Thanks, Barry. Before I
23
stand up to give the last presentation of the
24
morning, we have an opportunity for an open public
25
hearing. So, if there is anybody
in the audience
87
1
that wishes to address the committee, this is the
2
opportunity to do so. I would ask
that if you are
3
going to do that you come to the front of the room
4 to
the podium and identify yourself by name and
5
affiliation.
6 Open Public Hearing
7
MR. RAKOFF: Wayne Rakoff, Johnson
&
8
Johnson. Just a quick question,
that came up this
9
morning that I would like to hear discussed during
10 the
discussion, is with regard to the FDA guidance
11 on
data reduction in oncology trials. It
would be
12
important to us to know if there are any variances
13 in
that with regard to pediatric studies.
14
DR. SANTANA: Steve or Rick, do
you want
15 to
address that now or do you want to address it
16
during the discussion period?
17
DR. HIRSCHFELD: We can address it
in a
18
little more detail but, in brief, that is a global
19
commentary and there isn't a specific pediatric
20
component to it. I think that is
a good suggestion
21
that maybe we should consider in the future, a
22 pediatric
specific component.
23
DR. SANTANA: Any other comments
from the
24
audience?
25
[No response]
88
1 Monitoring Procedures at a Private
2 Children's Hospital
3
DR. SANTANA: First of all, I want
to
4
thank Steve, Richard and the rest of the FDA for
5
always bringing the pediatric oncologists to set
6
examples in these initiatives. I
am personally
7
very appreciative of all the efforts that we have
8 had
on behalf of the issues that we deal with in
9
pediatric oncology.
10
My task this morning, as I was charged to
11 do,
is to bring a perspective from a private
12
institution with the caveat that St. Jude really is
13 an
NCI cancer designated center so a lot of what we
14 do
in terms of our own monitoring is reflective of
15
what we have to do to comply with the NCI
16
regulations.
17
What I would like to do over the next 20
18
minutes or 25 minutes or so is talk to you about
19 two
issues. One is how we set forth
monitoring of
20 our
St. Jude studies--not the cooperative group
21
studies for which we still have to comply with COG,
22 but
our own intra-institutional studies that follow
23 a
parallel system to the NCI monitoring plan, and
24
what that monitoring plan involves and what
25
parameters we have designated for monitoring.
89
1
Then, a bigger part of my talk will be on a project
2
that Don Workman and I worked on in terms of trying
3 to
handle adverse event reporting within the
4
institution and tried to develop an interactive
5
web-based model to try to get a handle on that.
6
With that, I will go ahead and get
7
started. As Barry has already
said, monitoring of
8
trials is really an ongoing, continuous review of
9 the
conduct of the trial. For the purpose of
10
distinction, I will make the note that to me
11
monitoring occurs while the study is ongoing.
12
Whereas a lot of people use the word auditing, to
13 me
auditing is a post facto thing that happens
14
after the study has been completed.
Then you go
15
back and see if the study was conducted the way it
16 was
supposed to be; if the data is good enough; if
17
there is quality in the data; and if there have
18
been any other issues that occurred during that
19
post facto process. So, to me,
monitoring occurs
20
real time whereas auditing occurs after the study
21 has
been completed.
22
Monitoring is really a shared
23
responsibility of many individuals.
We always talk
24
about monitoring being the responsibility of maybe
25 one
particular group but at St. Jude we have the
90
1
notion that this is really the responsibility of
2 the
research team. We always talk about the
3
principal investigator but it is really the
4
research team. The research team
has many
5
components to it of which, hopefully, the principal
6
investigator is the lead person but there are
7
research nurses, there are CRAs, there are other
8
members of the study team who also have
9
responsibility for this process.
10
Institutional officials have a major role
11 in
this, not only in terms or providing
12
infrastructure resources to conduct some of this
13
monitoring, but also to set a culture and example
14
that is transparent to make sure that things occur
15
very openly and that everybody is knowledgeable
16
about what is happening. Then,
the oversight
17
committee--you heard a little bit about DSMBs which
18 I
won't talk about and IRBs and other committees
19
that may be involved in this process.
20
Eric had a little figure this morning of a
21
triangle. I didn't know he had a
triangle so I
22
brought a triangle too, but my triangle is a little
23 bit
different. It makes a different
point. The
24
point of this triangle is that in the center of the
25
process are the participant in the research but
91
1
there are many other people involved in this whole
2
process in which, as I mentioned to you earlier,
3 the
partnership includes the investigator, the
4
research team, the IRB, other oversight committees
5 and
then institutional officials. So, I view
this
6
more as a partnership, not just the responsibility
7 of
one individual.
8
One of the things I want to cover is point
9
number one and point number three on this slide,
10
which is how can we systematically approach some of
11
these problems in terms of monitoring and adverse
12
event reporting.
13
So, I think the first step whenever you
14
deal with a promise to define a problem in this
15
case is what needs to be monitored and what needs
16 to
be reported. I think that is a good
point to
17
start and I will talk about that in a minute; then,
18
dividing the role, the different committees that
19
provide some of this oversight and I really won't
20 go
into detail on that although I could during the
21
discussion if anybody has any questions; and,
22
lastly, developing an infrastructure to allow this
23 to
happen so that the reporting occurs, that there
24 is
a process of evaluating the reports, and then a
25
process of acting in a timely manner when there are
92
1
concerns. So, that will be the
latter part of my
2
talk.
3
As I mentioned to you, we are an NCI
4
cancer designated center so we also had to comply
5 and
submit an institutional data safety monitoring
6
plan to the NCI a few years back that was reviewed,
7
approved, etc., etc., and now we provide our
8
monitoring under the umbrella of what that plan
9
says.
10
So, the first thing was to define what
11
elements we were going to monitor.
So, we have
12
kind of followed the parallel system that the NCI
13
designated in the clinical data update system of
14
what data should be collected. We
look at patient
15
specific data, the demographics, date of birth,
16
gender, those things that we have to collect; the
17
date of entry into the study; the treatment status,
18 if
the patient has been previously treated, on what
19
protocols and what therapy the patient was on; and,
20 if
they were off therapy, for what reasons.
All
21
that gets captured as part of the monitoring of the
22
patient on the study.
23
Then, there are subgroup data elements
24
that are also captured. Barry
mentioned, very
25
appropriately in his talk, the issue of eligibility
93
1 and
determining that the right patients go on the
2
right studies. One of the things
we have done at
3 St.
Jude in the last ten years is we have
4
established a separate office, which is called the
5
protocol office which is actually an office that
6
provides the infrastructure to help investigators
7
deal with many of these issues.
The protocol
8
office, obviously, is manned by a group of people
9 and
one of the responsibilities, for example, is
10
that when an investigator enrolls a patient on a
11
study we have to fill out electronically an
12
eligibility check list. The
eligibility check list
13 gets
faxed to that office and a patient-specific
14
consent is generated for that patient on that
15
study. So, right at the beginning
there are some
16
checks and balances in terms of the eligibility of
17 the
patient so that the right patient is put on the
18
right study and the correct consent is used for
19
that patient. So, that is an
ongoing process that
20
occurs early on during the trial and the patient
21
enrollment of the trial.
22
Once the patient receives the therapy,
23
they monitor the cycle or the course of therapy.
24 If
is a Phase I study, what dose level the patient
25 is
currently being treated with; the start date;
94
1
some other parameters like BSA and weight. They
2
monitor, particularly in Phase I studies, the
3
agent; the dose of the agent; if there have been
4 any
modifications, why there have been
5
modifications. We will talk a little
bit about
6
adverse event reporting later on.
Then, as part of
7 the
monitoring during certain periods of the trial,
8 the
patients will be monitored in terms of response
9
because the trials will have stopping rules based
10 on
response, not only in terms of toxicity but also
11 in
terms of response so a Phase II trial that has
12
some response built-in stopping rules will be
13
stopped at the right point once the monitoring is
14
occurring in terms of the response that has been
15
achieved.
16
I tried to summarize this in two or three
17
slides. This is kind of how we do
it at St. Jude
18 in
terms of our own institutional Phase I/Phase II.
19 We
don't do many Phase III but we do have an
20
auditing plan for Phase III studies and for some
21
studies in which we hold the IND.
22
So, for Phase I studies the central
23
elements in terms of demographics, eligibility and
24
informed consent, that is monitored continuously.
25 It
is monitored continuously because I told you
95
1
that there is a check at the beginning in terms of
2
eligibility and in terms of informed consent that
3
occurs in real time when the patient gets
4
registered. So, that is done
continuously as the
5
patients go on a study in a Phase I study.
6
The protocol office also is monitoring the
7
study in terms of the data elements for the study
8 so
there are templates very similar to the RDE
9
system that is developed by COG, templates of data
10
capture forms. Those data capture
forms are
11
electronic and the monitor on a monthly basis that
12 he
or she is assigned will go through those and
13
will see if there is data that is missing. If
14
there is data that is missing, a report is
15
generated to the principal investigator that data
16 is
missing on a monthly basis. So, it is a
good
17
system in terms that it keeps the research team
18
kind of continuously on top of making sure the data
19 is
being collected.
20
On a quarterly basis for a Phase I study
21
there is a report that is generated.
I will show
22 you
in a minute where the reports go but, in a
23
nutshell, it goes, obviously, to the principal
24
investigator and to the research team, and then it
25
goes to the subcommittee of the scientific review
96
1
committee that also oversees monitoring to make
2
sure that they are separate from the protocol
3
office and from the investigator looking at this
4
data.
5
Then, for every Phase I study that we are
6 the
primary sponsor of at St. Jude, the first three
7
patients enrolled in the study are monitored.
8
Then, once the first three patients are monitored,
9 one
additional patient per dose level is monitored
10 in
real time. The idea of doing the first
three
11
patients is that in many studies usually within the
12
first three patients you know if your systems are
13 in
the right checks and balances so that you want
14 to
monitor those first three patients very acutely
15 so
if there is a problem with the system, with the
16
templates, with potentially things not going right,
17 you
can pick it up very quickly and make the right
18
adjustment so that for the subsequent dose levels,
19 if
you monitor one patient in real time, you should
20
have resolved all of that.
21
We do a lot of Phase II studies at St.
22
Jude and we also do the eligibility, essential
23
elements and consents as outlined here.
We also do
24
missing data reports on a quarterly basis.
25
Obviously, in Phase II, just like in Phase I, you
97
1 are
interested in adverse events and those are
2
reported quarterly. Then, on a
semiannual basis
3 the
monitors will verify the coding of response so
4
that the studies can be stopped if the response
5
criteria for stopping rules have been met. There
6 are
reports semiannually or more frequently or less
7
frequently, as defined by the protocol, in terms of
8 the
individual monitoring plan that the protocol
9 may
have.
10
In Phase II we always monitor the first
11 two
patients plus at least--and the clever word
12 here
is "at least" ten percent of the total
13
patients that are being accrued.
It could be
14
greater than ten percent. It
depends obviously on
15 the
resources that you have available and the
16
workload that the specific monitor may have but at
17 a
minimum ten percent of the patients on any Phase
18 II
study at any given time should be under active
19
monitoring.
20
We don't do many Phase III studies at St.
21
Jude but we do have a marching plan in the event
22
that there is a Phase III study and it parallels
23 the
Phase II monitoring plan, with the exception
24
that there may be other primary objectives in the
25
Phase III trials that also require some monitoring.
98
1
St. Jude holds INDs or IDEs for a few
2
products so under those circumstances, they could
3 be
Phase I or Phase II trials or whatever, but
4
separately from those, if there is a particular IND
5 or
IDE for which St. Jude is the "sponsor" then
6
there is a specific monitoring plan that is
7
assigned to that study, and it will depend on the
8
risk, what is known about the IND drug, what is
9
known about the device, etc., etc., and may be more
10
strict but at least it will be just like Phase I or
11
Phase II studies I described to you before.
12
Usually, under some circumstances like some novel
13
therapy, it may be a little bit stricter in that
14 the
studies are being monitored a little bit more
15
aggressively.
16
So, this is kind of in a nutshell how we
17
kind of agree with the NCI in our data safety
18
monitoring plan and how we would monitor our
19
studies. Having said that, there
is also auditing
20
that occurs. So, there is a
different auditing
21
plan that I am going to give a lot of detail about,
22 but
for most auditing plans the monitors, once the
23
study is done, will make sure that at least 20
24
percent of the patients have had a full audit of
25
their records. But that is after
the study is done
99
1 and
that occurs over a long period of time.
It is
2 not
as active as the actual monitoring which is
3
occurring in real time.
4
I want to switch now and talk a little bit
5
about the issue of adverse event reporting which
6 has
to do with monitoring and safety. We, at
St.
7
Jude, also have struggled with this issue and we
8
struggle because there are a lot of problems in
9
reporting. There tends to be a
lot of
10
over-reporting. That is,
anticipated adverse
11
events that are known in the investigator's
12
brochure or known from other clinical trials are
13
being reported on a continuous basis and that
14
creates a big backlog of data that is important but
15 not
important in real time in terms of monitoring.
16
As you all know, there is increased
17
research in new drugs and biologics.
There is more
18
oversight and scrutiny by federal agencies. Just
19
like in many other places, we tend to get
20
saturation effects. There comes a
point where you
21 see
so many reports that it doesn't ring a bell; it
22
doesn't ring any whistles or anything like that.
23 So,
we have to be careful that we don't over-report
24
because then it gets us into the saturation effect
25 and
we don't react appropriately when there are red
100
1
flags that we should be paying attention to.
2
But one of the problems we have at St.
3
Jude, which is very common for pediatric
4
institutions, is that there are no denominators for
5 how
to make any sense of this; what constitutes a
6 red
flag? Where do you cut the line to say
this is
7
important or this is not important?
There is no
8
normative data for each of the populations that we
9
have to deal with for Phase I studies, for Phase II
10
studies and for the studies I mentioned to you.
11 So,
trying to approach this problem, we have tried
12 to
deal with this I think in a prospective way.
13
In terms of review, there are a lot of
14
external events that we get from study sponsors.
15 If
there happens to be a drug that we are doing a
16
study with but the drug is being used in adult
17
studies or in other institutions, you know, the
18
sponsors package a lot AEs and send them to you and
19 we
have to deal with those too. The problem
with
20
those is that sometimes the information is very
21
sketchy and there is no opportunity for
22 clarifications
or for questions so that then you
23 can
put that in the context of your own experience
24
with your own patients at your own institution.
25
The other thing is that the IRB is not a
101
1
DSMB. A DSMB has a very specific
role; the IRB has
2 to
deal with a lot of other issues. They
have to
3
deal with adverse events and they should be looking
4 at
them and they should be judging them, but it is
5
clearly in the context of the whole package of the
6
research, whereas the DSMB has very specific roles
7 and
responsibilities.
8
The IRB is not the FDA who holds the IND
9
file for the drug and knows everything.
So, the
10 IRB
over here is getting little pieces of
11
information and trying to make sense out of it in a
12
more global sense. Then, the IRB
also needs to
13
rely on the local investigators to interpret the
14
meaning of the adverse events that they are
15
receiving from the outside, from the sponsors,
16
because clearly the IRB doesn't have the expertise
17 or
the knowledge to put that in contextual features
18 in
terms of the study as it is being conducted at
19
other institutions.
20
So, at St. Jude we decided to approach
21
this problem first by doing quality improvement
22
projects, trying to figure out where the problems
23
were and where we could attach the problems. One
24 of
the first issues that we addressed is that at
25 the
beginning the PI or the research team needs to
102
1
report and categorize the events, but there was no
2
systematic way of doing that. I
mean, it was being
3
done in paper form; there were different versions
4 of
that paper form.
5
One of the things that Don Workman and I
6
recognized is that at least if at the beginning we
7
could make this a standardized way and force
8
everybody to do it the same way, then five, ten
9
years later we actually would have a system in
10
place that would provide a lot of the normative
11
data that we would need in order then to do some
12
process improvement.
13
So, the first thing that we did is to
14
create this electronic submission that I will
15
describe to you in a few minutes.
This electronic
16
submission is pretty neat I think, to use words of
17 my
nephew--it is pretty neat because it allows you
18
then to disseminate that information very quickly
19 to
all the key players in the field and then they
20 can
do their own assessment the same time that the
21 IRB
is doing their assessment. So, the IRB
will
22 get
a copy of this electronic adverse event and the
23 IRB
will do their own assessment of the adverse
24
event and certainly give feedback and follow-up to
25 the
investigator. At the same time that it
goes to
103
1 the
IRB, it goes to our office of regulatory
2
affairs which is also charged with making sure that
3
agencies that have to be notified about these
4
adverse events are also notified.
So, it kind of
5
takes the IRB and the investigator away from that
6
responsibility of having do to that paperwork but
7 it
goes to a central office that then now deals
8
with all the external agencies that have to look at
9
this data.
10
Internally, it goes in a different
11
direction. It goes to the vice
president of
12
clinical trials for internal reporting and internal
13
processing so that the St. Jude DSMB or what we
14
call our scientific review council which is called
15 the
CPSRMC, the clinical protocol scientific review
16
monitoring committee, is really the scientific
17
council which also has a function in terms of the
18
cancer center doing monitoring. They also get a
19
copy of the report and then they deal with it
20
internally and then they can give also feedback to
21 the
principal investigator.
22
Don and I were very concerned with the
23
first step in this process to try and make it
24
uniform and to try to make it normative so that we
25
could then create a system that, hopefully, would
104
1
help us in retrospect. So, we
started this about
2 18
months ago. The first thing we did is we
said
3
let's create a form that is standardized. We can
4
then make sure that people understand what is
5
important in that form before we convert it into an
6
electronic format. Then we were
able, as we
7
designed the form, to start thinking prospectively
8 of
how that same data could be captured
9
electronically.
10
Then we developed a flow diagram as a
11
quality improvement project of where this web-based
12
report could go, which is a little bit of what I
13
just showed you. We had to deal
with some issues
14 of
security access and then we also had to deal
15
with some issues of electronic signature that we
16
eventually resolved.
17
One of the key features of this, which is
18 a
recurrent problem in adverse event reporting, is
19
that there are databases and the databases don't
20
talk to each other. So, one of
the key features
21
that we wanted to cover in this was to make sure
22
that this adverse event electronic reporter was
23
talking to the other databases in the hospital and
24 was
capturing information from the protocol office
25 in
terms of the protocol that the patient was
105
1
registered on and the additional protocols was that
2 the
patient was registered on because there could
3 be
some cross-talk between adverse events on
4
different protocols or different PIs.
I will show
5 you
an example at the end.
6
We also wanted to make this user friendly
7 and
make sure that anybody who is part of the
8
research team could do this at any place in the
9
hospital. Through a security pass
they could
10
access this web site and could potentially feed in
11 the
information in a very quick manner, without
12
having to go to a dark office somewhere and grab
13
papers and try to do it. So,
there were some
14
security access issues that got resolved but it was
15
made available to anybody on the research team
16
electronically.
17
We then tried to address the issue of
18
internal reporting, that is studies in which
19 adverse events are occurring in our patients
at our
20
institution versus the information of adverse
21
events that are occurring at other sites that are
22
being fed into our protocols in terms of the
23
cooperative group studies, and so on and so forth.
24 So,
one of the things that we had to address is how
25 we
could link protocols so that the information
106
1
could be identified very easily.
If a patient was
2
registered on one protocol and the adverse event
3
occurred on that protocol, we wanted to know what
4
additional studies that patient was enrolled on so
5
that when the IRB or the subcommittees reviewed
6
this they could begin to get trends if there were
7
complementary adverse events that were occurring
8
from complementary studies and there could have
9
been a red flag there that we needed to address.
10
In addition, we could share the
11 information
with the PIs of the other studies
12
because they also have to be kept in the loop in
13
terms of what is happening to patients that
14
potentially may also be enrolled in their own
15
studies concomitantly, for example therapeutic
16
versus non-therapeutic studies.
17
Then, for external reports we wanted the
18
investigators to help us sort that out because we
19
couldn't sort it out. So, the
investigators had to
20
invest some time at the beginning sorting out
21
external reports before they submitted them to us
22 so
that they would be more meaningful to us.
23
Then, the functional outcomes would be
24
that there would be real-time reporting and that
25 the
IRB would acknowledge that through some
107
1
electronic time stamping mechanism.
There are
2
forced choices so that everybody has to do it the
3
same way; no incomplete data submissions so we
4
wouldn't have to address the issue of going back
5 and
asking for more clarification and more
6
questions; easy access so it would be friendly;
7
ability to generate single incident reports;
8
ability to generate reports in a given time period.
9 If
you were noting a trend that something was
10
occurring in a particular study over some period of
11
time, you could capture that and, as you will see
12 in
the end, provide cumulative data that you could
13 sort
out to look at trends that potentially could
14 be
occurring. Quicker reporting times;
ability for
15 the
IRB office to generate reports based on
16
protocols; specific events across subjects, across
17
protocols to give us some functionality at the IRB
18
level to look at the data in different ways;
19
generate internal denominators of trends that we
20
wanted to look at; use standardized NCI toxicity
21
tables for the oncology trials; and be able to
22
record the IRB actions and updates from
23
investigators onto previous reports.
So, it wasn't
24 a
dead system. It was a system that the
25
investigator could go back and add more information
108
1 or,
when the IRB reviewed it, could add more
2
information so it became a living document as the
3
report was being done.
4
Let me give you an example of how this
5
works. I couldn't get it
electronically. It was
6
going to cost me money to be able to do this
7
electronically so I did some snapshots of what it
8
looks like.
9
So, this page is accessible to anybody who
10 is
identified at St. Jude as a principal
11
investigator or a member of a research team. So,
12 if
you are listed on the protocol as the nurse for
13
that study, as the statistician for that study, as
14 a
pharmacist for that study, automatically you get
15
access to this through a user ID and your own
16
password. So, it is available to
anybody who is
17
part of the research team.
18
This is how you log in. Here I
logged in
19 and
it says, "welcome, Victor Santana."
Then it
20
gives a listing of all the events that have
21
accumulated during a particular period of time. It
22
gives the event ID which is an internal working
23
number. It gives the event
date. It gives an
24
identifier that I have erased here for a particular
25
patient. It is usually a
numerical number. If it
109
1 is
an external event, then there is a way to code
2
that to an external number.
Sometimes you get an
3
event from a sponsor and it is coded ABXY235, well,
4
there is a way that you can code that the same way
5
here so you can track it and use the same codifier
6 if
you ever have to go back to the data.
7
The status tells me, as an investigator,
8 whether I have reviewed this or not. So, when I
9
copied this the other day I only had one adverse
10
event that I had yet to review that somebody sent
11 to
me for comment. Then, it tells me the
date that
12 the
event was reviewed by me or that I modified it
13 or
I did anything to it.
14
Very quickly, it goes through a couple of
15
screens that provide some general information. It
16
tells you whether it is a St. Jude patient or not
17
because if it is not, it throws you in a different
18
direction in terms of the data that you need to
19
capture because, clearly, the data is being
20
captured for external adverse events a little bit
21
differently than it is for internal.
There is some
22
information here in terms of the patient.
23
Then, it begins to do its own internal
24
processing once it identifies the patient. It
25
tells us, as you see at the top of the screen, all
110
1 the
protocols that this patient is registered on.
2 So,
it goes back and talks to the data warehouse.
3 If
this patient is enrolled on ten studies, it will
4
pull and identify all those ten studies.
Then it
5
will ask me, as the person putting in the
6
information, under what study am I following this
7
report. So, it identifies
primarily the study and
8 the
adverse event, but it also tells me all the
9
other studies the patient is on, and this is
10
critical because this report will go to the PIs of
11 all
those other studies too. You will see it
at
12 the
end for their comments. So, it provides
a
13
little bit of a cross-talk among studies.
14
Then, it clearly identifies the type of
15
adverse event that is being reported.
You have all
16
seen this in different variations.
For adverse
17
events that require a CTC code it takes you to the
18 CTC
code so there is a link too so you don't have
19 to
scramble through 50 books looking for those
20
codes but automatically it links you to those
21
codes. Then, it allows you to put
the descriptor,
22
etc., etc. So, it is all being
captured in a
23
uniform language.
24
Then it goes to a page that allows the
25
person who is submitting the information to do some
111
1
attribution on the adverse event.
It is a click
2
system but it reminds people, because we all tend
3 to
forget, what each one of those words means.
So,
4 it
reminds me that I need to read when something is
5
serious; when something is unexpected.
It defines
6 it
very clearly because there are always a lot of
7
questions from members of the research team what
8
constitutes something that is unexpected versus
9
expected. Well, there it is. It is, hopefully,
10
black and white and then you select, based on your
11
interpretation. It allows you to
do one selection
12
across lines horizontally for each one of those.
13
Then, there is a page that allows you to
14
provide more information. One of
the problems
15
always with electronic information is that
16
sometimes you can't capture everything in a unique
17
format. So, there is a page that
allows you to do
18 a
little more narrative form of how this all
19
happened, and so on and so forth, so it can give
20 you
some additional data that you can comment on.
21
Then it asks you do you think, based on
22
your interpretation of what has happened with the
23
adverse event, that there is a follow-up that is
24
needed. If you say there is a
follow-up needed,
25
then it links back to a reminder within 30 days
112
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