I certify that I attended the March 17, 2004 meeting of the
Pediatric Oncology Subcommittee of the Oncologic Drugs Advisory Committee and
that these minutes accurately reflect what transpired.
______//S//_______________ _______//S//________________
Johanna Clifford, MS, RN Victor
Santana, M.D.
All external requests for the meeting transcripts should be submitted to the CDER Freedom of Information office.
Prior to the meeting, the members and the invited consultants had been
provided the background material from the FDA. There were no sponsors in
attendance at this meeting. The meeting was called to order by Victor Santana
M.D. (Committee chair); the conflict of interest statement was read into the
record by Johanna Clifford (Executive Secretary). There were approximately 50
persons in attendance. There were no
scheduled speakers in either session for the Open Public Hearing.
Attendance:
Oncologic Drugs Advisory
Committee Members Present (Voting):
Donna Przepiorka, M.D., Ph.D. (ODAC Chair), Pamela J. Haylock, RN (ODAC
Consumer Representative) and Antonio Grillo-Lopez, M.D. (Acting Industry
Representative, non-voting)
Pediatric Oncology Subcommittee Consultants
(Voting):
Victor Santana, M.D.
(Subcommittee Chair), Peter Adamson, M.D., Alice Ettinger, M.S., RN, Peter
Houghton, M.D., Eric Kodish, M.D. (via telephone), C. Patrick Reynolds, M.D.,
Susan Weiner, Ph.D., Ruth Hoffman (Patient representative).
Government Employee Participants (Voting):
Barry Anderson,
M.D., Ph.D., Lee J. Helman, M.D., Malcolm Smith, M.D. Ph.D.
FDA Participants
Richard Pazdur, M.D., Patricia Keegan, M.D., Susan Ellenberg, M.D.,
Grant Williams, M.D., Steven Hirschfeld, M.D., Ph.D., Patricia Dinndorf, M.D.,
Ramzi Dagher, M.D.
The subcommittee met
to discuss safety monitoring in clinical studies enrolling children with cancer
in the a.m. session and the use of non-clinical data to complement clinical
data for pediatric oncology in the p.m. session
Introduction Richard
Pazdur, M.D.
Director,
Oncology Drug Products, FDA
Introduction of Issues and Agenda Steven
Hirschfeld, M.D., Ph.D.
Oncology Group Leader, Office of Cellular and GeneTherapy Center for Biologics Evaluation and Research, FDA
Protecting Children in Cancer Eric Kodish, M.D.
Research: What Really Matters Director,
Legal Responsibilities for HHS Michael Carome, M.D.
Supported Studies Associate
Director for Regulatory Affairs
Office
for Human Research Protection, HHS
Legal Responsibilities for Studies with Steven
Hirschfeld, M.D., Ph.D.
FDA Regulated Products Oncology
Group Leader, Office of Cellular and Gene Therapy Center
for Biologics Evaluation and Research, FDA
Break
Enrollment and Monitoring Procedures Barry Anderson, M.D., Ph.D.
for NCI Funded Studies Cancer
Treatment Evaluation Program National
Cancer Institute
National
Institutes of Health
Monitoring Procedures in a Private Victor Santana,
M.D., Head
Children’s Hospital Division
Director, Solid Tumor Malignancies
St.
Jude Children’s Hospital
Committee Discussion
Lunch
What are Microarrays and How Paul Meltzer, Acting
Chief
Can They Help Us with Clinical
Studies Cancer Genetics
Branch
In Pediatric Oncology National
Human Genome Research Institute
National
Institutes of Health
Advantages and Limitations of Cell Peter Adamson,
M.D.
Culture Models in Pediatric Drug Chief,
Division of Clinical Pharmacology
Developments &
Therapeutics
Children’s
Committee Discussion
Break
Human Cell-Animal Xenografts: Peter
Houghton, Ph.D.
The Current Status, Potential
and Member and
Chair,
Limits of Informing Us about Department of Molecular
Pharmacology
Clinical Studies St.
Jude Children’s
An Integrated and Comparative Chand Khanna, DVM,
Ph.D, DACVIM
Approach to Preclinical/Clinical Head, Comparative
Oncology Program &
Drug Development Head,
Tumor and Metastasis Biology Section
National
Cancer Institute
National
Institutes of Health
What Can Be Learned About Safety? Kenneth Hastings,
Ph.D.
Center
for Drug Evaluation and Research, FDA
Committee Discussion
Assessing Anti-tumor Activity in Malcolm
Smith, M.D., Ph.D., Section Head
Non-clinical Models of Childhood Treatment
Evaluation Program
Cancer National
Cancer Institutes National
Institutes of Health
Questions for Discussion
Adjourn
Questions to the
Committee: A.M. Session
The tolerance for risk in
cancer therapeutics is different than for most other medical therapies. It is
also recognized that children are a particularly vulnerable population and
regulations and procedures have been implemented to provide protection to
children participating in clinical research. The following questions relate to
the setting of children with cancer participating in clinical trials.
Principles:
1.
What are the principles that should be addressed
in safety monitoring of clinical studies that enroll children with cancer? If the principles are adequately stated in
existing documents, statues, or regulations, please identify the relevant
documents and sections.
The principles stated in the
Practice:
2. Recognizing that particular populations, disease settings, and products may have specific requirements, what general parameters should be monitored for safety in all clinical studies?
The parameters for monitoring are context
dependent and may vary based upon the different study phases of product development (Phase I, II,
III, etc) and the type of disease. In all cases, the standard of care for the
disease should be taken as a minimum threshold with any particular agent. Specific
toxicities guiding further monitoring. Information from relevant non-clinical
models and adult Phase I studies may be informative, especially for early phase
pediatric studies. Eligibility criteria and waivers for assent should be
monitored. Pediatric specific concerns that should be monitored are effects on
growth, neurocognitive development and other late effects. Late effect
monitoring has not been systematically undertaken by the pharmaceutical
industry, so if it is to occur it is dependent upon cooperative group
resources.
3.
Based on the
response to the previous question, how often should the parameters be monitored?
The committee maintained that there is
currently no need for a prescriptive plan and that frequency is phase dependent
and agent specific. Earlier phase studies should have frequent monitoring
guided by any previous clinical experience and non-clinical data. Later phase
studies monitoring should be guided by the general standard of care for the
disease or condition.
4.
Based on the
response to question 2, who should do the monitoring? Is it adequate to have
the personnel involved in the study be responsible for
safety monitoring?
The committee recommended a flexible approach
with the personnel involved in performing safety monitoring independent upon
the phase of the study. There was
consensus that phase I studies, which are primarily dose-finding
and toxicity assessments are best served by close monitoring by the
research team, whereas later phase
studies should have additional layers of data safety monitoring
independent of the investigator The general principle is to avoid conflicting
roles for an individual. Individual investigator studies at single institutions
should seek outside monitoring, even it if is another member of the same
institution. In all cases safety monitoring should be based on a prospective
plan ideally defined in the protocol document and monitoring of the
consent/assent/eligibility process should be independent of the investigators.
It was noted that the pharmaceutical industry generally does not have external
review of early phase studies.
What circumstances would
benefit from a Data Monitoring Committee (Data Safety Review Board) oversight?
The committee agreed that the following
circumstances consistent with National Cancer Institute policy should have the
oversight of a Data Monitoring Committee:
a.
Phase III Studies
b.
Multi-institutional trials
c.
High-risk therapy
d.
Complex treatment regimens
e.
Vulnerable population
f.
Phase II upfront “window” trials in
previously untreated patients
g.
Gene transfer studies
The composition of a Data Monitoring Committee should
be prospectively stated in a charter and should include non health care
professionals.
5.
Are there
additional recommendations for safety monitoring?
There is an absence of normative data for toxicity and
adverse events across clinical studies and a need to collect and analyze such
data.
Institutions lack resources to properly
process the volume of safety reports and in addition safety reports are being
routed to many parties including investigators, IRBs, regulatory authorities,
data monitoring committees, and others. There is a lack of coordination among
the recipients and often a lack of context, where the cumulative numerator of
the event and denominator of the relevant patient population is not known. To
effectively monitor studies, coordination and data sharing are essential. In
addition a filtering mechanism was discussed whereby only the serious and
unexpected events would have expedited reporting In addition a filtering
mechanism that would either flag pediatric cases or eliminate possibly
uninformative cases based on age, diagnosis, or other criteria was discussed.
Questions to the Committee: P.M. Session
Because of the limited number of pediatric oncology
patients and because of problems unique to pediatric drug development, it may
not always be feasible to evaluate all aspects of efficacy and safety in
clinical studies. In some settings,
extrapolation of results from non-clinical studies may be appropriate.
1.
What types of
questions are of potential clinical relevance but are not feasible or
acceptable to answer in a clinical study could be addressed by non-clinical
studies?
Examples may include the need for repeated tissue
sampling, assessment of long term effects of treatment, effects on
reproduction, access to critical anatomic structures, exposure to toxic
reagents, evaluation of non-monitorable or irreversible toxicities,
identification of biomarkers for clinical monitoring.
In
addition to the proposed list, which was noted to be useful and weighted toward
host effects, additional uses for non-clinical data would be validation of
combination therapies, target validation, and establishing criteria for patient
selection.
Given
the need to correlate findings from most non-clinical models with clinical outcomes, the
committee recommended that studies would be informative if done in parallel
with clinical studies Exploratory non-clinical studies should not delay
clinical development.
2.
What type of
evidence and data would be recommended in each of the following domains to
allow extrapolation from non-clinical data and be informative for a clinical
condition?
a. Pharmacology and pharmacokinetics
b. Safety
c. Efficacy
d. Behavior
e. Long
term effects
f.
Developmental
aspects
g.
Other domains?
The
committee noted that currently most non-clinical model systems do not have
systematic data correlation with clinical outcomes. In addition, the data may
be biased. It is therefore important to examine models in a systematic manner.
An additional domain proposed to the suggested list is pharmacodynamics.
Examples where correlations do exist are in
the use of xenograft models for pharmacology and pharmacokinetics where the
same parameter using the same technique is used in the clinical and non-clinical
setting. Further approaches that may be used by non-clinical models to inform
clinical findings are using validated surrogates for a molecular target, the
use of prior clinical knowledge to test a non-clinical model, prospective
parallel testing studies using standard Phase II clinical endpoints such as
response rate, and the use of biological correlates that address disease or
drug mechanism. The value of negative predication was discussed as a mechanism
to minimize exposure of patients to inactive agents. Additional uses of
non-clinical models discussed were hypothesis testing of mechanisms of action
and providing explanations for clinical findings-especially negative findings.
It was noted that non-clinical model validation can be context dependent subject
to the disease, stage, and patient population. It is unlikely that any model
will be universally predictive.
The
National Cancer Institute is beginning a 5 year program to formally examine the
validity of various non-clinical models in pediatric cancers for predicting
clinical response,
3.
Are there
additional recommendations for the effective use of non-clinical
data? For example,
will open literature reports be generally acceptable? Is documentation of
compliance with Good Laboratory Practice (GLP) necessary to evaluate animal
data? Should non-clinical data be
submitted as an independent report with a presentation of primary data
sufficient for verification and review?
The
subcommittee discussed issues surrounding the documentation and submission of
animal data. The subcommittee acknowledged that full compliance with GLP may be
difficult in an academic setting.