CONSORTIUM THERAPEUTIC STUDIES OF PRIMARY CENTRAL NERVOUS SYSTEM MALIGNANCIES
IN ADULTS
RELEASE DATE: January 16, 2003
RFA: CA-04-001 (Reissued as RFA-CA-08-504)
National Cancer Institute (NCI)
(http://www.nci.nih.gov/)
LETTER OF INTENT RECEIPT DATE: February 21, 2003
APPLICATION RECEIPT DATE: March 28, 2003
This RFA is a reissue of RFA CA-97-002, which was published in the NIH
Guide on November 22, 1996.
THIS RFA CONTAINS THE FOLLOWING INFORMATION
o Purpose of this RFA
o Research Objectives
o Mechanism of Support
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations
PURPOSE OF THIS RFA
The purpose of this RFA is for the Cancer Therapy Evaluation Program
(CTEP) and the Radiation Research Program (RRP) of the Division of
Cancer Treatment and Diagnosis (DCTD) at the National Cancer Institute
(NCI) to invite the members of the North American Brain Tumor
Consortium (NABTC) and the New Approaches to Brain Tumor Therapy
(NABTT) consortium to submit new or competing continuation cooperative
agreement applications. Each consortium of institutions will be
referred to as a Central Nervous System Consortium (CNSC) for the
purpose of this RFA. Members from both CNSCs will again be expected to
perform Phase I and II clinical evaluations of promising new
therapeutic agents or approaches for the treatment of primary CNS
malignancies in adult patients, especially glioblastoma multiforme and
other high-grade gliomas, and to perform ancillary laboratory studies
of aspects of CNS tumor biology with potential clinical implications.
The NCI desires to continue its support of talented scientists who will
interact with other members of the consortium, and with NCI in a
concerted way to conceive, create, and evaluate new approaches to the
therapy of CNS tumors. The NCI anticipates continued funding of two
CNSCs.
Separate applications are requested from each current full and
provisional member institution interested in continuing participation
in their respective CNSC. Applications will only be accepted from
current full and provisional member institutions of NABTC or NABTT.
Each CNSC will include a single Central Operations Office/Coordinating
Center responsible for meeting the administrative/regulatory
requirements of the Consortium and for collecting/analyzing clinical
data from participating institutions, a Pharmacokinetics Center, and a
cohort of Participant Member Institutions providing patient resources.
The proposed Central Operations Office/Coordinating Center of each CNSC
should indicate which participating institutions will provide
organizational support, scientific leadership, laboratory capabilities,
and/or patient resources as well as pharmacokinetics
expertise/facilities. Applications should indicate whether they are
for the Central Operations Office/Coordinating Center, Pharmacokinetics
Center, or Participant Member Institution providing patient resources.
While a single application may propose only one of these roles,
eligible institutions may submit separate applications for one or more
of these different roles. It is anticipated that there will be only
one application for the Central Operations Office/Coordinating Center
of each CNSC. It is also anticipated that there will be only one
application for the Pharmacokinetics Center of each CNSC.
RESEARCH OBJECTIVES
A. Background
Primary malignant brain tumors are diagnosed in approximately 35,000
adults annually in the US and have been increasing in incidence,
especially in the elderly. Meaningful therapeutic improvement has been
made for the less common histologic types such as ependymomas,
oligodendrogliomas, and CNS lymphomas. However, for the largest
category, astrocytomas of various grades, little progress has been
made. Aggressive multimodality therapy has been shown to improve short
term survival by two- to three-fold, but average survival for patients
with high-grade gliomas is only 9-15 months and, despite the fact that
these cancers rarely metastasize, they remain essentially 100 percent
lethal.
Limited therapeutic success is related to many factors, including the
unique biology of high-grade gliomas and the susceptibility of adjacent
normal brain to adverse effects of treatment. There have also been few
identified agents with therapeutic activity, which may well reflect
inherent resistance to conventional classes of agents. However, in
part, it may also reflect the fact that relatively few compounds had
received thorough clinical evaluation to the standards now in place in
the CNSCs. Brain tumor clinical trials are particularly challenging in
that tumor status, the adverse sequelae of therapy, and the effects of
ancillary treatments (such as steroids) are difficult to segregate when
assessed either by clinical examination or conventional diagnostic
imaging. Optimal response evaluation and management of these patients
continues to require complex and well coordinated interdisciplinary
management involving neurosurgeons, neurologists, medical and radiation
oncologists, neuroradiologists, and neuropathologists, so that
relatively few programs have been optimally suited to undertake such
trials.
Clinical investigations of new strategies to treat such tumors are
needed. Collaborative interactions between clinicians and laboratory
scientists and between clinicians, diagnostic imagers, and pathologists
are essential features of these investigations. NCI is therefore
interested in continuing support for multidisciplinary and multi-
institutional teams of talented scientists from research organizations
who will interact with CTEP and RRP in a concerted way to conceive,
create, and evaluate new approaches to therapy of CNS malignancies.
Scientific approaches should be broad and reflect the creativity and
capabilities of team participants, including expertise in neurosurgery,
medical oncology, neurology, radiation oncology, neuroradiology,
laboratory medicine and biostatistics.
New clinical research opportunities exist with the development of novel
cytotoxic drugs, drug resistance inhibitors, radiation enhancers and
new radiation delivery technology, radiosurgery, antiangiogenic agents,
signal transduction inhibitors, immune modulators, regional delivery
techniques, and new approaches to gene therapy. Team objectives and
approaches will be investigator-originated but consistent with program
aims of improving the survival and quality of life for persons with
primary CNS malignancies, particularly high-grade gliomas, and
providing fundamental insights into the biology of these tumors.
B. Definitions
COOPERATIVE AGREEMENT - An assistance mechanism in which substantial
NCI programmatic involvement with the recipient is anticipated during
performance of the planned activity.
CENTRAL NERVOUS SYSTEM CONSORTIUM (CNSC) - The consortium of
institutions currently existing as either NABTC or NABTT who are
submitting research grant applications to conduct Phase I/II clinical
trials and ancillary laboratory studies. Each CNSC contains a Central
Operations Office/Coordinating Center, a Pharmacokinetics Center, and a
minimum of five Participant Member Institutions providing patient
resources. Each consortium will consist of talented and experienced
individuals in multiple disciplines (e.g. medical oncology,
neurosurgery, neurology, radiation oncology, radiobiology,
pharmacology, molecular biology, neuropathology, neuroradiology, and
biostatistics).
CENTRAL OPERATIONS OFFICE/COORDINATING CENTER - An administrative unit
that coordinates all CNSC activities. Responsibilities include
administrative management, coordination of protocol development and
submission, study conduct, quality control and protocol performance
monitoring, statistical analyses, adherence to requirements regarding
NCI drug accountability and FDA, OHRP and HHS regulations, and protocol
and institutional performance reporting. Statistical responsibilities
include experimental design, participation in study planning and
coordination, collection and analysis of patient and laboratory data,
data management and analysis, data monitoring, and reporting of data.
The Central Operations Office/Coordinating Center may be comprised of a
small consortium of institutions where for example the operations and
statistical components are at different institutions. The lead
institution for this small consortium must be a current full or
provisional member of NABTC or NABTT.
PHARMACOKINETICS CENTER - A central unit that performs or oversees
performance of pharmacokinetic (PK) testing in support of clinical
trials for the CNSC. Because of the complexity of performing timely PK
analysis on specimens from multiple trials at multiple sites,
applicants should thoroughly describe the logistics of sample
acquisition and registration. This description would be particularly
important if the PK studies are to be performed at more than one site.
The PK Center may be comprised of a small consortium of institutions
where for example different studies are performed at different
institutions. The lead institution for this small consortium must be a
current full or provisional member of NABTC or NABTT. It is anticipated
that the Pharmacokinetics Center (as well as other CNSC components) may
want to pursue laboratory projects other than PK projects directly
linked to the clinical protocols. While this is encouraged, very
limited support is available as discussed under "Research Goals and
Scope".
GROUP LEADER- The person who submits the application for the NABTT or
NABTC Central Operations Office/Coordinating Center and who is
responsible for the CNSC as a whole. The consortium of Participant
Member Institutions must agree to work together with the Group Leader.
The Group Leader is responsible for coordinating the CNSC activities
scientifically and administratively. The Group Leader may also be the
principal investigator on a Participant Member Institution application.
The Group Leader need not be the Chair of the Steering Committee.
PARTICIPANT MEMBER INSTITUTION - The individual research grant
application from an institution that is participating in the CNSC at a
clinical member institution or the Pharmacokinetics Center. The
Participant Member Institution may conduct clinical trials and/or
laboratory studies.
PRINCIPAL INVESTIGATOR - The person who submits the single application
for the Participant Member Institution and who is responsible for
performance of the key personnel of that application. The Principal
Investigator (PI) provides the scientific leadership for the
Participant Member Institution.
PROTOCOL CHAIRPERSON – The CNSC representative who is responsible for
the overall design, performance, interpretation and publishing of a
particular study for the CNSC.
NCI SCIENTIFIC COORDINATOR - The Senior Investigator, Clinical
Investigations Branch, CTEP, DCTD, NCI, (cited in the INQUIRIES
SECTION) who interacts scientifically with the Applicant/Awardee
Institutions.
INVESTIGATIONAL DRUG BRANCH INVESTIGATOR - The Senior Investigator,
Investigational Drug Branch, CTEP, DCTD, NCI, who is assigned to a
particular DCTD IND agent and assists in the coordination of its
development.
NCI PROGRAM DIRECTOR - The extramural grants staff member, Clinical
Grants and Contracts Branch, CTEP, DCTD, NCI, (cited in the INQUIRIES
SECTION) who will coordinate DCTD interactions and provide guidance for
the overall program within the NCI. He/she also serves in a back-up
role for the NCI Scientific Coordinator.
STEERING COMMITTEE - Each consortium's steering committee will be
composed of the Group Leader, PIs, and the NCI Scientific Coordinator,
and will be the main oversight body of the consortium.
DISCRETIONARY FUND - A fixed portion ($125,000) of the award to the
Central Operations Office/Coordinating Center that will be allocated
according to the instructions of the Steering Committee. Appropriate
uses may include seed funding for laboratory projects, shipment of
samples, supplementation of existing budgets for patient accrual or
special clinical costs, auditing of clinical trials, or other purposes.
C. Research Goals and Scope
The primary goal of this initiative is to stimulate clinical research
in the treatment of primary CNS malignancies in adult patients,
particularly malignant gliomas, by providing support for consortia of
institutions to take advantage of promising new developments and
perform Phase I and II clinical evaluations of innovative approaches or
agents.
A secondary goal is to utilize the consortia as a mechanism for sharing
human brain tumor specimens collected to a high quality control
standard, and associated with clinical data, in order to facilitate
collaborative NCI programs of molecular and genetic characterization of
human gliomas.
It is anticipated that two consortia will continue to be funded. Each
CNSC will exist for the purpose of: (1) conducting multi-institutional
phase I and II clinical trials to provide adequate patient populations
and timely completion; (2) sharing expertise of researchers in multiple
disciplines; and (3) sharing of tumor specimens and data useful in the
conduct of clinical pharmacologic and correlative laboratory studies.
Each CNSC will select the specific agents to be tested in accord with
their scientific interest and expertise and will continue to develop a
series of appropriate phase I or phase II trials with supporting
protocol documents. Each applicant institution should submit
documentation of participation in the CNSC in terms of patient accrual,
study activation, study leadership, and correlative studies. Each
application should document and describe the number of patients
accrued, studies activated, correlative studies conducted, abstracts
presented, and paper published. Each application should also document
papers in press, abstracts to be presented, and studies pending as well
participatory and accrual targets for the proposed cooperative
agreement.
Each CNSC must be able to document access to adequate numbers of
patients with CNS tumors and a history of accrual of patients to
clinical trials adequate to support 6-8 phase I or II trials per year.
See below for more specific accrual requirements. In addition, the
CNSC taken as an organization must have: (1) adequate radiotherapy
support for clinical trials utilizing radiation in combination with
other modalities; (2) adequate central data collection and processing
capabilities as well as biostatistical expertise; (3) adequate
pathology support for both institutional tumor classification and
central neuropathology review and for banking and distribution of tumor
tissues for concurrent and future laboratory studies; (4) mechanisms to
collect and store patient specimens for collaborative laboratory
studies, including immediately processed frozen tumors; (5) expertise
in antineoplastic drug pharmacology/pharmacokinetics; (6) expertise in
neuroimmunology relevant to potential clinical trials; and (7)
capability for electronic exchange of patient imaging data, with
appropriate protections, to support future research in new methods for
identifying target effects of new agents.
Each CNSC, with the assistance of the NCI Scientific Coordinator and
Program Director, will develop a plan for prioritization of
investigational trials. The NCI will provide assistance in design of
trials and may provide NCI-sponsored IND agents or provide assistance
to the awardee(s) by sponsoring or cross-referencing INDs for selected
agents. Each CNSC is also encouraged to carry out some of its trials
with agents or other interventions that are not sponsored by NCI.
The correlative laboratory research program in a CNSC should have
demonstrable capabilities to carry out correlative research into the
biology of human malignant gliomas with some potential for future
clinical relevance. Examples of research fields for laboratory studies
include: molecular genetics and cytogenetics, gene function and
expression, signal transduction pathways, radiobiology, growth
regulation, metabolism, differentiation and gene modulation by
investigational agents, intracellular metabolism, mechanisms of drug
resistance in tumor cells, CNS pharmacokinetics, blood-brain barrier
research, mechanisms of invasion and spread, microenvironment, cytokine
production or interactions, immune function and antigen expression, or
other aspects that may have clinical implications or lead to new
therapeutic approaches.
It is not expected that funding for these clinical consortia will be
adequate to support to completion high quality laboratory projects
(other than pharmacokinetic projects directly linked to the clinical
protocols). Some funding for laboratory pilot studies will be
available through the CNSC Discretionary Fund. However, the
expectation is that investigators from within the consortium membership
will have in place or will seek other funding for laboratory projects
that can draw upon and utilize the substantial tissue and clinical data
resources of the CNSCs. The CNSCs will be encouraged to establish
scientific interactions with Brain Tumor SPOREs and centers with funded
Program Project Grants for brain tumor research. Such arrangements
could be expected to leverage the relative strengths and funding of
these differently focused NCI-supported programs. The intent is that
each CNSC should establish under these cooperative agreements an
infrastructure that will promote this type of interaction.
Correlative laboratory studies need not be directly related to
individual clinical Phase I/II trials but should attempt to utilize the
large clinical database that will be generated by the consortium to
identify potential correlates of tumor behavior. Laboratory studies
should naturally be based on strong and testable hypotheses.
It is not expected that funding for these clinical consortia will be
adequate to support to completion high quality imaging projects (other
than imaging projects directly linked to the clinical protocols). Some
funding for pilot studies will be available through the CNSC
Discretionary Fund. However, the expectation is that investigators
from within the consortium membership will have in place or will seek
other funding for imaging projects that can draw upon and utilize
clinical data and image resources of the CNSCs. The intent is that
each CNSC should establish under these cooperative agreements an
infrastructure that will promote this type of interaction.
The cooperative approach outlined in this RFA allows for interactions
among successful applicants, with the assistance of NCI extramural
staff, to perform Phase I and Phase II trials of therapeutic approaches
and ancillary laboratory studies. This mechanism retains the decision-
making prerogatives of the Principal Investigator and his/her
colleagues, but at the same time, permits the active participation of
NCI in research activities in such areas as access to NCI
investigational agents, potential collaborations, when appropriate,
between the two adult CNSCs and/or the Pediatric Brain Tumor
Consortium, and development of various standards that promote efficient
clinical research, including integration of novel imaging technology
into early clinical trials. (See Terms and Conditions of Award)
SUPPLEMENTAL REQUIREMENTS
The Central Operations Office/Coordinating Center as lead institution
should submit a research grant application which lists the anticipated
participant institutions, and include examples of ongoing and proposed
new clinical protocols. (The Central Operations Office/Coordinating
Center application must be a separate document from any application
from a participant institution; if a single institution will be
applying for both participation in clinical and/or laboratory studies
and as the Central Operations Office/Coordinating Center, more than one
application will be necessary.) Each participant institution should
submit an individual research grant application and should indicate the
Central Operations Office/Coordinating Center of the CNSC consortium of
which they are a participating member site. Participant institutions
conducting clinical trials may include copies of specific proposed CNSC
clinical protocols in the Appendix, but this is not mandatory.
For the Central Operation Office/Coordinating Center application only,
there is a limit of 75 pages for the Research Plan sections A-D of the
application. However, all other sections of applications for the
Central Operation Office/Coordinating Center must adhere to the page
limits in the PHS 398 instructions. All sections of applications for
the Pharmacokinetics Center and Participant Member Institution
providing patient resources must adhere to the page limitations in the
PHS 398 instructions.
Because the Terms and Conditions of Award discussed below will be
included in all awards issued as a result of this RFA, it is critical
that each applicant include specific plans for responding to these
terms. Plans must describe how the applicant will comply with NCI
staff involvement.
The CNSC and the members of each proposed Consortium must demonstrate
in the application the ability to meet the following requirements:
A. Requirements for the Consortium (CNSC) as a whole:
1. A commitment to participate in multi-institutional protocols and
documentation of facilities and professional personnel available,
committed, and expert in conducting brain tumor clinical trials. This
includes assignment of appropriate specialist collaborators including,
but not limited to, medical oncologists, radiation oncologists,
neurologists, neurosurgeons, neuroimagers, neuropathologists, and
neuroimmunologists.
2. A Central Operations Office/Coordinating Center for biostatistical
support, collection, analysis, reporting, and quality control of data
from Phase I and II trials and related laboratory investigations.
Detailed requirements will be found below.
3. The applicant CNSC and each of its participating clinical
institutions must have adequate central data collection and processing
capabilities and the capability to meet FDA and HHS requirements for
the conduct of research using investigational agents.
4. Each CNSC, a minimum of 5 institutions, must have the demonstrated
capability of accruing a minimum of 60-80 fully evaluable patients with
histologically confirmed high-grade gliomas per year who would be
appropriate candidates for Phase I or Phase II clinical trials, and who
have acceptable performance status and organ function to enter such
trials. In the case of a consortium (CNSC) with more than 5 clinical
member institutions, a minimum of 15-20 such evaluable patients per
institution per year will be required.
5. Each CNSC must demonstrate an active program at one or more of its
participant institutions that utilizes human glioma specimens or cell
lines and conducts laboratory studies relevant to the biology, clinical
behavior, or response to therapeutic interventions of CNS tumors,
particularly malignant gliomas. Experience with gliomas and/or other
human CNS tumors must be documented by a record of publications or
peer-reviewed grant support.
6. Each CNSC must demonstrate laboratory capabilities among one or
more of its participant institutions sufficient to perform up to 5
comprehensive pharmacokinetic studies per year of selected Phase I or
Phase II drugs being evaluated by the consortium. Experience with
pharmacokinetic data analysis and correlation of these data with
clinical drug response must be documented, as must familiarity with the
latest technology for the detection and quantitation of drugs and their
metabolites in physiological fluids and tissues.
7. Each CNSC must demonstrate that at least 2 of its participating
member sites will be capable of collecting and sharing human frozen
brain tumor specimens collected to a high quality control standard from
20 or more gliomas per year, along with appropriate longitudinal
clinical data, in support of collaborative NCI programs of molecular
and genetic characterization of human gliomas.
8. Each CNSC must demonstrate among its investigator membership
expertise in clinically relevant aspects of neuroimmunology and the
development of immunologic therapeutics.
9. Each CNSC must have a plan in place for ongoing evaluation of
institutional (member) performance in the context of consortium goals
and for bringing on potential new sites
B. Each participant institution in the CNSC must have a mechanism to
collect and ship patient specimens to other members of the CNSC and
other consortia under the guidelines established for the individual
studies. Institutions involved in laboratory studies must have the
capability to receive and conduct research studies on patient specimens
not only from within their own centers, but also from other members of
the CNSC and other consortia funded by this RFA. There must also be a
mechanism in place for the collection and transfer of patient and
laboratory data to the Central Operations Office/Coordinating Center
for analysis.
C. Each institution participating in the clinical trials of the
consortium must meet the following requirements:
1. Experienced full-time physician investigators associated with the
project who have demonstrated expertise in Phase I/II studies.
2. A multi-disciplinary neuro-oncology team with clinician members
representing expertise in the disciplines of medical and radiation
oncology, neurology/neurosurgery, neuropathology and neuroradiology.
3. Adequate physician, nursing and data management resources to comply
with all data reporting requirements of NCI-sponsored Phase I and II
trials.
4. Patient populations to support adequate patient accrual (criteria
determined by the consortium) with annual monitoring to assure
continued enrollment of patients on Phase I and II trials.
5. Availability of state-of-the-art instrumentation for advanced
neuro-imaging and for radiation therapy, as well as available
instrumentation for exchange of imaging data to a planned future
central imaging center for the CNS consortia.
6. Appropriate drug control procedures as required for utilization of
NCI-supplied experimental agents.
7. Capability of meeting FDA requirements in A3 above.
All costs required for these studies must be included in the
application and must be fully justified. These costs include the
additional costs of clinical research associated with Phase I and Phase
II studies including costs for patient accrual, sample handling,
laboratory studies, quality assurance, data management and data
analysis, study monitoring, and travel. Each CNSC should anticipate
the need to attend two meetings per year to share data and to
coordinate activities. Travel funds for two representatives from the
Central Operations Office/Coordinating Center and one or two
representative(s) from each participant clinical and/or laboratory
member institution should be included in the budget.
MECHANISM OF SUPPORT
This RFA will use the NIH U01 award mechanism. The NIH U01 is a
cooperative agreement award mechanism in which the Principal
Investigator retains the primary responsibility and dominant role for
planning, directing, and executing the proposed project, with NIH staff
being substantially involved as a partner with the Principal
Investigator, as described under the section "Cooperative Agreement
Terms and Conditions of Award".
FUNDS AVAILABLE
NCI intends to commit approximately $3.3 million in total costs for FY
2004 to fund two CNSCs. Applicants may request a project period of up
to five years. Because the nature and scope of the proposed research
will vary from application to application, it is anticipated that the
size and duration of each award will also vary. Although the financial
plans of NCI provide support for this program, awards pursuant to this
RFA are contingent upon the availability of funds and the receipt of a
sufficient number of meritorious applications.
ELIGIBLE INSTITUTIONS
Only current full and provisional members of either NABTC or NABTT are
eligible to apply.
INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS
Any individual with the skills, knowledge, and resources necessary to
carry out the proposed research is invited to work with their eligible
institution to develop an application for support. Individuals from
underrepresented racial and ethnic groups as well as individuals with
disabilities are always encouraged to apply for NIH programs.
SPECIAL REQUIREMENTS
Cooperative Agreement Terms and Conditions of Award
The administrative and funding instrument used for this program is a
cooperative agreement (U01), an "assistance" mechanism (rather than an
"acquisition" mechanism) in which substantial NIH scientific and/or
programmatic involvement with the awardee is anticipated during
performance of the activity. Under the cooperative agreement, the NIH
purpose is to support and/or stimulate the recipient's activity by
involvement in and otherwise working jointly with the award recipient
in a partner role, but it is not to assume direction, prime
responsibility, or a dominant role in the activity. Consistent with
this concept, the dominant role and prime responsibility for the
activity resides with the awardee for the project as a whole, although
specific tasks and activities in carrying out the studies will be
shared among the awardee and the NCI Project Scientist. The role of
the Cancer Therapy Evaluation Program (CTEP) staff as described
throughout these terms and conditions of award is to facilitate and
assist but not to direct research activities. This cooperative
agreement is part of a larger program of investigational agent
development in the NCI. Each of the CTEP staff listed below has very
specific and well defined responsibilities in terms of investigational
agent development and the role of DCTD as a drug sponsor as defined in
CFR 21 Part 312.
1. Awardees Rights and Responsibilities
It is the responsibility of each CNSC (as represented by the Protocol
Chairperson) to develop the details of the research design, including
definition of objectives and approaches, planning, implementation,
analysis, and publication of results, interpretations and conclusions
of studies. A protocol is the detailed written plan of a clinical
experiment. The protocol must be mutually acceptable to the CNSC and
to the CTEP Protocol Review Committee (PRC), which must review and
approve every protocol.
The CNSC Central Operations Office/Coordinating Center, under the
leadership of the Group Leader and with CTEP assistance, is responsible
for coordinating protocol development, protocol submission, study
conduct, quality control and study monitoring, drug ordering, data
management, statistical analysis, protocol amendments/status changes,
adherence to requirements regarding investigational drug management and
federally mandated regulations and protocol and performance reporting.
All the scientific and administrative decisions related to the CNSC
funded activities and made by the CNSC institutions or affiliates will
be coordinated by the Group Leader with the assistance of the CNSC
Central Operations Office/Coordinating Center.
a. Clinical Trial Conduct
The clinical trials must be conducted in accordance with the
instructions in the INVESTIGATOR'S HANDBOOK, A Manual for Participants
in Clinical Trials of Investigational Agents Sponsored by the Division
of Cancer Treatment and Diagnosis, National Cancer Institute (URL:
http://ctep.cancer.gov/handbook/)
The Investigator's Handbook contains information on the following:
Protocol Development and Submission
Ordering Investigational Drugs from NCI
Accountability and Storage of Investigational Drugs
Reporting of Results to CTEP [including the Clinical Trials Monitoring
Service
(CTMS) and the Clinical Data Update System (CDUS)]
Reporting Adverse Drug Reactions [including Adverse Event Expedited
Reporting
System (AdEERS) and the Common Toxicity Criteria (CTC)]
Monitoring and Quality Assurance
All Protocols utilizing investigational agents must include the NCI
Standard Protocol Language
(http://ctep.cancer.gov/guidelines/templates.html) and be conducted in
accordance with the terms of the Intellectual Property Option to
Collaborator. The Intellectual Property Option to Collaborator
document may be accessed at http://ctep.cancer.gov/industry/ipo.html or
may be obtained from the Regulatory Affairs Branch, CTEP, DCTD, NCI at
301-496-7912.
b. Protocol Development and submission
It is anticipated that decisions in all CNSC activities will be reached
by consensus of the collaborating member institutions under the
leadership of the CNSC Group Leader. The Group Leader shall designate
a Protocol Chairperson for each proposed study. The Group Leader along
with coordinating Central Operations Office/Coordinating Center staff
will be responsible for communication with the appropriate CTEP staff.
The CNSC Central Operations Office/Coordinating Center, under the
leadership of the Group Leader, will submit CNSC protocols to the CTEP
Protocol and Information Office in a timely fashion for review and
approval by NCI.
All protocols involving NCI sponsored agents should be preceded by an
electronic Letter of Intent (LOI) from the CNSC to the CTEP LOI
Coordinator declaring interest in conducting a particular study and
using the suggested format described in the INVESTIGATOR'S HANDBOOK in
Appendix VII, GUIDELINES FOR SUBMITTING LOIs - Letter of Intent/
INVESTIGATIONAL DRUG TRIAL. The LOI Submission Form is available at
http://ctep.CANCER.GOV/guidelines/index.html. The LOI shall describe
the hypothesis to be investigated, the general design of the
contemplated trial plus relevant information on accrual capabilities to
document feasibility of expeditious completion of the proposed study.
The LOI must describe the rationale for correlative studies. If
funding for correlative studies is not through the CNSC, the LOI must
indicate the source of funding or plans to secure funding. LOIs may be
submitted in response to a CTEP solicitation of proposals to conduct
clinical trials with specific NCI-held IND agents or at any time
through the investigator's own initiative. The LOI is reviewed by CTEP
Protocol Review Committee for scientific merit and need based on the
development plan. The LOI may be rejected, approved with the
requirement for recommendations to be incorporated, or fully approved.
If the LOI is approved, the CNSC must, with CTEP assistance, develop
protocols and submit them for PRC review within 30-45 days of LOI
approval (timeline determined at time of LOI approval). For some novel
agents, CTEP may provide protocol templates to reduce the effort of
multiple investigators duplicating similar efforts in repetitive
aspects of protocol development. The protocol should define the
scientific objectives and experimental approaches for the specific
agent for which CTEP holds an IND. The protocol should define for
reference, procedures for pharmacokinetic and other correlative
studies.
For all protocols, whether or not employing an NCI-supplied agent, the
CNSC must designate a Protocol Chairperson for each proposed study.
The Protocol Chairperson will be responsible for communication with the
appropriate CTEP staff. The PI is responsible for coordinating
protocol development, protocol submission, study conduct, quality
control and study monitoring, drug ordering, data management and
analysis, protocol amendments/status changes, adherence to requirements
for reporting serious adverse events and adherence to requirements
regarding investigational drug management and federally mandated
regulations and protocol and performance reporting.
The CNSC must electronically submit (as .doc or .pdf files) protocols
to the CTEP Protocol and Information Office, the receiving office for
all protocols sent to CTEP, for review as appropriate, prior to their
implementation.
Protocols will be developed and submitted and studies will be conducted
in accordance with the INVESTIGATOR'S HANDBOOK. The Group Leader, with
the assistance of the Central Operations Office/Coordinating Center
staff, will communicate the results of the NCI review of protocols to
the CNSC participating institutions.
c. Protocol Review, Revision and Implementation
Communication between the CNSC and CTEP at the various stages of
protocol development and conduct is encouraged as necessary to promote
efficient and well informed protocol development and implementation.
The PRC will review each protocol (generally within 2 weeks of
submission) and the Protocol Chairperson will receive electronically a
Consensus Review (generally within 3 weeks of submission). Numbered
comments may include comments requiring a response, recommendations
and/or comments concerning the consent requiring a response, as well as
recommendations and/or comments from the industrial cosponsor, if any.
Each numbered comment must be addressed point by point in a cover
letter that accompanies the revised protocol. For CTEP-sponsored
agents, the revised protocol and cover letter must be received by the
PIO within 2-4 weeks of the date on the Consensus Review (which will
correspond with the date the Review is sent by e-mail to the Protocol
Chairperson). The reasonable time to respond to the Consensus Review
will be determined by CTEP based on the extent and complexity of
required revisions. If the CNSC has not received the Consensus review
within 4 weeks from protocol submission, the PI should contact the PIO.
Access to e-mail and ability to attach, send and receive documents (for
example, protocols, amendments, and correspondence) via e-mail is
required.
Protocols can only be activated after review and approval by the
Institutional Review Board (Form OMB No.0990-0263 Protection of Human
Subjects: Assurance Identifications/IRB Certification/Declaration of
Exemption (Common Rule) must be submitted. See OHRP website
http://www.hhs.gov/ohrp/assurances/assurances_index.html under
Related Forms and Procedures) the PRC, and the CTEP Coordinator and
only after receipt of the protocol approval letter from NCI.
The specific requirements of Protocol Submission, Review and Approval
are described in the INVESTIGATOR'S HANDBOOK.
The CNSC must notify the Protocol and Information Office in writing of
each study status change at the time of status change. (For definition
of study status see the INVESTIGATOR'S HANDBOOK).
d. Study Conduct and Monitoring
The CNSC and each awardee institution is responsible for the ensuring
accurate and timely progress of each study and reporting of results to
CTEP as the study sponsor through:
1) screening, registering and treating the planned number of patients
on study in the time frame agreed to at the time of LOI or protocol
approval;
2) appropriate patient follow-ups beyond that specified in the protocol
(e.g., after adverse events, progressive disease or patient
withdrawal);
3) establishing procedures for assigning dose level at the time a new
patient is entered, and assuring that the required observation period
has elapsed before beginning a higher dose level, and assuring the all
the relevant parties (nursing and pharmacy staff) are notified of the
current dose level and assigned dose level for an individual patient;
4) registration, tracking and reporting of patient accrual and
adherence to defined accrual goals; appropriate attempts to accrue
patients who fulfill NIH Guidelines for accrual of women and minorities
to clinical trials with appropriate documentation and reporting of
accrual as specified by NIH Guidelines;
5) ongoing assessment of patient eligibility and evaluability;
6) timely medical review and assessment of patient data; by the study
chairperson and PI Investigator;
7) rapid reporting of serious treatment-related morbidity (adverse
event reactions) electronically through AdEERS in compliance with FDA
regulations and measures to ensure communication of this information to
all parties [http://ctep.cancer.gov/reporting/adeers.html];
8) interim evaluation and consideration of measures of outcome, as
consistent with patient safety and good clinical trials practice;
9) conduct of pharmacokinetics and other laboratory correlative studies
throughout the course of the clinical trial, to facilitate optimal
utilization of data generated by such research efforts; and
10) timely communication of interim and final results of studies to
CTEP and timely preparation, submission and publication of manuscripts
to ensure communication to the scientific community.
e. Data Management, Analysis and Reporting
The CNSC and each awardee will develop procedures to ensure that data
collection and management have: a) acceptable quality assurance
standards; and b) procedures that are as simple as appropriate in order
to encourage maximum participation of physicians entering patients and
to avoid unnecessary expense. Quality assurance at a minimum must
consist of:
1) Pathology: Verification of pathologic diagnosis in cases where
known variability in the accuracy of histologic diagnosis is a
potentially serious problem and where pathology data may provide
important prognostic information.
2) Radiation Therapy: Review (either concurrent or retrospective) of
simulation and port films as well as compliance with protocol-specified
doses and target volumes for individual patients, where relevant.
Determination of adequacy of radiation delivery with respect to
treatment equipment, treatment planning, and quality assurance.
3) Chemotherapy: Review of pharmacy orders, investigational drug
record keeping, drug administration, flow sheets and drug distribution
with determination of protocol compliance in dose administration and
dosage modification.
4) Surgery: Assessment of adequacy of protocol-specified surgical
procedures (where relevant) through review of operative notes and
study-specific surgical forms.
5) Imaging: Assessment of adequacy of protocol-specified imaging
procedures. This would include (1) methods for acquisition and display
of images; (2) methods for monitoring quality of image interpretation
including quantitative measurement of lesions; and (3) methods of data
archiving and retrieval as appropriate to specific studies.
6) Laboratory: For pharmacokinetic and correlative studies, quality
assurance procedures for the laboratory assays must be established.
These may include such elements as assay validation procedures,
calibration curves, check samples, standards for accepting or rejecting
data such as Shewart charts, positive and negative controls, etc., as
well as external quality assurance if it is available. Procedures for
ensuring patient privacy and sample tracking must be established by the
CNSC
7) Reporting of pharmacokinetic results: For certain specific CTEP
investigational agents, pharmacokinetic data results may be required to
be reported to the Clinical Trials Monitoring Service (CTMS) using case
report forms available from Theradex. It is anticipated that most
studies will involve assays in (near) real time during the course of
the study. The schedule for sample assay should be established in the
written protocol (e.g., for each patient in real time, or for a cohort
of patients at a particular dose, or after each nth patient as
appropriate for a specific study).
8) Reporting of correlative studies results: The performance of
correlative studies, including the number of patients studied; the
number of samples; imaging studies or other procedures done; the number
of samples or other procedures completed with results; and overall
conclusions of these studies to date should be reported to the CDUS or
CTMS as determined by the written protocol.
f. Investigational Drug Management
Investigators performing trials in the CNSCs must be NCI registered
investigators (Form FDA 1572) and will be expected to implement CTEP
requirements described in the INVESTIGATORS' HANDBOOK for storage and
accounting for investigational agents, to abide by NCI/HHS Drug
Accountability Records (DAR) procedures, and to comply with all FDA
requirements for investigational agents.
g. Compliance with Federally Mandated Regulatory Requirements
Each awardee is responsible for establishing procedures to comply with
FDA regulations for studies involving investigational agents and Office
for Human Research Protections (OHRP) requirements for the protection
of human subjects, and NIH requirements for data and safety monitoring
of clinical trials
https://grants.nih.gov/grants/guide/notice-files/not98-084.html
with additional description at
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html.
These procedures are:
1) Methods for ensuring that the each awardee institution has a
current, approved assurance on file with the OHRP; that each protocol
is reviewed and approved by the responsible Institutional Review Board
(IRB) and CTEP PRC prior to patient entry; that each protocol is
reviewed at least annually by the IRB so long as the protocol is
active; that amendments are approved by the IRB; that each investigator
is registered with the Drug Management and Authorization Section
(DMAS), CTEP with a current 1572 form on file; and that each patient
(or legal representative) gives written informed consent prior to entry
on study. In the case of multi-center protocols, the PI must assure
that full IRB approval is obtained prior to patient entry at any
subcontracted institution, that yearly reapprovals are conducted in a
timely fashion and that amendments and serious adverse events are
properly reported to each subcontracted institution's IRB. The PI must
maintain documentation of initial approval, yearly reapproval,
amendment reviews and reporting of serious adverse events for all
participating institutions.
2) A system for ensuring timely reporting of all serious and unexpected
toxicities to the Investigational Drug Branch, (IDB), CTEP according to
CTEP guidelines (mailed annually to all registered investigators).
http://ctep.cancer.gov/reporting/adeers.html.
This will require reporting Adverse Event Reactions (AERs) through
AdEERS and/or by telephone to the responsible IDB Senior Clinical
Investigator within 24 hours of the event and requires a written report
to follow within 10 working days. (See 2. NCI Staff Responsibilities
for definition of responsible IDB Senior Clinical Investigator
Physician.)
3) A described system for ensuring that data safety monitoring is
performed in accordance with NIH requirements
h. Reporting Requirements:
1) Routine Protocol Reporting. Reporting requirements will be in
agreement with FDA regulations and NCI procedures. The timely and
accurate reporting of data from investigational drug trials to the
sponsor in a format that is easily integrated is a critical
responsibility for Good Clinical Practice and is an important
responsibility of investigators doing research with IND drugs. The
receipt of these data in a timely fashion is not an arbitrary
requirement. The information contained in them is the material, which
informs CTEP of the progress of the development of the drug, ensures
safety and suggests promising new directions. The material is required
by CTEP to meet its obligations under FDA regulations to (a) monitor
the study and (b) submit regular reports of current findings to that
agency.
2) All trials conducted by the CNSCs will require NCI-sponsored data
monitoring.
Some trials will require monitoring by the Clinical Trials Monitoring
Services (CTMS). Information must be provided to the CTMS at two week
intervals and includes: registration of each patient entered onto the
protocol within the previous two week period, and all data obtained on
each registered patient within the previous two weeks. Investigators
are reminded that a course does not need to be complete to submit
interval data to CTMS, as this system is designed to accept partial
information and additional information for each case report form as it
is generated.
Most of trials performed by the CNSCs will have data submission via the
Clinical Data Update System (CDUS), with less frequent reporting
requirements (monthly or quarterly rather than biweekly). This
reporting system is generally used for studies later in the development
of a specific agent when substantial safety information suggests that
frequent oversight by the IND sponsor is less critical for patient
safety.
3) Adverse Events Reporting
CNSC investigators must promptly report adverse events (AEs) in
accordance with the NCI Guidelines for Adverse Event Reporting found at
the following URL: http://ctep.cancer.gov/reporting/adeers.html.
CTEP has developed operational definitions of Adverse Events (AEs) that
apply to anticancer drug trials. These definitions are described in
the Common Toxicity Criteria, Version 2.0 (CTC v2.0) available at the
following URL: http://ctep.cancer.gov/reporting/ctc.html.
Additional information about reporting adverse events is included in
the CTC Manual and other CTC sources at:
http://ctep.cancer.gov/reporting/ctc.html. The prompt reporting of AEs
to CTEP is the responsibility of each investigator engaged in clinical
research with investigational drugs supplied by the NCI and of the PI
for the award. It should be noted that verbal/telephone communication
of all new adverse events as well as all life-threatening (Grade 4,
unless otherwise defined in the specific protocol) or lethal (Grade 5)
adverse events is mandated for this process and facilitates discussion
and assessment by both sponsor and investigator. See the above
referenced URL for specific requirements for Adverse Event Reporting.
These should be detailed in the text of the protocols using the CTEP
table and additional protocol specific information. All adverse events
for NCI-sponsored trials are reported using CTC Version 3.0 as
documented in the protocol.
i. On-site Audits:
These will be carried out at appropriate intervals at all participating
performance sites, in accordance with policies for CTEP-sponsored
trials, as outlined in the INVESTIGATORS HANDBOOK.
j. Publication of Data:
Timely publication of major findings is encouraged. Publication or
oral presentation of work done under this agreement will require
appropriate acknowledgment of NCI support. The NCI will have access to
all data generated under this cooperative agreement, will periodically
review the data and may perform special analyses of the data. The
awardees will retain custody and primary rights to the data consistent
with current HHS, PHS, and NIH policies.
k. Intellectual Property
Awardees agree to promptly notify the NCI and the commercial
Collaborator, if appropriate, in writing of any inventions, discoveries
or innovations made by the Awardees' investigators or any other
employees or agents of Awardees, whether patentable or not, which are
conceived and/or first actually reduced to practice in the performance
of this study using the commercial Collaborator's Agent (hereinafter
"Awardee Inventions"). Awardees agree to notify NCI and Collaborator
in writing upon the filing of any patent applications related to the
research with the Agent.
Awardees agree to grant to Collaborator: (i) a paid-up nonexclusive,
nontransferable, royalty-free, world-wide license to all Awardee
Inventions for research purposes only; and (ii) a time-limited first
option to negotiate an exclusive, world-wide royalty-bearing license
for all commercial purposes, including the right to grant sub-licenses,
to all Awardee Inventions on terms to be negotiated in good faith by
Collaborator and Awardees. Collaborator shall notify Awardees, in
writing, of its interest in obtaining an exclusive license to any
Awardee Invention within six (6) months of Collaborator's receipt of
written notice of such Awardee Invention(s). In the event that
Collaborator fails to so notify Awardees, or elects not to obtain an
exclusive license, then Collaborator's option shall expire with respect
to that Awardee Invention, and Awardees will be free to dispose of its
interests in such Awardee Invention in accordance with Awardee
policies. If Awardee and Collaborator fail to reach agreement within
ninety (90) days, (or such additional period as Collaborator and
Awardees may agree) on the terms for an exclusive license for a
particular Awardee Invention, then for a period of six (6) months
thereafter Awardee shall not offer to license the Awardee Invention to
any third party on materially better terms than those last offered to
Collaborator without first offering such terms to Collaborator, in
which case collaborator shall have a period of thirty (30) days in
which to accept or reject the offer.
Awardees agree that notwithstanding anything herein to the contrary,
any inventions, discoveries or innovations, whether patentable or not,
which are not Subject Inventions as defined in 35 USC 201(e),* arising
out of any unauthorized use of the Collaborator's Agent and/or any
modifications to the Agent, shall be the property of the Collaborator
(hereinafter "Collaborator Inventions"). Awardees will promptly notify
the NCI and Collaborator in writing of any such Collaborator Inventions
and, at Collaborator's request and expense, Awardees will request
permission from the NIH*, if necessary, to cause to be assigned to
Collaborator all right, title and interest in and to any
such Collaborator Inventions and provide Collaborator with reasonable
assistance to obtain patents (including causing the execution of any
invention assignment or other documents). Awardees may also be
conducting other more basic research using the Agent under the
authority of a separate Material Transfer Agreement (MTA), or other
such agreement with the NCI or Collaborator. Inventions arising there
under shall be subject to the terms of the separate MTA, and not to
this clause.
* 35 USC 201 (e): The term 'subject invention' means any invention of
the contractor conceived or first actually reduced to practice in the
performance of work under a funding agreement: Provided, That in the
case of a variety of plant, the date of determination (as defined in
section 41(d) (FOOTNOTE 1) of the Plant Variety Protection Act (7
U.S.C. 2401(d))) must also occur during the period of contract
performance.
2. NCI Staff Responsibilities
It is expected that the dominant role and prime responsibility for the
activity will reside with the awardee(s) for the project as a whole,
although specific tasks and activities in carrying out the studies will
be shared among the awardees and the NCI Scientific Coordinator who
will provide expert advice to the awardee on specific scientific and/or
analytic issues as described below.
The NCI Program Director will be the contact point for interactions
with the awardee related to monitoring of the award. The NCI Program
Director will also serve in a back-up role for the NCI Scientific
Coordinator. An Investigational Drug Branch Senior Clinical
Investigator is assigned to each DCTD IND agent to assist in the
coordination of its development.
The role of CTEP staff as described throughout these terms and
conditions of award is to facilitate and assist but not to direct
research activities. This cooperative agreement is part of a larger
program of investigational agent development in the NCI. Each of the
CTEP staff listed below has very specific and well-defined
responsibilities in terms of investigational agent development and the
role of DCTD as a drug sponsor as defined in CFR 21 Part 312.
In general NCI staff will be expected to serve as a resource with
respect to other ongoing NCI activities that may be relevant to the
protocol to facilitate compatibility and avoid unnecessary duplication
of effort. NCI staff will provide advice in the management and
technical performance of the investigations, coordinating clearances
for investigational agents held by NCI. NCI staff will also review and
approve protocols to insure they are within the scope of peer review
and for safety considerations, as required by Federal regulations. NCI
staff will monitor protocol progress, and may request that a protocol
study be closed to accrual for reasons described below (see CTEP
Involvement in Protocol Closure).
Specific NCI responsibilities include:
a. Provision of NCI-sponsored Investigational Agents and
Responsibilities of IND Sponsor
CTEP will supply some of the investigational agents to be studied and
will be the IND Sponsor for these agents. CTEP will submit
Investigational New Drug Applications to the FDA permitting DCTD to act
as a drug sponsor. As a sponsor of an investigational drug, DCTD, and
specifically CTEP, is responsible for seeing that clinical trials
proceed safely and rationally from the initial dose-finding studies
through the definitive evaluation of the new drug in the treatment of
one or more specific cancers.
b. CTEP as a Scientific Resource for NCI-supported Phase I and II
Clinical Investigations and CTEP Assistance in Protocol Development
The NCI Scientific Coordinator and the responsible Investigational Drug
Branch investigator will serve as a resource available to the Principal
Investigator (PI) for specific scientific information with respect to
treatment regimens and clinical trial design. The NCI Scientific
Coordinator and/or responsible Investigational Drug Branch investigator
will advise the PI of potential studies that will be relevant to new
avenues of cancer therapy. The NCI Scientific Coordinator and/or the
responsible Investigational Drug Branch investigator will work
collaboratively with the PI and Protocol Chairperson to define the
objectives and experimental approaches. The NCI Scientific Coordinator
and/or responsible Investigational Drug Branch investigator will assist
the PI as appropriate in developing information concerning the
scientific basis for specific trials and also will advise the PI of the
nature and results of relevant trials being carried out under NCI
sponsorship. The NCI Scientific Coordinator and/or responsible
Investigational Drug Branch investigator will also provide updated
information on the efficacy and toxicity of investigational new agents
supplied to the PI under an Investigational New Drug (IND) Application
sponsored by the DCTD. CTEP provides each investigator working with
agents under CTEP IND with copies of all serious adverse event reports
filed with the FDA for that agent. Because several portions of
protocols are based on generic information about the agent under study,
the Investigational Drug Branch investigator will endeavor to provide
protocol templates with agent specific information and other generic
information to the investigators. This facilitates both protocol
writing and protocol review.
c. Protocol Review
The CTEP Protocol Review Committee (PRC), must review and approve every
protocol proposed for the CNSCs, whether or not they involve DCTD
investigational agents. The PRC, which meets weekly, is chaired by the
Associate Director, CTEP, and is comprised of professional staff of the
DCTD including the Investigational Drug Branch investigators, Clinical
Investigations Branch disease coordinators, biostatisticians, Radiation
Research Program staff, and NCI experts in surgery, diagnostic
radiology, and cancer biomarker research, regulatory staff, pharmacy
staff and ad hoc reviewers external to NCI when deemed appropriate by
the PRC chairperson. The major considerations include: 1) the
strength of the scientific rationale supporting the study; 2) the
medical importance of the question being posed; 3) the probability that
the trial design will provide a clear answer to the questions posed, 4)
the avoidance of unnecessary duplication with other ongoing studies; 5)
the appropriateness of study design with respect to development of any
IND agent; 6) a satisfactory projected accrual rate and follow-up
period; 7) patient safety; 8) plans for compliance and track record of
compliance with federal regulatory requirements; 9) adequacy of data
management; 10) appropriateness of patient selection, evaluation,
assessment of toxicity, response to therapy and follow-up 11) clarity
of methods and quality assurance measures for correlative studies
Following the review of the protocol by the PRC, the responsible
Investigational Drug Branch investigator will provide the PI with a
consensus review. The consensus review summarizes the PRC review and
describes required or recommended modifications and other suggestions,
as appropriate. (See the INVESTIGATOR'S HANDBOOK, for further
information regarding protocol review at CTEP).
If a proposed protocol is disapproved, the specific reasons for lack of
approval will be communicated to the PI as a consensus review within 30
days of protocol receipt by the NCI. The NCI Scientific Coordinator
and/or responsible Investigational Drug Branch investigator will be
available to assist the PI in developing a mutually acceptable
protocol, consistent with the research interests, abilities and
strategic plans of the PI and of the NCI. An arbitration system, as
detailed below, will be available to resolve disagreements between the
NCI and the awardee.
NCI will not provide investigational agents or permit expenditure of
NCI funds for a protocol that it has not approved unless CTEP's
disapproval has been modified by the arbitration process outlined
below.
The PRC will also formally review Letters of Intent (LOI) for CTEP-
supplied investigational agents. Following LOI review, the responsible
Investigational Drug Branch investigator will provide a Program
response to the PI and will address the following issues for approved
LOI: 1) the existence and nature of concurrent clinical trials in the
area of research, pointing out possible duplication of effort; 2)
information including relevant pharmacokinetic and pharmacodynamic data
concerning investigational agents; 3) availability of investigational
agents; 4) the scientific rationale and value of the proposed study,
the design, the statistical requirements; 5) the projected accrual
rate; 6) correlative laboratory studies; and 7) the implementation of
the study, if indicated. The LOI mechanism is designed for preliminary
review and is recommended to expedite protocol development and
implementation, to avoid duplication and to facilitate agreement on
study priority and design (see the DCTD INVESTIGATORS HANDBOOK,
available at web site http://ctep.cancer.gov/handbook/.
d. CTEP Review of Federally Mandated Regulatory Requirements
The NCI Scientific Coordinator and/or the Chief, Regulatory Affairs
Branch (RAB), CTEP, will advise investigators of specific requirements
and changes in requirements concerning IND sponsorship that the FDA may
mandate. Investigators performing trials under cooperative agreements
will be expected, in cooperation with the NCI, to comply with all FDA
monitoring and reporting requirements for investigational agents. The
NCI Scientific Coordinator and/or the Chief, RAB, CTEP, will advise the
investigators of the specific clinical information that will be needed
from the clinical trials for that information to be acceptable to the
FDA for inclusion in a new drug application (NDA).
The Chief, Clinical Trials Monitoring Branch (CTMB) will review
protocols to determine if the awardee's mechanisms for meeting FDA
regulatory requirements for studies involving DCTD-sponsored
investigational agents and the Office Human Research Protection (OHRP)
requirements for the protection of human subjects are sufficient.
These comments are incorporated into the protocol consensus review.
(See Awardee's Rights and Responsibilities).
As sponsor for investigational agents and the funding agency for cancer
clinical trials, FDA regulations require the DCTD to maintain a
monitoring program. Furthermore, DHHS regulations require monitoring
plans for all clinical trials done under NIH sponsorship. The NCI must
ensure that research data generated under its sponsorship are of high
quality, reliable and verifiable. On-site monitoring is a requirement
for investigators conducting clinical trials under NCI sponsorship. The
Clinical Trials Monitoring Branch of CTEP provides direct oversight of
the monitoring programs which includes auditing. The purpose of the
audit is to document the accuracy of submitted data and to verify
investigator's compliance with protocol and regulatory requirements.
One of the objectives of conducting site visits is to bring the FDA
regulatory requirements which affect various aspects of the conduct of
clinical studies to the attention of individual investigators. The
examination/audit will include, but may not be limited to the
following:
1) Full and non-contingent Institutional Review Board (IRB) approvals
and reapprovals; 2) copies of the IRB approval, including approvals
for all amendments; 3) copies of the annual reports on the progress of
the study and copies of IRB reapprovals for studies continuing beyond
the first anniversary of the IRB approval date; 4) written informed
consent obtained on the form approved by the IRB and the documentation
of written informed consent for all the patients entered onto a study.
The informed consent form signed by the patient at the time of study
entry must be the most current version available from the IRB; 5)
adherence to the protocol details; 6) adverse events and medical
records to review classification of adverse experiences and the
reporting to the IRB and the NCI of unusual or unexpected events, as
well as events defined as requiring expedited reporting (serious and
unexpected events) and all adverse events reported in case report
forms; 7) record keeping and record retention in accordance with the
regulatory requirements; 8) investigational agent accountability.
e. CTEP Involvement in Protocol Closure
The NCI Scientific Coordinator and/or responsible Investigational Drug
Branch investigator and the Chief, CTMB will monitor protocol progress.
The NCI Program Director or the responsible Investigational Drug Branch
investigator may request that a protocol be closed to accrual for
reasons including: 1) insufficient accrual rate; 2) accrual goal met;
3) poor protocol performance; 4) patient safety and regulatory
concerns; 5) study results are already conclusive; 6) emergence of new
information that diminishes the scientific importance of the study
question; and 7) failure to collect or transmit data in a timely
manner. NCI will not provide investigational agents or permit
expenditures of NCI funds for a study after requesting closure (except
for patients already on-study). If disagreements develop over NCI-
recommended study closure for reasons other than patient safety or
regulatory concerns, NCI will establish an arbitration process to
resolve disagreements between the NCI and the awardee.
f. Access to Data
The NCI will have real-time access to all data generated under this
cooperative agreement, will periodically review the data and may
perform special data analyses. Data must also be available for
external monitoring as required by NCI's Drug Master File Agreement
with the FDA relative to the responsibility of the NCI as an IND agent
sponsor. The awardee will retain custody of and primary rights to the
data consistent with current HHS, PHS, and NIH policies.
g. CTEP Review of Progress
Progress will be reviewed annually by the NCI Scientific Coordinator
and the NCI Program Director on the basis of the information provided
at the semi-annual meetings, in the continuation application, and in
the study summary reports submitted to CTEP via CDUD or CTMS. In
addition, periodic accrual information may be requested from the PI by
the NCI Program Director for all active studies when deemed
appropriate.
Insufficient patient accrual or progress, or noncompliance with the
terms of award, including these Special Terms and Conditions of Award,
may result in a reduction of budget, withholding of support, suspension
or termination of the award.
3. Collaborative Responsibilities
Steering Committee
The Steering Committee for each CNSC will be composed of the Group
Leader, Principal Investigators of Participant Member Institutions, and
NCI Scientific Coordinator. The Group Leader will serve as Chairperson
of the Steering Committee. He/she is responsible for coordinating the
Committee activities, for preparing meeting agendas, and for scheduling
and chairing meetings. The Steering Committee has primary
responsibility to design research activities, establish priorities, and
develop and provide preliminary approval of protocols (prior to
submission to NCI and final NCI approval). The Steering Committee will
also authorize the spending of funds from the Discretionary Fund.
Appropriate uses may include funding for pilot laboratory studies,
shipment of specimens, and supplementing existing budgets for patient
accrual and auditing of clinical trials. The Steering Committee
Chairperson will document actions taken and progress in written reports
to the NCI Program Director, and will provide periodic supplementary
reports to designated NCI staff upon request.
The collaborative protocols will be developed by the Steering
Committee. Data will be submitted centrally to the Central Operations
Office/Coordinating Center. Protocols will define rules regarding
access to data and publications. Awardees will be required to accept
and implement the common protocol and procedures approved by the
Steering Committee.
An independent advisory board can be helpful in assisting the consortia
in prioritizing their programs, in serving as an independent monitoring
committee for particularly challenging studies, etc.
4. Arbitration
Any disagreement that may arise on scientific/programmatic matters
(within the scope of the award), between award recipients and the NCI
may be brought to arbitration. An arbitration panel will be composed
of three members - one selected by the Steering Committee (with the NCI
representation not voting) or by the individual awardee in the event of
an individual disagreement, a second member selected by NCI, and the
third member selected by the two prior selected members. This special
arbitration procedure in no way affects the awardee's right to appeal
an adverse action that is otherwise appealable in accordance with the
PHS regulations at 42 CFR Part 50, Subpart D and HHS regulation at 45
CFR Part 16.
WHERE TO SEND INQUIRIES
We encourage inquiries concerning this RFA and welcome the opportunity
to answer questions from potential applicants. Inquiries may fall into
three areas: scientific/research, peer review, and financial or grants
management issues:
Direct your questions about scientific/research issues to:
Richard Kaplan, M.D.
(NCI CNSC Scientific Coordinator)
Chief, Clinical Investigations Branch
Cancer Therapy Evaluation Program
Division of Cancer Therapy and Diagnosis
6130 Executive Boulevard, Room 7025, MSC 7436
Bethesda, MD 20892-7436
Telephone: (301) 496-2522
FAX: (301) 402-0557
Email: kaplanr@ctep.nci.nih.gov
or
Steven Krosnick, M.D.
(NCI CNSC Program Director)
Clinical Grants and Contracts Branch
Cancer Therapy Evaluation Program
Division of Cancer Therapy and Diagnosis
6130 Executive Boulevard, Room 7009, MSC 7432
Bethesda, MD 20892-7432
Telephone: (301) 496-8866
FAX: (301) 480-4663
Email: krosnicks@ctep.nci.nih.gov
Direct your questions about peer review issues to:
Referral Officer
Division of Extramural Activities
National Cancer Institute
6116 Executive Boulevard, Room 8041, MSC 8329
Bethesda, MD 20892-8329
Telephone: (301) 496-3428
FAX: (301) 402-0275
Email: ncirefof@dea.nci.nih.gov
Direct your questions about financial or grants management matters to:
Ms. Kelli Oster
National Cancer Institute
Executive Plaza South, Room 243
6120 Executive Boulevard MSC 7150
Bethesda, MD 20892-7150
Telephone: (301) 496-8627
FAX: (301) 496-8601
E-mail: ko31u@nih.gov
LETTER OF INTENT
Prospective applicants are asked to submit a letter of intent that
includes the following information:
o Descriptive title of the proposed research (indicate whether the
application represents the Central Operations Office/Coordinating
Center, the Pharmacokinetics Center, or a Participant Member
Institution providing patient resources)
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel
o Participating institutions (included under the application, not the
CNSC as a whole)
o Number and title of this RFA
Although a letter of intent is not required, is not binding, and does
not enter into the review of a subsequent application, the information
that it contains allows NCI staff to estimate the potential review
workload and plan the review.
The letter of intent is to be sent by the date listed at the beginning
of this document. The letter of intent should be sent to:
Steven Krosnick, M.D.
(NCI CNSC Program Director)
Clinical Grants and Contracts Branch
Cancer Therapy Evaluation Program
Division of Cancer Therapy and Diagnosis
6130 Executive Boulevard, Room 7009, MSC 7432
Bethesda, MD 20892-7432
Telephone: (301) 496-8866
FAX: (301) 480-4663
Email: krosnicks@ctep.nci.nih.gov
SUBMITTING AN APPLICATION
Applications must be prepared using the PHS 398 research grant
application instructions and forms (rev. 5/2001). The PHS 398 is
available at https://grants.nih.gov/grants/funding/phs398/phs398.html in
an interactive format. For further assistance contact GrantsInfo,
Telephone (301) 710-0267, Email: GrantsInfo@nih.gov.
USING THE RFA LABEL: The RFA label available in the PHS 398 (rev.
5/2001) application form must be affixed to the bottom of the face page
of the application. Type the RFA number on the label. Failure to use
this label could result in delayed processing of the application such
that it may not reach the review committee in time for review. In
addition, the RFA title and number must be typed on line 2 of the face
page of the application form and the YES box must be marked. The RFA
label is also available at:
https://grants.nih.gov/grants/funding/phs398/label-bk.pdf.
SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten
original of the application, including the Checklist, and three signed
photocopies, in one package to:
Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710
Bethesda, MD 20817 (for express/courier service)
At the time of submission, two additional copies of the application
must be sent to:
Referral Officer
Division of Extramural Activities
National Cancer Institute
6116 Executive Blvd., Room 8041, MSC-8329
Rockville, MD 20852 (express courier)
Bethesda MD 20892-8329
APPLICATIONS HAND-DELIVERED BY INDIVIDUALS TO THE NATIONAL CANCER
INSTITUTE WILL NO LONGER BE ACCEPTED. This policy does not apply to
courier deliveries (i.e. FEDEX, UPS, DHL, etc.)
(https://grants.nih.gov/grants/guide/notice-files/NOT-CA-02-002.html)
This change in practice is effective immediately. This policy is
similar to and consistent with the policy for applications addressed to
Centers for Scientific Review as published in the NIH Guide Notice
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-012.html.
APPLICATION PROCESSING: Applications must be received by the
application receipt date listed in the heading of this RFA. If an
application is received after that date, it will be returned to the
applicant without review.
The Center for Scientific Review (CSR) will not accept any application
in response to this RFA that is essentially the same as one currently
pending initial review, unless the applicant withdraws the pending
application. The CSR will not accept any application that is
essentially the same as one already reviewed. This does not preclude
the submission of substantial revisions of applications already
reviewed, but such applications must include an Introduction addressing
the previous critique.
PEER REVIEW PROCESS
Upon receipt, applications will be reviewed for completeness by the CSR
and for responsiveness by the NCI program staff.
Incomplete applications will be returned to the applicant without
further consideration. Applications that are complete and responsive
to the RFA will be evaluated for scientific and technical merit by an
appropriate peer review group convened by the Division of Extramural
Activities (DEA) at NCI in accordance with the review criteria stated
below. As part of the initial merit review all applications will:
o Receive a written critique
o Undergo a process in which only those applications deemed to have the
highest scientific merit, generally the top half of the applications
under review, will be discussed and assigned a priority score
o Receive a second level review by the National Cancer Advisory Board.
REVIEW CRITERIA
The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.
In the written comments, reviewers will be asked to discuss the
following aspects of an application in order to judge the likelihood
that the proposed research will have a substantial impact on the
pursuit of these goals:
o Significance
o Approach
o Innovation
o Investigator
o Environment
The scientific review group will address and consider each of these
criteria in assigning an application's overall score, weighting them as
appropriate for each application and type of submission (i.e., Central
Operations Office/Coordinating Center, the Pharmacokinetics Center, or
Participant Member Institutions providing patient resources). An
application does not need to be strong in all categories to be judged
likely to have major scientific impact and thus deserve a high priority
score. For example, you may propose to carry out important work that
by its nature is not innovative but is essential to move a field
forward.
(1) SIGNIFICANCE: Does the research plan address an important problem?
If the aims of the application are achieved, how do they advance
scientific knowledge? What will be the effect of these studies on the
concepts or methods that drive this field?
(2) APPROACH: Are the conceptual framework, design, methods, and
analyses adequately developed, scientifically meritorious, well
integrated, feasible and appropriate to the aims of the multi-
institutional project? Are potential problem areas acknowledged and
alternative tactics considered? Are there plans for effective
collaboration between laboratory and clinical investigators and the
Central Operations Office/Coordinating Center within the consortium as
well as with outside groups such as other consortia and NCI researchers
focusing on CNS tumors? Within the CNSC, though not necessarily at
each institution, is there a plan for developing one or more laboratory
programs that can utilize the resources provided by the CNSC's clinical
trials? Is there an established plan for prioritization and
distribution of specimens to collaborating laboratories?
Does the Center Operations Office/Coordinating Center demonstrate
effective plans for administration, experimental design, quality
control, study monitoring, data management and reporting, statistical
analysis, and compliance with regulatory requirements?
Do Participant Member Institutions conducting clinical trials
demonstrate plans for accrual, care, and follow-up of sufficient
numbers of evaluable patients for CNSC Phase I and II clinical trials?
Additionally, are there plans for data collection and data transfer to
the Central Operations Office/Coordinating Center? Do Participant
Member Institutions conducting clinical trials also demonstrate plans
for pathology support for tumor classification as well as distribution
of patient specimens for concurrent and future studies?
Does the Pharmacokinetics Center demonstrate the feasibility and
scientific merit of proposed studies and of plans to carry out
pharmacokinetic analyses in a timely and effective manner?
(3) INNOVATION: Does the application propose novel concepts,
strategies, approaches, or methods? Are the aims original and
innovative? Does the project challenge existing paradigms or develop
new methodologies or technologies? (It is understood that dose finding
and efficacy-seeking clinical trials may not be innovative. However,
innovative study designs may be proposed that consider the unique
biology and environment of high-grade gliomas within the central
nervous system. Also, proposed correlative studies may use innovative
approaches to better understand the mechanism of action of an
intervention as well as for the evaluation or prediction of patient
response.)
(4) INVESTIGATOR: Are the Group Leader, Principal Investigators, and
the key personnel appropriately trained and well suited to carry out
this work? Are the qualifications and research experience of the Group
Leader, Principal Investigators, and the key personnel appropriate for
the respective design and administration of multi-institutional
clinical, pharmacokinetic, and correlative laboratory oncology studies?
Is there evidence of commitment of the Group Leader, of each Principal
Investigator and of multidisciplinary key personnel to the goals of the
CNSC?
(5) ENVIRONMENT: Does the scientific environment in which the proposed
work will be done contribute to the probability of success? Do the
proposed experiments take advantage of unique features of the
scientific environment or employ useful collaborative arrangements? Is
there evidence of institutional support?
Does the Central Operations Office/Coordinating Center demonstrate
adequacy of the available facilities, data management resources, and
personnel? Does the Central Operations Office/Coordinating Center also
demonstrate evidence of the competence with regard to administration,
experimental design, quality control, study monitoring, data management
and reporting, statistical analysis, and compliance with regulatory
requirements?
Do both the Central Operations Office/Coordinating Center and
participant Member Institutions conducting clinical trials demonstrate
access to sufficient numbers of evaluable patients with gliomas for
Phase I and II clinical trials, the capacity to follow these patients
successfully, and access to adequately processed tissue samples from a
proportion of these patients?
Do Participant Member Institutions conducting clinical trials
demonstrate adequate expertise in the areas of medical or neuro-
oncology, surgery, radiation oncology, imaging, pathology, and data
management to carry out and/or care for patients on clinical trials?
Is there adequate state-of-the-art radiotherapy and imaging equipment?
(The availability of equipment for stereotactic radiosurgery and
brachytherapy as well as MRS, PET and other advanced imaging techniques
will be considered favorable additional assets for a Participant Member
Institution conducting clinical trials, although not required for this
application.)
Does the Pharmacokinetics Center demonstrate adequacy of equipment and
resources to carry out pharmacokinetic analyses in a timely and
effective manner, as well as appropriate experience of the personnel?
ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your
application will also be reviewed with respect to the following:
PROTECTIONS: The adequacy of the proposed protection for humans,
animals, or the environment, to the extent they may be adversely
affected by the project proposed in the application.
INCLUSION: The adequacy of plans to include subjects from both
genders, all racial and ethnic groups (and subgroups), and children as
appropriate for the scientific goals of the research. Plans for the
recruitment and retention of subjects will also be evaluated. (See
Inclusion Criteria included in the section on Federal Citations, below)
DATA SHARING: The adequacy of the proposed plan to share data.
BUDGET: The reasonableness of the proposed budget and the requested
period of support in relation to the proposed research.
RECEIPT AND REVIEW SCHEDULE
o Letter of Intent Receipt Date: February 21, 2003
o Application Receipt Date: March 28, 2003
o Peer Review Date: June-July 2003
o Council Review: September 2003
o Earliest Anticipated Start Date: December 2003
AWARD CRITERIA
Award criteria that will be used to make award decisions include:
o Scientific merit (as determined by peer review)
o Availability of funds
o Programmatic priorities.
REQUIRED FEDERAL CITATIONS
MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research
components involving Phase I and II clinical trials must include
provisions for assessment of patient eligibility and status, rigorous
data management, quality assurance, and auditing procedures. In
addition, it is NIH policy that all clinical trials require data and
safety monitoring, with the method and degree of monitoring being
commensurate with the risks (NIH Policy for Data Safety and Monitoring,
NIH Guide for Grants and Contracts, June 12, 1998:
https://grants.nih.gov/grants/guide/notice-files/not98-084.html).
Clinical trials supported or performed by NCI require special
considerations. The method and degree of monitoring should be
commensurate with the degree of risk involved in participation and the
size and complexity of the clinical trial. Monitoring exists on a
continuum from monitoring by the principal investigator/project manager
or NCI program staff or a Data and Safety Monitoring Board (DSMB).
These monitoring activities are distinct from the requirement for study
review and approval by an Institutional review Board (IRB). For
details about the Policy for the NCI for Data and Safety Monitoring of
Clinical trials see:
http://deainfo.nci.nih.gov/grantspolicies/datasafety.htm. For Phase I
and II clinical trials, investigators must submit a general description
of the data and safety monitoring plan as part of the research
application. See NIH Guide Notice on "Further Guidance on a Data and
Safety Monitoring for Phase I and II Trials" for additional information:
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html.
Information concerning essential elements of data safety monitoring plans
for clinical trials funded by the NCI is available:
http://www.cancer.gov/clinical_trials/.
INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the
policy of the NIH that women and members of minority groups and their
sub-populations must be included in all NIH-supported clinical research
projects unless a clear and compelling justification is provided
indicating that inclusion is inappropriate with respect to the health
of the subjects or the purpose of the research. This policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43).
All investigators proposing clinical research should read the AMENDMENT
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in
Clinical Research - Amended, October, 2001," published in the NIH Guide
for Grants and Contracts on October 9, 2001
(https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a
complete copy of the updated Guidelines are available at
https://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_
2001.htm. The amended policy incorporates: the use of an NIH
definition of clinical research; updated racial and ethnic categories
in compliance with the new OMB standards; clarification of language
governing NIH-defined Phase III clinical trials consistent with the new
PHS Form 398; and updated roles and responsibilities of NIH staff and
the extramural community. The policy continues to require for all NIH-
defined Phase III clinical trials that: a) all applications or
proposals and/or protocols must provide a description of plans to
conduct analyses, as appropriate, to address differences by sex/gender
and/or racial/ethnic groups, including subgroups if applicable; and b)
investigators must report annual accrual and progress in conducting
analyses, as appropriate, by sex/gender and/or racial/ethnic group
differences.
REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS:
NIH policy requires education on the protection of human subject
participants for all investigators submitting NIH proposals for
research involving human subjects. You will find this policy
announcement in the NIH Guide for Grants and Contracts Announcement,
dated June 5, 2000, at
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.
A continuing education program in the protection of human participants
in research in now available online at: http://cme.nci.nih.gov/.
HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of
research on hESCs can be found at
https://grants.nih.gov/grants/stem_cells.htm and at
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.
Guidance for investigators and institutional review boards regarding
research involving human embryonic stem cells, germ cells, and stem
cell-derived test articles can be found at
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-044.html.
Only research using hESC lines that are registered in the NIH Human
Embryonic Stem Cell Registry will be eligible for Federal funding (see
http://escr.nih.gov). It is the responsibility of the applicant to
provide the official NIH identifier(s)for the hESC line(s) to be used
in the proposed research. Applications that do not provide this
information will be returned without review.
PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT:
The Office of Management and Budget (OMB) Circular A-110 has been
revised to provide public access to research data through the Freedom
of Information Act (FOIA) under some circumstances. Data that are (1)
first produced in a project that is supported in whole or in part with
Federal funds and (2) cited publicly and officially by a Federal agency
in support of an action that has the force and effect of law (i.e., a
regulation) may be accessed through FOIA. It is important for
applicants to understand the basic scope of this amendment. NIH has
provided guidance at
https://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.
Applicants may wish to place data collected under this RFA in a public
archive, which can provide protections for the data and manage the
distribution for an indefinite period of time. If so, the application
should include a description of the archiving plan in the study design
and include information about this in the budget justification section
of the application. In addition, applicants should think about how to
structure informed consent statements and other human subjects
procedures given the potential for wider use of data collected under
this award.
URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and
proposals for NIH funding must be self-contained within specified page
limitations. Unless otherwise specified in an NIH solicitation,
Internet addresses (URLs) should not be used to provide information
necessary to the review because reviewers are under no obligation to
view the Internet sites. Furthermore, we caution reviewers that their
anonymity may be compromised when they directly access an Internet
site.
HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to
achieving the health promotion and disease prevention objectives of
"Healthy People 2010," a PHS-led national activity for setting priority
areas. This RFA is related to one or more of the priority areas.
Potential applicants may obtain a copy of "Healthy People 2010" at
http://www.health.gov/healthypeople/.
AUTHORITY AND REGULATIONS: This program is described in the Catalog of
Federal Domestic Assistance No. 93.395 and is not subject to the
intergovernmental review requirements of Executive Order 12372 or
Health Systems Agency review. Awards are made under authorization of
Sections 301 and 405 of the Public Health Service Act as amended (42
USC 241 and 284) and administered under NIH grants policies described
at https://grants.nih.gov/grants/policy/policy.htm and under Federal
Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.
The PHS strongly encourages all grant recipients to provide a smoke-
free workplace and discourage the use of all tobacco products. In
addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits
smoking in certain facilities (or in some cases, any portion of a
facility) in which regular or routine education, library, day care,
health care, or early childhood development services are provided to
children. This is consistent with the PHS mission to protect and
advance the physical and mental health of the American people.