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
http://grants.nih.gov/grants/guide/notice-files/not98-084.html
with additional description at 
http://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:  [email protected]

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:  [email protected]

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:  [email protected]

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:  [email protected]

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:  [email protected]

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 http://grants.nih.gov/grants/funding/phs398/phs398.html in 
an interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 710-0267, Email: [email protected].

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: 
http://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.) 
(http://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 
http://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: 
http://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:
http://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 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a 
complete copy of the updated Guidelines are available at 
http://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
http://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 
http://grants.nih.gov/grants/stem_cells.htm and at 
http://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 
http://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 
http://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 http://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.

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