EARLY CLINICAL TRIALS OF NEW ANTI-CANCER AGENTS WITH PHASE I EMPHASIS

Release Date:  November 19, 2001

RFA:  RFA-CA-02-011
 
National Cancer Institute
 
Letter of Intent Receipt Date:  February 14, 2002
Application Receipt Date:       March 21, 2002

This RFA is a reissue of RFA-CA-97-001 that was published in the NIH Guide on 
November 22, 1996.

PURPOSE
 
The purpose of this Request for Applications (RFA) is to provide funding to 
assess novel agents available through the NCI in early clinical, dose finding 
trials.  This initiative"s major objective is the timely completion of trials 
of promising anti-cancer agents and combinations of agents to establish safe 
and biologically active treatment schedules for patients with cancer and to 
establish proof of principle for new agents directed at novel molecular 
targets.  Most of these trials will include pharmacokinetic assessment.  Many 
of these trials will include assessment of drug exposure and effect.  These 
assessments may provide an understanding of the relationship between the 
drug"s doses and schedules and its effects.  

This RFA invites investigators to form teams of investigators and support 
staff to propose, develop, perform and analyze the results of early clinical 
trials.  These teams should include clinical investigators with expertise in 
the performance of early clinical trials, collaborating with researchers with 
expertise in clinical pharmacology and translational correlative studies as 
well as support staff.  Single Institution Phase I studies are preferred, 
although laboratory studies may be conducted with collaborators at other 
institutions.  Strong justification, evidence of well-established 
collaborations and clearly described procedures must be supplied for multi-
institutional applications. 

RESEARCH OBJECTIVES 

A.  Background 

Increasing numbers of anticancer agents, many of them developed to address 
newly identified molecular targets, are reaching clinical testing (from a 
total of 215 agents in trial for cancer in 1995 to 316 in 1997 to 402 in 
2000). An effective early clinical trials program must be able to evaluate 
these new approaches rapidly, conduct trials safely, and establish potentially 
useful doses and schedules for further evaluation.  In addition, early proof 
of principle trials will be used to assess the validity of the target and 
optimize drug administration regimens to produce expected effects on the 
putative targets or downstream processes. The increasing numbers of promising 
new agents with diverse and novel, but unproven mechanisms of action makes it 
desirable to continue NCI support in this area.

The discovery of specific molecular pathways and their exploitation in cancer 
drug discovery efforts presents the early clinical trials efforts with 
striking opportunities as well as challenges.  A safe, efficient and 
scientifically sound clinical trials system to evaluate these new treatment 
approaches requires rapid development, conduct and reporting of trials.  
Evaluation of new approaches to phase I studies using appropriate assays, 
tools or probes to provide early proof of principle, judge the validity of the 
target and optimize drug administration regimens are additional required 
elements.

Potential agents for early clinical development using NCI support are now 
evaluated by the Drug Development Group (DDG) with expert review provided by 
non-NCI scientists.  The DDG prioritizes use of NCI resources supporting pre-
clinical development by Developmental Therapeutics Program (DTP) as well as 
clinical development by Cancer Therapy Evaluation program (CTEP).  Agents may 
come to DDG from 1) the Developmental Therapeutics Program, 2) industry, 3) 
academia, and 4) internal NCI laboratories.  For agents approved by the DDG 
for clinical development, CTEP Senior Clinical Investigators (SCI) prepare a 
clinical development plan in collaboration with the originator of the agent, 
and other experts,  file the IND and solicit for, review and monitor protocols 
for phase I (and subsequent) trials.  

NCI currently holds over 150 active investigational new drug applications 
(INDs) for anticancer agents.  For agents originating from the NCI"s 
preclinical Developmental Therapeutics Program as well as from academia,  NCI 
often holds the only IND application. NCI may participate in collaborative 
clinical development of agents derived from pharmaceutical/biotechnology 
industries when co-development is deemed in the best interest of improving the 
treatment of cancer patients via advancing the community"s scientific 
understanding of the approach and extending the possible indications beyond 
those explored by the sponsor in NDA directed trials.  NCI often promotes the 
exploration of important scientific questions which may not be the primary 
focus of industry development, either because of limited industry resources in 
the case of small companies, the need to perform combination studies with 
other investigational agents for which NCI holds an IND, or because of small 
commercial markets due to the relatively low frequency of many human cancers. 
 NCI support facilitates the development of these important agents and 
indications.

The changing size and scope of the program is apparent in the existence of 
collaborative agreements active with approximately 75 industry partners for 
more than 150 of the 402 cancer agents currently in clinical development 
worldwide.  CTEP files approximately 20 IND applications annually, the 
majority are for novel agents in early clinical development. Agents under 
evaluation include small molecules, antibodies, vaccines, targeted toxins, and 
gene transfer agents. The classes of agents that are being studied include 
angiogenesis inhibitors, receptor tyrosine kinase inhibitors, signal 
transduction inhibitors, farnesyl transferase inhibitors, cell cycle 
inhibitors, histone deacetylase inhibitors and other agents to induce 
reexpression of critical genes, agents directed at novel targets such as the  
proteasome,  heat shock protein, and  vaccines as well as cytotoxic  agents 
directed at cell division and immunotoxins.  The phase I cooperative agreement 
has facilitated the development of phase 1 trial designs allowing evaluation 
of accelerated dose escalation, designs incorporating biological endpoints, as 
well as the introduction of tools to assess direct effects on molecular 
targets or their downstream consequences and dose-determining trials in 
patients with organ dysfunction. These and other innovations, such as 
pharmacogenetic studies, and evaluating combinations of investigational agents 
to improve the phase 1 evaluation of anti-cancer agents will be supported 
through this RFA.

This RFA provides an opportunity for clinicians and laboratory investigators 
to utilize their extensive experience and expertise to study investigational 
agents in comprehensive dose finding and proof of principle trials with 
appropriate laboratory, imaging and anatomic clinical correlations.  
Scientific approaches will reflect the interest, creativity and capabilities 
of participants and will frequently be investigator-originated as well as in 
response to solicitations for trials provided by CTEP.  The investigators 
bring to the collaboration their specific biological and pharmacological 
expertise, their ideas concerning research strategies unique to each agent, 
the necessary patient and investigative resources for study of the agent, and 
their data management and analytical abilities.  The investigators will help 
define the scientific objectives and experimental approaches consistent with 
the goals of early clinical trials. 

The Principal Investigators of these awards, the NCI Program Director(s) and 
CTEP Senior Clinical Investigators (SCI) will be members of an early clinical 
trials network.  This group of investigators has traditionally met at 
semiannual meetings.  Additional activities and responsibilities for a more 
formalized network may be proposed as part of this application (See 
Application Procedures).

In addition to the funding assistance offered to the investigator(s) by this 
RFA, NCI will sponsor or co-sponsor the agents under development in accordance 
with Food and Drug Administration requirements.  As sponsor of an 
investigational drug, DCTD and specifically, CTEP, is responsible for ensuring 
that clinical trials proceed safely and rationally from the initial 
dose-finding studies to a definitive evaluation of the role of the new drug in 
the treatment of one or more specific cancer(s).  Fulfillment of this goal 
obviously requires the active participation of CTEP staff throughout the 
entire process.  As supplier of the agents and holder of the IND of the 
investigational agents to be studied, CTEP has very specific and well defined 
responsibilities in terms of investigational agent development in its role as 
a drug sponsor as defined in CFR 21 Part 312.   An Investigational Drug Branch 
(IDB) Senior Clinical Investigator (SCI) is assigned to each CTEP IND to 
assist in the coordination of the agent"s development.   To ensure the 
fulfillment of these responsibilities of sponsorship, participation by NCI in 
the conduct of the trials is necessary since these agents are in an early 
stage of development and new information related to the agent must be rapidly 
communicated between investigators using the agents and the NCI, FDA and other 
industry partners.  The NCI will provide additional coordination by providing 
information regarding NCI priorities, information on ongoing efforts elsewhere 
in the scientific community and information on drug toxicities.  The NCI will 
provide technical assistance, through protocol templates and the protocol 
review and approval process, regarding methodology, feasibility, and adherence 
to regulatory requirements mandated by NCI"s role as a drug sponsor. The 
mechanisms for NCI involvement allow for systematic, safe and efficient 
development of investigational agents.  

B.  Objectives and Scope

Institutions responding to this Request for Applications (RFA) should be able 
to perform dose finding Phase I trials and establish the pharmacological 
characteristics of these agents, in parallel with assays, tools, or probes to 
study the biologic effects of these agents on cancer cells and normal tissues. 
 The investigators are expected to design and perform early dose-finding 
clinical trials of NCI-sponsored anticancer agents, to evaluate the biologic 
effect of NCI-sponsored anticancer agents on their molecular targets and 
determine clinically relevant correlates.  It is expected that 
pharmacokinetics and other laboratory correlative studies will be conducted in 
real-time, throughout the course of the clinical trial, to facilitate optimal 
utilization of the data in the design and coordination of clinical trials with 
the agent.  Applications from any one institution may focus on studies of one 
or more classes of agents or therapeutic approaches, reflecting the interest, 
expertise, and experience of the applicant investigators or a more general 
approach to the pharmacokinetic and pharmacodynamic evaluation of new agents 
may be developed.
 
The objectives of this program are: 

1.  to safely and efficiently conduct dose ranging clinical trials of single 
agents and combinations of novel agents to establish dose, schedule and 
scientific proof of principle for drug effect and establish appropriate doses 
for activity studies, characterize toxicity and pharmacology, and discover the 
scientific basis for subsequent prioritization of development plans for NCI 
sponsored agents of varying classes, many of which are directed at new cancer 
targets,

2. to characterize the effects of new agents on their targets through 
integration of suitable biochemical, pathological, immunologic, molecular or 
imaging methods and correlate those effects with clinically relevant 
endpoints,

3.  to develop new scientific insights into drug mechanisms and determinants 
of response, and

4.  to develop new paradigms suitable for the assessment of  novel agents that 
may not have classical phase 1 endpoints (i.e. toxicity) to guide the 
selection of doses and schedules and to avoid the futility and expense of 
carrying ineffective agents into full scale clinical development

Over the last 20 years the objectives of dose-finding phase I clinical trials 
of cancer therapeutics have been the characterization of drug toxicity, 
maximally tolerated dose and pharmacokinetics of drugs.  Recent advances in 
understanding cancers are leading to the development of a wide range of novel 
anti-cancer therapeutic agents that will undergo initial dose findings 
studies.  These agents include novel cytotoxic agents, as well as agents 
designed to affect novel cancer cell targets.  The target-directed agents may 
exert anti-cancer effects not only through classical cytotoxic mechanisms, but 
also through growth inhibiting mechanisms mediated by interrupting specific 
oncogene-associated biochemical functions, inhibiting protein synthesis, 
inducing differentiation and/or apoptosis, and inhibiting tumor angiogenesis 
and metastasis.  Direct assessment of effects on the target, or downstream 
consequences of drug-target interaction in dose ranging studies may provide 
biologic endpoints of drug activity that can form the basis for dose and 
schedule for subsequent studies.   These assessments may, in fact, be the only 
practicable methods of deciding on appropriate doses and schedules for certain 
drug classes. 

Thus, the goals of dose finding clinical trials of targeted agents should 
include studies that lead to a greater understanding of the relationship 
between drug administration and biological changes in cancer.  Appropriate 
laboratory studies for all dose finding trials of novel agents should include 
pharmacokinetic studies, including monitoring of relevant metabolites and 
intracellular products, or other relevant pharmacology correlative studies, 
when appropriate.  It is expected that these measures will be made in real 
time during the conduct of most dose finding trials.  In addition to 
pharmacokinetic analyses, other laboratory studies may include studies of 
pharmacogenetic variability in drug metabolism or effect.  Novel biochemical, 
pathological, pharmacologic, immunologic, molecular, or imaging methods should 
be incorporated, when available, to measure the effect of new target-directed 
drugs in proof-of-principle clinical trials. These correlative studies should 
characterize effects on agents on their targets, develop new scientific 
insights into drug mechanisms and/or characterize the molecular phenotypes of 
tumors to help identify patients suitable for treatment with specific target-
directed agents

The investigators will propose scientific objectives and experimental 
approaches consistent with the goals of dose finding clinical trials. The 
investigators will identify the specific NCI sponsored agents of interest in 
accordance with their areas of scientific interest and expertise, and will 
develop a series of appropriate trials with supporting protocol documents. 
CTEP will review the protocols and work collaboratively to refine the 
objectives and experimental approaches, have real time access to the data 
generated, will periodically review the data and may perform special analyses 
of the data.  However, the awardees will retain custody and primary rights to 
their data developed under these awards.  Clinical, pharmacokinetic and 
pharmacodynamic data will most commonly be submitted to the NCI"s Clinical 
Trials Monitoring Service every two weeks or, for the minority of trials, to 
the NCI"s CDUS on a monthly or quarterly basis.  Timely publication of 
findings to make information available to the larger scientific community will 
be strongly encouraged.  

Each Phase I awardee must have demonstrated experience in conducting dose 
finding trials with new agents and associated laboratory evaluations. 
Applicants must demonstrate that they have expertise in 1) cancer drug 
development, 2) the clinical management of patients with various cancers, 3) 
the clinical management of patients on phase 1 clinical trials, 4) phase I 
clinical trials methodology, 5) pharmacology, 6) pharmacokinetics and 6) 
pharmacodynamics.  They need to provide evidence of their own expertise, or 
collaborative access to such expertise, in diagnostic and functional imaging, 
interventional radiology, pathology, and other potentially relevant laboratory 
methodologies. Sufficient numbers of patients at the applicant institution 
should be available to allow completion of the trials in a timely manner.  In 
all categories of diseases, the Principal Investigator must select those 
patients for trial with the best performance status and with the minimum 
amount of prior treatment consistent with ethical medical practice. The 
Principal Investigator will ensure that these Phase I trials conform to 
accepted standards of patient care.   For examples of standards to be met, see 
Application Procedures.
 
Each applicant is responsible for coordinating the preparation and submission 
of letters of intent, protocol development and submission, study conduct, 
quality assurance, data management and analysis, adherence to NCI requirements 
for investigational agents, adherence to FDA/DHHS regulations, and reporting 
of data from the Phase I trials.

C.  Related NCI Initiatives

A number of interrelated initiatives have recently been developed or 
implemented to create a cohesive and integrated NCI program in drug discovery 
and clinical development focused on molecularly targeted new agents.  The 
awards for early clinical trials with Phase I emphasis will provide the major 
resource for rapid, efficient, systematic evaluation and determination of 
optimal dose/schedule for specific agents and combinations within the NCI 
portfolio of investigational agents. The following Web sites present detailed 
information on other related NCI initiatives in drug discovery for treatment 
of cancer, clinical trials, and imaging programs that may interact with a 
phase 1 awardee:

Interdisciplinary Research Teams for Molecular Target Assessment: These 
currently fund 4 teams addressing the discovery, development and validation of 
research tools that will make mechanism assessment in clinical trials for 
molecularly targeted agents consistently feasible.  These teams currently 
address agents that inhibit survival signaling, erbB targeted agents, 
antiangiogenic agents and immunomodulation. Promising assays and research 
tools will be incorporated in the early phase clinical trials.

In vivo Cellular and Molecular Imaging Centers:  
http://grants.nih.gov/grants/guide/rfa-files/RFA-CA-99-004.html and the Small-
Animal Imaging Resource Program. Imaging initiatives including: small animal 
imaging, imaging in therapeutic studies, and ICMIC:  Critical imaging 
technologies and tools developed by these initiatives may be used by the phase 
I cooperative agreement investigators.  RFA for imaging in therapeutic studies 
(http://grants.nih.gov/grants/guide/rfa-files/RFA-CA-98-023.html).

QuickTrials Grants (R21):  This mechanism is intended to provide an efficient 
funding mechanism to support hypothesis driven, investigator initiated 
clinical trials that advance the scientific understanding of cancer treatment. 
 This complementary pathway for clinical trials currently supports only 5 
grants with phase I trials of NCI-IND agents.  Correlative studies that 
contribute to elucidation of therapeutic hypotheses may receive support from 
this mechanism in conjunction with trials performed with support from this 
U01.  This mechanism should be considered for support of complementary 
laboratory studies for individual phase I trials under this RFA. 
(http://grants.nih.gov/grants/guide/pa-files/PA-99-070.html).

Translational Research Fund (TRF): The TRF provides an acquisition mechanisms 
(contract) to fund correlative studies characterizing specific effects of new 
agents on their targets in NCI-sponsored early clinical trials, including 
pharmacodynamic studies performed by UO1 investigators under this award.  The 
approved correlative studies must be linked to the clinical trials being 
conducted on NCI-sponsored trials with NCI-IND agents.  The TRF  will acquire 
 personnel time and procedures directly related to the laboratory correlative 
investigations, and the laboratory studies.  Because the type of assays, 
probes and tools may vary widely with the agents tested, these costs are not 
included in the funding under this RFA (see Application Procedures).

SPORES. These mechanisms support molecular target discovery and 
characterization for specific tumor sites,  
(http://spores.nci.nih.gov/)

Cancer Diagnosis Program What"s New (http://www-cdp.ims.nci.nih.gov)

SPECIAL REQUIREMENTS
 
Terms and Conditions of Award 

These special Terms of Award are in addition to and not in lieu of otherwise 
applicable OMB administrative guidelines, HHS Grant Administration Regulations 
at 45 CFR Parts 74 and 92, and other HHS, PHS, and NIH Grant Administration 
policy statements.

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 f the Principal Investigator (PI) 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 PI and to the CTEP Protocol Review Committee (PRC), which 
must review and approve every protocol involving DCTD investigational agents. 

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/industry/industry.html -  see bottom 
of web) 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 on the world wide web 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 

The PI should, with CTEP Assistance, develop letters of intent and protocols 
that define the scientific objectives and experimental approaches for 
anticancer agents under CTEP INDs, including agents identified by the NCI"s 
drug screening program or referred to NCI from other sources, including the 
pharmaceutical and biotechnology industry.  These include:

a)  Anticancer agents with novel mechanisms, including but not limited to:  
inhibitors of signal transduction, cell cycle, angiogenesis and metastasis, 
differentiating agents, gene reexpression agents, apoptosis-inducing agents, 
anti-sense oligonucleotides and related gene-specific therapeutic agents, and 
targeted cytotoxic agents.

b)  Combinations of anticancer agents with novel mechanisms and existing 
chemotherapeutic agents where there is a specific hypothesis and an 
experimental basis for enhanced effect, where drug potential drug interactions 
must be carefully defined, and where the hypothesis that combining the agents 
will produce enhanced effect can be evaluated in dose finding studies or

c)  Detailed evaluation of doses and schedules of novel agents in unique 
patient populations, such as those with abnormal elimination of agents due to 
renal or hepatic injury, those with pharmacogenetic variations in drug 
metabolism or drug effect, or those with other underlying processes that might 
be postulated to alter safety and activity.

c.  Protocol Submission

Submission of protocols for review by PRC should be preceded by a written 
declaration of interest in conducting a particular study from the principal 
investigator 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 must describe the 
hypothesis to be investigated with appropriate references or supporting data, 
the general design of the contemplated trial plus relevant information on 
accrual capabilities, competing trials and prioritization of trials to 
document the feasibility of expeditious completion of the proposed study. The 
LOI must describe the rationale for correlative studies.  If funding for 
supplemental studies has not been secured by the investigator, the LOI must 
indicate that funding will be needed through quick trials, TRF or other 
mechanisms.  If TRF support is sought, a tentative budget and brief budget 
justification must be included in the LOI.   The phase 1 awardee must submit a 
letter of intent (LOI) electronically to the CTEP Protocol and Information 
Office (who receives, logs in and schedules LOIs for review by the PRC) 
declaring interest in conducting a particular clinical study 
([email protected].)  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. (See 
INVESTIGATOR"S HANDBOOK, for a complete description of the LOI process.)  If 
the LOI is approved, the PI must, with CTEP assistance, develop Phase I 
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.

The PI must electronically submit (as .doc or .pdf files) the Phase I 
protocols to CTEP Protocol and Information Office, the receiving office for 
all protocols sent to CTEP, for review as appropriate, prior to their 
implementation.

The PI must designate a Protocol Chairperson for each proposed study.  The PI 
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.  

d.  Protocol Review, Revision and Implementation

Communication between the PI or Protocol Chairperson and CTEP Senior Clinical 
Investigators (SCI) 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 PI 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 co-
sponsor, if any.  Each numbered comment must be addressed point by point in a 
cover letter that accompanies the revised protocol.  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 PI).  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 PI 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 (an Optional Form 310 must be submitted), 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 PI 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). 

e.  Study Conduct and Monitoring

The 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 approval,

2) appropriate patient follow-ups beyond that specified in the protocol e.g. 
after adverse events, progressive disease or patient withdrawal,

3) establishing data management support capabilities that ensure that 
clinical, clinical laboratory, imaging and research laboratory data will be 
submitted via electronic transfer biweekly to NCI"s Clinical Trials Monitoring 
Service (CTMS). This data includes: registration of each patient entered onto 
a Phase I protocol within the previous two week period, and all data obtained 
on each registered patient within the previous two weeks as specified by the 
NCI/DCTD Case Report Form and the individual protocol. 
 
4) 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. 

5) 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,

6) ongoing assessment of patient eligibility and evaluability, 
 
7) timely medical review and assessment of patient data,  by the study 
chairperson and PI Investigator,
 
8) 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], 
 
9) interim evaluation and consideration of measures of outcome, as consistent 
with patient safety and good clinical trials practice, 
 
10) real-time 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

11) 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.

f.  Data Management, Analysis and Reporting

The 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 port 
films and compliance with protocol-specified doses for individual patients, 
where relevant.  Determination of adequacy of radiation delivery with the 
assistance of the Radiological Physics Center (RPC), whose functions usually 
include equipment dosimetry, periodic institutional visits and other aspects 
of physics review.

3) Chemotherapy:  Review of pharmacy orders, 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 PI

7) Reporting of pharmacokinetic results - Pharmacokinetic data results must 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 conclustions of these studies 
to date should be reported to the CTMS or CDUS as determined by the written 
protocol.  Reports of study performance to CTMS/CDUS will be the basis for 
reimbursing invoices under any associated correlative studies funded under 
contract with the Translational Research Fund (TRF).

g.  Investigational Drug Management

Investigators performing trials under cooperative agreements involving a 
Division of Cancer Treatment and Diagnosis (DCTD) investigational agent 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.

h.  Compliance with Federally Mandated Regulatory Requirements 

The 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 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 system for ensuring that the required data is provided biweekly to the 
CTMS.

4) A described system for ensuring that data safety monitoring is performed in 
accordance with NIH requirements

i.  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) The majority of dose finding 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.

A fraction of the trials performed 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 (eg, later 
combination studies) when substantial safety information suggests that 
frequent oversight by the IND sponsor is less critical for patient safety.

3) Adverse Events Reporting 

The Contractor 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.  

Because many antineoplastic agents have a very narrow therapeutic index, and 
many dose finding studies are done with agents being evaluated for the first 
time in patients, toxic effects of treatment commonly accompany drug 
administration.  CTEP has developed operational definitions of Adverse Events 
(AEs) which 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.

4) Pharmacokinetic/Pharmacodynamic and Correlative Laboratory Study Reports

The PI should provide CTEP, via CTMS or CDUS as specified, sample acquisition 
or procedure performance on a biweekly (or quarterly) basis.  The PI must also 
provide actual data in spreadsheet format for the pd/pk/correlative studies.  
At the time a protocol with correlative studies is approved, the schedule for 
delivery of these data will be established. Pharmacokinetic data will be 
reported as it is generated, biweekly to CTMS.  Other data (e.g., imaging 
data) may also be reported biweekly.  For correlative studies analyzed in 
batches, quarterly reporting may be proposed in the protocol.  In special 
cases where these results will affect the prosecution of the study, data may 
be required monthly.  The PI must provide a descriptive report at the 
completion of the study summarizing the accrual to correlative studies, the 
results and conclusions, and problems encountered and recommendations for 
future studies.  Because most correlative studies beyond pharmacokinetics will 
likely be funded outside of the U01 budget itself, via either R21 grants or 
Translational Research Fund (TRF) contracts, timely reporting of acquisition 
of specimens and results will be necessary for reimbursement under a TRF 
subcontract.

5) Annual Progress Reports:

Annual progress reports must be submitted to the NCI in a non-competing 
continuation application. These reports must also be provided as electronic 
spreadsheets.  The spreadsheet must include at a minimum, a list of LOIs 
submitted (Identified by NCI LOI number and title, status of LOI 
(approved/disapproved/on hold), the date the LOI was approved and the date the 
subsequent protocol was submitted.   A second spreadsheet must list the 
protocols submitted activated and completed (identified by NCI protocol number 
and title), the initial protocol submission date, the protocol activation 
date, annual and cumulative accrual to studies and whether the protocol did or 
did not have correlative laboratory studies, as well as a brief interim 
narrative on active and completed studies summarizing the findings to date.  
For trials involving PK and/or correlative studies, the following information 
by trial should be provided: title of correlative study (test or assay or 
imaging procedure), number of samples collected/procedures performed, number 
of samples/procedures analyzed/reported, results, and a progress summary 
including problems and how the data may affect future studies.  Any problems 
that have arisen related to accrual or prosecution of trials should be 
addressed in the annual progress report.  Copies of the most recent annual 
report to the IRB for each study should be included.

6) Final Protocol Report:

For each protocol, a final protocol report is to be submitted.  The draft of a 
manuscript (or manuscripts) for publication is the preferred format for this 
report, which should be provided within 3 months of accrual of the last 
patient for a study.

j. On-site Audits:

The investigators must be available for on-site audits by the Clinical Trials 
Monitoring Service (CTMS) three times each year.  The examination/audit will 
require the following resources at the awardee institution:

1) A physician/ administrator to discuss the institution"s overall 
organizational structure, protocol development, protocol monitoring, patient 
selection and data collection.

2) The PI who will meet with the audit team leader to discuss the protocol(s) 
for audit.

3) An institutional staff member to describe the institution"s chart 
organization, and demonstrate where the auditors would usually find various 
types of data.

4) A workroom with an x-ray view box.  The room must be large enough to 
accommodate the audit team.

5) Inpatient, outpatient and oncology clinic/research records and any computer 
generated printouts.

6) Informed consent documents and IRB documents, including those from 
affiliate sites for patients being reviewed.

7) An inspection of the investigational drug storage area and a responsible 
individual with whom to discuss inventory control methods, agent storing and 
dispensing.  The NCI Drug Accountability Record Forms must be available for 
review.

k.  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 awardee will retain custody and 
primary rights to the data consistent with current HHS, PHS, and NIH policies.

l.  Intellectual Property

Awardee agrees to promptly notify the NCI and the commercial Collaborator, if 
appropriate, in writing of any inventions, discoveries or innovations made by 
the Awardee"s investigator or any other employees or agents of Awardee, 
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").  Awardee agrees to 
notify NCI and Collaborator in writing upon the filing of any patent 
applications related to the research with the Agent.

Awardee agrees 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 Awardee. Collaborator shall 
notify Awardee, 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 Awardee, or elects not to obtain an exclusive license, then 
Collaborator"s option shall expire with respect to that Awardee Invention, and 
Awardee 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 Awardee 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.

Awardee agrees 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").  Awardee will promptly notify the NCI and Collaborator in 
writing of any such Collaborator Inventions and, at Collaborator"s request and 
expense, Awardee 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). Awardee 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  

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.

a.  Provision of NCI-sponsored Investigational Agents and Responsibilities of 
IND Sponsor

CTEP will supply 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 Clinical 
Investigations and CTEP Assistance in Protocol Development

An Investigational Drug Branch (IDB) Senior Clinical Investigator (SCI) is 
assigned to each DCTD IND agent to assist in the coordination of its 
development.  The NCI Program Director    and the responsible IDB SCI 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 Program Director and/or responsible IDB SCI will advise the 
PI of potential studies that will be relevant to new avenues of cancer 
therapy.  The NCI Program Director and/or the IDB SCI will work 
collaboratively with the PI and Protocol Chairperson to define the objectives 
and experimental approaches.  The NCI Program Director and/or responsible IDB 
SCI 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 Program Director and/or responsible IDB SCI 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 IDB SCI 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 involving 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 IDB SCIs, Clinical Investigations Branch 
disease coordinators, biostatisticians, diagnostic experts, regulatory staff, 
pharmacy staff and ad hoc reviewers external to NCI when deemed appropriate by 
the PRC chairperson.  

The PRC will formally review the Letter of Intent (LOI).  Following LOI 
review, the responsible IDB SCI will provide a Program response to the PI and 
will address the following issues for approved LOI:  a) the existence and 
nature of concurrent clinical trials in the area of research, pointing out 
possible duplication of effort, b) information including relevant 
pharmacokinetic and pharmacodynamic data concerning investigational agents, c) 
availability of investigational agents, d) the scientific rationale and value 
of the proposed study, the design, the statistical requirements, e) the 
projected accrual rate, f) correlative laboratory studies, and g) 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 Investigator"s Handbook, available at web 
site http://ctep.cancer.gov/handbook/.  

The PRC will formally review the protocol.  The major considerations relevant 
to LOI and Protocol Review by CTEP include:  a) the strength of the scientific 
rationale supporting the study, b) the medical importance of the question 
being posed, c ) the probability that the trial design will provide a clear 
answer to the questions posed, d) the avoidance of unnecessary duplication 
with other ongoing studies, e) the appropriateness of study design with 
respect to development of the IND agent, f) a satisfactory projected accrual 
rate and follow-up period, g) patient safety, h) plans for  compliance and 
track record of compliance with federal regulatory requirements, i) adequacy 
of data management, j) appropriateness of patient selection, evaluation, 
assessment of toxicity, response to therapy and follow-up k) clarity of 
methods and quality assurance measures for correlative studies and l) track 
record of the study chair/site in successfully completing similar trials.

Following the review of the protocol by the PRC, the responsible IDB SCI 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 Program Director and/or responsible 
IDB SCI 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.

d.  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.

e.  CTEP Involvement in Protocol Closure

The NCI Program Director and/or responsible IDB SCI and the Chief, Clinical 
Trials Monitoring Branch (CTMB) will monitor protocol progress.  The NCI 
Program Director or the responsible IDB SCI may request that a protocol be 
closed to accrual for reasons including:  a) insufficient accrual rate, b) 
accrual goal met, c) poor protocol performance, d) patient safety and 
regulatory concerns, e) study results are already conclusive, f) emergence of 
new information that diminishes the scientific importance of the study 
question, and g) 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.  CTEP involvement in Investigational New Drug Applications 

1) The NCI Program Director 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.

2) The NCI Program Director 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).

g.  CTEP Review of Federally Mandated Regulatory Requirements 

The Chief, 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 Awardees 
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 
(CTMB) 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. For Phase I trials with NCI-sponsored investigational 
agents, the NCI has contracted for a Clinical Trials Monitoring Service (CTMS) 
to document regulatory compliance, to maintain a computerized data base of the 
Phase I investigator data submissions (biweekly), and to produce periodic 
reports of the results and special reports as necessary.  A small fraction of 
dose finding trials, usually those done later in an agent"s development, may 
use the simplified CDUS reporting system, with monthly or q 3 month reporting. 
Theradex 7, a Clinical Trials Monitoring Service (CTMS) contractor, 
administers the site visit audit program on the behalf of CTMB. Theradex7 is a 
pharmaceutical consulting and development company. The audit teams who conduct 
the on-site audits are composed of experienced clinical research associates, 
pharmacists and outside physicians and CTMB staff, as necessary, who have 
specialized experience and expertise relevant to the types of protocols being 
reviewed.   The awardee institution"s source documentation will be reviewed 
on-site three times per year by the CTMS. 

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.

h.  CTEP Review of Progress

Progress will be reviewed quarterly by the NCI Program Director on the basis 
of the information provided at the semi-annual Phase I meetings, in the 
continuation application, in the study summary reports submitted via CTMS 
reports (or CDUS reports).  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

a.  The Principal Investigators, the NCI Program Director(s) and CTEP SCI will 
be members of an early clinical trials network.  This group of investigators 
has traditionally met at semiannual meetings.  

b.  Although it is envisioned that the majority of phase I trials will be 
performed at a single institution, investigators may collaborate to perform 
specific pharmacologic and correlative studies.  As examples, one site may be 
identified to do PK assays for 3 trials of an agent that is sufficiently 
stable to batch and ship samples, to minimize duplication of effort in assay 
validation and quality assurance procedures, in three planned trials, site A 
may perform correlative studies on biopsies from site A, B, and C, while site 
B performs a different correlative study for the same three trials, or several 
sites may collaborate in phase I trials for unusual populations, such as 
patients with renal insufficiency.  CTEP SCI will assist investigators in the 
ongoing coordination required for such collaborations.

c.  Phase I strategy meetings

The NCI Program Director(s) will sponsor semi-annual Phase I strategy meetings 
with the PIs to review relevant scientific information, to review progress in 
the clinical trials, and to review the status of newly available 
investigational agents in order to plan future activities.  The PI and Co-
Investigators will be responsible for making scientific reports at these 
meetings as requested by Program Staff.  The PI is expected to attend all of 
these meetings.

4.  Arbitration 

Any disagreement that may arise on scientific/programmatic matters (within the 
scope of the award), excluding patient safety issues or regulatory compliance, 
between award recipients and the NCI may be brought to arbitration.  An 
arbitration panel composed of one awardee nominee, one NCI nominee, and a 
third member with clinical trials expertise chosen by the other two nominees 
will be formed to review the CTEP decision and recommend an appropriate course 
of action to the Director, DCTD.  The arbitration procedures in no way affect 
the awardee"s right to appeal an adverse determination under the terms of 42 
CFR Part 50, Subpart D, and 45 CFR Part 16.  
  
MECHANISM OF SUPPORT

The administrative and funding instrument to be used for this program will be 
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.  
Details of the responsibilities, relationships and governance of the study to 
be funded under cooperative agreement(s) are discussed later in this document 
under the section Terms and Conditions of Award.

The total project period for an application submitted in response to this RFA 
may not exceed 5 years.  The anticipated award date is February 1, 2003.  This 
RFA is a one-time solicitation.  At this time the NCI has not determined 
whether or how this solicitation will be continued beyond the present RFA.  If 
it is determined that there is a continuing program need, the NCI will either 
invite recipients of awards under this RFA to submit competitive continuation 
cooperative agreement applications for review or reissue the RFA for re-
competition. If the NCI does not continue the program, awardees may submit 
grant applications through the usual investigator-initiated grants program. 

Awards and level of support depend on receipt of a sufficient number of 
applications of high scientific merit.  
 
FUNDS AVAILABLE

The NCI intends to commit in FY2003 approximately $7,200,000 including direct 
costs and costs for Facilities and Administration to fund 14-15 new and/or 
competing continuation cooperative agreements in response to this RFA.  An 
applicant may request a project period of up to five years.  Because the 
nature and scope of the research proposed may vary, it is anticipated that the 
size of each award will also vary.  The NCI policy that R01 and U01 
applications cannot exceed an increase of 20% over the direct cost award level 
in the last non-competing (type 5) year does not apply to the applications 
received in response to this RFA.  Although the financial plans of the 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.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign for-profit and 
non-profit organizations, public and private, such as universities, colleges, 
hospitals, laboratories, units of State and local governments, and eligible 
agencies of the Federal Government.  Applications from minority individuals, 
women, and persons with disabilities, are encouraged to apply as principal 
investigators. 

INQUIRIES
 
Written and telephone inquiries concerning the objectives and scope of this 
RFA and inquiries about whether or not specific proposed research would be 
responsive are strongly encouraged and may be directed to the program staff 
listed below.  The program staff welcome the opportunity to clarify any issues 
or questions from potential applicants. 
  
Direct inquiries regarding programmatic issues to: 
 
Dr. Louise B. Grochow
Chief, Investigational Drug Branch 
Cancer Therapy Evaluation Program 
Division of Cancer Treatment and Diagnosis
National Cancer Institute 
Executive Plaza North, Room 7131
6130 EXECUTIVE BLVD MSC 7426
BETHESDA, MD  20892-7432 
Telephone:  (301) 496-1196 
FAX:  (301) 402-0428
E-mail:  [email protected]

Direct inquiries regarding review issues to:

Referral Officer 
Division of Extramural Activities 
National Cancer Institute 
6116 Executive Blvd., Room 8109, MSC-8329
Rockville, MD  20852 (express courier)
Bethesda MD  20892-8329
Telephone:  (301) 496-3428
Fax:  (301) 402-0275
Email:  [email protected]

Direct inquiries regarding fiscal 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]
Bethesda, MD  20892 

LETTER OF INTENT
 
Prospective applicants are asked to submit, by February 14, 2002, a Letter of 
Intent that includes a descriptive title of the proposed research, the name, 
address, telephone and fax numbers, and email address of the Principal 
Investigator, and the number and title of the RFA in response to which the 
application may be submitted.  Although a Letter of Intent is not required, is 
not binding, and does not enter into the review of a subsequent application, 
it allows NCI staff to estimate the potential review workload and plan the 
review. The Letter of Intent is to be sent to Louise B. Grochow, M.D listed 
under INQUIRIES by the Letter of Intent receipt date.

SCHEDULE
 
Letter of Intent Receipt:         February 14, 2002
Application Receipt Date:         March 21, 2002
Peer Review Date:                 July/2002
Review by NCAB Advisory Board:    September/2002
Earliest Anticipated Start Date:  February 1, 2003

APPLICATION PROCEDURES
 
The PHS 398 research grant application instructions and forms (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html must be used in 
applying for these cooperative agreements.  This version of the PHS 398 is 
available in an interactive, searchable format.  For further assistance 
contact GrantsInfo, Telephone 301/710-0267, Email:  [email protected].

An application from a currently funded program will be a competing 
continuation and must include a progress report, which at a minimum consists 
of a summary of prior Phase I activities/accomplishments, including a clear 
presentation of pharmacokinetic studies, pharmacodynamic or other correlative 
studies and results, conclusions of correlative laboratory studies and annual 
accrual over the funding period.  A summary of accrual by gender and race 
and/or ethnicity to all Phase I trials (reported by trial) conducted during 
the project period must be provided.  An application from a program that is 
not currently funded should include a similar section in preliminary data, 
which should consist of a summary of prior dose finding trials performed under 
other sponsorship, including the same information described in the paragraph 
above to the extent that it is available.  (See PHS 398 (rev 5/2001) Research 
Plan, section c. Preliminary Studies/Progress Report).  

A summary of accrual to all cancer treatment trials at the applicant 
institution (excerpted, for example, from annual progress reports for the 
Cancer Center) should be included.  Tables of the current budget and supported 
FTEs with a justification for any request for additional resources should be 
included.

ALL Applicants

1.  The form PHS 398 should be modified as follows.   The number of pages 
allowed for the "Research Plan" is increased from 25 to 45.

2.  Investigators should include in the APPENDIX of the cooperative agreement 
application.

a.  Draft copies of some proposed protocol(s) that might be undertaken in the 
first year and should identify the particular areas of laboratory expertise 
that would be utilized in the performance of these trials.  

b.  Examples of quality assurance procedures for pharmacokinetic and 
translational endpoints may be included in draft protocols in the Appendix.

c.  A summary of all publications resulting from prior CTEP phase I support, 
indicating which publications cited CTEP support with an *, should be included 
in the appendix. 

d.  A list of early clinical trials that have requested grant support under 
the Quick Trials mechanism, and indicate which requests were funded.
 
3.  The applicant must demonstrate in the application the ability to meet the 
following requirements: 
 
a.  Documented numbers of eligible patients with a history of adequate accrual 
at the applicant institution to complete on average two to three Phase I 
trials annually.  A table listing NCI sponsored and industry or locally 
sponsored Phase I trials indicating the date of initial IRB approval and 
annual accrual for a recent 24 month period (split into 1 year accruals). When 
multiple phase I trials have been performed at a site, evidence of 
investigators" commitment to timely completion of NCI sponsored phase I trials 
should be incorporated.
 
b.  Laboratory support to perform pharmacokinetic studies of cytotoxic, 
differentiation-inducing, molecularly targeted, and/or other novel anti-cancer 
agents, including monitoring of metabolites and intracellular products when 
appropriate, or other relevant pharmacology correlative studies, documentation 
of ongoing collaboration with laboratory investigators should be incorporated

c.  Laboratory support to measure relevant indicators of pharmacodynamic or 
biologic response (e.g., changes in signal transduction pathways, induction or 
suppression of specific gene function, other indications of differentiation 
induction, or induction of apoptosis, etc), document ongoing collaboration(s)

d.  Interventional radiology to support the acquisition of CT directed 
biopsies adequate to perform suitable assays of drug effect when needed, 
functional imaging with MRI and PET scan facilities to support studies of non-
invasive probes of drug effect

e.  Adequate central data collection and processing capabilities in order to 
meet FDA requirements for the conduct of research using investigational 
agents.  These specifically include: 

1) the capability to transmit patient data to the NCI"s Clinical Trials 
Monitoring Service (CTMS) on a biweekly basis, and via the Clinical Data 
Update System (CDUS).

2) the capability of prompt reporting of AERs via AdEERS to CTEP for 
investigational agents supplied by NCI in accordance with the CTEP guidelines 
(mailed annually to all registered investigators). 
 
f.  Adequate pathology support for tumor classification and for banking and 
distribution of tumor tissues for concurrent and future studies. 

g.  Timely medical review and assessment of patient data, by the study 
chairperson and PI Investigator.  The application should specify how this 
review will be arranged.  
 
h.  For pharmacokinetic and correlative studies, quality assurance procedures 
for the laboratory assays.  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 ensurng patient privacy and sample tracking must be established 
by the PI.   [As noted above, examples of quality assurance procedures for 
pharmacokinetic and translational endpoints may be included in the Appendix].

i.  Adequate mechanisms in place to ensure that all patients: 
 
1) have histologically confirmed diagnosis of cancer, 
 
2) be staged by conventional methods and found to have locally extensive or 
disseminated disease not amenable to therapy with curative intent using 
surgery, chemotherapy, and/or radiotherapy or any other form of known 
effective therapy, 

3) have already received and no longer be receiving benefit from customary 
systemic or local treatment likely to prolong survival or improve symptoms.  
For diseases for which curative systemic treatment exists (e.g., the acute 
leukemias, diffuse non-Hodgkin"s lymphomas, Hodgkin"s disease, testicular 
cancer, limited small cell lung cancer, ovarian carcinoma), patients should 
have received the minimum extent of prior treatment compatible with current 
ethical standards of care, and should have a high performance status.  For 
other diseases in which non-curative therapy of limited benefit to only some 
patients is available (e.g., carcinomas of the head and neck, 
hormone-refractory prostatic carcinoma, bladder and stomach cancer, sarcomas, 
renal cell carcinoma), entry of patients with no prior therapy may be 
acceptable. 

4) have acceptable performance status and acceptable renal, liver, and 
hematologic function, and 
 
5) have given signed informed consent in accordance with 45 CFR Part 46, 
Protection of Human Subjects, indicating that they are aware of the 
investigational nature of the studies involved. 

j.  Evidence of a level of supportive care appropriate for the treatment of 
patients with advanced malignancies, 

k.  Intensive care, subspecialty consultation in non-oncology fields and blood 
bank facilities on-site and functioning 24 hours per day. 
 
l.  Adequate physician and nursing resources to comply with all reporting 
requirements of NCI-sponsored Phase I trials. 
 
m.  Appropriate drug accountability procedures as required for utilization of 
NCI-supplied investigational agents. 
 
4.  Additional activities and responsibilities for a clinical trials network 
may be proposed as part of this application.  The early clinical trials 
network may meet as needed in working groups, either via travel or via 
teleconferences.  Additional experts identified by members of the network may 
be invited to participate in specific working group meetings to provide 
expertise in specific agents, targets, and/or trial designs.  Members of the 
early clinical trials network may choose to form agent/class specific study 
teams to facilitate the identification of appropriate scientists to assist in 
collaborative studies, evaluate new agents for the need to develop additional 
research plans addressing aspects of drug metabolism, pharmacogenetics, 
imaging, novel trial designs and correlative endpoints that are not available 
at the time of DDG review, arrange for collaborations within the network (or 
beyond the network) between individual dose finding trials, and provide 
information to the NCI Program Director(s) and CTEP Senior Clinical 
Investigators (SCI) to assist in the preparation of solicitations for early 
clinical trials.  Members of the early clinical trials network may also work 
together to develop policy recommendations for early clinical trials, position 
papers, agenda for semiannual meetings, etc.

For applicants who find participation in an early clinical trials network 
study team desirable, a description of the process that would be undertaken to 
form an agent study group and the measures that might be undertaken to 
evaluate the function and productivity of such study groups should be included 
in the application.  Specific examples of such measures include evaluating the 
level of effort required to initiate a trial, the quality of the applications 
received, the speed of trial initiation and completion, the productivity 
evidenced by publications, and the quality of the trial results.  Some agents 
might be selected for a network study team committee and measures of the 
development plans for these agents could be compared to agents that are 
developed with the conventional informal input currently provided to CTEP from 
extramural scientists.

5.  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 studies including costs related to 
patient accrual, data collection, sample handling, additional staff time, 
specific supply needs related to required laboratory pharmacokinetic studies, 
quality assurance, data management and data analysis, study monitoring, travel 
to semiannual early clinical trials meetings and national meetings to present 
results, and biweekly electronic data submissions to the NCI"s Clinical Trials 
Monitoring Service as required by the reporting requirements for 
investigational agents.  Costs for the support of translational correlative 
studies planned in conjunction with phase I trials will not be supported via 
the U01, but a sample budget for such efforts may be included with the 
protocol(s) in the appendix to provide evidence of the applicant"s 
understanding of the scope and planning of such projects.  These correlative 
studies may be funded via other mechanisms (such as R01 or R21 Quick Trials or 
via acquisition (contract) mechanisms, e.g., as subcontracts via the 
Translational Research Fund). Decisions to acquire correlative studies will be 
made at the time of LOI approval, and detailed budgets for correlative studies 
with budget justifications should be provided at the time of protocol 
submission to CTEP.

6.  The approximate number of patients expected to be accrued annually should 
be specified.

7.  If capitation costs are requested as reimbursement for patient accruals, 
the cost per patient must be broken down and justified, e.g.: 
 
a. estimate of physician time spent on research (e.g., to obtain informed 
consent, to fill out data forms, and others) and the resultant cost.  Time 
spent delivering standard medical care is not allowable. 
 
b. estimate of Clinical Research Associate/data manager or nurse time to meet 
research requirements (e.g., compiling and mailing data, specimens) and the 
resultant cost. 
 
c. cost of mailing or handling research-related patient specimens, forms, 
materials (e.g., slides, X-ray) 
 
d.  other consultant costs (e.g., pathology, radiology). 

8.  Travel funds for two NCI meetings per year for two representatives from 
the awardee institution should be included in the budget, as well as travel 
fund for one representative to two working group meetings and funds for two 
presenters for major national meetings. 

9.  Applications must include a description of plans to accommodate the Terms 
and Conditions of Award, including the NCI staff involvement.  

10.  All clinical trials supported or performed by NCI require some form of 
monitoring.  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 to 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 of the NCI for Data 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 to 
http://www.nci.nih.gov/clinicaltrials/conducting/dsm-guidelines.

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.

 
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
(20817 for express service)
 
At the time of submission, two additional copies of the application must also 
be sent to:

Referral Officer 
Division of Extramural Activities 
National Cancer Institute 
6116 Executive Blvd., Room 8109, MSC-8329 
Rockville, MD  20852 (express courier)
Bethesda, MD  20892-8329

Applications must be received by March 21, 2002.  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 announcement 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 a 
substantial revision of an application already reviewed, but such an 
application must include an Introduction addressing the previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by CSR and 
responsiveness by the National Cancer Institute.  Incomplete and/or non-
responsive 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 of the National Cancer Institute in 
accordance with the review criteria stated below.  As part of the initial 
merit review, all applications will receive a written critique and 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 assigned a priority score, and receive a second level review by the 
National Cancer Advisory Board.

Review Criteria

1. Significance: scientific, technical, medical significance and originality 
of proposed research as reflected in the protocols, research plans and 
strategies that address the clinical and laboratory considerations for Phase I 
studies using novel agents alone or in combination, evidence that the proposed 
scientific studies would contribute to a greater understanding of the nature 
of the therapeutic agent which may include but are not limited to an 
understanding of its mechanism of action, mechanisms of resistance, or 
differences among patients with respect to drug  metabolism, elimination, 
distribution, or effect on specific molecular targets.  

2. Approach: appropriateness and adequacy of the experimental approach and 
methodology proposed to carry out the research including: 
 
a. adequacy of plans for the development, implementation, conduct and analysis 
of Phase I clinical trials.

b. adequacy of available patient populations and adequacy of accrual to dose 
finding trials, demonstrated ability to complete 2-3 phase I trials/year.

c. adequacy of plans, equipment and resources to carry out pharmacokinetic and 
pharmacodynamic analyses in a timely manner.

d. adequacy of plans for correlative laboratory studies and evaluation of the 
data with respect to treatment administration or treatment outcome, 
availability of interventional and functional imaging teams to collaborate 
with dose finding trials.
 
e. adequacy of statistical approach for correlating research studies with 
treatment outcomes in Phase I trials. 
 
f. adequacy of plans for effective collaboration among laboratory, imaging,  
clinical, and statistical investigators. 
 
g. adequacy of mechanisms for quality assurance, study monitoring, data 
management and reporting, data analysis, investigational drug management, and 
compliance with regulatory requirements

h. If additional responsibilities of an early clinical trials network are 
proposed, reviewers are asked to provide a detailed assessment of their 
significance to the drug development program, feasibility of the proposed 
approach, adequacy of the proposal to assess the effect of drug study teams 
and other proposed elements 

3.  Innovation: It is understood that dose finding clinical trials per se may 
not be innovative.  However, the potential for proposed correlative studies to 
use innovative approaches to contribute to a greater understanding of the 
effect of a specific novel target on cancer control and to a greater 
understanding of the mechanism of action of a novel agent should be considered 
under innovation. 
 
4. Investigator: qualifications and research experience of the Principal 
Investigator and staff, particularly, but not exclusively, in the area of the 
proposed research including: 
 
a. experience, competence and productivity of the Principal Investigator and 
clinical investigators in the development, implementation and analysis of 
Phase I trials. 
 
b. experience in the daily management and treatment of patients with various 
malignant tumors and assessment of eligibility/evaluability of these patients 
in cancer clinical trials. 
 
c. experience and productivity of the investigators in obtaining blood and/or 
tissue specimens for research purposes from patients entered onto clinical 
trials and the evaluation of those data with respect to treatment administered 
or treatment outcome. 
 
d. experience in performance of pharmacokinetic/pharmacodynamic 
laboratory/correlative studies relevant to the development of a class of 
anticancer therapeutic agents and evaluation of the data with respect to 
treatment administration or treatment outcome 

e. experience in collaboration with laboratory investigators, including 
experience in multicenter research efforts if proposed by the applicant
 
5. Environment: availability of resources necessary to perform the research 
including: 

a. adequacy of the available facilities for evaluation and clinical care of 
patients in dose finding trials

b. adequacy of the resources for pharmacokinetic/pharmacodynamic 
laboratory/correlative studies and for data management resources. 
 
c. demonstration of availability of and access to appropriate numbers of 
patients eligible to receive defined treatments on phase I clinical trials 
and/or to human tissue with the associated pathological data and clinical 
follow-up.

d. adequacy of patient population to support the completion of at least 2 
innovative dose finding trials each year and to support the accrual stated by 
the applicant 

e.  adequacy of the available facilities for comprehensive multidisciplinary 
assessment and medical management of patients with advanced malignancies

6.  Adequacy of provisions for the protection of human subjects and the humane 
treatment of animals (if laboratory studies involving animals are proposed). 
 
7.  Commitment to accept provisions outlined under the Terms and Conditions of 
Award.
 
The initial review group will also examine: 

a.  the appropriateness of proposed project budget and duration, 
b.  the adequacy of plans to include both genders, minorities (and their 
subgroups), and children as appropriate for the scientific goals of the 
research and plans for the recruitment and retention of subjects, 
c.  the provisions for the protection of human and animal subjects, 
d.  the safety of the research environment,
e.  the adequacy of the proposed plan to share data.
 
AWARD CRITERIA

Applications recommended by the National Cancer Advisory Board will be 
considered for award based upon the following:

a.  scientific merit (as determined by peer review)
b.  availability of funds
c.  programmatic priorities.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS
 
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.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS.

It is the policy of NIH that children (i.e., individuals under the age of 21) 
must be included in all human subjects research, conducted or supported by the 
NIH, unless there are clear and compelling scientific and ethical reasons not 
to include them.  This policy applies to all initial (Type 1) applications 
submitted for receipt dates after October 1, 1998.

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines on the Inclusion of Children as Participants in 
Research Involving Human Subjects" that was published in the NIH Guide for 
Grants and Contracts, March 6, 1998, and is available at the following URL 
address:  http://grants.nih.gov/grants/guide/notice-files/not98-024.html.

Investigators may also obtain copies of these policies from the program staff 
listed under INQUIRIES.  Program staff may also provide additional relevant 
information concerning the policy.

REQUIRED EDUCATION IN THE PROTECTION OF HUMAN RESEARCH PARTICIPANTS

All investigators proposing research involving human subjects should read the 
NIH policy on education in the protection of human research participants now 
required for all investigators, which is published in the NIH Guide for Grants 
and Contracts, June 5, 2000 (Revised August 25, 2000), available at the 
following URL address:  
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 is now available online at http://cme.nci.nih.gov/.

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.  Reviewers are cautioned 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, Phase I Clinical Trials of New 
Anti-Cancer Agents, is related to priority area of cancer treatment.  
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, Cancer Treatment Research. 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 and Federal Regulations 42 
CFR 52 and 45 CFR Parts 74 and 92.  This program is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and promote the non-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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